Tiffany Chan

Markers of survival and metastatic potential in childhood CNS primitive neuro-ectodermal brain tumours: an integrative genomic analysis

BACKGROUND Childhood CNS primitive neuro-ectodermal brain tumours (PNETs) are very aggressive brain tumours for which the molecular features and best treatment approaches are unknown. We assessed a large cohort of these rare tumours to identify molecular markers to enhance clinical management of this disease. METHODS We obtained 142 primary hemispheric CNS PNET samples from 20 institutions in nine countries and examined transcriptional profiles for a subset of 51 samples and copy number profiles for a subset of 77 samples. We used clustering, gene, and pathway enrichment analyses to identify tumour subgroups and group-specific molecular markers, and applied immunohistochemical and gene-expression analyses to validate and assess the clinical significance of the subgroup markers. FINDINGS We identified three molecular subgroups of CNS PNETs that were distinguished by primitive neural (group 1), oligoneural (group 2), and mesenchymal lineage (group 3) gene-expression signatures with differential expression of cell-lineage markers LIN28 and OLIG2. Patients with group 1 tumours were most often female (male:female ratio 0·61 for group 1 vs 1·25 for group 2 and 1·63 for group 3; p=0·043 [group 1 vs groups 2 and 3]), youngest (median age at diagnosis 2·9 years [95% CI 2·4-5·2] for group 1 vs 7·9 years [6·0-9·7] for group 2 and 5·9 years [4·9-7·8] for group 3; p=0·005), and had poorest survival (median survival 0·8 years [95% CI 0·5-1·2] in group 1, 1·8 years [1·4-2·3] in group 2 and 4·3 years [0·8-7·8] in group 3; p=0·019). Patients with group 3 tumours had the highest incidence of metastases at diagnosis (no distant metastasis:metastasis ratio 0·90 for group 3 vs 2·80 for group 1 and 5·67 for group 2; p=0·037). INTERPRETATION LIN28 and OLIG2 are promising diagnostic and prognostic molecular markers for CNS PNET that warrant further assessment in prospective clinical trials. FUNDING Canadian Institute of Health Research, Brainchild/SickKids Foundation, and the Samantha Dickson Brain Tumour Trust.

Molecular subgroups of atypical teratoid rhabdoid tumours in children: an integrated genomic and clinicopathological analysis

BACKGROUND Rhabdoid brain tumours, also called atypical teratoid rhabdoid tumours, are lethal childhood cancers with characteristic genetic alterations of SMARCB1/hSNF5. Lack of biological understanding of the substantial clinical heterogeneity of these tumours restricts therapeutic advances. We integrated genomic and clinicopathological analyses of a cohort of patients with atypical teratoid rhabdoid tumours to find out the molecular basis for clinical heterogeneity in these tumours. METHODS We obtained 259 rhabdoid tumours from 37 international institutions and assessed transcriptional profiles in 43 primary tumours and copy number profiles in 38 primary tumours to discover molecular subgroups of atypical teratoid rhabdoid tumours. We used gene and pathway enrichment analyses to discover group-specific molecular markers and did immunohistochemical analyses on 125 primary tumours to evaluate clinicopathological significance of molecular subgroup and ASCL1-NOTCH signalling. FINDINGS Transcriptional analyses identified two atypical teratoid rhabdoid tumour subgroups with differential enrichment of genetic pathways, and distinct clinicopathological and survival features. Expression of ASCL1, a regulator of NOTCH signalling, correlated with supratentorial location (p=0·004) and superior 5-year overall survival (35%, 95% CI 13-57, and 20%, 6-34, for ASCL1-positive and ASCL1-negative tumours, respectively; p=0·033) in 70 patients who received multimodal treatment. ASCL1 expression also correlated with superior 5-year overall survival (34%, 7-61, and 9%, 0-21, for ASCL1-positive and ASCL1-negative tumours, respectively; p=0·001) in 39 patients who received only chemotherapy without radiation. Cox hazard ratios for overall survival in patients with differential ASCL1 enrichment treated with chemotherapy with or without radiation were 2·02 (95% CI 1·04-3·85; p=0·038) and 3·98 (1·71-9·26; p=0·001). Integrated analyses of molecular subgroupings with clinical prognostic factors showed three distinct clinical risk groups of tumours with different therapeutic outcomes. INTERPRETATION An integration of clinical risk factors and tumour molecular groups can be used to identify patients who are likely to have improved long-term radiation-free survival and might help therapeutic stratification of patients with atypical teratoid rhabdoid tumours. FUNDING C17 Research Network, Genome Canada, b.r.a.i.n.child, Mitchell Duckman, Tal Doron and Suri Boon foundations.

Aurora kinase B is a potential therapeutic target in pediatric diffuse intrinsic pontine glioma.

Pediatric high‐grade astrocytomas (HGAs) account for 15–20% of all pediatric central nervous system tumors. These neoplasms predominantly involve the supratentorial hemispheres or the pons—diffuse intrinsic pontine gliomas (DIPG). Assumptions that pediatric HGAs are biologically similar to adult HGAs have recently been challenged, and the development of effective therapeutic modalities for DIPG and supratentorial HGA hinges on a better understanding of their biological properties. Here, 20 pediatric HGAs (9 DIPGs and 11 supratentorial HGAs) were subject to gene expression profiling following approval by the research ethics board at our institution. Many of these tumors showed expression signatures composed of genes that promote G1/S and G2/M cell cycle progression. In particular, Aurora kinase B (AURKB) was consistently and highly overexpressed in 6/9 DIPGs and 8/11 HGAs. Array data were validated using quantitative real‐time PCR and immunohistochemistry, as well as cross‐validation of our data set with previously published series. Inhibition of Aurora B activity in DIPG and in pediatric HGA cell lines resulted in growth arrest accompanied by morphological changes, cell cycle aberrations, nuclear fractionation and polyploidy as well as a reduction in colony formation. Our data highlight Aurora B as a potential therapeutic target in DIPG.

Fluoroquinolone antimicrobial drugs

Fluoroquinolones are bactericidal agents that inhibit DNA synthesis in bacteria. Early fluoroquinolones (e.g., ciprofloxacin) primarily target gram-negative bacteria, including Pseudomonas species. Newer agents (e.g., levofloxacin and moxifloxacin) have expanded coverage against gram-positive

Basic Science of Pediatric Brain Tumors

Recent advances in genomic and transcriptomic technologies have revolutionized our knowledge of the genetic and molecular basis of pediatric brain tumors. These discoveries have pinpointed novel genes and pathways, identified distinct molecular subgroups, and have led to developments of new mouse models. This chapter details our current understanding of the basic science of pediatric brain tumors, providing an outline of disease mechanisms and potential targets for molecular therapy.

JPO2/CDCA7L and LEDGF/p75 Are Novel Mediators of PI3K/AKT Signaling and Aggressive Phenotypes in Medulloblastoma

Substantial evidence links Myc-PI3K/AKT signaling to the most aggressive subtype of medulloblastoma and this axis in medulloblastoma therapy. In this study, we advance understanding of how Myc-PI3K/AKT signaling contributes to this malignancy, specifically, in identifying the Myc-interacting protein JPO2 and its partner binding protein LEDGF/p75 as critical modulators of PI3K/AKT signaling and metastasis in medulloblastoma. JPO2 overexpression induced metastatic medulloblastoma in vivo through two synergistic feed-forward regulatory circuits involving LEDGF/p75 and AKT that promote metastatic phenotypes in this setting. Overall, our findings highlight two novel prometastatic loci in medulloblastoma and point to the JPO2:LEDGF/p75 protein complex as a potentially new targetable component of PI3K/AKT signaling in medulloblastoma. Cancer Res; 76(9); 2802-12. ©2016 AACR.

Rubella in a returned traveller

A 42-year-old previously healthy man, born in the Philippines, presented to the emergency department with fever and rash. Three days after returning from a two-month visit to the Philippines where he had visited friends and family, the patient had sore throat, headaches and muscle pain. Four days

Embryonal Brain Tumors

Central nervous system embryonal brain tumors comprise a heterogeneous group which includes medulloblastoma (MB), central nervous system primitive neuroectodermal tumors (CNS-PNETs), and pineoblastoma. They are highly aggressive malignant tumors that often arise in children, are difficult to treat, and cause significant cancer-related morbidity or mortality. There has been tremendous gain in the survival of localized MB in recent years. However, treatment remains highly toxic and punishing and is much less effective for metastatic MB and non-MB PNET while recurrent MB remains largely incurable—underscoring the need to better define diagnostic and therapeutic approaches to this wide spectrum of biological diseases that receive similar multimodal therapeutic regimens. Global genomic studies have now separated embryonal tumors into clinically relevant molecular classes and are paving the way for a new era of biology-informed clinical management of these tumors. This chapter will review current clinical understanding of MB, CNS-PNET, and pineoblastoma and insights into novel therapeutic approaches for these diseases.

Impact of Defaulting to Single-Lumen Peripherally Inserted Central Catheters on Patient Outcomes: An Interrupted Time Series Study

Defaulting to single-lumen peripherally inserted central catheters (PICCs) ordered from non-critical care units resulted in a sustained reduction in PICC-related complications. This system of care is transferrable to other institutions, with potential for improved patient safety and efficiency in outpatient parenteral antimicrobial therapy clinics.

Zika virus infection in a pregnant Canadian traveler with congenital fetal malformations noted by ultrasonography at 14-weeks gestation

BackgroundFollowing emergence of Zika virus in the Americas, a devastating new congenital syndrome has been documented, leading to significant morbidity among Zika-infected fetuses and neonates.Case presentationA 29-year-old pregnant woman infected with Zika virus at 9-weeks gestation in Trinidad presented with one-month of fever, headache, and myalgia with persistent viremia. Significant fetal abnormalities were identified at 14-week ultrasound, which is the earliest ultrasound to describe a severely affected fetus following Zika virus infection to our knowledge.ConclusionsWe discuss the implications of prolonged maternal viremia and the spectrum of congenital Zika syndrome detectable by fetal ultrasound.