David D Eisenstat

David D Eisenstat
University of Melbourne | MSD · Department of Paediatrics

Doctor of Medicine

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191
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Introduction
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Publications

Publications (191)
Article
INTRODUCTION: Secondary meningiomas are a late effect in children who received cranial irradiation, frequently with a long latency. The molecular genetic profile of primary meningiomas is well studied; however, few studies describe the genomic landscape of radiation-induced meningiomas (RIM). METHODS: Patients followed at the Stollery Children’s Ho...
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As a key component of the RNA-induced silencing complex (RISC), Argonaute2 (Ago2) exhibits a dual function regulatory role in tumor progression. However, the mechanistic basis of differential regulation remains elusive. p63 is a homolog of the tumor suppressor p53. p63 isoforms play a critical role in tumorigenesis and metastasis. Herein, we show t...
Article
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Forebrain development in vertebrates is regulated by transcription factors encoded by homeobox, bHLH and forkhead gene families throughout the progressive and overlapping stages of neural induction and patterning, regional specification and generation of neurons and glia from central nervous system (CNS) progenitor cells. Moreover, cell fate decisi...
Article
Introduction: The Australian Technical Advisory Group on Immunisation and New Zealand Ministry of Health recommend all children aged ≥ 5 years receive either of the two mRNA COVID-19 vaccines: Comirnaty (Pfizer), available in both Australia and New Zealand, or Spikevax (Moderna), available in Australia only. Both vaccines are efficacious and safe...
Article
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Background Diffuse intrinsic pontine glioma (DIPG) is a fatal childhood brainstem tumor for which radiation is the only treatment. Case studies report a clinical response to ONC201 for patients with H3K27M-mutant gliomas. Oncoceutics (ONC201) is only available in the United States and Japan; however, in Germany, DIPG patients can be prescribed and...
Article
Background: Children and adolescents diagnosed with cancer are at high risk of experiencing severe side effects from cancer treatment, many of which are amenable to physical therapy. These side effects can negatively impact a child's quality of life and ability to participate in daily activities (e.g. play and attendance at school). Researchers ha...
Article
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Background Patients in Alberta, Canada are referred to the United States (US) for proton treatment. The Alberta Ministry of Health pays for the proton treatment and the cost of flights to and from the United States. This study aimed to determine the out-of-pocket expenses incurred by patients or patients’ families. Methods An electronic survey was...
Article
Children with low‐grade gliomas have excellent long‐term survival outcomes. The development of therapies targeted to the driver mutations along the Mitogen Activated Protein (MAP) kinase signalling pathway are providing long‐term stability for many patients with these tumours. Given the frequency of these tumours residing within or near the suprase...
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Introduction Cranial irradiation remains part of childhood cancer therapy and secondary meningiomas are a late effect. Secondary meningiomas are reported in patients who received low and high dose cranial irradiation and arise ~ 20 years post exposure. The molecular and genetic profile of primary meningiomas has been well studied; however, only a f...
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High-grade gliomas harboring H3 G34R/V mutations exclusively occur in the cerebral hemispheres of adolescents and young adults, suggesting a distinct neurodevelopmental origin. Combining multimodal bulk and single-cell genomics with unbiased genome-scale CRISPR/Cas9 approaches, we here describe a GABAergic interneuron progenitor lineage as the most...
Article
This article summarizes the background, content and outcomes of a special meeting that was convened among oncologists and scientists to discuss the role of pharmacogenetic (PGx) testing in pediatric clinical oncology practice. This meeting provided an opportunity for what the lead author (AM Issa) refers to as the ‘voice of the clinician’ dynamic t...
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Significant advances in our understanding of the molecular genetics of pediatric and adult brain tumors and the resulting rapid expansion of clinical molecular neuropathology have led to improvements in diagnostic accuracy and identified new targets for therapy. Moreover, there have been major improvements in all facets of clinical care, including...
Article
Doxorubicin is a very effective anticancer agent that is widely used in pediatric cancer patients. Nevertheless, doxorubicin is known to have cardiotoxic effects that may progress to cardiomyopathy later in life. We have recently shown that co‐treatment of resveratrol with doxorubicin in juvenile mice attenuates late‐onset hypertension‐induced card...
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The major clinical problem in human cancer is metastasis. Metastases are the cause of 90% of human cancer deaths. TAp63 is a critical suppressor of tumorigenesis and metastasis. ΔNp63 acts as a dominant-negative inhibitor to block the function of p53 and TAp63. Although several ubiquitin E3 ligases have been reported to regulate p63 stability, the...
Article
Pirh2 is an E3 ligase belonging to the RING-H2 family and shown to bind, ubiquitinate, and downregulate p73 tumor suppressor function without altering p73 protein levels. AIP4, an E3 ligase belonging to the HECT domain family, has been reported to be a negative regulatory protein that promotes p73 ubiquitination and degradation. Herein, we found th...
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Primary CNS tumors are the leading cause of cancer-related death in pediatrics. It is essential to understand treatment trends to interpret national survival data. In Canada, children with CNS tumors are treated at one of 16 tertiary care centers. We surveyed pediatric neuro-oncologists to create a national standard of practice to be used in the ab...
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BACKGROUND Proton therapy for benign and malignant tumors has dosimetric and clinical advantages over photon therapy. Patients in Alberta, Canada are referred to the United States for proton treatment. The Alberta Heath Care Insurance Plan (AHCIP) pays for the proton treatment and the cost of flights to and from the United States (direct costs). Th...
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BACKGROUND The identification of H3.3/H3.1K27M in most DIPG has changed our understanding of this disease. H3K27M mutations usually demonstrate global loss of H3K27 trimethylation (me3) with gain of H3K27 acetylation (ac). Single cell RNAseq has identified the putative cell of origin as oligodendroglial progenitor cells (OPC). The distalless gene f...
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INTRODUCTION Irradiation-sparing approaches are used in young children with medulloblastoma (MB) given the vulnerability of the developing brain to neurocognitive impairment. Limited data are available following relapse for these patients. We aimed to describe the management and outcomes of young children with MB who relapsed after initial treatmen...
Article
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Children with pediatric gliomas harboring BRAF V600E mutation have a poor outcome with current chemoradiation strategies. Our aim was to study the role of targeted BRAF inhibition in these tumors. We collected clinical, imaging, molecular and outcome information from BRAF V600E glioma patients treated with BRAFi across 29 centers from multiple coun...
Article
INTRODUCTION Irradiation-sparing approaches are used in young children with medulloblastoma (MB) given the vulnerability of the developing brain to neurocognitive impairment. Limited data are available following relapse for these patients. We aimed to describe the management and outcomes of young children with MB who relapsed after initial treatmen...
Conference Paper
Introduction: Over 4300 children, adolescents, and young adults (CAYA) are diagnosed with cancer each year in Canada, 1/3 of whom will have refractory or metastatic disease or will relapse with a very poor prognosis. Most CAYA cancer survivors suffer significant late effects that impose an enormous burden to them, their family and the health care s...
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Background Diffuse intrinsic pontine gliomas (DIPG) are midline gliomas that arise from the pons and the majority are lethal within a few months after diagnosis. Due to the lack of histological diagnosis the epidemiology of DIPG is not completely understood. The aim of this report is to provide population-based data to characterize the descriptive...
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Osteosarcoma affects both adolescents and adults, and some improvement in the survival rate for affected patients has been reached in the last decade. Still, non-specificity and systemic toxicity may limit traditional therapeutic approaches to some extent. The insulin growth factor 1 (IGF1) and its binding protein (IGFBP3) have been implicated in t...
Article
PURPOSE Children with pediatric gliomas harboring a BRAF V600E mutation have poor outcomes with current chemoradiotherapy strategies. Our aim was to study the role of targeted BRAF inhibition in these tumors. PATIENTS AND METHODS We collected clinical, imaging, molecular, and outcome information from patients with BRAF V600E–mutated glioma treated...
Preprint
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In this study, we demonstrate that mouse DLX2 binds to the Olig2 gene locus in mouse embryonic forebrain in vivo. We further confirm the specificity and the transcriptional repressive effect of the binding in vitro. Furthermore, loss of Dlx1/2 function leads to increased Olig2 expression in the ventral embryonic mouse forebrain in vivo. As well, we...
Conference Paper
BACKGROUND Children with pediatric low grade glioma’s (PLGG) harboring BRAF V600E mutation have poor outcome due to relative resistance to chemo-radiation and higher risk of malignant transformation. However, the role of targeted BRAF inhibition in these tumors is poorly defined. METHODS We assembled an international cohort of children with BRAF V...
Article
Purpose: Children and adolescents with cancer who undergo cancer treatment are at high risk of developing adverse effects, many of which may be amenable to physical rehabilitation. We aimed to identify the current clinical physical rehabilitation practice patterns, services, and programmes available for children and adolescents with cancer in Canad...
Poster
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Sulforaphane is a natural compound that occurs in broccoli sprouts. Several reports describe that sulforaphane induces apoptosis specifically in cancer cells but not in normal cells at the same dose. In vivo, sulforaphane is metabolized to sulforaphane N- acetyl cysteine which has the ability to cross the blood brain barrier. Our research aims to t...
Article
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Osteosarcoma (OS) is an aggressive primary bone malignancy that has peak incidence in children and young adults <25 years of age. Despite current multimodal treatments, no significant change in patient outcome has been observed in two decades. Presently, there is a lack of established, reliable baseline prognostic markers for aggressive OS, other t...
Conference Paper
The BRAF-V600E mutation is found in 15–20% of pediatric low grade gliomas (PLGG) and result in worse outcome and higher risk of transformation to high grade gliomas (PHGG). Although ongoing trials are assessing the role of BRAF inhibitors (BRAFi) in these children, data are still limited. We aimed to report overall response rates and predictors of...
Article
INTRODUCTION: Diffuse intrinsic pontine glioma (DIPG) have an extremely poor prognosis. Mutations of the genes encoding histone H3K27, especially H3K27M, are highly prevalent. There is reduced expression of the homeobox gene Dlx2 in DIPG with H3K27M mutations. Single cell RNA sequencing suggests that the cell of origin is an oligodendroglial progen...
Article
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Purpose: The Children's Oncology Group trial ACNS0121 estimated event-free survival (EFS) and overall survival for children with intracranial ependymoma treated with surgery, radiation therapy, and-selectively-with chemotherapy. Treatment was administered according to tumor location, histologic grade, and extent of resection. The impacts of histol...
Chapter
Chromatin immunoprecipitation assays permit the isolation and subsequent identification of genomic DNA (gDNA) fragments bound directly or indirectly to proteins of interest, including transcription factors, co-factors, or chromatin remodeling proteins. These isolated DNA fragments may include gene regulatory regions from enhancers, super-enhancers,...
Article
INTRODUCTION Diffuse intrinsic pontine glioma (DIPG) is refractory to current therapy with less than 2% long term survivors. The identification of histone H3.1/H3.3 K27M mutations in most DIPG has provided new insights into the biology of this fatal disease. The DLX homeobox genes are expressed in the developing forebrain. The Dlx1/Dlx2 double knoc...
Article
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The BH3-only family member BNIP3 has been described as either promoting cell survival or cell death. This depends upon the level of BNIP3 expression and its cellular localization. Increased BNIP3 expression under hypoxia contributes to cell death through increased mitochondrial dysfunction. Furthermore, mice lacking BNIP3 show inhibition of ischemi...
Data
MEF cells lacking BNIP3 have diminished levels of Cyclin D1 compared to MEF cells expressing BNIP3 after cell cycle synchronization. Similar to EdU assay, MEF cells expressing or lacking BNIP3 were serum starved overnight to synchronize cell cycle. In the morning, cells were supplied with 10% serum for 4 hours, and lysed for total protein. This tim...
Data
Morphology and cellularity of E18.5 wild-type and BNIP3 knockout mice. E18.5 embryos were obtained from a single heterozygous cross. Brains were fixed by overnight immersion in paraformaldehyde, followed by paraffin embedding, horizontal sectioning and staining with hematoxylin and eosin. Images captured at 40x magnification revealed no significant...
Data
Expression of neuronal and astrocyte markers in wild type and BNIP3-/- mouse brain. Wild-type and BNIP3-/- mice were sacrificed at 8–32 weeks of age and brains were cryopreserved as described in Materials and Methods. (A) Detection of the astrocyte marker GFAP (glial fibrillary acidic protein) in adult (8 week) mouse brain by immunofluorescence. (B...
Data
BNIP3 protein expression in mouse brain. Total cell lysates were generated from cryo-preserved brain tissue extracted from wild-type, heterozygous and BNIP3-null adult mice. Lysates were analyzed for BNIP3 expression by Western blot, with actin as a loading control; each lane represents a different mouse. Mice were sacrificed by cervical dislocatio...
Article
Triple negative breast cancer (TNBC) is a subtype of breast cancer with a poor prognosis and high mortality rate. The tumor suppressor PTEN plays an important role in cell proliferation and cell migration by negatively regulating the PI3K/Akt pathway. PTEN is down-regulated by microRNAs in multiple cancers. However, few microRNAs have been reported...
Conference Paper
Activation of the MAPK pathway represents a hallmark of pediatric low-grade glioma (pLGG) and is frequently caused by BRAF alterations. BRAF-V600E represent an aggressive type of pLGG with less than optimal response to conventional chemo-radiation approaches. While clinical trials using BRAF-V600E inhibitors are ongoing, these data are not yet avai...
Article
BACKGROUND IGTS is a rare phenomenon of paradoxical germ cell tumor (GCT) growth during or following treatment despite normalization of tumor markers. We sought to evaluate the frequency, clinical characteristics and outcome of IGTS in patients in 21 North-American and Australian institutions. METHODS Patients with IGTS diagnosed from 2000-2017 we...
Article
DIPG is refractory to current therapies. The identification of histone H3.1/H3.3 K27M mutations in most DIPG has provided novel insights. DLX (distal-less) genes are expressed in the developing forebrain. The Dlx1/Dlx2 double knockout (DKO) mouse (dies at P0) has loss of tangential GABAergic interneuron migration to the neocortex. We have identifie...
Article
BACKGROUND: IGTS is a rare phenomenon of paradoxical germ cell tumor (GCT) growth during or following treatment despite normalization of tumor markers. We sought to evaluate the frequency, clinical characteristics and outcome of IGTS in patients in 21 North-American and Australian institutions. METHODS: Patients with IGTS diagnosed from 2000-2017 w...
Article
Full-text available
INTRODUCTION: Gangliogliomas (GGs) are neuroepithelial tumours of the central nervous system (CNS) composed of mature ganglion cells or a mixed population of ganglion and glial cells. Microarray data of low grade gliomas (LGG) including GGs revealed overexpression of the Dlx2 gene, a homeobox gene essential for interneuron migration and differentia...
Article
BACKGROUND: Adult medulloblastomas account for less than 1% of adult neoplasms. They are challenging to treat due to their rarity and the heterogeneity of treatment options, all of which have limited evidence. In this retrospective review, we examined cases of adult medulloblastoma diagnosed in Alberta during a 70-year period. METHODS: We reviewed...
Article
Full-text available
Introduction: Diffuse intrinsic pontine glioma (DIPG) is refractory to therapy. The identification of histone H3.1/H3.3 K27M mutations in most DIPG has provided new insights. The DLX homeobox genes are expressed in the developing forebrain. The Dlx1/Dlx2 double knockout (DKO) mouse loses tangential GABAergic interneuron migration to the neocortex....
Article
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: Primary objective To evaluate the efficacy of physical therapy intervention on the quality of life (QoL) outcomes of children and adolescents who have been diagnosed with cancer. Participants must be between the ages of 0 and 19 years at the time of the physical...
Article
Full-text available
Posterior fossa ependymomas (EPN_PF) in children comprise two morphologically identical, but biologically distinct tumor entities. Group-A (EPN_PFA) tumors have a poor prognosis and require intensive therapy. In contrast, group-B tumors (EPN_PFB) exhibit excellent prognosis and the current consensus opinion recommends future clinical trials to test...
Article
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GABA is the key inhibitory neurotransmitter in the cortex but regulation of its synthesis during forebrain development is poorly understood. In the telencephalon, members of the distal-less (Dlx) homeobox gene family are expressed in, and regulate the development of, the basal ganglia primodia from which many GABAergic neurons originate and migrate...
Chapter
In pediatric neuro-oncology practice, cerebellar tumors are often referred to as infratentorial tumors or tumors of the posterior fossa (a differential diagnosis is provided in Table 1). This anatomic region also contains the pons and medulla, which along with the midbrain comprise the brainstem. In Part I of this comprehensive review, three import...
Chapter
Medulloblastoma (MB) is the most common malignant primary brain tumor in children and is currently classified into five distinct molecular subtypes (WNT, SHH-TP53 wild type, SHH-TP53 mutant, Group 3, and Group 4), based on genomic alterations, gene expression profiles, responses to treatment, and developmental cell of origin. The standard treatment...
Article
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Purpose BRAF V600E is a potentially highly targetable mutation detected in a subset of pediatric low-grade gliomas (PLGGs). Its biologic and clinical effect within this diverse group of tumors remains unknown. Patients and Methods A combined clinical and genetic institutional study of patients with PLGGs with long-term follow-up was performed (N =...
Article
Purpose BRAF V600E is a potentially highly targetable mutation detected in a subset of pediatric low-grade gliomas (PLGGs). Its biologic and clinical effect within this diverse group of tumors remains unknown. Patients and Methods A combined clinical and genetic institutional study of patients with PLGGs with long-term follow-up was performed (N =...
Article
Full-text available
Embryonal tumors are a heterogeneous group of central nervous system (CNS) tumors whose subgroups have varying incidence and outcome. Despite these differences, they are often grouped as a single entity for study purposes. To date, there are no Canadian multi-institutional studies examining the incidence and outcome of all embryonal subtypes. The c...
Article
BACKGROUND: Generation of disease-specific models and development of new treatments for non-WNT/non-SHH medulloblastomas (MB) is an urgent need. Group 3 MB is characterized by amplifications of MYC and/or OTX2. Furthermore, transcriptional profiling of group 3 MB shows dysregulation of GABAergic and/or photoreceptor gene expression. The distalless/...
Article
The p53 protein plays a critical role in preventing tumor development. Although numerous factors have been shown to directly or indirectly regulate p53, the mechanism of how microRNAs (miRNAs) modulate p53 remains unclear. Here, we identified miR-1301, a microRNA that regulates the activity and function of p53, by directly targeting the ubiquitinat...
Article
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Regulated retinal ganglion cell (RGC) differentiation and axonal guidance is required for a functional visual system. Homeodomain and basic helix loop helix transcription factors are required for retinogenesis, as well as patterning, differentiation and maintenance of specific retinal cell types. We hypothesized that Dlx1/Dlx2 and Brn3b homeobox ge...
Article
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While 2/3 of patients with ATRT are less than 3 years at diagnosis, the literature suggests younger children present with more aggressive disease and poorer outcome. However, little data exist on characteristics and outcome of patients diagnosed with ATRT in the first year of life. In particular, it is unclear whether they access similar treatments...
Article
Progress in the treatment of adult high-grade gliomas (HGG), including chemoradiation with concurrent and adjuvant temozolomide for glioblastoma, has not translated into significant therapeutic advances for pediatric HGG, where overall survival has plateaued at 15% to 20%, especially when considering specialized pediatric treatment in tertiary care...