Malignant CNS Tumors Research Articles

Phase I study of afatinib and radiotherapy (RT) with or without temozolomide (TMZ) in newly diagnosed glioblastoma (GB).

2036Background: GB is a malignant primary incurable CNS tumor with poor prognosis. RT + TMZ is standard treatment for newly diagnosed GB suitable for radical treatment. ErbB pathway dysregulation h...

Immunotherapy in CNS cancers: the role of immune cell trafficking.

Glioblastoma (GBM) is a highly malignant CNS tumor with very poor survival despite intervention with conventional therapeutic strategies. Although the CNS is separated from the immune system by the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier, emerging evidence of immune surveillance and the selective infiltration of GBMs by immune suppressive cells indicates that there is breakdown or compromise of these physical barriers. This in turn offers hope that immunotherapy can be applied to specifically target and reduce tumor burden. One of the major setbacks in translating immunotherapy strategies is the hostile microenvironment of the tumor that inhibits trafficking of effector immune cells such as cytotoxic T lymphocytes into the CNS. Incorporating important findings from autoimmune disorders such as multiple sclerosis to understand and thereby enhance cytotoxic lymphocyte infiltration into GBM could augment immunotherapy strategies to treat this disease. However, although these therapies are designed to evoke a potent immune response, limited space in the brain and cranial vault reduces tolerance for immune therapy-induced inflammation and resultant brain edema. Therefore, successful immunotherapy requires that a delicate balance be maintained between activating and retaining lasting antitumor immunity.

Inhibition of polo-like kinase 4 (PLK4): a new therapeutic option for rhabdoid tumors and pediatric medulloblastoma.

Rhabdoid tumors (RT) are highly aggressive and vastly unresponsive embryonal tumors. They are the most common malignant CNS tumors in infants below 6 months of age. Medulloblastomas (MB) are embryonal tumors that arise in the cerebellum and are the most frequent pediatric malignant brain tumors. Despite the advances in recent years, especially for the most favorable molecular subtypes of MB, the prognosis of patients with embryonal tumors remains modest with treatment related toxicity dreadfully high. Therefore, new targeted therapies are needed.The polo-like kinase 4 (PLK4) is a critical regulator of centriole duplication and consequently, mitotic progression. We previously established that PLK4 is overexpressed in RT and MB. We also demonstrated that inhibiting PLK4 with a small molecule inhibitor resulted in impairment of proliferation, survival, migration and invasion of RT cells.Here, we showed in MB the same effects that we previously described for RT. We also demonstrated that PLK4 inhibition induced apoptosis, senescence and polyploidy in RT and MB cells, thereby increasing the susceptibility of cancer cells to DNA-damaging agents. In order to test the hypothesis that PLK4 is a CNS druggable target, we demonstrated efficacy with oral administration to an orthotropic xenograft model.Based on these results, we postulate that targeting PLK4 with small-molecule inhibitors could be a novel strategy for the treatment of RT and MB and that PLK4 inhibitors (PLK4i) might be promising agents to be used solo or in combination with cytotoxic agents.

Hereditary tumor syndromes in neuropathology

Neoplasms in the central (CNS) and peripheral nervous system (PNS) in hereditary tumor syndromes play an important role in the neuropathological diagnostics. The benign and malignant PNS and CNS tumors that occur in the frequent neurofibromatosis type 1 (NF1) and type 2 (NF2) often represent essential factors for the course of the disease in those affected. Furthermore, certain clinical constellations (e.g. bilateral schwannomas of the auditory nerve, schwannomas at a young age and multiple meningiomas) can be important indications for a previously undiagnosed hereditary tumor disease. Other tumors occur practically regularly in association with certain germline defects, e.g. subependymal giant cell astrocytoma (SEGA) in tuberous sclerosis and dysplastic gangliocytoma of the cerebellum in Cowden's syndrome and can be indications in the diagnostics for an extended genetic counselling. This is not only important because many germline defects are based on new mutations, but also for the now established targeted therapy of certain tumors, e.g. inhibition of the mammalian target of rapamycin (mTOR) signaling pathway using temsirolimus for SEGA. Furthermore, knowledge about the possible constellations of genetic mosaics in hereditary tumor syndromes with the resulting (incomplete) syndrome manifestations is useful. This review article summarizes the most important hereditary tumor syndromes with involvement of the PNS and CNS.

PP75. DROSOPHILA MELANOGASTER AS A MODEL ORGANISM TO STUDY GLIOMA: LOCATION AND IDENTIFICATION OF FOLLISTATIN

Gliomas are the most common, malignant brain tumour found in the central nervous system. The main characteristics of gliomas is their rapid proliferation, resistance to current chemotherapies and their ability to infiltrate the brain. Brain tumours have a low survival rate due to the lack of available treatments. In the UK between 2010 and 2011, the survival rate was 14% for 10 or more year. The mortality rates for malignant brain and CNS tumours have increased by up to 24% in the UK between 1970 and 2012. As there is difficulty obtaining glioma samples, it is important to identify a suitable model organism. The main signalling pathways seen to be activated in human glioma development are the epithelial growth factor receptor (EGFR) and phosphatidylinositol-3 kinase (PI3K) pathways. The homologous EFGR and PI3K pathways have been studied greatly in drosophila, and show that there must be co-activation of the EGFR and PI3K pathways for cancer development to occur; leading to an increase in glial cell numbers by 50-100x fold. Follistatin is a protein which has been identified as a biomarker in malignant gliomas; by comparing normal serum to glioma serum it has shown that there is an overexpression of follistatin. Gliomas can be replicated in drosophila as there has been a high level of homology identified in human diseased states and in neural development. Follistatin studies have shown it has important roles in development and differentiation of tissues and organs. It acts as an inhibitor, binding to activin, bone morphogenetic proteins and other proteins which can be found in vertebrates. Follistatin has been identified within a number of different cancer types (such as prostate and ovarian), and plays an important role in cancer metastasis and angiogenesis. Serum studies have revealed follistatin is present in the early stages of cancer development; however the location and role of follistatin in cancer development has not been identified. Drosophila contain a homolog of follistatin, which will allow studies of follistatin in cancer within drosophila. By using drosophila as a model organism it will allow the location of follistatin and its involvement in glioma development to be identified. Immunohistochemistry is used to identify the location and distribution of a protein within a tissue or an organ. It is commonly used to identify which proteins are present in specific types of cancer. Follistatin has been identified to play a role in the early stages of glioma development. Therefore by using immunohistochemistry follistatin can be identified throughout the different stages of glioma development and possibly identify its role in this development. The aim of the research is to identify and locate the protein follistatin in drosophila by using immunohistochemistry. Using different larval instar stages, this will identify the distribution of follistatin in different stages of neural development. The hypothesis would be that follistatin is involved in the early stages of glial development and the distribution is important in glioma development compared to normal neural development.

Enhanced radiation efficiency by gold nanoparticles after proton beam irradiation in medulloblastoma cell lines

Introduction: In pediatric oncology, one quarter of patients is diagnosed with a tumor of the CNS. Although outcome did improve significantly during the last decade, prognosis of malignant CNS-tumors in childhood is still lagging behind and needs further improvement. Especially for relapse patients, prognosis is worse and curative therapy approaches are missed. Besides radical resection and chemotherapy, radiotherapy is standard of care. However, secondary malignancy after treatment of CNS-tumors in childhood occurs in 5.5% of cases, thus accounting for 19% of all secondary cancers in childhood tumors. Although proton beam irradiation allows to cover target volumes comparable to those achieved by photons, the main advantage of proton beams is sparing of healthy tissues. Recent in vitro and in vivo studies demonstrated an enhanced biological effect of proton therapy in the presence of gold nanoparticles. This held true both for irradiated cancer cells in vitro and in vivo. In this study we wanted to extend these findings to preclinical medulloblastoma models using proton beams and well-defined gold nanoparticles. Materials and methods: Three different medulloblastoma cell lines (DAOY, ONS76 and UW228) were cultured and treated with proton beam irradiation after incubation with gold nanoparticles or without. Three different doses of irradiation (6, 10 and 20 Gy) were evaluated. Stock solutions of gold nanoparticles were used in serial dilutions. Viability of medulloblastoma cells was evaluated by using MTT assays 72 hours after irradiation. Results: As expected, proton beam irradiation had the main effect on medulloblastoma cell viability. However, in our study gold nanoparticles had a cytotoxic effect at high concentrations (> 400 µg/ml). Proton beam irradiation in the presence of gold nanoparticles decreased the IC50 that was observed when cells were irradiated only. Conclusion: Confirming published data we could show enhanced biological effectiveness of proton beam irradiation in medulloblastoma cell lines in the presence of gold nanoparticles. Sensitization was directly correlated with radiation dose and the amount of gold nanoparticles per cell. Further investigation on the impact of particle size on toxicity as well as on enhanced radiation efficiency is needed.

Immune infiltration, glioma stratification, and therapeutic implications

By definition, gliomas are brain tumors emanating from glial precursor cells. Gliomas include glioblastoma (GBM), astrocytoma, oligodendroglioma, and ependymoma. The World Health Organization (WHO) traditionally classifies brain tumors according to their pathological features, with GBM having the highest grade (IV), while lower grades (mostly II, III) are typically assigned to various types of astrocytic, oligodendroglial, and ependymal tumors (1), which collectively are referred to as lower grade gliomas (LGG). In the latest NCI SEER (Surveillance, Epidemiology, and End Results) report and projection, the estimated 2016 incidence and deaths for brain and other CNS tumors is 23,770 and 16,050, respectively (2). According to CBTRUS (Central Brain Tumor Registry of the United States), glioma represents about 27% of all, and 80% of malignant brain and CNS tumors (3). The majority (55.1%) of gliomas are classified as GBMs. For GBMs, the current standard of care consists of surgical resection, radiotherapy with chemotherapy (temozolomide or TMZ). The median survival rate, which ranges from 14.5 to 16.6 months [see (4,5) for review], remains dismally poor despite decades of research and discoveries, leading up to the current era of genomics, targeted therapeutics, and immunotherapeutics. LGGs on the other hand have more favorable clinical outcome, especially cases possessing IDH mutation and co-deletion of 1p and 19q chromosomal arms.

Abstract 2696: Four new brain tumor entities emerge from molecular classification of CNS-PNETs

Abstract CNS-primitive neuroectodermal tumors (CNS PNETs) are highly aggressive, poorly differentiated embryonal tumors occurring predominantly in young children but also affecting adolescents and adults. Histological diagnosis is complicated by morphological heterogeneity and divergent differentiation. Recent studies suggest the existence of molecular subgroups of CNS-PNETs sharing biological characteristics with other CNS tumors. To investigate this we have analyzed 323 fresh-frozen or paraffin-embedded institutionally diagnosed CNS-PNETs using DNA methylation and expression arrays. Data were compared to 211 reference cases of other pediatric and adult brain tumors representing more than 20 well-known entities. DNA methylation and gene expression patterns showed that a significant proportion of CNS PNETs display molecular profiles indistinguishable from those of various other well defined CNS tumor entities. Hallmark genetic alterations for each of these well-defined entities, such as amplification of 19q13.42, mutations in IDH1 or H3F3A, mutations/deletions of the SMARCB1 locus, or RELA fusions, were frequently detected among the reclassified cases. From the remaining fraction of CNS PNETs we have identified four new CNS tumor entities, each associated with a unique recurrent genetic alteration and distinct histopathological and clinical features. Based on these findings we designated these four new entities as “CNS neuroblastoma with FOXR2 activation (CNS NB FOXR2)”, “CNS Ewing sarcoma family tumor with CIC alteration (CNS EFT CIC)”, “CNS high grade neuroepithelial tumor with MN1 alteration (CNS HGNET MN1)”, and “CNS high grade neuroepithelial tumor with BCOR alteration (CNS HGNET BCOR)”. Our findings reinforce the importance of incorporating molecular information into the next revision of the WHO classification of CNS tumors, and warrant a replacement of the term “CNS PNET” with biologically specific designations. Our study provides an innovative framework for improving diagnostic accuracy and prognostication in malignant CNS tumors. The approach is amenable to retrospective analyses of patients treated with current regimens and will facilitate the design of more meaningful clinical trials for patients with malignant brain tumors. Citation Format: Dominik Sturm, Brent Orr, Umut H. Toprak, Volker Hovestadt, David T.W. Jones, David Capper, Peter Lichter, Andrey Korshunov, Stefan M. Pfister, David W. Ellison, Marcel Kool. Four new brain tumor entities emerge from molecular classification of CNS-PNETs. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2696.

Distinctive Cancer Associations in Patients With Neurofibromatosis Type 1.

The current study was designed to determine the risk of cancer in patients with neurofibromatosis type 1 (NF1) by cancer type, age, and sex with unprecedented accuracy to be achieved by combining two total population-based registers. A population-based series of patients with NF1 (N = 1,404; 19,076 person-years) was linked to incident cancers recorded in the Finnish Cancer Registry and deaths recorded in the national Population Register Centre between 1987 and 2012. Standardized incidence ratios (SIRs) and standardized mortality ratios (SMRs) were calculated for selected cancer types. Survival of the patients with cancer with and without NF1 was compared. In malignant peripheral nerve sheath tumors and CNS tumors, the cancers traditionally associated with NF1, we observed SIRs of 2,056 (95% CI, 1,561 to 2,658), and 37.5 (95% CI, 30.2 to 46.0), respectively, and SMRs of 2,301 (95% CI, 1,652 to 3,122) and 30.2 (95% CI, 19.1 to 45.2), respectively. We found an unequivocally increased risk for breast cancer. In particular, SIR was 11.1 (95% CI, 5.56 to 19.5) for breast cancer in women with NF1 age < 40 years; the overall SMR for breast cancer was 5.20 (95% CI, 2.38 to 9.88). Particularly high overall SIRs were observed in patients with NF1 age < 15 years: women, 87.6 (95% CI, 58.6 to 125); men, 45.6 (95% CI, 28.4 to 68.5). An estimated lifetime cancer risk for patients with NF1 was 59.6%. The 5-year survival of patients with cancer and NF1, excluding nervous tissue cancers, was worse than that of comparable patients with cancers without NF1 (54.0% v 67.5%; P = .01). Our results emphasize the general cancer proclivity of patients with NF1. These findings should translate to clinical practices to determine clinical interventions and focused follow-up of patients with NF1.

Safety, efficacy and survival of patients (pts) with primary CNS tumors in phase 1 (Ph1) trials: A 12-year single institution experience.

2043Background: Malignant primary CNS tumors constitute less than 2% of all malignancies and carry a dismal prognosis. Treatment (tx) options at relapse are limited. First-in-human solid tumor stud...

Atypical teratoid/rhabdoid tumors-current concepts, advances in biology, and potential future therapies.

Atypical teratoid/rhabdoid tumor (AT/RT) is the most common malignant CNS tumor of children below 6 months of age. The majority of AT/RTs demonstrate genomic alterations in SMARCB1 (INI1, SNF5, BAF47) or, to a lesser extent, SMARCA4 (BRG1) of the SWItch/sucrose nonfermentable chromatin remodeling complex. Recent transcription and methylation profiling studies suggest the existence of molecular subgroups. Thus, at the root of these seemingly enigmatic tumors lies a network of factors related to epigenetic regulation, which is not yet completely understood. While conventional-type chemotherapy may have significant survival benefit for certain patients, it remains to be determined which patients will eventually prove resistant to chemotherapy and thus need novel therapeutic strategies. Elucidation of the molecular consequences of a disturbed epigenome has led to the identification of a series of transduction cascades, which may be targeted for therapy. Among these are the pathways of cyclin D1/cyclin-dependent kinases 4 and 6, Hedgehog/GLI1, Wnt/ß-catenin, enhancer of zeste homolog 2, and aurora kinase A, among others. Compounds specifically targeting these pathways or agents that alter the epigenetic state of the cell are currently being evaluated in preclinical settings and in experimental clinical trials for AT/RT.

Primary Central Nervous System Lymphoma: A Critical Review of the Role of Surgery for Resection.

Primary central nervous system lymphomas (PCNSL) are rare CNS tumors that carry a poor prognosis, with most patients suffering recurrence. Progress has been made in the treatment of this pathology, notably with the widespread use of systemic high dose methotrexate. However, unlike most other malignant CNS neoplasms, surgery for cytoreduction is not routinely performed for this disease, mainly as a result of negative experiences decades ago. Since these studies were published, the availability of intraoperative monitoring, MR imaging and neuro-navigation as well as surgical adjuncts such as fluorescence- guided resection have greatly improved the safety of intracranial procedures. More recent data is suggestive of a potential survival benefit for resection of single PCNSL lesions when patients are subsequently treated with modern regimen high-dose methotrexate, yet this evidence is limited, and should be interpreted conservatively. A systematic review of the literature was performed to identify trials evaluating surgical options for the treatment of PCNSL. In this review, we provide a critical overview of the evidence favoring and discouraging resection for PCNSL. This literature suffers from several biases and limitations that must be considered in the context of the extrapolation of this literature into clinical decision-making.

ATPS-71EFFICACY OF TEMOZOLOMIDE IN AN ADULT WITH MEDULLOBLASTOMA, REVIEW OF SERIES OF TWO PATIENTS

Medulloblastoma is a malignant CNS tumor which is essentially a disease of childhood. It occurs infrequently in adults accounting for less than 1% of all intracranial tumors in adults. Due to the relative infrequency in adults, the clinical characteristics of this disease are not well defined in adults in comparison to children, and optimal treatment is not well established. Complete tumor resection with CSI radiation is the standard of care for treatment of adult medulloblastoma. In contrast to childhood medulloblastoma, the role of chemotherapy in adult population is undetermined. A number of chemotherapy agents in treatment of pediatric medulloblastoma have been evaluated and used including vincristine, CCNU, cisplatin, carboplatin, and cyclophosphamide. We report a case series of two patients diagnosed with medulloblastoma who underwent surgical resection followed by radiation therapy. Both patients underwent 24 cycles of chemotherapy with temozolamide over a period of 2 years with minimal toxicity. They were monitored with multiple MRIs of brain which have not revealed any disease recurrence so far rendering one patient disease free for eight and a half years and the other for six months. Very few cases of medulloblastoma treated with temozolamide have been reported. Our case series shows the antitumor effect of temozolamide in treatment of medulloblastoma with minimal toxicity. Most of the literature is based on retrospective analysis rather than randomized studies due to the small number of adult cases reported with this disease compared to the pediatric population. The optimal treatment regimen is not well established for this tumor and because of its rarity a multi-institutional clinical trial will be necessary to define the best treatment.

CNS Anticancer Drug Discovery and Development Conference White Paper.

Following the first CNS Anticancer Drug Discovery and Development Conference, the speakers from the first 4 sessions and organizers of the conference created this White Paper hoping to stimulate more and better CNS anticancer drug discovery and development. The first part of the White Paper reviews, comments, and, in some cases, expands on the 4 session areas critical to new drug development: pharmacological challenges, recent drug approaches, drug targets and discovery, and clinical paths. Following this concise review of the science and clinical aspects of new CNS anticancer drug discovery and development, we discuss, under the rubric "Accelerating Drug Discovery and Development for Brain Tumors," further reasons why the pharmaceutical industry and academia have failed to develop new anticancer drugs for CNS malignancies and what it will take to change the current status quo and develop the drugs so desperately needed by our patients with malignant CNS tumors. While this White Paper is not a formal roadmap to that end, it should be an educational guide to clinicians and scientists to help move a stagnant field forward.

Abstract 3275: A novel approach to treat medulloblastoma: The omega-3 fatty acids DHA and EPA reduce medulloblastoma tumor growth in vitro and in vivo

Abstract Background: The omega-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) exert antitumoral properties shown in several cancer types. DHA is found in abundance in the brain and is of importance in normal brain development and maintenance of function including cognitive functions. Medulloblastoma is the most common malignant CNS tumor of childhood. Intensive multimodal treatment is necessary including surgery, radiotherapy and chemotherapy. However, treatment often results in significant neurological sequelae and the risk of resistant relapses is still significant. The neuroprotective and antitumoral properties of omega-3 could therefore be of great benefit. Our aim was to investigate the effect of DHA and EPA on medulloblastoma in vitro and in vivo. Methods: In a panel of medulloblastoma cell lines the cytotoxic activity of DHA and EPA was studied using cell viability assays. The molecular mechanisms were characterized using cell- and molecular biology techniques. Mice with human medulloblastoma xenografts were treated with; DHA alone or with DHA and EPA for 30 days from time of tumor take while tumor growth was monitored. Control mice were fed with normal chow. The incorporation of fatty acids was analyzed in tumors, erythrocytes and brain tissue by LS-MS/MS. Results: DHA and EPA induced medulloblastoma cell toxicity with IC50 values ranging from 1.9 to 68 μM in six medulloblastoma cell lines. DHA reduced the prostaglandin E2 production, indicating a possible mechanism of action. In vivo, omega-3 supplementation resulted in significant reduction of tumor growth when established tumors were treated. DHA levels were increased in both tumor tissue and erythrocyte membrane compared to control. The in vivo treatment was non-toxic. Conclusions: DHA and EPA exert toxic effect on medulloblastoma cells in vitro and reduce tumor growth in vivo. These omega-3 fatty acids could therefore be good candidates for improving current therapy and at the same time protect healthy neurons from therapy-induced toxicity promoting cognitive function in survivors. Thus, omega-3 fatty acid supplementation has the potential of reducing tumor growth as well as reducing sequelae. Citation Format: Linda M. Ljungblad, John-Inge Johnsen, Malin Wickström, Per Kogner, Helena Gleissman. A novel approach to treat medulloblastoma: The omega-3 fatty acids DHA and EPA reduce medulloblastoma tumor growth in vitro and in vivo. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3275. doi:10.1158/1538-7445.AM2015-3275

The effects of alternating electric fields in glioblastoma: current evidence on therapeutic mechanisms and clinical outcomes

Glioblastoma is both the most common and most lethal primary CNS malignancy in adults, accounting for 45.6% of all malignant CNS tumors, with a 5-year survival rate of only 5.0%, despite the utilization of multimodal therapy including resection, chemotherapy, and radiation. Currently available treatment options for glioblastoma often remain limited, offering brief periods of improved survival, but with substantial side effects. As such, improvements in current treatment strategies or, more likely, the implementation of novel strategies altogether are warranted. In this topic review, the authors provide a comprehensive review on the potential of alternating electric fields (AEFs) in the treatment of glioblastoma. Alternating electric fields-also known as tumor-treating fields (TTFs)-represent an entirely original therapeutic modality with preliminary studies suggesting comparable, and at times improved, efficacy to standard chemotherapeutic agents in the treatment of recurrent glioblastoma. A recent multicenter, Phase III, randomized clinical trial comparing NovoTTF-100A monotherapy to physician's best choice chemotherapy in patients with recurrent glioblastoma revealed that AEFs have similar efficacy to standard chemotherapeutic agents with a more favorable side-effects profile and improved quality of life. In particular, AEFs were shown to have limited systemic adverse effects, with the most common side effect being contact dermatitis on the scalp at the sites of transducer placement. This study prompted FDA approval of the NovoTTF-100A system in April 2011 as a standalone therapy for treatment of recurrent glioblastoma refractory to surgical and radiation treatment. In addition to discussing the available clinical evidence regarding the utilization of AEFs in glioblastoma, this article provides essential information regarding the supposed therapeutic mechanism as well as modes of potential tumor resistance to such novel therapy, delineating future perspectives regarding basic science research on the issue.

Current Therapeutic Advances Targeting EGFR and EGFRvIII in Glioblastoma.

Epidermal growth factor receptor (EGFR) and EGFRvIII analysis is of current interest in glioblastoma – the most common malignant primary CNS tumor, because of new EGFRvIII vaccine trials underway. EGFR activation in glioblastoma promotes cellular proliferation via activation of MAPK and PI3K–Akt pathways, and EGFRvIII is the most common variant, leading to constitutively active EGFR. This review explains EGFR and EGFRvIII signaling in GBM; describes targeted therapy approaches to date including tyrosine kinase inhibitor, antibody-based therapies, vaccines and pre-clinical RNA-based therapies, and discusses the difficulties encountered with these approaches including pathway redundancy and intratumoral heterogeneity.

Alex's Lemonade Stand Foundation Infant and Childhood Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2007-2011.

The CBTRUS Statistical Report: Alex's Lemonade Stand Foundation Infant and Childhood Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2007–2011 comprehensively describes the current population-based incidence of primary malignant and non-malignant brain and CNS tumors in children ages 0–14 years, collected and reported by central cancer registries covering approximately 99.8% of the United States population (for 2011 only, data were available for 50 out of 51 registries). Overall, brain and CNS tumors are the most common solid tumor, the most common cancer, and the most common cause of cancer death in infants and children 0–14 years. This report aims to serve as a useful resource for researchers, clinicians, patients, and families.

Expression Patterns of Insulin-Like Growth Factor Binding Protein Isoforms in Medulloblastoma Subtypes and Clinical Correlation

Background: Insulin-like growth factor binding proteins (IGFBPs) are known to be differentially expressed in brain tumours. The role of some IGFBPs in malignant CNS tumours, except glioblastoma, is unknown. We evaluated the protein expression of 3 IGFBP isoforms (IGFBP-2, -3, -5) in medulloblastoma and correlated them with histological subtypes and clinical parameters. Methods: The expression of IGFBP-2, -3 and -5 was analysed in 67 samples of medulloblastoma by immunohistochemistry and correlated with histological subtypes and patient prognosis. Results: IGFBP-3 expression was seen in 37.3% of cases and IGFBP-5 expression in 80.6% of cases. IGFBP-2 expression was totally absent in medulloblastoma. The extent of IGFBP-3 expression was higher in anaplastic when compared to classical and desmoplastic subtypes (p < 0.05). IGFBP-5 expression was significantly higher in classical and anaplastic subtypes when compared to desmoplastic medulloblastoma (p < 0.05). No influence of IGFBPs on survival was noted. Conclusions: This is the first study to report expression of 3 cancer-related biomarkers - IGFBP-2, -3, -5 in medulloblastoma. Significantly higher extents of expression of IGFBP-3 in large cell variant and IGFBP-5 in classical and anaplastic subtypes suggest a plausible role of these molecules in specific molecular pathways of medulloblastoma.

CN-03 * LONG-TERM FOLLOW-UP OF ENDOCRINE FUNCTION AMONG YOUNG CHILDREN WITH NEWLY-DIAGNOSED MALIGNANT CENTRAL NERVOUS SYSTEM (CNS) TUMORS TREATED WITH IRRADIATION-AVOIDING REGIMENS: THE CHILDREN'S HOSPITAL LOS ANGELES (CHLA) EXPERIENCE

BACKGROUND: The adverse effects of radiation therapy on endocrine function among pediatric brain tumor patients have been well-documented. Brief (less than 5 months) intensive induction chemotherapy followed by marrow-ablative chemotherapy with autologous hematopoietic cell rescue (AuHCR) and avoidance of CNS irradiation has demonstrated efficacy in the treatment of very young children (less than 6 years of age) with malignant CNS tumors. This study assessed the long-term growth and endocrine effects of young children following chemotherapy-only treatment regimens. METHODS: A retrospective chart review was performed on 99 patients less than 6 years of age with newly-diagnosed malignant brain tumors between May 1991 and October 2010 treated with irradiation-avoiding strategies at CHLA. Thirty patients survived relapse-free post-AuHCR without cranial irradiation for a mean of 8.1 years (range 3.0–22.25 years); one patient expired of a TP53-related adrenocortical carcinoma. The patient cohort consisted of 18 males and 12 females with a mean age at AuHCR of 2.5 years (range: 0.8 to 5.1 years). Tumor pathologies included 20 medulloblastomas, 6 choroid plexus carcinomas, 3 CNS PNET and 1 anaplastic ependymoma. RESULTS: All patients had documented normal age-related free T4, TSH, IGFBP3, prolactin, testosterone and estradiol levels. IGF1 age-related levels were abnormal in one child. FSH and LH levels among females, and cortisol levels, were normal in 93%, 97% and 97%, respectively. Growth charts demonstrated age-associated growth within 2 standard deviations of the mean in 67% patients. Of 10 patients (33%) with short stature, 6 had proportional diminutions in both height and weight. CONCLUSIONS: These findings demonstrate that the use of relatively brief, intensive chemotherapy regimens including marrow-ablative chemotherapy with AuHCR, results in less endocrine and growth abnormalities than treatment schemes utilizing CNS irradiation. However, the documented adverse impact upon physical growth in a proportion of survivors needs to be evaluated further.