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Background: Despite available treatment approaches, including surgical resection along with chemotherapy and radiotherapy, glioblastoma (GBM), the most prevalent primary brain tumor, remains associated with a grim prognosis. Although radiotherapy is central to GBM treatment, its combination with bioenergetics regulators has not been validated in clinical practice. Here, we hypothesized that bioenergetics regulators can enhance the radio-sensitivity of GBM tumorspheres (TSs)., Methods: Gene expression profiles of GBM patient-derived TSs were obtained through microarray and RNA-seq. In vitro treatment efficacy was assessed using clonogenic assay, 3D invasion assay, neurosphere formation assay, and flow cytometry. Protein expression was measured via western blot, and γH2AX foci were detected via immunofluorescence. In vivo efficacy was confirmed in an orthotopic xenograft model., Results: Based on radiation response-associated gene expression, GBM TSs were classified into high- or low-radioresistant groups. Among the five bioenergetics regulators, the pentose phosphate pathway inhibitor DHEA and the glycolysis inhibitor 2-DG notably enhanced the efficacy of ionizing radiation (IR) efficacy in vitro, reducing the survival fraction, stemness, and invasiveness in high- and low-radioresistant TSs. Combination with 2-DG further stimulated IR-induced DNA damage response and apoptosis in low-radioresistant GBM TSs. RNA-seq analysis revealed a downregulation of bioenergetics- and cell cycle-associated genes, whereas extracellular matrix- and cell adhesion-associated genes were enhanced by combined IR and 2-DG treatment. This therapeutic regimen extended survival and diminished tumor size in mouse xenograft models., Conclusions: Our data suggest that combination with bioenergetics regulator 2-DG enhances the radio-sensitivity of GBM TSs, highlighting the clinical potential of this combined regimen., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The author is an Editorial Board Member/Editor-in-Chief/Associate Editor/Guest Editor for [Journal name] and was not involved in the editorial review or the decision to publish this article., (Copyright © 2024. Published by Elsevier Inc.)

Background: Glioblastoma (GBM), a primary malignant brain tumor, has a poor prognosis, even with standard treatments such as radiotherapy and chemotherapy. In this study, we explored the anticancer effects of the synergistic combination of perphenazine (PER), a dopamine receptor D2/3 (DRD2/3) antagonist, and temozolomide (TMZ), a standard treatment for GBM, in patient-derived human GBM tumorspheres (TSs)., Methods: The biological effects of the combination of PER and TMZ in GBM TSs were assessed by measuring cell viability, ATP, stemness, invasiveness, and apoptosis. Changes in protein and mRNA expression were analyzed using western blotting and RNA sequencing. Co-administration of PER and TMZ was evaluated in vivo using a mouse orthotopic xenograft model., Results: The Severance dataset showed that DRD2 and DRD3 expression was higher in tumor tissues than in the tumor-free cortex of patients with GBM. DRD2/3 knockout by CRISPR/Cas9 in patient-derived human GBM TSs inhibited cell growth and ATP production. The combined treatment with PER and TMZ resulted in superior effects on cell viability and ATP assays compared to those in single treatment groups. Flow cytometry, western blotting, and RNA sequencing confirmed elevated apoptosis in GBM TSs following combination treatment. Additionally, the combination of PER and TMZ downregulated the expression of protein and mRNA associated with stemness and invasiveness. In vivo evaluation showed that combining PER and TMZ extended the survival period of the mouse orthotopic xenograft model., Conclusions: The synergistic combination of PER and TMZ has potential as a novel combination treatment strategy for GBM., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Cancer cells need nutrients to grow and proliferate. During nutrient stress in the microenvironment, it is unclear if or how cancer cells can adopt alternative resources to re-wire and survive in patients. We discovered a 6-factor-secretome remarkably sustains a critical cell mass during nutrient stress in a pediatric embryonal brain tumor, atypical teratoid rhabdoid tumor (ATRT). Specific ATRT subtypes emerged as secretome-enriched, matching macrophage-enrichment patterns and were high-relapse-risk subtypes. The secretome alters drug response, protects against cell death, and provides pro-survival niches to rescue drugged cells. Secretome-grown tumor cells rearrange into a web-like architecture-stable during drug exposure, suggesting a mechanism for therapy resistance. Secretome prevents tumor cell death in aggressive tumor models, and in cerebrospinal dissemination, suggesting a role in tumor resistance/relapse. Our results unravel, a previously unexplored role of a specific 6-factor-secretome, providing an alternative fuel to sustain cancer cells during nutrient stress, and implications in relapse subtypes., Competing Interests: There is a provisional patent filed related to this work., (© 2024 The Author(s).)

Radiation is one of the standard therapies for pediatric high-grade glioma (pHGG), of which the prognosis remains poor. To gain an in-depth understanding of biological consequences beyond the classic DNA damage, we treated 9 patient-derived orthotopic xenograft (PDOX) models, including one with DNA mismatch repair (MMR) deficiency, with fractionated radiations (2 Gy/day x 5 days). Extension of survival time was noted in 5 PDOX models (P < 0.05) accompanied by γH2AX positivity in >95 % tumor cells in tumor core and >85 % in the invasive foci as well as ∼30 % apoptotic and mitotic catastrophic cell death. The model with DNA MMR (IC-1406HGG) was the most responsive to radiation with a reduction of Ki-67(+) cells. Altered metabolism, including mitochondria number elevation, COX IV activation and reactive oxygen species accumulation, were detected together with the enrichment of CD133 + tumor cells. The latter was caused by the entry of quiescent G 0 cells into cell cycle and the activation of self-renewal (SOX2 and BMI1) and epithelial mesenchymal transition (fibronectin) genes. These novel insights about the cellular and molecular mechanisms of fractionated radiation in vivo should support the development of new radio-sensitizing therapies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Background: Diffuse invasion remains a primary cause of treatment failure in pediatric high-grade glioma (pHGG). Identifying cellular driver(s) of pHGG invasion is needed for anti-invasion therapies., Methods: Ten highly invasive patient-derived orthotopic xenograft (PDOX) models of pHGG were subjected to isolation of matching pairs of invasive (HGG INV ) and tumor core (HGG TC ) cells., Results: pHGG INV cells were intrinsically more invasive than their matching pHGG TC cells. CSC profiling revealed co-positivity of CD133 and CD57 and identified CD57 + CD133 - cells as the most abundant CSCs in the invasive front. In addition to discovering a new order of self-renewal capacities, i.e., CD57 + CD133 - > CD57 + CD133 + > CD57 - CD133 +  > CD57 - CD133 - cells, we showed that CSC hierarchy was impacted by their spatial locations, and the highest self-renewal capacities were found in CD57 + CD133 - cells in the HGG INV front (HGG INV /CD57 + CD133 - cells) mediated by NANOG and SHH over-expression. Direct implantation of CD57 + (CD57 + /CD133 - and CD57 + /CD133 + ) cells into mouse brains reconstituted diffusely invasion, while depleting CD57 + cells (i.e., CD57 - CD133 + ) abrogated pHGG invasion., Conclusion: We revealed significantly increased invasive capacities in HGG INV cells, confirmed CD57 as a novel glioma stem cell marker, identified CD57 + CD133 - and CD57 + CD133 + cells as a new cellular driver of pHGG invasion and suggested a new dual-mode hierarchy of HGG stem cells., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Despite multimodality therapies, the prognosis of patients with malignant brain tumors remains extremely poor. One of the major obstacles that hinders development of effective therapies is the limited availability of clinically relevant and biologically accurate (CRBA) mouse models. Methods: We have developed a freehand surgical technique that allows for rapid and safe injection of fresh human brain tumor specimens directly into the matching locations (cerebrum, cerebellum, or brainstem) in the brains of SCID mice. Results: Using this technique, we successfully developed 188 PDOX models from 408 brain tumor patient samples (both high-and low-grade) with a success rate of 72.3% in high-grade glioma, 64.2% in medulloblastoma, 50% in ATRT, 33.8% in ependymoma, and 11.6% in low-grade gliomas. Detailed characterization confirmed their replication of the histopathological and genetic abnormalities of the original patient tumors. Conclusions: The protocol is easy to follow, without a sterotactic frame, in order to generate large cohorts of tumor-bearing mice to meet the needs of biological studies and preclinical drug testing.

Background: Atopic dermatitis (AD) is a complex inflammatory disease with a strong genetic component. A singular approach of genome wide association studies (GWAS) can identify AD-associated genetic variants, but is unable to explain their functional relevance in AD. This study aims to characterize AD-associated genetic variants and elucidate the mechanisms leading to AD through a multi-omics approach., Methods: GWAS identified an association between genetic variants at 6p21.32 locus and AD. Genotypes of 6p21.32 locus variants were evaluated against LOC100294145 expression in peripheral blood mononuclear cells (PBMCs). Their influence on LOC100294145 promoter activity was measured in vitro via a dual-luciferase assay. The function of LOC100294145 was then elucidated through a combination of co-expression analyses and gene enrichment with g:Profiler. Mendelian randomization was further used to assess the causal regulatory effect of LOC100294145 on its co-expressed genes., Results: Minor alleles of rs116160149 and rs115388857 at 6p21.32 locus were associated with increased AD risk ( p  = 2.175 × 10 -8 , OR = 1.552; p  = 2.805 × 10 -9 , OR = 1.55) and higher LOC100294145 expression in PBMCs ( adjusted p  = 0.182; 8.267 × 10 -12 ). LOC100294145 expression was also found to be increased in those with AD ( adjusted p  = 3.653 × 10 -2 ). The genotype effect of 6p21.32 locus on LOC100294145 promoter activity was further validated in vitro . Co-expression analyses predicted LOC100294145 protein's involvement in interleukin-27 and type 1 interferon signaling, which was further substantiated through mendelian randomization., Conclusion: Genetic variants at 6p21.32 locus increase AD susceptibility through raising LOC100294145 expression. A multi-omics approach enabled the deduction of its pathogenesis model comprising dysregulation of hub genes involved in type 1 interferon and interleukin 27 signaling., Competing Interests: The authors declare no competing interests., (© 2024 The Authors.)

Background: We see increasing evidence that dietary and nutrients factors play a pivotal role in allergic diseases and recent global findings suggest that dietary habits influence the pathogenesis of atopic dermatitis (AD). Frequent consumption of fast food diets is associated with AD development. Despite the rising prevalence of AD in Asia, efforts in investigating the role of dietary habits and AD in adults are still lacking., Methods: We evaluated the association between the dietary intake of 16 food types and AD manifestations using our Singapore/Malaysia Cross-sectional Genetics Epidemiology Study (SMCGES) population. Dietary habits profiles of 11,494 young Chinese adults (1,550 AD cases/2,978 non-atopic controls/6,386 atopic controls) were assessed by an investigator-administered questionnaire. AD cases were further evaluated for their chronicity (550 chronic) and severity (628 moderate-to-severe). Additionally, we derived a novel food index, Quality of Diet based on Glycaemic Index Score (QDGIS), to examine the association between dietary intake of glycaemic index (GI) and various AD phenotypes., Results: The majority of AD subjects are distributed in the good (37.1%) and moderate (36.2%) QDGIS classes. From the multivariable analyses for age and gender, a moderate QDGIS class was significantly associated with a lower odds of AD (adjusted odds ratio (AOR): 0.844; 95% confidence interval (CI): 0.719-0.991; p &lt; 0.05) and moderate-to-severe AD (AOR: 0.839; 95% CI: 0.714-0.985; p &lt; 0.05). A good QDGIS class was only significantly associated with a lower odds of chronic AD (AOR: 0.769; 95% CI: 0.606-0.976; p &lt; 0.05). Among high GI foods, frequent consumption of burgers/fast food was strongly associated with an increased risk of chronic and moderate-to-severe AD. Among low GI foods, increased intake frequencies of fruits, vegetables, and pulses decreased the odds of AD. Finally, we identified significant associations between frequent seafood, margarine, butter, and pasta consumption with an increased odds of AD despite them having little GI values., Conclusion: While genetic components are well-established in their risks associated with increased AD prevalence, there is still a lack of a focus epidemiology study associating dietary influence with AD. Based on the first allergic epidemiology study conducted here in Singapore and Malaysia, it laid the groundwork to guide potential dietary interventions from changing personal dietary habits., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Background: Animal models representing different molecular subtypes of glioblastoma multiforme (GBM) is desired for developing new therapies. SVV-001 is an oncolytic virus selectively targeting cancer cells. It's capacity of passing through the blood brain barrier makes is an attractive novel approach for GBM., Materials and Methods: 23 patient tumor samples were implanted into the brains of NOD/SCID mice (1 × 10 5 cells/mouse). Tumor histology, gene expression (RNAseq), and growth rate of the developed patient-derived orthotopic xenograft (PDOX) models were compared with the originating patient tumors during serial subtransplantations. Anti-tumor activities of SVV-001 were examined in vivo; and therapeutic efficacy validated in vivo via single i.v. injection (1 × 10 11 viral particle) with or without fractionated (2 Gy/day x 5 days) radiation followed by analysis of animal survival times, viral infection, and DNA damage., Results: PDOX formation was confirmed in 17/23 (73.9%) GBMs while maintaining key histopathological features and diffuse invasion of the patient tumors. Using differentially expressed genes, we subclassified PDOX models into proneural, classic and mesenchymal groups. Animal survival times were inversely correlated with the implanted tumor cells. SVV-001 was active in vitro by killing primary monolayer culture (4/13 models), 3D neurospheres (7/13 models) and glioma stem cells. In 2/2 models, SVV-001 infected PDOX cells in vivo without harming normal brain cells and significantly prolonged survival times in 2/2 models. When combined with radiation, SVV-001 enhanced DNA damages and further prolonged animal survival times., Conclusion: A panel of 17 clinically relevant and molecularly annotated PDOX modes of GBM is developed, and SVV-001 exhibited strong anti-tumor activities in vitro and in vivo., (© 2023. The Author(s).)

The purpose of this study is to (1) to determine if treatment of underlying allergic rhinitis (AR) in children will affect epistaxis outcome, (2) to compare efficacy of three outpatient AR treatment regimens in epistaxis outcomes, and (3) to investigate potential factors in the pathogenesis of epistaxis with underlying AR. A single-blind randomized-controlled study was conducted in the Otolaryngology clinic in KK Women's and Children's Hospital. Sixty children aged below 18 years with underlying untreated AR, with first presentation of epistaxis, were randomized to three different AR treatments: treatment 1, antihistamine (20 patients); treatment 2, nasal steroid spray (20 patients); and treatment 3, both antihistamine and nasal steroid spray (20 patients). Epistaxis severity and frequency were assessed. Pre-treatment, 95% of patients within each of the three treatment groups described epistaxis symptoms. Post-treatment, there was improvement in epistaxis outcome (resolution of epistaxis) with 20% (4/20), 40% (8/20), and 60% (12/20) of patients in treatment groups 1 (antihistamine), 2 (nasal steroid spray), and 3 (combined therapy) respectively, who reported resolution of epistaxis. Treatment regimens containing nasal steroid spray resulted in greater improvement of epistaxis severity and frequency. Combined therapy (treatment 3) resulted in the best epistaxis outcome at 1-month follow-up. Majority (90%) reported nose-picking/rubbing behavior., Conclusions: Intranasal corticosteroids are superior to oral antihistamines in relieving itch or rhinorrhea in AR. Intranasal corticosteroids may be important in treating epistaxis with underlying AR, because digital trauma from itch/rhinorrhea-related nose-picking/rubbing frequently leads to epistaxis. Results from this study will be important to primary and emergency physicians, community pediatricians, and pediatric allergists and otolaryngologists., What Is Known: • Childhood epistaxis commonly co-exists with allergic rhinitis (AR), causing significant symptoms and distress to patients. • There are currently no studies reporti ng on epistaxis outcome aft er treatment of underlying AR., What Is New: • This is a single-blind randomized-controlled study of 60 children aged below 18 years with underlying untreated AR, with first presentation of epistaxis to a children's hospital in Singapore Patients were randomized to three different regimens to treat AR: treatment 1, antihistamine; treatment 2, nasal steroid spray; and treatment 3, both antihistamine and nasal steroid spray. • Treatment regimens containing nasal steroid spray improved epistaxis outcomes, with combined therapy of antihistamine and nasal steroid spray resulting in the best outcome for resolution of epistaxis among the three treatment regimens., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

There is a growing interest in the use of alternative medical systems (AMS), such as traditional Chinese medicine (TCM), ayurveda, homeopathy, and naturopathy, among chronic kidney disease patients. This review summarizes the efficacy and safety of AMS interventions in chronic kidney disease (CKD) patients. A systematic review was conducted in MEDLINE, Embase, Scopus, CINAHL, CENTRAL, and PsycINFO in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Synthesis without meta-analysis (SWiM) guidelines. Randomized controlled trials (RCTs) which evaluated the use of AMS among adult CKD patients were included. The efficacy of each AMS was assessed based on improvement in biochemical markers or reduction in symptom severity scores. All adverse reactions were recorded. Of the 14,583 articles retrieved, 33 RCTs were included. TCM (n=20) and ayurveda (n=6) were the most well-studied. Majority of studies (66.7%) had a sample size <100. Common indications evaluated included improvement in renal function (n=12), proteinuria (n=5), and uremic pruritus (n=5). Among TCM, acupuncture and syndromes-based TCM granules formulation were shown to improve estimated glomerular filtration rate (eGFR) by 5.1-15.5% and 7.07-8.12% respectively. Acupuncture reduced uremic pruritus symptoms by 54.7-60.2% while Huangkui, Shenqi granules, and Tripterygium wilfordii Hook F reduced proteinuria by 18.6-50.7%, 61.8%, and 32.1% respectively. For Ayurveda, camel milk and Nigella sativa oil improved eGFR by 16.9% and 86.8%, respectively, while capsaicin reduced pruritus scores by 84.3%. Homeopathic verum medication reduced pruritus scores by 29.2-41.5%. Nausea was the most common adverse effect reported with alpha-keto amino acids (0.07%), Nigella sativa oil (7.04%), and silymarin (10%). TCM and ayurveda were more well-studied AMS therapies that demonstrated efficacy in CKD patients. RCTs with larger sample sizes are needed to ascertain the efficacy and safety of promising AMS., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Teo et al.)

Purpose: Limited treatment options are currently available for glioblastoma (GBM), an extremely lethal type of brain cancer. For a variety of tumor types, bioenergetic deprivation through inhibition of cancer-specific metabolic pathways has proven to be an effective therapeutic strategy. Here, we evaluated the therapeutic effects and underlying mechanisms of dual inhibition of carnitine palmitoyltransferase 1A (CPT1A) and glucose-6-phosphate dehydrogenase (G6PD) critical for fatty acid oxidation (FAO) and the pentose phosphate pathway (PPP), respectively, against GBM tumorspheres (TSs)., Methods: Therapeutic efficacy against GBM TSs was determined by assessing cell viability, neurosphere formation, and 3D invasion. Liquid chromatography-mass spectrometry (LC-MS) and RNA sequencing were employed for metabolite and gene expression profiling, respectively. Anticancer efficacy in vivo was examined using an orthotopic xenograft model., Results: CPT1A and G6PD were highly expressed in GBM tumor tissues. Notably, siRNA-mediated knockdown of both genes led to reduced viability, ATP levels, and expression of genes associated with stemness and invasiveness. Similar results were obtained upon combined treatment with etomoxir and dehydroepiandrosterone (DHEA). Transcriptome analyses further confirmed these results. Data from LC-MS analysis showed that this treatment regimen induced a considerable reduction in the levels of metabolites associated with the TCA cycle and PPP. Additionally, the combination of etomoxir and DHEA inhibited tumor growth and extended survival in orthotopic xenograft model mice., Conclusion: Our collective findings support the utility of dual suppression of CPT1A and G6PD with selective inhibitors, etomoxir and DHEA, as an efficacious therapeutic approach for GBM., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Atopic Dermatitis (AD) is a highly pruritic, chronic-recurrent inflammatory skin condition associated with erythematous lesions that affect a significant proportion of the population. Although AD is a non-communicable disease, it can cause pain, unbearable itchiness, sleep disturbance, loss of work productivity, and reduced quality of life. As a heterogeneous disease, AD is influenced by multiple genes and environmental triggers. As such, it is imperative to gain a deeper insight into the intricate gene-environment relationship that results in the manifestation of AD., Methods: There are 3 objectives in our study. We first aim to update the epidemiological status of AD amongst young adults in Singapore and Malaysia, in particular amongst the Chinese ethnic background. Next, we re-evaluated the possible associated risk factors, identified in our previous meta-analysis and review studies, on the current cohort. Finally, we described here a detailed disease presentation and symptoms profile of our Singapore and Malaysia Cross-Sectional Genetics Epidemiology Study (SMCGES) cohort, which forms the base population for the discovery of associated genetic factors in relation to asthma, allergic diseases and skin conditions. Based on a skin prick test (SPT) and investigator-administered medical history responses, we assessed the AD profiles of 11 494 participants and the significant modifiable and non-modifiable factors associated with disease presentation., Results: The prevalence of AD in the combined population was 13.5%. Chronic and moderate/severe AD were observed in 35.5% and 40.5% of the individuals with AD, respectively. Family history of atopic diseases, prior history of drug allergies, a history of acne, increased household family monthly income, higher number of individuals in the shared household, parental education, sedentary lifestyle, physical activities, alcoholic consumption, and even quality of diet was significantly associated with AD presentation, chronicity, and severity. Among all the factors evaluated, family and personal history of atopic diseases imposed the strongest associated risk., Conclusions: These findings supported our previous review studies and affirmed that familial history or genetic factors critically influence the development of AD in our population and environment. Environmental and other modifiable factors can also trigger AD throughout the lifetime of individuals who have especially inherited the atopic disease disposition. A better understanding of how these risk factors affect AD individuals in our population can facilitate disease surveillance, monitor disease control, and serve as a description for our future genetic epidemiology studies., (© 2022 The Author(s).)

Recurrence is frequent in pediatric ependymoma (EPN). Our longitudinal integrated analysis of 30 patient-matched repeated relapses (3.67 ± 1.76 times) over 13 years (5.8 ± 3.8) reveals stable molecular subtypes (RELA and PFA) and convergent DNA methylation reprogramming during serial relapses accompanied by increased orthotopic patient derived xenograft (PDX) (13/27) formation in the late recurrences. A set of differentially methylated CpGs (DMCs) and DNA methylation regions (DMRs) are found to persist in primary and relapse tumors (potential driver DMCs) and are acquired exclusively in the relapses (potential booster DMCs). Integrating with RNAseq reveals differentially expressed genes regulated by potential driver DMRs (CACNA1H, SLC12A7, RARA in RELA and HSPB8, GMPR, ITGB4 in PFA) and potential booster DMRs (PLEKHG1 in RELA and NOTCH, EPHA2, SUFU, FOXJ1 in PFA tumors). DMCs predicators of relapse are also identified in the primary tumors. This study provides a high-resolution epigenetic roadmap of serial EPN relapses and 13 orthotopic PDX models to facilitate biological and preclinical studies., (© 2022. The Author(s).)

Introduction: The importance of fatty acid oxidation (FAO) in the bioenergetics of glioblastoma (GBM) is being realized. Etomoxir (ETO), a carnitine palmitoyltransferase 1 (CPT1) inhibitor exerts cytotoxic effects in GBM, which involve interrupting the FAO pathway. We hypothesized that FAO inhibition could affect the outcomes of current standard temozolomide (TMZ) chemotherapy against GBM., Methods: The FAO-related gene expression was compared between GBM and the tumor-free cortex. Using four different GBM tumorspheres (TSs), the effects of ETO and/or TMZ was analyzed on cell viability, tricarboxylate (TCA) cycle intermediates and adenosine triphosphate (ATP) production to assess metabolic changes. Alterations in tumor stemness, invasiveness, and associated transcriptional changes were also measured. Mouse orthotopic xenograft model was used to elucidate the combinatory effect of TMZ and ETO., Results: GBM tissues exhibited overexpression of FAO-related genes, especially CPT1A, compared to the tumor-free cortex. The combined use of ETO and TMZ further inhibited TCA cycle and ATP production than single uses. This combination treatment showed superior suppression effects compared to treatment with individual agents on the viability, stemness, and invasiveness of GBM TSs, as well as better downregulation of FAO-related gene expression. The results of in vivo study showed prolonged survival outcomes in the combination treatment group., Conclusion: ETO, an FAO inhibitor, causes a lethal energy reduction in the GBM TSs. When used in combination with TMZ, ETO effectively reduces GBM cell stemness and invasiveness and further improves survival. These results suggest a potential novel treatment option for GBM., (© 2022. The Author(s).)

Background: Allergic rhinitis (AR) is characterized by the occurrence of at least 2 symptoms of nasal itching, nasal blockage, rhinorrhea, and sneezing, when not afflicted with a cold or flu, with defined atopic sensitization demonstrated by skin prick test or specific IgE responses. Besides the detriment to standard of living and economic burden of AR, both multicentre and single-cohort studies have observed an increase in AR prevalence in Asia over time., Methods: In total, 12 872 individuals, with mean age 22.1 years (SD = 4.8), were recruited from universities in Singapore and Malaysia. Each participant provided epidemiological data based on an investigator-administered questionnaire adapted from the validated International Study of Allergies and Asthma in Childhood (ISAAC) protocol, and atopy status was determined using a skin prick test (SPT) performed by qualified staff. AR was diagnosed according to Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines and a positive SPT result., Results: Sensitization (determined by SPT) to either Blomia tropicalis or Dermatophagoides pteronyssinus was prevalent in 66.5% of the cohort. Current rhinitis (manifesting ≥2 rhinitis symptoms, within the past 12 months) was observed in 48.9% of our population, while AR, which included atopy status, was estimated at 39.4%. Sneezing and rhinorrhea were the most common symptoms among AR cases. AR prevalence decreased with increasing age (OR: 0.979; 95% CI: 0.969-0.989), while male gender (OR: 2.053; 95% CI: 1.839-2.294), and a parental history of allergic diseases (OR: 2.750; 95% CI: 2.284-3.316) were significant risk factors for AR. Upon adjustment for age, gender, and parental history, housing type (OR: 0.632; 95% CI: 0.543-0.736) and income level (>$6000 vs <$2000; OR: 2.461; 95% CI: 2.058-2.947) remained as significant risk factors for AR, while ever having kept a pet (OR: 1.167; 95% CI: 1.025-1.328) emerged as a risk factor. Conflicting results were obtained for indicators of sedentary lifestyle: frequent physical activity (OR: 1.394; 95% CI: 1.150-1.694) and increased duration spent using the TV/computer (OR: 1.224; 95% CI: 1.006-1.489) both increased the risk of AR. Lastly, we used the Quality of Diet based on Glycaemic Index Score (QDGIS) to assess the Glycaemic Index (GI) level of overall diet. We identified lower GI level of overall diet as a protective factor against AR manifestation (OR: 0.682; 95% CI: 0.577-0.807)., Conclusion: While the previously established non-modifiable risk factors for AR were present in our study population, the identification of modifiable risk factors, such as TV/computer usage, and dietary habits, opens a new area for research, both in the areas of gene-environment interaction, and management of AR., (© 2022 The Author(s).)

Forkhead Box M1 (FOXM1) is known to regulate cell proliferation, apoptosis and tumorigenesis. The lignan, (-)-(2R,3R)-1,4-O-diferuloylsecoisolariciresinol (DFS), from Alnus japonica has shown anti-cancer effects against colon cancer cells by suppressing FOXM1. The present study hypothesized that DFS can have anti-cancer effects against glioblastoma (GBM) tumorspheres (TSs). Immunoprecipitation and luciferase reporter assays were performed to evaluate the ability of DFS to suppress nuclear translocation of β-catenin through β-catenin/FOXM1 binding. DFS-pretreated GBM TSs were evaluated to assess the ability of DFS to inhibit GBM TSs and their transcriptional profiles. The in vivo efficacy was examined in orthotopic xenograft models of GBM. Expression of FOXM1 was higher in GBM than in normal tissues. DFS-induced FOXM1 protein degradation blocked β-catenin translocation into the nucleus and consequently suppressed downstream target genes of FOXM1 pathways. DFS inhibited cell viability and ATP levels, while increasing apoptosis, and it reduced tumorsphere formation and the invasiveness of GBM TSs. And DFS reduced the activities of transcription factors related to tumorigenesis, stemness, and invasiveness. DFS significantly inhibited tumor growth and prolonged the survival rate of mice in orthotopic xenograft models of GBM. It suggests that DFS inhibits the proliferation of GBM TSs by suppressing FOXM1. DFS may be a potential therapeutic agent to treat GBM., (© 2022. The Author(s).)

Clinical outcomes in patients with WHO grade II/III astrocytoma, oligodendroglioma or secondary glioblastoma remain poor. Isocitrate dehydrogenase 1 (IDH1) is mutated in > 70% of these tumors, making it an attractive therapeutic target. To determine the efficacy of our newly developed mutant IDH1 inhibitor, SYC-435 (1-hydroxypyridin-2-one), we treated orthotopic glioma xenograft model (IC-BT142AOA) carrying R132H mutation and our newly established orthotopic patient-derived xenograft (PDX) model of recurrent anaplastic oligoastrocytoma (IC-V0914AOA) bearing R132C mutation. In addition to suppressing IDH1 mutant cell proliferation in vitro, SYC-435 (15 mg/kg, daily x 28 days) synergistically prolonged animal survival times with standard therapies (Temozolomide + fractionated radiation) mediated by reduction of H3K4/H3K9 methylation and expression of mitochondrial DNA (mtDNA)-encoded molecules. Furthermore, RNA-seq of the remnant tumors identified genes (MYO1F, CTC1 and BCL9) and pathways (base excision repair, TCA cycle II, sirtuin signaling, protein kinase A, eukaryotic initiation factor 2 and α-adrenergic signaling) as mediators of therapy resistance. Our data demonstrated the efficacy SYC-435 in targeting IDH1 mutant gliomas when combined with standard therapy and identified a novel set of genes that should be prioritized for future studies to overcome SYC-435 resistance., (Copyright © 2022. Published by Elsevier Inc.)

Purpose: Glioblastoma (GBM) is a rapidly growing tumor in the central nervous system with altered metabolism. Depleting the bioenergetics of tumors with biguanides have been suggested as an effective therapeutic approach for treating GBMs. The purpose of this study was to determine the effects of IM1761065, a novel biguanide with improved pharmacokinetics, on GBM-tumorspheres (TSs)., Methods: The biological activities of IM1761065 on GBM-TSs, including their effects on viability, ATP levels, cell cycle, stemness, invasive properties, and transcriptomes were examined. The in vivo efficacy of IM1761065 was tested in a mouse orthotopic xenograft model., Results: IM1761065 decreased the viability and ATP levels of GBM-TSs in a dose-dependent manner, and reduced basal and spare respiratory capacity in patient-derived GBM-TS, as measured by the oxygen consumption rate. Sphere formation, expression of stemness-related proteins, and invasive capacity of GBM-TSs were also significantly suppressed by IM1761065. A gene-ontology comparison of IM1761065-treated groups showed that the expression levels of stemness-related, epithelial mesenchymal transition-related, and mitochondrial complex I genes were also significantly downregulated by IM1761065. An orthotopic xenograft mouse model showed decreased bioluminescence in IM1761065-treated cell-injected mice at 5 weeks. IM1761065-treated group showed longer survival than the control group (P = 0.0289, log-rank test)., Conclusion: IM1761065 is a potent inhibitor of oxidative phosphorylation. The inhibitory effect of IM1761065 on the bioenergetics of GBM-TS suggests that this novel compound could be used as a new drug for the treatment of GBM., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Diffuse invasion is the primary cause of treatment failure of glioblastoma (GBM). Previous studies on GBM invasion have long been forced to use the resected tumor mass cells. Here, a strategy to reliably isolate matching pairs of invasive (GBM INV ) and tumor core (GBM TC ) cells from the brains of 6 highly invasive patient-derived orthotopic models is described. Direct comparison of these GBM INV and GBM TC cells reveals a significantly elevated invasion capacity in GBM INV cells, detects 23/768 miRNAs over-expressed in the GBM INV cells (miRNA INV ) and 22/768 in the GBM TC cells (miRNA TC ), respectively. Silencing the top 3 miRNAs INV (miR-126, miR-369-5p, miR-487b) successfully blocks invasion of GBM INV cells in vitro and in mouse brains. Integrated analysis with mRNA expression identifies miRNA INV target genes and discovers KCNA1 as the sole common computational target gene of which 3 inhibitors significantly suppress invasion in vitro. Furthermore, in vivo treatment with 4-aminopyridine (4-AP) effectively eliminates GBM invasion and significantly prolongs animal survival times (P = 0.035). The results highlight the power of spatial dissection of functionally accurate GBM INV and GBM TC cells in identifying novel drivers of GBM invasion and provide strong rationale to support the use of biologically accurate starting materials in understanding cancer invasion and metastasis., (© 2021 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Atypical teratoid rhabdoid tumor (ATRT) is an aggressive embryonal brain tumor among infants and young children. Two challenges exist for preclinical testing in ATRT. First, genetically quiet, ATRT is a difficult tumor to target molecularly. Tumor cells need to divide to propagate tumor growth-intercepting the common crossroads in cell cycle progression is a feasible strategy. KIF11 is needed for bipolar spindle formation in metaphase. We identified KIF11 as a universal target of all ATRT-molecular-subtypes. Ispinesib, a KIF11-inhibitor, effectively inhibited tumor proliferation in all seven cell lines. A second challenge-a major challenge in preclinical drug testing in-vivo among aggressive tumor models, is the narrow therapeutic window to administer drugs within the limited murine lifespan. Our most aggressive ATRT tumor model was lethal in all mice within ~ 1 month of tumor implantation. Such short-surviving mouse models are difficult to employ for preclinical drug testing due to the narrow time window to administer drugs. To overcome this time restriction, we developed a clinical staging system which allowed physically-fit mice to continue treatment, in contrast to the conventional method of fixed drug-dose-duration regimen in preclinical testing which will not be feasible in such short-surviving mouse models. We validated this approach in a second embryonal brain tumor, medulloblastoma. This is a clinically relevant, cost-efficient approach in preclinical testing for cancer and non-cancer disease phenotypes. Widely used preclinical mouse models are not the most accurate and lack the aggressive tumor spectrum found within a single tumor type. Mice bearing the most aggressive tumor spectrum progress rapidly in the limited murine life-span, resulting in a narrow therapeutic window to administer drugs, and are thus difficult to employ in preclinical testing. Our approach overcomes this challenge. We discovered ispinesib is efficacious against two embryonal brain tumor types.

Background: Driver genes of GBM may be crucial for the onset of isocitrate dehydrogenase (IDH)-wildtype (WT) glioblastoma (GBM). However, it is still unknown whether the genes are expressed in the identical cluster of cells. Here, we have examined the gene expression patterns of GBM tissues and patient-derived tumorspheres (TSs) and aimed to find a progression-related gene., Methods: We retrospectively collected primary IDH-WT GBM tissue samples (n = 58) and tumor-free cortical tissue samples (control, n = 20). TSs are isolated from the IDH-WT GBM tissue with B27 neurobasal medium. Associations among the driver genes were explored in the bulk tissue, bulk cell, and a single cell RNAsequencing techniques (scRNAseq) considering the alteration status of TP53, PTEN, EGFR, and TERT promoter as well as MGMT promoter methylation. Transcriptomic perturbation by temozolomide (TMZ) was examined in the two TSs., Results: We comprehensively compared the gene expression of the known driver genes as well as MGMT, PTPRZ1, or IDH1. Bulk RNAseq databases of the primary GBM tissue revealed a significant association between TERT and TP53 (p < 0.001, R = 0.28) and its association increased in the recurrent tumor (p  < 0.001, R = 0.86). TSs reflected the tissue-level patterns of association between the two genes (p < 0.01, R = 0.59, n = 20). A scRNAseq data of a TS revealed the TERT and TP53 expressing cells are in a same single cell cluster. The driver-enriched cluster dominantly expressed the glioma-associated long noncoding RNAs. Most of the driver-associated genes were downregulated after TMZ except IGFBP5., Conclusions: GBM tissue level expression patterns of EGFR, TERT, PTEN, IDH1, PTPRZ1, and MGMT are observed in the GBM TSs. The driver gene-associated cluster of the GBM single cells were enriched with the glioma-associated long noncoding RNAs.

Brain tumor is the leading cause of cancer related death in children. Clinically relevant animals are critical for new therapy development. To address the potential impact of animal gender on tumorigenicity rate, xenograft growth and in vivo drug responses, we retrospectively analyzed 99 of our established patient derived orthotopic xenograft mouse models (orthotopic PDX or PDOX). From 27 patient tumors, including 5 glioblastomas (GBMs), 11 medulloblastomas (MBs), 4 ependymomas (EPNs), 4 atypical teratoid/rhabdoid tumors (ATRTs) and 3 diffuse intrinsic pontine gliomas (DIPGs), that were directly implanted into matching locations in the brains of approximately equal numbers of male and female animals (n = 310) in age-matched (within 2-week age-difference) SCID mice, the tumor formation rate was 50.6 ± 21.5% in male and 52.7 ± 23.5% in female mice with animal survival times of 192.6 ± 31.7 days in male and 173.9 ± 34.5 days in female mice (P = 0.46) regardless of pathological diagnosis. Once established, PDOX tumors were serially subtransplanted for up to VII passage. Analysis of 1,595 mice from 59 PDOX models (18 GBMs, 18 MBs, 5 ATRTs, 6 EPNs, 7 DIPGs and 5 PENTs) during passage II and VII revealed similar tumor take rates of the 6 different tumor types between male (85.4 ± 15.5%) and female mice (84.7 ± 15.2%) (P = 0.74), and animal survival times were 96.7 ± 23.3 days in male mice and 99.7 ± 20 days in female (P = 0.25). A total of 284 mice from 7 GBM, 2 MB, 1 ATRT, 1 EPN, 2 DIPG and 1 PNET were treated with a series of standard and investigational drugs/compounds. The overall survival times were 106.9 ± 25.7 days in male mice, and 110.9 ± 31.8 days in female mice (P = 0.41), similar results were observed when different types/models were analyzed separately. In conclusion, our data demonstrated that the gender of SCID mice did not have a major impact on animal model development nor drug responses in vivo, and SCID mice of both genders are appropriate for use., (Copyright © 2020. Published by Elsevier B.V.)

Objectives: For a large part of the coronavirus disease 2019 (COVID-19) pandemic, Singapore had managed to keep local cases in the single digits daily, with decisive measures. Yet, we saw this critical time point when the imported cases surged through our borders. The gaps which we can and have efficiently closed, using a public health approach and global border containment strategies, are aptly illustrated through this case. This critical point of imported case surge has resulted in a large spike of daily local cases sustained through community transmission, up to 120/day within a very short time frame. We were able to rapidly bring this under control., Study Design: This is a case study of a patient who passed through our borders, with COVID-19 masquerading as a resolved sore throat., Methods: The events were prospectively documented., Results: We present a case of a 21-year-old student returning from Nottingham. He presented with sore throat as the only symptom the few days prior his return, and on arrival at our border (day 7 from initial symptoms), his sore throat had already resolved. The events leading up to his COVID-19 diagnosis highlight the gaps of the international screening processes at the global border entry and the potential consequences of community chain transmission through imported COVID-19 cases., Conclusions: An important global border control measure to implement quickly will be to expand the symptom list to isolated sore throat and/or a prior history of recent symptoms (resolved). This may capture a larger proportion of imported cases at border entry point for more effective containment. This piece will be equally relevant to the general physicians, emergency care physicians, otolaryngologists and anaesthetists, who are at higher risk of encountering a throat visualization during intubation and routine examination. This information can be useful to countries with low resources or insufficient COVID-19 testing kits., (Copyright © 2020 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.)

Background: Congenital diaphragmatic hernia (CDH) is a common birth defect associated with significant mortality and morbidity. There is limited outcome data on CDH in the Southeast Asian region. Rapid accessibility to our CDH Perinatal Center, as a consequence of the small geographic size of our country and efficient land transportation system, has largely eliminated deaths of live outborn babies prior arrival at our center. We selected a study period when extracorporeal membrane oxygenation (ECMO) support was not available at our institution. The data will therefore be relevant in developing management guidelines and antenatal counselling for perinatal centers in this region managing CDH with limited resources, without ECMO facilities., Methods: A retrospective study of antenatally or postnatally diagnosed CDH infants born between January 2002 and June 2005 was performed. We selected this study period as ECMO support was not available over this period. We studied the demographics, clinical characteristics, postnatal predictors of mortality and outcomes of CDH infants in a single tertiary institution., Results: A total of 24 patients with CDH were identified. Seventy-nine percent of liveborns with CDH survived to hospital discharge. Antenatal detection rate was 83.3%. Significant postnatal predictors of mortality were preoperative pneumothorax (p = 0.035), high CRIB score (p = 0.007), low one- and five-minute Apgar score (p = 0.011, p = 0.026 respectively) and high pCO2 on initial arterial blood gas (p = 0.007). At one-year follow-up, three patients had delayed gross motor milestones which resolved subsequently. Re-admissions were required for recurrent bronchiolitis (33%) and oesophageal reflux which resolved in all cases. Two (13.3%) infants had surgical complications and needed re-admission for probable adhesive intestinal obstruction; one required adhesiolysis and the other was managed conservatively with good outcome., Conclusion: A single-center CDH outcome in Singapore, without ECMO use, was good. This is a cohort now with long-term survival outcome which will be valuable to the neonatology community., Competing Interests: Declaration of Competing Interest There is no conflict of interest involved in this study., (Copyright © 2020. Published by Elsevier B.V.)

Glioblastoma multiforme (GBM), a deadly cancer, is the most lethal and common malignant brain tumor, and the leading cause of death in adult brain tumors. While genomic data continues to rocket, clinical application and translation to patient care are lagging behind. Big data now deposited in the TCGA network offers a window to generate novel clinical hypotheses. We hypothesized that a TCGA-derived gene-classifier can be applied across different gene profiling platforms and population groups. This gene-classifier validated three robust GBM-subtypes across six different platforms, among Caucasian, Korean and Chinese populations: Three Caucasian-predominant TCGA-cohorts (Affymetrix U133A = 548, Agilent Custom-Array = 588, RNA-seq = 168), and three Asian-cohorts (Affymetrix Human Gene 1.0ST-Array = 61, Illumina = 52, Agilent 4 × 44 K = 60). To understand subtype-relevance in patient therapy, we investigated retrospective TCGA patient clinical sets. Subtype-specific patient survival outcome was similarly poor and reflected the net result of a mixture of treatment regimens with/without surgical resection. As a proof-of-concept, in subtype-specific patient-derived orthotopic xenograft (PDOX) mice, Classical-subtype demonstrated no survival difference comparing radiation-therapy versus temozolomide monotherapies. Though preliminary, a PDOX model of Proneural/Neural-subtype demonstrated significantly improved survival with temozolomide compared to radiation-therapy. A larger scale study using this gene-classifier may be useful in clinical outcome prediction and patient selection for trials based on subtyping.

Metastatic intracranial germinoma is difficult to treat. Although the proto-oncogene KIT is recognized as one of the most frequent genetic abnormalities in CNS germinoma, the development of new target therapeutic agents for CNS germinoma is hampered by the lack of clinically-relevant animal models that replicate the mutated or over-expressed KIT. CNS germinoma tumor cells from five pediatric patients were directly implanted into the brains of Rag2/severe combined immune deficiency mice. Once established, the xenograft tumors were sub-transplanted in vivo in mouse brains. Characterization of xenograft tumors were performed through histologic and immunohistochemical staining, and KIT mutation analysed with quantitative pyro-sequencing. Expression of putative cancer stem cell markers (CD133, CD15, CD24, CD44, CD49f) was analyzed through flow cytometry. Two patient-derived orthotopic xenograft (PDOX) models (IC-6999GCT and IC-9302GCT) were established from metastatic germinoma and serially sub-transplanted five times in mouse brains. Similar to the original patient tumors, they both exhibited faint expression (+) of PLAP, no expression (-) of β-HCG and strong (+++) expression of KIT. KIT mutation (D816H), however, was only found in IC-9320GCT. This mutation was maintained during the five in vivo tumor passages with an increased mutant allele frequency compared to the patient tumor. Expression of putative cancer stem cell markers CD49f and CD15 was also detected in a small population of tumor cells in both models. This new pair of PDOX models replicated the key biological features of pediatric intracranial germinoma and should facilitate the biological and pre-clinical studies for metastatic intracranial germinomas.

Immunobiology of medulloblastoma (MB), the most common malignant brain tumor in children, is poorly understood. Although tumor cells in some MBs were recently shown to express CD1d and be susceptible to Vα24-invariant natural killer T (NKT)-cell cytotoxicity, the clinical relevance of CD1d expression in MB patients remains unknown. We investigated the expression of CD1d in pediatric MBs and correlated with molecular and clinical characteristics. Specifically, we explored if NKT cell therapy can be targeted at a subset of pediatric MBs with poorer prognosis. Particularly, infantile MBs have a worse outcome because radiotherapy is delayed to avoid neurocognitive sequelae. Immunohistochemistry for CD1d was performed on a screening set of 38 primary pediatric MBs. Gene expression of the membrane form of M2 macrophage marker, CD163, was studied in an expanded cohort of 60 tumors. Outcome data was collected prospectively. Thirteen of 38 MBs (34.2 %) expressed CD1d on immunohistochemistry. CD1d was expressed mainly on MB tumor cells, and on some tumor-associated macrophages. Majority (18/22, 82 %) of non sonic-hedgehog/Wingless-activated MBs (group 3 and 4) were CD1d-negative (p = 0.05). A subset of infantile MBs (4/9, 44.4 %) expressed CD1d. Macrophages infiltrating MB expressed CD163 apart from CD1d. Molecular subtypes demonstrated statistical differences in CD163 expression, SHH-tumors were the most enriched (p = 0.006). Molecular and clinical subtypes of pediatric MB exhibit distinct differences in CD1d expression, which have important therapeutic implications. High CD1d expression in infantile MBs offers potential new immunotherapeutic treatment with NKT cell therapy in infants, where treatment is suboptimal due delayed radiotherapy.

The authors describe a series of 15 intracranial germ cell tumors (IGCTs) excluding mature teratomas; 3 cases in children younger than 3 years of age who were treated at 3 different international institutions over the course of 20 years, and 12 from a PubMed search. These tumors, with possible in utero origins, often occur in atypical locations. The clinical behavior differed significantly from these tumors' counterparts in older children. In this young age group germinoma is highly aggressive, whereas nongerminomatous germ cell tumors may be cured without radiotherapy. Ongoing genomic studies reveal insights to attain an understanding of the biology of these tumors. New treatment strategies are needed to improve outcomes for IGCTs in this age group, particularly for germinomas.

Purpose: Central nervous system tumors account for the largest number of cancer deaths in childhood. Brain tumors in infants less than 3 years of age are rare; symptoms and signs are often non-specific. Patent anterior fontanelles/unfused cranial sutures in infants can accommodate rising intracranial pressure without acutely compromising the neurological status. We hypothesize that vomiting as the initial symptom, in infants with brain tumors, can possibly lead to extensive gastrointestinal evaluation, delaying the diagnosis of intracranial pathology., Methods: We conducted a retrospective chart review of infants less than 3 years of age diagnosed with brain tumors over the period of 4.7 years from February 2008 to October 2012 at Inova Children's Hospital, Virginia., Results: We identified three of 21 patients (14.3 %) who presented with vomiting and underwent initial or extensive abdominal imaging investigations. All patients were relatively young (median age, 5.4 months). Working diagnoses were pyloric stenosis, viral gastritis, or gastroesophageal reflux. All patients eventually had computed tomography of the head to rule out increased intracranial pressure and were found to have large brain tumors with obstructive hydrocephalus. Tumor locations were cerebral hemispheres (2/3) and posterior fossa (1/3). All patients had biologically aggressive high-grade tumors (glioblastoma multiforme, atypical teratoid rhabdoid tumor, and anaplastic/large cell medulloblastoma) and died within weeks of diagnosis., Conclusions: Our study highlights a clinical challenge of persistent vomiting in infants, which in the absence of convincing gastrointestinal pathology after evaluation should raise the physician's suspicion of an underlying intracranial pathology even if neurological features are absent.

Background: Medulloblastoma (MB) comprises of four molecular subtypes, Sonic hedgehog (SHH), Wingless (WNT), Groups 3 and 4. WNT-subtype MBs were found to arise from midline of the brainstem occupying the fourth ventricle while SHH-subtype occupied the cerebellar hemisphere in a small subset of patients., Procedure: We tested this hypothesis in a large cohort of pediatric MBs comprising of all four molecular subtypes., Results: We validated in the first comprehensive analysis of tumor location of 60 human MBs representative of the four molecular subtypes, that hemispheric tumors are significantly associated with SHH-subtype MBs while midline tumors with WNT-subtype, Group 3 and 4 MBs (P < 0.001). Nearly half of SHH-subtype MBs were midline., Conclusions: Tumor location should not be generalized to MB subtypes. SHH-subtype MBs are not exclusively hemispheric and hemispheric MBs are not always SHH-activated. It is imperative to identify subtypes in conjunction with tumor location when exploring currently available targeted therapy., (Copyright © 2013 Wiley Periodicals, Inc.)

Aim: Bony complaints are well-recognised symptoms of childhood haematological malignancy. However, this elusive symptom complex of haematological malignancy is not easily recognised in the emergency room (ER) where musculoskeletal problems are frequent. This study reviews bony complaints of childhood haematological malignancy in the ER., Methods: This was a retrospective study of 148 children diagnosed with haematological malignancy between March 2002 and February 2007., Results: Twenty-one cases (14.2%) presented with bony complaints to the ER within 3 months prior diagnosis of malignancy. The median age was 5.1 years, and majority (90.5%) had acute lymphoblastic leukaemia. Fifteen cases were undiagnosed for malignancy at first visit; diagnoses included pulled elbow, lower limb sprain and septic arthritis, with 21 days median time to correct diagnosis. In this undiagnosed group, history of trauma, fever, multiple bony site involvement, normal radiography and blood counts were common. Undiagnosed cases were referred to orthopaedics, paediatrics, rheumatology or the general practitioner, hospitalised or discharged without follow-up., Conclusion: The diagnosis of childhood haematological malignancy with first bony presentation to the ER was challenging, with a high prevalence of 71.4% undiagnosed cases at first visit. We highlight the common misdiagnoses because failure to correctly diagnose could delay timely institution of treatment. Trauma or normal investigations do not exclude an underlying haematological malignancy. This rare diagnosis in the ER should always be considered when challenged with recurrent bony complaints., (© 2011 The Authors. Journal of Paediatrics and Child Health © 2011 Paediatrics and Child Health Division (Royal Australasian College of Physicians).)

Introduction: Parainfluenza type 3 virus (PIV-3) is an important nosocomial pathogen which causes pneumonia and bronchiolitis in infants. We report an outbreak of PIV-3 respiratory infection which occurred in the neonatal unit of KK Hospital in June 2005. This is the second PIV-3 outbreak in our unit after the fi rst in December 1994., Materials and Methods: The clinical characteristics and outcome of 7 infants tested positive for PIV-3 on nasopharyngeal aspirate in June 2005 were reviewed retrospectively., Results: Seven cases were infected with PIV-3 during this outbreak. The median birthweight of affected infants was 970 g (range, 740 to 2585 g), gestational age was 27 weeks and 4 days (range, 24 to 35 weeks), and postnatal age was 84 days (range, 28 to 250 days). Apnoeas and bradycardias were significant symptoms in 3 infants, 5 infants had progressive respiratory distress while the remaining 2 infants had flu-like illness. Five infants required ventilatory support and there were no deaths. The index case was an infant with chronic lung disease who was on oxygen supplementation and subsequently required ventilatory support with nasal CPAP. Despite implementation of control measures to prevent the spread of infection through early identification with strict cohorting of infected cases, contact tracing/screening, and reinforcement of hand hygiene precautions, the outbreak lasted for 24 days., Conclusion: PIV-3 respiratory infection in preterm infants can present with non-specific symptoms, leading to significant morbidity especially in those with underlying pulmonary pathology. Early recognition of symptoms and diagnosis by physicians, and prompt institution of control measures are necessary to prevent the spread of infection.

Background: Neurological presentations of conversion disorders in children are not uncommon. Conversion disorders mimicking neurological conditions constitute a group of underdiagnosed conditions., Methods: This was a retrospective study of 13 children with neurological presentations of conversion disorders who were admitted to hospital. Patients were followed for 1-4 years., Results: Paralysis was the most common neurological symptom, patients presented with multiple, complex conversion symptoms and other neurological symptoms such as seizures and headache. The affected children underwent complete physical, neurological examination and psychological evaluation. Investigations included blood tests, cranial imaging and electroencephalography. Most common external environmental factors detected were school stress and change in family situation. Five of 13 patients had family members who were reported to have medical conditions with presentations similar to patients' neurological and psychological problem. All the patients were admitted, five patients required multiple admissions. Ten patients eventually had good outcome in terms of academic grades and social functioning., Conclusion: Diagnosis of conversion disorders mimicking neurological conditions can be challenging. There is a need to heighten awareness of this entity for early recognition and diagnosis. Awareness of this entity coupled with a high index of suspicion can facilitate accurate and earlier diagnosis.

Introduction: Hyperuricaemia in tumour lysis syndrome (TLS) can cause acute renal failure (ARF), necessitating dialysis. Recombinant urate oxidase (rasburicase) converts uric acid to soluble allantoin, which is excreted easily., Case Report: An 8-year-old boy with stage 3 Burkitt's lymphoma, TLS was successfully treated with hyper-hydration, diuretics and rasburicase, without dialysis. This is the first paediatric case in Kandang Kerbau Women's & Children's Hospital (KKH) in which rasburicase was used. We review the literature on the effectiveness of urate oxidase in avoiding dialysis in TLS., Treatment and Outcome: Our patient developed rapidly rising serum uric acid (SUA) and progressive renal impairment. Hyper-hydration and rasburicase (0.2mg/kg) were administered. SUA rapidly decreased from 1308 to 437 mmol/L within 12 hours. Urate oxidase has shown better results than allopurinol. There was a need for dialysis in 0.4% to 1.7% of patients with haematological malignancies given rasburicase, compared to 20% in patients given allopurinol., Conclusions: Rasburicase can reverse renal insufficiency. Though expensive, it may be cost-effective by lowering incidence of dialysis, shortening the duration of intensive care and hospitalisation, allowing early chemotherapy.

Introduction: Medulloblastoma/primitive neuroectodermal tumour is the most common type of malignant brain tumour in children. Long-term survival rates have improved over the years with a combination of surgical, radiotherapeutic and chemotherapeutic treatment modalities in the developed world. This paper aims to analyse the epidemiology and outcome of medulloblastoma in Singapore and compare our results with those reported in the literature., Materials and Methods: A 9-year retrospective study was done using data reported to the Singapore Children's Cancer Registry from June 1997 to June 2005. Only 39 children up to the age of 15 years diagnosed histologically with medulloblastoma or primitive neuroectodermal tumour arising from the cerebellum were included in the study. Follow-up data were collected up to June 2006 and analysed using SPSS v 13.0 software., Results: Medulloblastoma/primitive neuroectodermal tumour was the most common type of brain tumour, accounting for 40.7% of all brain tumours diagnosed in children in Singapore. The 5-year event-free survival rate was 44.5%, while the 5- year overall survival rate was 51.5%. Nearly half (41%) of our patients had spinal metastasis at presentation and this was associated with a worse event-free survival (6.3% vs 71.9%, P = 0). Children under 36 months of age had a significantly poorer overall survival (28.8% vs 52.2%, P = 0.041)., Conclusions: The outcome of medulloblastoma in Singapore was inferior to reported figures in the literature. We need to close identified gaps in care, like standardising assessment and treatment protocols, in order to improve our results. Research into molecular and genetic characteristics may also throw light on whether the disease is inherently more aggressive in our population.

Introduction: Stenotrophomonas maltophilia is an aerobic gram-negative bacillus that is a frequent coloniser of fluids used in the hospital setting. It causes infection in immunosuppressed hosts, especially those who are neutropaenic, on chemotherapy and broad spectrum antibiotics. Skin and soft tissue manifestations of Stenotrophomonas maltophilia infection are becoming an increasingly recognised entity; the clinical spectrum ranges from mucocutaneous, skin to soft tissue infections., Materials and Methods: We present a case of an 8-year-old girl with acute myeloid leukaemia who developed metastatic skin lesions secondary to Stenotrophomonas maltophilia bacteraemia. The authors reviewed a total of 24 reported cases of mucocutaneous, skin and soft tissue infections by Stenotrophomonas maltophilia. The presentations include metastatic cellulitis, primary cellulitis and infected mucocutaneous ulcers., Results: This is the first locally reported case of metastatic nodular skin lesions caused by Stenotrophomonas maltophilia bacteraemia. This is also the first reported paediatric case of embolic skin lesions caused by Stenotrophomonas maltophilia. Of the 6 cases of Stenotrophomonas maltophilia bacteraemia seen in the paediatric oncology patients from year 2000 to 2004 at our hospital, only 1 case developed metastatic skin lesions., Conclusion: Stenotrophomonas maltophilia skin infection should be included into the list of differential diagnoses for metastatic skin lesions in neutropaenic patients, especially with an underlying haematologic malignancy who has received recent chemotherapy and broad spectrum antibiotics. Haematologic malignancy, transplantation, neutropaenic, immunosuppressive therapy and a high severity of illness score were important prognostic factors.

Introduction: The development of secondary tumours as a result of radiation therapy is a rare but serious complication., Clinical Picture: This is a case report of a 45-year-old Chinese male who developed postirradiation sarcoma of the sphenoid bone in less than 5 years after radiation therapy for Stage T3N1M0 nasopharyngeal carcinoma., Discussion: In the literature, the only case of postirradiation osteosarcoma of the sphenoid bone was after radiation therapy for craniopharyngioma. There was no previously reported case of postirradiation sarcoma of the sphenoid bone after radiation therapy for nasopharyngeal carcinoma., Conclusion: This is the first case of postirradiation malignant fibrous histiocytoma of the sphenoid to be reported. Of about 3000 patients treated with radiotherapy for nasopharyngeal carcinoma over a 10-year period in Singapore, only 1 patient developed postirradiation tumour of the sphenoid bone.