Pediatric CNS Tumors Research Articles

IMPS-13IMMUNOLOGIC PROFILING OF PEDIATRIC CNS MALIGNANCIES FOR THE RATIONAL SELECTION OF IMUNOTHERAPEUTIC TRIALS

BACKGROUND: Although clinical trials have resulted in significant improvements in childhood brain cancer treatments, further progress using strategically targeted, potentially less toxic modalities are needed. Immunotherapy is one such emerging treatment approach. The degree of tumor-infiltrating cytotoxic T-lymphocytes (CTLs) directly correlates with prognosis for several cancer types. MHC Class I is down-regulated in 40-90% of adult cancers, rendering them resistant to CTL attack, correlating with poorer prognosis. MHC I expression in medulloblastomas is associated with poor prognostic factors, a pattern opposite of most other cancer-MHC I associations described. Natural Killer (NK)-cell based therapies, dependent upon low MHC I expression, are therefore proposed as an immunotherapeutic approach to medulloblastomas. Very little literature exists classifying MHC I expression in other pediatric brain cancers, despite several ongoing trials using MHC I-dependent strategies. This lack of data raises uncertainty of which immunotherapies are optimal for these diseases. Toward this end, we classified key immunologic characteristics of pediatric brain tumors. METHODS: We interrogated pre-clinical and clinical mRNA microarray databases to identify tumor types which exhibit MHC I and the associated b-2-microglobulin molecule expression. We up-regulated MHC I expression in vitro in pediatric CNS tumor cell lines and identified intra-tumoral innate and adaptive immunologic cellular infiltrates within pediatric CNS tumor samples through immunohistochemistry. RESULTS: We found that atypical teratoid/rhabdoid tumors (AT/RT) and ependymomas exhibit decreased, whereas medulloblastomas and glioblastomas express higher MHC I mRNA levels than most other pediatric cancer types. We discovered MHC I can be up-regulated in vitro in medulloblastomas and AT/RT's, indicating a reversible epigenetic mechanism for down-regulation. There were decreased NK and regulatory T-cell, while increased CTL infiltrates in recurred versus diagnostic pediatric glioblastoma tumor samples. CONCLUSIONS: The immunologic profiling of pediatric brain cancers will guide rational selection of immune-based therapies, serving as an important biomarker for patient inclusion in immunotherapeutic trials.

EPID-02AN UNUSUAL PEDIATRIC HYPOTHALAMIC PILOCYTIC ASTROCYTOMA

BACKGROUND: Hypothalamic/chiasmatic tumors (H/C) constitute 7-10% of pediatric primary CNS tumors and are typically pilocytic astrocytomas. Local extension is seen in 75% of patients but metastatic spinal cord involvement without intracranial dissemination is rare. We describe an unusual multifocal H/C and spinal cord pilocytic astrocytoma in an 8 year old boy. CASE REPORT: The patient was found to have a pineal cyst 1 year prior to diagnosis when he had a CT scan following minor head trauma. Ten months later he presented with lower back pain. MRI (sacrum) showed distortion of L5 nerve roots. Over 3 months his sacral pain worsened and he developed headaches, emesis and gait disturbance. MRI (brain) showed an enhancing hypothalamic mass and hydrocephalus. Spinal cord MRI revealed an intramedullary T2 hyperintense C2-C5 mass, an intramedullary T2 hyperintense focus at T6 and a cystic lesion bordering S1/S2 nerve roots. Spinal cord lesions enhanced less than the hypothalamic lesion. Additional T2 hyperintense foci of uncertain origin were seen in the midbrain tectum, superior cerebellar peduncles and cerebellar hemispheres. Optic chiasm was eccentrically thickened on the right but without abnormal enhancement. CSF was negative for tumor cells and NF1 studies were negative. The hypothalamic and cervical spinal cord lesions were biopsied/debulked respectively. Microscopic examination (both specimens) revealed low-grade astrocytoma without mitotic activity, necrosis or microvascular endothelial proliferation and only occasional Rosenthal fibers (hypothalamic specimen). Immunostain for neurofilament protein (both specimens) suggested an infiltrative growth pattern but IDH-1 immunostain was negative. Both specimens were BRAF(7q34) duplication(+). Ki67 proliferative index was 2-3%. The patient is currently receiving treatment with vincristine/carboplatin with partial improvement of symptoms. CONCLUSION: Since our patient's CSF was negative for tumor cells it is unclear whether this case represents two genetically distinct (multicentric) tumors or a metastatic pilocytic astrocytoma with a hypothalamic or spinal cord primary lesion.

TMOD-04NOVEL ORTHOTOPIC XENOGRAFT MOUSE MODELS OF TWO PEDIATRIC METASTATIC INTRACRANIAL GERMINOMAS: MODEL DEVELOPMENT AND CHARACTERIZATION

INTRODUCTION: Despite comprising up to 10% of pediatric CNS tumors, an animal model of intracranial germinoma has not been previously established. Standard of care for germinoma is radiation therapy, with recent evidence that neo-adjuvant chemotherapy may allow reduction of radiation dose, but concern for neuro-cognitive toxicity remains despite the reduction of radiation. A clinically relevant animal model of germinoma would facilitate investigation and discovery of novel agents which may obviate the need for radiation in the future. METHODS: To develop xenograft mouse models, we implanted germinoma tumor cells from two children with metastatic disease, one from a surgical specimen of a cervical metastatic tumor and the second from disseminated tumor cells in the CSF, directly into the right cerebral hemispheres of NOD-SCID mice. RESULTS: The germinoma tumors have been serially passaged in xenografts 5 times, with each passaged tumor maintaining the ability to generate tumors, suggestive of the persistence of viable tumorigenic/tumor stem cells. Both patient tumor samples have whole exome sequencing; one of the two models has a germinoma-associated mutation in kit. This mutation was confirmed by pyrosequencing and was maintained in all 5 xenograft tumor passages. In the kit wildtype model, kit was over-expressed as documented by IHC staining. Histopathologic staining demonstrated that both models maintain similarity with the original patient tumors. Cultured cells were grown as a monolayer from one model, and a cell line was established. CONCLUSIONS: Our orthotopic xenograft murine models of two metastatic pediatric germinomas are the first to be established for this tumor type. These models will allow much needed pre-clinical drug testing of chemotherapeutics and combination therapies as well as further biologic characterization of pediatric germinomas.

A new clinical guideline from the Royal College of Paediatrics and Child Health with a national awareness campaign accelerates brain tumor diagnosis in UK children--"HeadSmart: Be Brain Tumour Aware".

A national survey in 2006 identified that UK referral practice for pediatric CNS tumors ranked poorly in international comparisons, which led to new National Health Service (NHS) Evidence accredited referral guidelines published in 2008 by the Royal College of Paediatrics and Child Health and a campaign to raise awareness of early features of CNS tumors and the need for timely imaging. The "HeadSmart: Be Brain Tumour Aware" campaign was launched in June 2011 across the UK as a quality improvement strategy directed at reducing the total diagnostic interval (TDI) from a pre-campaign (2006) median of 14 (mean, 35.4) weeks to a target of 5 weeks in order to equal the best reported internationally. Professional and public awareness was measured by questionnaire surveys. TDI was collected by clinical champions in 18 regional children's cancer centers and the public campaign was coordinated by a national charity, working with a network of community champions. The guidelines and campaign raised awareness among pediatricians and were associated with reduction in TDI to a median of 6.7 (mean, 21.3) weeks by May 2013. This change in referral practice was most pronounced in the time from first medical contact to CNS imaging, for which the median was reduced from 3.3 to 1.4 weeks between January 2011 and May 2013 (P = .009). This strategy to accelerate brain tumor diagnosis by the NHS using a public and professional awareness campaign is a "world first" in pediatric cancer and is being emulated internationally and acknowledged by a series of NHS and charity awards for excellence.

Phase 1 trial of p28 (NSC745104), a non-HDM2 mediated peptide inhibitor of p53 ubiquitination in children with recurrent or progressive CNS tumors: A final report from the Pediatric Brain Tumor Consortium.

10059 Background: Wild type and mutated TP53 are common in pediatric CNS tumors. p28 is a cell penetrating peptide that preferentially enters cancer cells and binds to wild type and mutant p53 prot...

TR-10 * AUTOPHAGY INHIBITION REVERSES RESISTANCE TO TARGETED BRAF THERAPY IN PEDIATRIC CNS TUMORS

Autophagy inhibition is a potential therapeutic strategy in cancer. We have previously shown that autophagy-dependent tumors, such as those with BRAFV600E, there may be broad potential application of autophagy inhibition. Targeted inhibition against the BRAFV600E mutation (BRAFi) has been identified as important in pediatric CNS tumors and is being more broadly provided to these patients. Patients treated with BRAFi will develop resistance mechanisms and new approaches to reversing this resistance are needed. Our findings suggest that pediatric CNS tumors with BRAFV600E are autophagy-dependent in parental tumors and those with inherent or acquired BRAFi resistance. Autophagy was evaluated by flow cytometry and Western blot. Autophagy was inhibited by clinically available chloroquine and BRAFi was provided by vemurafenib. Cell survival was evaluated using a variety of techniques. Ex vivo organotypic culture of resistant tumor was used to verify in vitro findings. We found that mutant (but not WT) cells display high rates of induced autophagy, and these levels remain similar in BRAFi resistant cells. Both parental and resistant cells are sensitive to autophagy inhibition and display synergy when chloroquine was combined with BRAFi. We also demonstrate chloroquine can improve vemurafenib sensitivity in a resistant ex vivo primary culture. Autophagy inhibition decreases the ratio of pERK:ERK levels when used in combination with BRAFi in resistant tumor cells, suggesting a potential mechanism for improved response in combination treatment. Importantly, chloroquine improved vemurafenib sensitivity in a patient with acquired BRAFi resistance and improved clinical outcomes. These data highlight an exciting possibility for identifying genetic markers, such as BRAFV600E, which sensitize tumors to autophagy inhibition combination therapy. Synergy was identified in both parental and resistant cells suggesting that autophagy-dependence is driven by its underlying mutations. Therefore, in autophagy-dependent BRAFV600E tumors there may be broad potential application of autophagy inhibition in both BRAFi naive and resistant patients.

Intraoperative consultation on pediatric central nervous system tumors by squash cytology

Squash cytology (SC) is a very useful procedure during neurosurgical intraoperative consultation (IOC), and it is especially recommended for the evaluation of soft tumors or tumors that are highly cellular (just the characteristics of pediatric central nervous system [CNS] tumors). The aim of this review is to familiarize pathologists with the range of cytomorphologic appearances that can occur during IOC for pediatric CNS tumors and with the diagnostic dilemmas and pitfalls encountered in this setting. This article is based on the medical literature and the authors' experience with a large series of cases accrued over a 12-year period at 3 institutions. SC is a specially recommended procedure in IOC for pediatric CNS tumors; it reveals the fine cellular details and background features in a manner not seen in corresponding frozen sections. Indeed, a differential diagnosis between histologically look-alike processes can be achieved with more confidence if SC is employed.

MicroRNAs in pediatric central nervous system embryonal neoplasms: the known unknown.

MicroRNAs (miRNAs) are endogenous short non-coding RNAs that repress post-transcriptional regulation of gene expression, while embryonal central nervous system tumors are the foremost cause of mortality in children suffering from a neoplasm. MiRNAs and their regulatory mechanisms are new to understand, while pediatric CNS tumors are difficult to comprehend. Therefore, identification of the link between them composes a major scientific challenge. The present study, reviewed the current knowledge on the role of miRNA in pediatric CNS embryonal tumors, attempting to collect the existing information in one piece of work that could ideally be used as a guide for future reference and research.

Altered self-perception in adult survivors treated for a CNS tumor in childhood or adolescence: population-based outcomes compared with the general population.

Survivors of pediatric CNS tumors are at risk for persistent tumor/treatment-related morbidity, physical disability and social consequences that may alter self-perception, vital for self-identity, mental health and quality of survival. We studied the long-term impact of childhood CNS tumors and their treatment on the self-perception of adult survivors and compared outcomes with those of the general population. The cohort included 697 Swedish survivors diagnosed with a primary CNS tumor during 1982-2001. Comparison data were randomly collected from a stratified general population sample. Survivors and general population individuals were compared as regards self-perception in 5 domains: body image, sports/physical activities, peers, work, and family, and with a global self-esteem index. Within the survivor group, determinants of impact on self-perception were identified. The final analyzed sample included 528 survivors, 75.8% of the entire national cohort. The control sample consisted of 995, 41% of 2500 addressed. Survivors had significantly poorer self-perception outcomes in domains of peers, work, body image, and sports/physical activities, and in the global self-perception measure, compared with those of the general population (all P < .001). Within the survivor group, female gender and persistent visible physical sequelae predicted poorer outcomes in several of the studied domains. Tumor type and a history of cranial radiation therapy were associated with outcomes. An altered self-perception is a potential late effect in adult survivors of pediatric CNS tumors. Self-perception and self-esteem are significant elements of identity, mental health and quality of survival. Therefore, care and psychosocial follow-up of survivors should include measures for identifying disturbances and for assessing the need for psychosocial intervention.

Abstract 3382: Nifurtimox enhances the therapeutic efficacy of radiation by inducing reactive oxygen species and related pathways: Pre-clinical study in medulloblastoma

Abstract Medulloblastoma (MB) is the most common malignant brain tumor in children, accounting for about 20% of pediatric CNS tumors. Multimodality treatments including surgery, radiotherapy (XRT) and chemotherapy have greatly improved disease outcome but survivors often suffer from deleterious effects of aggressive treatment with XRT. The aim of this study is to use novel strategies to enhance the response of XRT in a pre-clinical model for MB. XRT is known to cause DNA damage and cell death by inducing reactive oxygen species (ROS). Induction of ROS causes perturbation in antioxidant defense system thereby causing cell damage and death. Therefore, induction of ROS may serve as a promising strategy in cancer therapy. Nifurtimox (Nfx), a nitrofuran compound used to treat the parasitic infection Chagas’ disease, is known to induce ROS in pre-clinical models for neuroblastoma (NB) and MB. It is currently in clinical trials for treating NB and MB in children. In this study, we investigated the effects of Nfx in augmenting the efficacy of XRT in MB cell lines. DAOY and D283 cells were treated with varying dose of Nfx (5-70 µg/ml) or XRT (2-10 Gy) and cell viability was assessed using CellTiter-Glo for up to 5 days. The effect of combination therapy on cell viability, apoptosis, ROS levels and catalase activity was evaluated using optimized dose of Nfx and XRT. Results revealed that combination treatment significantly inhibited MB cell growth when compared to the effect of either Nfx or XRT alone. This was accompanied by the activation of apoptotic cell death as determined by increased annexin V staining and caspase 3/7 activity. An increase in ROS was also observed following combination treatment with Nfx and XRT which correlated with cell growth inhibition. Interestingly, catalase activity was unaltered following the treatment with single or double agents suggesting a contribution of impaired antioxidant system in causing MB cell growth inhibition. To further delineate the underlying mechanisms and to identify other candidates modulated by this combination therapy, we undertook molecular profiling approach using Affimetrix gene expression arrays (Human Gene 2.0 ST Array). We examined differentially expressed genes and affiliated pathways, and biological processes underlying tumor cell responses to Nfx and XRT. Our results identified genes that are statistically enriched for biological functions related to tumorigenesis, including cancer cell death and survival, cell cycle, and other functions relating to cancer disease. Several transcription factors and their downstream targets were also found to be enriched including the NRF2-mediated oxidative stress response pathway that responds to various stimuli including ROS. In conclusion, this pre-clinical study demonstrates that Nfx has the potential to enhance the therapeutic efficacy of radiation in MB cell lines. Citation Format: Don Eslin, Umesh T. Sankpal, Chris M. Lee, Giselle Saulnier Sholler, Robert M. Sutphin, Paul Bowman, Jeffrey C. Murray, Riyaz M. Basha. Nifurtimox enhances the therapeutic efficacy of radiation by inducing reactive oxygen species and related pathways: Pre-clinical study in medulloblastoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3382. doi:10.1158/1538-7445.AM2014-3382

Abstract 1193: Establishment of patient tumor-derived orthotopic xenograft models of metastatic pediatric germinoma

Abstract Despite comprising up to 10% of pediatric CNS tumors, an animal model of intracranial germinoma has not been previously established. Standard of case for germinoma is radiation therapy, with recent evidence that neo-adjuvant chemotherapy may allow reduction of radiation dose, but concern for neuro-cognitive toxicity remains despite the reduction of radiation. A clinically relevant animal model of germinoma would facilitate investigation and discovery of novel agents which may obviate the need for radiation in the future. To develop xenograft mouse models, we implanted germinoma tumor cells from two children with metastatic disease, one from a surgical specimen of a cervical metastatic tumor and the second from disseminated tumor cells in the CSF, directly into the right cerebral hemispheres of NOD-SCID mice. Both patient tumor samples have undergone whole exome sequencing; one of the two models has a germinoma-associated mutation in c-kit. The tumors have been serially passaged in xenografts for 3-5 times, with each passaged tumor maintaining the ability to generate tumors, suggestive of the persistence of viable tumorigenic/tumor stem cells. Data from additional tumor models established by our lab have confirmed molecular and genetic fidelity between xenograft-initiating human brain tumors and their corresponding murine models. The orthotopic location in the mouse brain of the xenograft model should also reasonably replicate the human germinoma tumor microenvironment. Cultured cells are currently growing from both tumor models in order to establish germinoma cell lines. In summary, our orthotopic xenograft murine models of two metastatic pediatric germinomas are the first to be established for this tumor type. These models will allow much needed pre-clinical drug testing of chemotherapeutics and combination therapies as well as further biologic characterization of pediatric germinomas. Citation Format: Holly B. Lindsay, Mari Kogiso, Lin Qi, Teo Wan Yee, Yulun Huang, Hua Mao, Frank Lin, Patricia Baxter, Jack M. Su, Keita Terashima, Laszlo Perlaky, Ching C. Lau, Donald W. Parsons, Murali Chintagumpala, Xiao-Nan Li. Establishment of patient tumor-derived orthotopic xenograft models of metastatic pediatric germinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1193. doi:10.1158/1538-7445.AM2014-1193

Comparison of survival between the UK and US after surgery for most common pediatric CNS tumors

We report a population-based study examining long-term outcomes for common pediatric CNS tumors comparing results from the UK with the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) data set and with the literature. No such international study has previously been reported. Data between 1996 and 2005 from the UK National Registry of Childhood Tumours (NRCT) and the SEER registry were analyzed. We calculated actuarial survival at each time point from histological diagnosis, with death from any cause as the endpoint. Kaplan-Meier estimation and log-rank testing (Cox proportional hazards regression analysis) were used to calculate survival differences among tumor subtypes, adjusting for age at diagnosis. Population-based outcomes for each tumor type are presented. Overall age-adjusted survival, stratifying for histology (combining pilocytic astrocytoma, anaplastic astrocytoma, glioblastoma, primitive neuroectodermal tumor, medulloblastoma, and ependymoma), is significantly lower for NRCT than SEER (hazard ratio 0.71, P < .001) and at 1, 5, and 10 years. Both NRCT and SEER outcomes are worse than those reported from trials. Analyzing data from comprehensive registries minimizes bias associated with trials and institutional studies. The reasons for the poorer outcomes in children treated in the UK are unclear. Likewise, the differences in outcomes between patients in trials and those not in trials need further investigation. We recommend that all children with CNS tumors be recruited into studies-even if these are observational studies. We also suggest that registries be suitably funded to publish independent outcome data (including morbidity) at both a national and an institutional level.

PDE5 inhibitors enhance the lethality of standard of care chemotherapy in pediatric CNS tumor cells

We determined whether clinically relevant phosphodiesterase 5 (PDE5) inhibitors interacted with clinically relevant chemotherapies to kill medulloblastoma cells. In medulloblastoma cells PDE5 inhibitors interacted in a greater than additive fashion with vincristine/etoposide/cisplatin to cause cell death. Knockdown of PDE5 expression recapitulated the combination effects of PDE5 inhibitor drugs with chemotherapy drugs. Expression of dominant negative caspase 9 did not significantly inhibit chemotherapy lethality but did significantly reduce enhanced killing in combination with the PDE5 inhibitor sildenafil. Overexpression of BCL-XL and c-FLIP-s suppressed individual and combination drug toxicities. Knockdown of CD95 or FADD suppressed drug combination toxicity. Treatment with PDE5 inhibitors and chemotherapy drugs promoted autophagy which was maximal at ~12 h post-treatment, and in a cell type-dependent manner knockdown of Beclin1 or ATG5 either suppressed or enhanced drug combination lethality. PDE5 inhibitors enhanced the induction of chemotherapy-induced DNA damage in a nitric oxide synthase-dependent fashion. In conclusion, our data demonstrate that the combination of PDE5 inhibitors with standard of care chemotherapy agents for medulloblastoma represents a possible novel modality for future treatment of this disease.

Activation of ErbB2- ErbB3 signaling pathway supports potential therapeutic activity of ErbB inhibitors in AT/RT

To the Editor, With interest, we read Fouladi and colleagues’ results from a molecular biology and phase II trial of lapatinib in children with refractory CNS malignancies [1]. We share the authors’ interest in finding new therapeutic options for pediatric CNS tumors that are refractory to treatment. Our focus of interest is atypical teratoid rhabdoid tumors (AT/ RTs), which are associated with significantly worse overall survival when compared to other pediatric CNS tumors. Here, we would like to share our results obtained through high throughput gene expression (GE) profiling in a series of frozen tumor samples that underwent surgical excision at our institution. Our results suggest that ErbB inhibitors, including lapatinid, could be beneficial to treat AT/RT patients. Because only one AT/RT patient was enrolled in the phase I trial [2] of the above mentioned study, and no AT/RT patient was included in the phase II trial [1], we put

Antiangiogenic treatment of pediatric CNS tumors in Hungary with the Kieran schedule

In Hungary a new oral antiangiogenic treatment was introduced in cases of primary chemoresistant or recurrent pediatric CNS tumors, called Kieran schedule. The early results of this treatment were analyzed. From 2010 at Semmelweis University on individual decisions a daily combined per oral treatment was introduced in pediatric patients with recurrent or progressive CNS tumor (Kieran schedule: thalidomid, celecoxib, etoposid and cyclophosphamid). Efficacy of therapy was analyzed in terms of demographic data, histology, side effects and tolerability in a retrospective manner. From 2010 through 2013, twenty patients were treated with Kieran schedule (medulloblastoma: 3, ependymoma: 5, anaplastic astrocytoma: 2, GBM: 4, plexus choroideus carcinoma: 1, central primitive neuroectodermal tumor: 1, optic glioma: 2, brainstem tumor: 2). Median treatment time and median progression-free survival were 0.60 and 0.61 years, respectively. Based on the preliminary analysis of a limited cohort of patients, the therapy was efficient in those cases of medulloblastoma, ependymoma, high-grade and optic gliomas, where the expected survival time was more than 3 months at start of treatment. Side effects were slight myelosuppresion in terms of previous therapy, 16% transient ischemic attack (TIA)-like episodes. During therapy patients could live their everyday life. Kieran schedule was well-tolerable and efficient with good quality of life in certain cases of pediatric CNS tumors.

Neurosurgical treatment of oligodendroglial tumors in children and adolescents: a single-institution series of 35 consecutive patients

The object of this study was to delineate long-term results of the surgical treatment of pediatric CNS tumors classified as oligodendroglioma (OD) or oligoastrocytoma (OA) WHO Grade II or III. A cohort of 45 consecutive patients 19 years or younger who had undergone primary resection of CNS tumors originally described as oligodendroglial during the years 1970-2009 at a single institution were reviewed in this retrospective study of surgical morbidity, mortality, and academic achievement and/or work participation. Gross motor function and activities of daily living were scored using the Barthel Index (BI). Patient records for 35 consecutive children and adolescents who had undergone resection for an OA (17 patients) or OD (18 patients) were included in this study. Of the 35 patients, 12 were in the 1st decade of life at the first surgery, whereas 23 were in the 2nd decade. The male/female ratio was 1.19 (19/16). No patient was lost to follow-up. The tumor was localized to the supratentorial compartment in 33 patients, the posterior fossa in 1 patient, and the cervical medulla in 1 patient. Twenty-four tumors were considered to be WHO Grade II, and 11 were classified as WHO Grade III. Among these latter lesions were 2 tumors initially classified as WHO Grade II and later reclassified as WHO Grade III following repeat surgery. Fifty-four tumor resections were performed. Two patients underwent repeat tumor resection within 5 days of the initial procedure, after MRI confirmed residual tumor. Another 10 patients underwent a second resection because of clinical deterioration and progressive disease at time points ranging from 1 month to 10 years after the initial operation. Six patients underwent a third resection, and 1 patient underwent a fourth excision following tumor dissemination to the spinal canal. Sixteen (46%) of the 35 children received adjuvant therapy: 7, fractionated radiotherapy; 4, chemotherapy; and 5, both fractionated radiotherapy and chemotherapy. One patient with primary supratentorial disease experienced clinically malignant development with widespread intraspinal dissemination 9 years after initial treatment. Only 2 patients needed treatment for persistent hydrocephalus. In this series there was no surgical mortality, which was defined as death within 30 days of resection. However, 12 patients in the study, with follow-up times from 1 month to 33 years, died. Twenty-three patients, with follow-up times from 4 to 31 years, remained alive. Among these survivors, the BI was 100 (normal) in 22 patients and 80 in 1 patient. Nineteen patients had full- or part-time work or were in normal school programs. Pediatric oligodendroglial tumors are mainly localized to the supratentorial compartment and more often occur in the 2nd decade of life rather than the 1st. Two-thirds of the patients remained alive after follow-ups from 4 to 31 years. Twelve children succumbed to their disease, 9 of them within 3 years of resection despite combined treatment with radio- and chemotherapy. Three of them remained alive from 9 to 33 years after primary resection. Among the 23 survivors, a stable, very long-term result was attainable in at least 20. Five-, 10-, 20-, and 30-year overall survival in patients with Grade II tumors was 92%, 92%, 92%, and 88%, respectively.

Epidemiology of pediatric primary malignant central nervous system tumors in Iran: A 10 year report of National Cancer Registry

BackgroundCNS tumors are the leading cause of cancer related deaths among children and adolescents. Nonetheless, the incidence of pediatric CNS tumors in developing countries is poorly understood. We aimed to provide epidemiologic features of primary malignant CNS tumors in Iranian children 0–19 years of age using National Cancer Registry (NCR) data bank. MethodsThe data recorded by NCR over a 10 year period (2000–2010) were reviewed. ResultsOf 1948 tumor cases, 93.3% were located in brain, 5.1% were found in the spinal cord & cauda equina, and 1.6% affected cranial nerves and other parts of the nervous system. The overall average annual age specific incidence rate was 1.43 per 100,000. Males were more likely to develop CNS tumors (1.65 per 100,000) compared to females (1.21 per 100,000, p<0.01). Children under 5 years of age had the highest age specific incidence rate (1.86 per 100,000). Astrocytic tumors with the incidence rate of 0.61 per 100,000 were the most frequent specific histology followed by embryonal (0.38 per 100,000), and ependymal tumors (0.10 per 100,000). With regard to the histological distribution of tumors, some unique features including the high proportion of unspecified malignant neoplasms (7.6%) were noted. ConclusionThe overall incidence rate was markedly lower than western findings. Major differences were also observed in incidence rates of specific histologies. Although the discrepancies may be attributable to diversity in classification schemes and registration practices, a real ethnic and geographical variation in predisposition to development of pediatric CNS cancers is strongly suggested.

Optic pathway gliomas: a review.

Optic pathway gliomas account for 3-5% of all pediatric CNS tumors and represent the most common intrinsic optic nerve tumors. These tumors occur preferentially during the first decade of life and are particularly frequent in children with neurofibromatosis type 1. Although optic pathway gliomas are low-grade tumors, their behavior can be aggressive, and their management is often challenging. Their management includes observation, surgery, chemotherapy and radiation. The role of each modality is discussed as well as current and future developments in treatment, in particular targeted therapies that are currently being investigated.

H3F3A K27M Mutation in Pediatric CNS Tumors

Brain tumors are one of the most common childhood malignancies. Diffuse high-grade gliomas represent approximately 10% of pediatric brain tumors. Exon sequencing has identified a mutation in K27M of the histone H3.3 gene (H3F3A K27M and G34R/V) in about 20% of pediatric glioblastomas, but it remains to be seen whether these mutations can be considered specific for pediatric diffuse high-grade astrocytomas or also occur in other pediatric brain tumors. We performed a pyrosequencing-based analysis for the identification of H3F3A codon 27 and codon 34 mutations in 338 pediatric brain tumors. The K27M mutation occurred in 35 of 129 glioblastomas (27.1%) and in 5 of 28 (17.9%) anaplastic astrocytomas. None of the other tumor entities showed H3F3A K27M mutation. Because H3F3A K27M mutations occur exclusively in pediatric diffuse high-grade astrocytomas, analysis of codon 27 mutational status could be useful in the differential diagnosis of these neoplasms.

Pediatric high-grade gliomas: survival at what cost?

Survival of children with tumors of the central nervous system has improved over the past three decades with more than 70% of patients now expected to survive at least five years (1). However, pediatric CNS tumors are histologically heterogeneous, affect children over a wide span of developmental stages, and have vastly different treatment approaches.