Paediatric ventriculoperitoneal shunt failures: 12-year experience from a Singapore children's hospital.

PURPOSE: Cerebrospinal fluid (CSF) shunt failures in children are devastating. The primary aims of this study are to, firstly, review our institutional series of ventriculoperitoneal shunt (VPS) insertions and identify factors associated with shunt failure. METHODS: This is a single-institution, retrospective study conducted over a 12-year period. All patients under 18 years old with VPS inserted were included. Variables of interest such as patient characteristics, hydrocephalus aetiology, shunt implant details, and outcomes were subjected to statistical analyses. RESULTS: A total of 214 VPS patients were selected for this study. The mean age at VPS insertion was 6 months with a mean follow-up duration of 44 months. The most common type of hydrocephalus was obstructive (n = 142, 66.4%), and the most frequent aetiology was tumour-related (n = 66, 30.8%). The 30-day shunt failure rate was 9.3%: 9 infections (4.2%), 7 occlusions (3.3%), and 4 others (1.9%). After multivariable analysis, only recent central nervous system (CNS) infection prior to VPS insertion remained significant (OR 15.4 (1.3-175), p = 0.028). CONCLUSION: This is the first, large-scale local study focused on the shunt failure in Singaporean children. Significant findings in our study demonstrate that recently treated CNS infection is a factor associated with 30-day shunt failure while the values of CSF constituents were not contributory.

Outcomes of intracranial non-germinomatous germ cell tumors: a retrospective Asian multinational study on treatment strategies and prognostic factors.

PURPOSE: Non-germinomatous germ cell tumors (NGGCTs) are rare pediatric conditions. This multicenter study using Asian multinational patient data investigated treatment outcomes and prognostic factors for NGGCTs. METHODS: Medical records of 251 patients with NGGCTs treated from 1995 to 2015 were retrospectively analyzed from participating centers in Asian countries (Korea, Taiwan, Singapore, and Japan). RESULTS: The median follow up was 8.5 years (95% CI 7.8-9.9). In the total cohort, 5-year event-free survival (EFS) and overall survival (OS) rates were 78.2% and 85.4%, respectively. In 17.9% of the patients, diagnosis was determined by tumor markers alone (alpha-fetoprotein ≥ 10 ng/mL (Korea) or > 25 ng/mL (Taiwan and Singapore), and/or ß-human chorionic gonadotropin (ß-hCG) ≥ 50 mIU/mL). Patients with immature teratomas and mature teratomas comprised 12.0% and 8.4%, respectively. The 5-year EFS rate was higher in patients with histologically confirmed germinoma with elevated ß-hCG (n = 28) than those in patients with malignant NGGCTs (n = 127). Among malignant NGGCTs, patients with choriocarcinoma showed the highest 5-year OS of 87.6%, while yolk sac tumors showed the lowest OS (68.8%). For malignant NGGCT subgroups, an increase in serum ß-hCG levels by 100 mIU/mL was identified as a significant prognostic factor associated with the EFS and OS. CONCLUSION: Our result shows excellent survival outcomes of overall CNS NGGCT. However, treatment outcome varied widely across the histopathologic subgroup of NGGCT. Hence, this study suggests the necessity for accurate diagnosis by surgical biopsy and further optimization of diagnosis and treatment according to the histopathology of NGGCTs. Future clinical trials should be designed for individualized treatments for different NGGCTs subsets.

Paediatric Cerebral Arteriovenous Malformation: Outcomes from a Singapore Children's Hospital.

OBJECTIVES: Paediatric brain arteriovenous malformation (bAVM) is a rare and distinct clinical entity. There is a growing body of literature that support the success of multimodality approaches for this difficult condition. The authors aim to firstly, describe our institutional experience with a consecutive series of patients and next, corroborate our results with current literature. MATERIAL AND METHODS: This is a single institution, retrospective study conducted over a 20-year period. Patients less than 19 years old with bAVM were included. Variables of interest included patient demographics, clinical presentation, neuroimaging features, bAVM characteristics and treatment modality. Functional outcomes were measured with modified Rankin scale (mRS). RESULTS: There were 58 paediatric bAVMs, presenting at a mean age of 8.7 ± 4.2 years, and followed up for a mean duration of 7.7 years. Thirty-six patients (62.1%) underwent microsurgical resection, 10 patients had stereotactic radiosurgery (17.2%) and 2 patients had endovascular treatment (3.4%). 50 patients (86.2%) had a favourable outcome at 1-year follow up. Microsurgical resection and SRS had similar obliteration rates (resection 83.3%; SRS 80.0%) and recurrence (resection 10.0%; SRS 12.5%). There were 6 cases of bAVM recurrence (12.8%). This subgroup was noted to be less than 7.5 years old at presentation (OR 15.0, 95% CI 1.56 - 144), and less likely to present with bAVM rupture (OR 0.11, 95% CI 0.01 - 0.96). CONCLUSION: This study describes our experience in managing paediatric bAVM, whereby monomodal therapy can still be effective. Of note, we also demonstrate the role of extended surveillance to detect recurrence.

Molecular exploration of paediatric intracranial germinomas from multi-ethnic Singapore.

BACKGROUND: Germinomas (IG) account for up to 50% of all intracranial germ cell tumours. These tumours are reputed to be more prevalent in Oriental populations in comparison to Western cohorts. Biological characteristics of IG in other ethnic groups are unknown. Singapore is a multi-ethnic country with diverse cultures. Owing to inter-racial heterogeneity, the authors hypothesize there are molecular differences between paediatric IG patients in our local population. The aims of this study are exploratory: firstly, to identify molecular characteristics in this tumour type and circulating CSF unique to different racial cohorts; and next, to corroborate our findings with published literature. METHODS: This is a single-institution, retrospective study of prospectively collected data. Inclusion criteria encompass all paediatric patients with histologically confirmed IG. Excess CSF and brain tumour tissues are collected for molecular analysis. Tumour tissues are subjected to a next generation sequencing (NGS) targeted panel for KIT and PDGRA. All CSF samples are profiled via a high-throughput miRNA multiplexed workflow. Results are then corroborated with existing literature and public databases. RESULTS: In our cohort of 14 patients, there are KIT exon variants in the tumour tissues and CSF miRNAs corroborative with published studies. Separately, there are also KIT exon variants and miRNAs not previously highlighted in IG. A subgroup analysis demonstrates differential CSF miRNAs between Chinese and Malay IG patients. CONCLUSION: This is the first in-depth molecular study of a mixed ethnic population of paediatric IGs from a Southeast Asian cohort. Validation studies are required to assess the relevance of novel findings in our study.

Generation and multi-dimensional profiling of a childhood cancer cell line atlas defines new therapeutic opportunities.

Pediatric solid and central nervous system tumors are the leading cause of cancer-related death among children. Identifying new targeted therapies necessitates the use of pediatric cancer models that faithfully recapitulate the patient's disease. However, the generation and characterization of pediatric cancer models has significantly lagged behind adult cancers, underscoring the urgent need to develop pediatric-focused cell line resources. Herein, we establish a single-site collection of 261 cell lines, including 224 pediatric cell lines representing 18 distinct extracranial and brain childhood tumor types. We subjected 182 cell lines to multi-omics analyses (DNA sequencing, RNA sequencing, DNA methylation), and in parallel performed pharmacological and genetic CRISPR-Cas9 loss-of-function screens to identify pediatric-specific treatment opportunities and biomarkers. Our work provides insight into specific pathway vulnerabilities in molecularly defined pediatric tumor classes and uncovers biomarker-linked therapeutic opportunities of clinical relevance. Cell line data and resources are provided in an open access portal.

Outcomes of intracranial germinoma-A retrospective multinational Asian study on effect of clinical presentation and differential treatment strategies.

BACKGROUND: This multinational study was conducted to report clinical presentations and treatment strategies in patients with intracranial germinomas across selected Asian centers, including failure patterns, risk factors, and outcomes. METHODS: A retrospective data collection and analysis of these patients, treated between 1995 and 2015 from eight healthcare institutions across four countries was undertaken. RESULTS: From the results, 418 patients were analyzed, with a median follow-up of 8.9 years; 79.9% of the patients were M0, and 87.6% had ß-human chorionic gonadotropin values <50 mIU/mL. The 5/10-year overall survival (OS) and recurrence-free survival (RFS) rates were 97.2%/96.2% and 89.9%/86.9%, respectively. RFS was predicted by the radiotherapy (RT) field, with focal RT having the worst outcome, whereas chemotherapy usage had no impact on survival. Among patients who received chemotherapy, response to chemotherapy did not predict survival outcomes. In M0 patients, primary basal ganglia tumors predicted a worse RFS. In patients with bifocal tumors, an extended field RT was associated with better outcomes. In multivariable analysis, only RT fields were associated with RFS. In relapsed patients, salvage rates were high at 85.7%. Additionally, patients who received salvage RT had a better outcome (91.6% vs. 66.7%). CONCLUSIONS: Survival outcomes of patients with germinoma were excellent. Thus, the focus of treatment for intracranial germinoma should be on survivorship. Further studies are warranted to find the optimal intensity and volume of radiation, including the role of chemotherapy in the survival of patients with intracranial germinomas, considering age, primary tumor location, and extent of disease.

Clinical relevance of screening checklists for detecting cancer predisposition syndromes in Asian childhood tumours.

Assessment of cancer predisposition syndromes (CPS) in childhood tumours is challenging to paediatric oncologists due to inconsistent recognizable clinical phenotypes and family histories, especially in cohorts with unknown prevalence of germline mutations. Screening checklists were developed to facilitate CPS detection in paediatric patients; however, their clinical value have yet been validated. Our study aims to assess the utility of clinical screening checklists validated by genetic sequencing in an Asian cohort of childhood tumours. We evaluated 102 patients under age 18 years recruited over a period of 31 months. Patient records were reviewed against two published checklists and germline mutations in 100 cancer-associated genes were profiled through a combination of whole-exome sequencing and multiplex ligation-dependent probe amplification on blood-derived genomic DNA. Pathogenic germline mutations were identified in ten (10%) patients across six known cancer predisposition genes: TP53, DICER1, NF1, FH, SDHD and VHL. Fifty-four (53%) patients screened positive on both checklists, including all ten pathogenic germline carriers. TP53 was most frequently mutated, affecting five children with adrenocortical carcinoma, sarcomas and diffuse astrocytoma. Disparity in prevalence of germline mutations across tumour types suggested variable genetic susceptibility and implied potential contribution of novel susceptibility genes. Only five (50%) children with pathogenic germline mutations had a family history of cancer. We conclude that CPS screening checklists are adequately sensitive to detect at-risk children and are relevant for clinical application. In addition, our study showed that 10% of Asian paediatric solid tumours have a heritable component, consistent with other populations.

MicroRNA as potential modulators in chemoresistant high-grade gliomas.

Gliomas account for 70% of human malignant primary brain tumours. The most common form is glioblastoma multiforme, World Health Organization grade IV. Despite the implementation of post-operative adjuvant radiotherapy with concurrent temozolomide (TMZ), the disease's overall prognosis remains dismal. TMZ is currently the only mono-chemotherapeutic agent for newly-diagnosed high-grade glioma patients and acquired resistance inevitably occurs in the majority of such patients, further limiting treatment options. Therefore, there is an urgent need to better understand the underlying mechanisms involved in TMZ resistance, a critical step to developing effective, targeted treatments. An emerging body of evidence suggests the intimate involvement of a novel class of nucleic acid, microRNA (miRNA), in tumorigenesis and disease progression for a number of human malignancies, including primary brain tumours. miRNA are short, single-stranded, non-coding RNA (∼22 nucleotides) that function as post-transcriptional regulators of gene expression. This review provides an overview of the key treatment obstacles faced in patients with high-grade gliomas, especially in the context of recurrent, chemoresistant tumours and the potential roles of miRNA in chemoresistance and management of this disease.