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Papers by Jack Su

Pituitary, 2009

Germinomas arising in the sella turcica are difficult to differentiate from autoimmune hypophysit... more Germinomas arising in the sella turcica are difficult to differentiate from autoimmune hypophysitis because of similar clinical and pathological features. This differentiation, nevertheless, is critical for patient care due to different treatments of the two diseases. We ...

Journal of neuro-oncology, Jan 8, 2016

Metastatic intracranial germinoma is difficult to treat. Although the proto-oncogene KIT is recog... more 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 seria...

International Journal of Radiation Oncology*Biology*Physics, 2015

The clinical significance of magnetic resonance imaging (MRI) changes after radiation therapy (RT... more The clinical significance of magnetic resonance imaging (MRI) changes after radiation therapy (RT) in children with ependymoma is not well defined. We compared imaging changes following proton beam radiation therapy (PBRT) to those after photon-based intensity modulated RT (IMRT). Seventy-two patients with nonmetastatic intracranial ependymoma who received postoperative RT (37 PBRT, 35 IMRT) were analyzed retrospectively. MRI images were reviewed by 2 neuroradiologists. Sixteen PBRT patients (43%) developed postradiation MRI changes at 3.8 months (median) with resolution by 6.1 months. Six IMRT patients (17%) developed changes at 5.3 months (median) with 8.3 months to resolution. Mean age at radiation was 4.4 and 6.9 years for PBRT and IMRT, respectively (P=.06). Age at diagnosis (>3 years) and time of radiation (≥3 years) was associated with fewer imaging changes on univariate analysis (odds ratio [OR]: 0.35, P=.048; OR: 0.36, P=.05). PBRT (compared to IMRT) was associated with more frequent imaging changes, both on univariate (OR: 3.68, P=.019) and multivariate (OR: 3.89, P=.024) analyses. Seven (3 IMRT, 4 PBRT) of 22 patients with changes had symptoms requiring intervention. Most patients were treated with steroids; some PBRT patients also received bevacizumab and hyperbaric oxygen therapy. None of the IMRT patients had lasting deficits, but 2 patients died from recurrent disease. Three PBRT patients had persistent neurological deficits, and 1 child died secondarily to complications from radiation necrosis. Postradiation MRI changes are more common with PBRT and in patients less than 3 years of age at diagnosis and treatment. It is difficult to predict causes for development of imaging changes that progress to clinical significance. These changes are usually self-limiting, but some require medical intervention, especially those involving the brainstem.

Neuro-oncology, 2011

Difficulties of drug delivery across the blood-brain barrier (BBB) and failure to eliminate cance... more Difficulties of drug delivery across the blood-brain barrier (BBB) and failure to eliminate cancer stem cells (CSCs) are believed to be the major causes of tumor recurrences in children with medulloblastoma (MB). Seneca Valley virus-001 (SVV-001) is a naturally occurring oncolytic picornavirus that can be systemically administered. Here, we report its antitumor activities against MB cells in a panel of 10 primary tumor-based orthotopic xenograft mouse models. We found that SVV-001 killed the primary cultured xenograft cells, infected and replicated in tumor cells expressing CSC surface marker CD133, and eliminated tumor cells capable of forming neurospheres in vitro in 5 of the 10 xenograft models. We confirmed that SVV-001 could pass through BBB in vivo. A single i.v. injection of SVV-001 in 2 anaplastic MB models led to widespread infection of the preformed intracerebellar (ICb) xenografts, resulting in significant increase in survival (2.2-5.9-fold) in both models and complete el...

Cancer research, 2005

Juvenile pilocytic astrocytoma (JPA) is one of the most common brain tumors in children. The expr... more Juvenile pilocytic astrocytoma (JPA) is one of the most common brain tumors in children. The expression profiles of 21 JPAs, determined using Affymetrix GeneChip U133A, were compared with subjects with normal cerebella. The genes involved in neurogenesis, cell adhesion, synaptic transmission, central nervous system development, potassium ion transport, protein dephosphorylation, and cell differentiation were found to be significantly deregulated in JPA. These 21 JPAs were further clustered into two major groups by unsupervised hierarchical clustering using a set of 848 genes with high covariance (0.5-10). Supervised analysis with Significance Analysis of Microarrays software between these two potential subgroups identified a list of significant differentially expressed genes involved in cell adhesion, regulation of cell growth, cell motility, nerve ensheathment, and angiogenesis. Immunostaining of myelin basic protein on paraffin sections derived from 18 incompletely resected JPAs s...

Neuro-oncology, 2014

A phase I trial of veliparib (ABT-888), an oral poly(ADP-ribose) polymerase (PARP) inhibitor, and... more A phase I trial of veliparib (ABT-888), an oral poly(ADP-ribose) polymerase (PARP) inhibitor, and temozolomide (TMZ) was conducted in children with recurrent brain tumors to (i) estimate the maximum tolerated doses (MTDs) or recommended phase II doses (RP2Ds) of veliparib and TMZ; (ii) describe the toxicities of this regimen; and (iii) evaluate the plasma pharmacokinetic parameters and extent of PARP inhibition in peripheral blood mononuclear cells (PBMCs) following veliparib. TMZ was given once daily and veliparib twice daily for 5 days every 28 days. Veliparib concentrations and poly(ADP-ribose) (PAR) levels in PBMCs were measured on days 1 and 4. Analysis of pharmacokinetic and PBMC PAR levels were performed twice during study conduct to rationally guide dose modifications and to determine biologically optimal MTD/RP2D. Twenty-nine evaluable patients were enrolled. Myelosuppression (grade 4 neutropenia and thrombocytopenia) were dose limiting. The RP2Ds are veliparib 25 mg/m(2) b...

Journal of Neuro-Oncology, 2014

Immunobiology of medulloblastoma (MB), the most common malignant brain tumor in children, is poor... more 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.

Journal of Neurosurgery: Pediatrics, 2014

The authors describe a series of 15 intracranial germ cell tumors (IGCTs) excluding mature terato... more 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.

Stem Cells, 2008

need for animal models that will not only replicate the biology of these tumors, but also preserv... more need for animal models that will not only replicate the biology of these tumors, but also preserve their cancer stem cell pool. We hypothesize that direct injection of fresh surgical specimen of MB and high-grade glioma tissues into anatomically equivalent locations in immune-deficient mouse brains will facilitate the formation of clinically accurate xenograft tumors by allowing brain tumor stem cells, together with their non-stem tumor and stromal cells, to grow in a microenvironment that is the closest to human brains. Eight of the 14 MBs (57.1%) and two of the three high-grade gliomas (66.7%) in this study developed transplantable (up to 12 passages) xenografts in mouse cerebellum and cerebrum, respectively. These xenografts are patient specific, replicating the histopathologic, immunopheno-typic, invasive/metastatic, and major genetic (analyzed with 10K single nucleotide polymorphism array) abnormalities of the original tumors. The xenograft tumor cells have also been successfully cryopreserved for long-term preservation of tumorigenicity, ensuring a sustained supply of the animal models. More importantly, the CD133 ؉ tumor cells, ranging from 0.2%-10.4%, were preserved in all the xenograft models following repeated orthotopic subtransplantations in vivo. The isolated CD133 ؉ tumor cells formed neurospheres and displayed multi-lineage differentiation capabilities in vitro. In summary, our study demonstrates that direct orthotopic transplantation of fresh primary tumor cells is a powerful approach in developing novel clinical relevant animal models that can reliably preserve CD133 ؉ tumor cell pools even during serial in vivo subtransplantations. STEM

Pediatric Blood & Cancer, 2013

We performed a phase-1 pharmacokinetic optimal dosing study of intraventricular topotecan (IT), a... more We performed a phase-1 pharmacokinetic optimal dosing study of intraventricular topotecan (IT), administered daily 5×, to determine whether, the maximum tolerated dose of IT topotecan was also the pharmacokinetic optimal dose. Patients received topotecan administered through an intraventricular access device (0.1 or 0.2 mg/dose), daily × 5 every other week 2× (Induction); every 3 weeks × 2 (Consolidation); then every 4 weeks for up to 11 courses (Maintenance). Ventricular CSF pharmacokinetic studies were performed on day 1, week 1 of induction, and in a subset of patients after a single intralumbar topotecan dose on day 1, week 3. Nineteen patients were enrolled. All were evaluable for toxicity and 18 were assessable for pharmacokinetics. Arachnoiditis requiring corticosteroid therapy occurred in or one of three patients at the 0.1 mg dose level and two of the initial three patients enrolled at the 0.2 mg dose level. All subsequent patients were therefore treated with concomitant dexamethasone. Pharmacokinetic evaluation after accrual of the first seven patients revealed that a topotecan lactone concentration >1 ng/ml for 8 hours was attained in all patients and thus, further dose escalation was not pursued. Results of simulation studies showed that at the dose levels evaluated, >99.9% of patients are expected to achieve CSF topotecan lactone concentrations >1 ng/ml for at least 8 hours. Intraventricular topotecan, 0.2 mg, administered daily for 5 days with concomitant dexamethasone is well tolerated and was defined to be the pharmacokinetic optimal dose in this trial.

Pediatric Blood & Cancer, 2014

Intracranial germ cell tumors (GCTs) are rare and heterogeneous with very little is known about t... more Intracranial germ cell tumors (GCTs) are rare and heterogeneous with very little is known about their pathogenesis and underlying genetic abnormalities. In order to identify candidate genes and pathways which are involved in the pathogenesis of these tumors, we have profiled 62 intracranial GCTs for DNA copy number alterations (CNAs) and loss of heterozygosity (LOH) by using single nucleotide polymorphism (SNP) array and quantitative real time PCR (qPCR). Initially 27 cases of tumor tissues with matched blood samples were fully analyzed by SNP microarray and qPCR. Statistical analysis using the genomic identification of significant targets in cancer (GISTIC) tool identified 10 regions of significant copy number gain and 11 regions of significant copy number loss. While overall pattern of genomic aberration was similar between germinoma and nongerminomatous germ cell tumors (NGGCTs), a few subtype-specific peak regions were identified. Analysis by SNP array and qPCR was replicated using an independent cohort of 35 cases. Frequent aberrations of CCND2 (12p13) and RB1 (13q14) suggest that Cyclin/CDK-RB-E2F pathway might play a critical role in the pathogenesis of intracranial GCTs. Frequent gain of PRDM14 (8q13) implies that transcriptional regulation of primordial germ cell specification might be an important factor in the development of this tumor.

Neuropathology and Applied Neurobiology, 2007

Survivin, a member of the inhibitor of apoptosis protein family, is implicated in the dysregulati... more Survivin, a member of the inhibitor of apoptosis protein family, is implicated in the dysregulation of apoptosis in human cancers. Survivin and survivin-deltaEx3, one of its two alternatively spliced isoforms, confer anti-apoptotic activities in human tumours, while survivin-2B antagonizes such anti-apoptotic properties. The current study was undertaken to examine the mRNA expression of survivin isoforms and their correlation with clinical staging and outcome in 20 medulloblastoma (MB) tumours, three MB cell lines and normal brain tissues (a foetal and an adult cerebellum) by densitometry scanning of 32p-dCTP incorporated reverse transcription polymerase chain reaction (RT-PCR) products and quantitative real-time PCR. Our results showed that the normal adult brain only expressed low levels of survivin-deltaEx3 mRNA, while the foetal brain expressed all three isoforms, with wild-type survivin as the dominant transcript. All three survivin isoforms were detected in all the MB cell lines and tumours analysed. Immunohistochemical staining also demonstrated survivin protein expressions in all five paraffin-embedded MBs, with predominant nuclear localization. Although overexpressions of survivin were not associated with the presence of metastatic MB or tumour histological subtypes, elevated expressions of survivin-deltaEx3 were significantly associated with progressive/recurrent tumours (P-value = 0.024). Our data demonstrated that overexpression of survivin mRNA is a common feature in MBs, may contribute to their anti-apoptosis properties and clinical behaviours, and predicts a poor clinical outcome, independent of clinical staging or tumour histology.

Neuro-Oncology, 2014

Background. Supratentorial primitive neuroectodermal tumor (sPNET) is a malignant brain tumor wit... more Background. Supratentorial primitive neuroectodermal tumor (sPNET) is a malignant brain tumor with poor prognosis. New model systems that replicate sPNET's molecular subtype(s) and maintain cancer stem cell (CSC) pool are needed.

Pituitary, 2009

Germinomas arising in the sella turcica are difficult to differentiate from autoimmune hypophysit... more Germinomas arising in the sella turcica are difficult to differentiate from autoimmune hypophysitis because of similar clinical and pathological features. This differentiation, nevertheless, is critical for patient care due to different treatments of the two diseases. We ...

Journal of neuro-oncology, Jan 8, 2016

Metastatic intracranial germinoma is difficult to treat. Although the proto-oncogene KIT is recog... more 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 seria...

International Journal of Radiation Oncology*Biology*Physics, 2015

The clinical significance of magnetic resonance imaging (MRI) changes after radiation therapy (RT... more The clinical significance of magnetic resonance imaging (MRI) changes after radiation therapy (RT) in children with ependymoma is not well defined. We compared imaging changes following proton beam radiation therapy (PBRT) to those after photon-based intensity modulated RT (IMRT). Seventy-two patients with nonmetastatic intracranial ependymoma who received postoperative RT (37 PBRT, 35 IMRT) were analyzed retrospectively. MRI images were reviewed by 2 neuroradiologists. Sixteen PBRT patients (43%) developed postradiation MRI changes at 3.8 months (median) with resolution by 6.1 months. Six IMRT patients (17%) developed changes at 5.3 months (median) with 8.3 months to resolution. Mean age at radiation was 4.4 and 6.9 years for PBRT and IMRT, respectively (P=.06). Age at diagnosis (>3 years) and time of radiation (≥3 years) was associated with fewer imaging changes on univariate analysis (odds ratio [OR]: 0.35, P=.048; OR: 0.36, P=.05). PBRT (compared to IMRT) was associated with more frequent imaging changes, both on univariate (OR: 3.68, P=.019) and multivariate (OR: 3.89, P=.024) analyses. Seven (3 IMRT, 4 PBRT) of 22 patients with changes had symptoms requiring intervention. Most patients were treated with steroids; some PBRT patients also received bevacizumab and hyperbaric oxygen therapy. None of the IMRT patients had lasting deficits, but 2 patients died from recurrent disease. Three PBRT patients had persistent neurological deficits, and 1 child died secondarily to complications from radiation necrosis. Postradiation MRI changes are more common with PBRT and in patients less than 3 years of age at diagnosis and treatment. It is difficult to predict causes for development of imaging changes that progress to clinical significance. These changes are usually self-limiting, but some require medical intervention, especially those involving the brainstem.

Neuro-oncology, 2011

Difficulties of drug delivery across the blood-brain barrier (BBB) and failure to eliminate cance... more Difficulties of drug delivery across the blood-brain barrier (BBB) and failure to eliminate cancer stem cells (CSCs) are believed to be the major causes of tumor recurrences in children with medulloblastoma (MB). Seneca Valley virus-001 (SVV-001) is a naturally occurring oncolytic picornavirus that can be systemically administered. Here, we report its antitumor activities against MB cells in a panel of 10 primary tumor-based orthotopic xenograft mouse models. We found that SVV-001 killed the primary cultured xenograft cells, infected and replicated in tumor cells expressing CSC surface marker CD133, and eliminated tumor cells capable of forming neurospheres in vitro in 5 of the 10 xenograft models. We confirmed that SVV-001 could pass through BBB in vivo. A single i.v. injection of SVV-001 in 2 anaplastic MB models led to widespread infection of the preformed intracerebellar (ICb) xenografts, resulting in significant increase in survival (2.2-5.9-fold) in both models and complete el...

Cancer research, 2005

Juvenile pilocytic astrocytoma (JPA) is one of the most common brain tumors in children. The expr... more Juvenile pilocytic astrocytoma (JPA) is one of the most common brain tumors in children. The expression profiles of 21 JPAs, determined using Affymetrix GeneChip U133A, were compared with subjects with normal cerebella. The genes involved in neurogenesis, cell adhesion, synaptic transmission, central nervous system development, potassium ion transport, protein dephosphorylation, and cell differentiation were found to be significantly deregulated in JPA. These 21 JPAs were further clustered into two major groups by unsupervised hierarchical clustering using a set of 848 genes with high covariance (0.5-10). Supervised analysis with Significance Analysis of Microarrays software between these two potential subgroups identified a list of significant differentially expressed genes involved in cell adhesion, regulation of cell growth, cell motility, nerve ensheathment, and angiogenesis. Immunostaining of myelin basic protein on paraffin sections derived from 18 incompletely resected JPAs s...

Neuro-oncology, 2014

A phase I trial of veliparib (ABT-888), an oral poly(ADP-ribose) polymerase (PARP) inhibitor, and... more A phase I trial of veliparib (ABT-888), an oral poly(ADP-ribose) polymerase (PARP) inhibitor, and temozolomide (TMZ) was conducted in children with recurrent brain tumors to (i) estimate the maximum tolerated doses (MTDs) or recommended phase II doses (RP2Ds) of veliparib and TMZ; (ii) describe the toxicities of this regimen; and (iii) evaluate the plasma pharmacokinetic parameters and extent of PARP inhibition in peripheral blood mononuclear cells (PBMCs) following veliparib. TMZ was given once daily and veliparib twice daily for 5 days every 28 days. Veliparib concentrations and poly(ADP-ribose) (PAR) levels in PBMCs were measured on days 1 and 4. Analysis of pharmacokinetic and PBMC PAR levels were performed twice during study conduct to rationally guide dose modifications and to determine biologically optimal MTD/RP2D. Twenty-nine evaluable patients were enrolled. Myelosuppression (grade 4 neutropenia and thrombocytopenia) were dose limiting. The RP2Ds are veliparib 25 mg/m(2) b...

Journal of Neuro-Oncology, 2014

Immunobiology of medulloblastoma (MB), the most common malignant brain tumor in children, is poor... more 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.

Journal of Neurosurgery: Pediatrics, 2014

The authors describe a series of 15 intracranial germ cell tumors (IGCTs) excluding mature terato... more 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.

Stem Cells, 2008

need for animal models that will not only replicate the biology of these tumors, but also preserv... more need for animal models that will not only replicate the biology of these tumors, but also preserve their cancer stem cell pool. We hypothesize that direct injection of fresh surgical specimen of MB and high-grade glioma tissues into anatomically equivalent locations in immune-deficient mouse brains will facilitate the formation of clinically accurate xenograft tumors by allowing brain tumor stem cells, together with their non-stem tumor and stromal cells, to grow in a microenvironment that is the closest to human brains. Eight of the 14 MBs (57.1%) and two of the three high-grade gliomas (66.7%) in this study developed transplantable (up to 12 passages) xenografts in mouse cerebellum and cerebrum, respectively. These xenografts are patient specific, replicating the histopathologic, immunopheno-typic, invasive/metastatic, and major genetic (analyzed with 10K single nucleotide polymorphism array) abnormalities of the original tumors. The xenograft tumor cells have also been successfully cryopreserved for long-term preservation of tumorigenicity, ensuring a sustained supply of the animal models. More importantly, the CD133 ؉ tumor cells, ranging from 0.2%-10.4%, were preserved in all the xenograft models following repeated orthotopic subtransplantations in vivo. The isolated CD133 ؉ tumor cells formed neurospheres and displayed multi-lineage differentiation capabilities in vitro. In summary, our study demonstrates that direct orthotopic transplantation of fresh primary tumor cells is a powerful approach in developing novel clinical relevant animal models that can reliably preserve CD133 ؉ tumor cell pools even during serial in vivo subtransplantations. STEM

Pediatric Blood & Cancer, 2013

We performed a phase-1 pharmacokinetic optimal dosing study of intraventricular topotecan (IT), a... more We performed a phase-1 pharmacokinetic optimal dosing study of intraventricular topotecan (IT), administered daily 5×, to determine whether, the maximum tolerated dose of IT topotecan was also the pharmacokinetic optimal dose. Patients received topotecan administered through an intraventricular access device (0.1 or 0.2 mg/dose), daily × 5 every other week 2× (Induction); every 3 weeks × 2 (Consolidation); then every 4 weeks for up to 11 courses (Maintenance). Ventricular CSF pharmacokinetic studies were performed on day 1, week 1 of induction, and in a subset of patients after a single intralumbar topotecan dose on day 1, week 3. Nineteen patients were enrolled. All were evaluable for toxicity and 18 were assessable for pharmacokinetics. Arachnoiditis requiring corticosteroid therapy occurred in or one of three patients at the 0.1 mg dose level and two of the initial three patients enrolled at the 0.2 mg dose level. All subsequent patients were therefore treated with concomitant dexamethasone. Pharmacokinetic evaluation after accrual of the first seven patients revealed that a topotecan lactone concentration >1 ng/ml for 8 hours was attained in all patients and thus, further dose escalation was not pursued. Results of simulation studies showed that at the dose levels evaluated, >99.9% of patients are expected to achieve CSF topotecan lactone concentrations >1 ng/ml for at least 8 hours. Intraventricular topotecan, 0.2 mg, administered daily for 5 days with concomitant dexamethasone is well tolerated and was defined to be the pharmacokinetic optimal dose in this trial.

Pediatric Blood & Cancer, 2014

Intracranial germ cell tumors (GCTs) are rare and heterogeneous with very little is known about t... more Intracranial germ cell tumors (GCTs) are rare and heterogeneous with very little is known about their pathogenesis and underlying genetic abnormalities. In order to identify candidate genes and pathways which are involved in the pathogenesis of these tumors, we have profiled 62 intracranial GCTs for DNA copy number alterations (CNAs) and loss of heterozygosity (LOH) by using single nucleotide polymorphism (SNP) array and quantitative real time PCR (qPCR). Initially 27 cases of tumor tissues with matched blood samples were fully analyzed by SNP microarray and qPCR. Statistical analysis using the genomic identification of significant targets in cancer (GISTIC) tool identified 10 regions of significant copy number gain and 11 regions of significant copy number loss. While overall pattern of genomic aberration was similar between germinoma and nongerminomatous germ cell tumors (NGGCTs), a few subtype-specific peak regions were identified. Analysis by SNP array and qPCR was replicated using an independent cohort of 35 cases. Frequent aberrations of CCND2 (12p13) and RB1 (13q14) suggest that Cyclin/CDK-RB-E2F pathway might play a critical role in the pathogenesis of intracranial GCTs. Frequent gain of PRDM14 (8q13) implies that transcriptional regulation of primordial germ cell specification might be an important factor in the development of this tumor.

Neuropathology and Applied Neurobiology, 2007

Survivin, a member of the inhibitor of apoptosis protein family, is implicated in the dysregulati... more Survivin, a member of the inhibitor of apoptosis protein family, is implicated in the dysregulation of apoptosis in human cancers. Survivin and survivin-deltaEx3, one of its two alternatively spliced isoforms, confer anti-apoptotic activities in human tumours, while survivin-2B antagonizes such anti-apoptotic properties. The current study was undertaken to examine the mRNA expression of survivin isoforms and their correlation with clinical staging and outcome in 20 medulloblastoma (MB) tumours, three MB cell lines and normal brain tissues (a foetal and an adult cerebellum) by densitometry scanning of 32p-dCTP incorporated reverse transcription polymerase chain reaction (RT-PCR) products and quantitative real-time PCR. Our results showed that the normal adult brain only expressed low levels of survivin-deltaEx3 mRNA, while the foetal brain expressed all three isoforms, with wild-type survivin as the dominant transcript. All three survivin isoforms were detected in all the MB cell lines and tumours analysed. Immunohistochemical staining also demonstrated survivin protein expressions in all five paraffin-embedded MBs, with predominant nuclear localization. Although overexpressions of survivin were not associated with the presence of metastatic MB or tumour histological subtypes, elevated expressions of survivin-deltaEx3 were significantly associated with progressive/recurrent tumours (P-value = 0.024). Our data demonstrated that overexpression of survivin mRNA is a common feature in MBs, may contribute to their anti-apoptosis properties and clinical behaviours, and predicts a poor clinical outcome, independent of clinical staging or tumour histology.

Neuro-Oncology, 2014

Background. Supratentorial primitive neuroectodermal tumor (sPNET) is a malignant brain tumor wit... more Background. Supratentorial primitive neuroectodermal tumor (sPNET) is a malignant brain tumor with poor prognosis. New model systems that replicate sPNET's molecular subtype(s) and maintain cancer stem cell (CSC) pool are needed.