Nervous System Malignancies Research Articles

SM-07 * A PILOT STUDY OF HIGH-DOSE INFLUENZA VACCINE IMMUNOGENICITY IN PATIENTS WITH PRIMARY CENTRAL NERVOUS SYSTEM MALIGNANCY

BACKGROUND: In a previous investigation, we demonstrated reduced immunogenicity to the standard trivalent inactivated influenza vaccine in patients with primary central nervous system (CNS) malignancy (Neuro-Oncol 2014, PMID 24714522). Other populations with similar reduced responses have shown improved immunogenicity to a high-dose vaccine. OBJECTIVE: A pilot prospective cohort study was designed to evaluate the immunogenicity of the Fluzone® High-Dose influenza vaccine in patients with CNS malignancy. METHODS: Baseline data on diagnosis, chemotherapy, radiation, glucocorticoids, and timing of treatment were collected. All patients underwent vaccination with of the Fluzone® High-Dose influenza vaccine. Serum samples are actively being collected at baseline, day 28, and 3 months following vaccine administration. Hemagglutination inhibition (HAI) titers will be measured to determine seroconversion (4-fold rise) and seroprotection (titer 1:40). RESULTS: A total of 27 patients were enrolled. Mean age at baseline was 52.7 years (+/-12.6); 41% male; 93% white and 7% black. Diagnoses included high-grade glioma (85%), CNS lymphoma (11%), and meningioma (4%). At enrollment, 8 patients (30%) were taking glucocorticoids, 4 (15%) were undergoing active radiation, 14 (52%) were on chemotherapy, and 5 (19%) began chemotherapy following vaccine administration. Prior radiation (n = 19, 70%) and chemotherapy (n = 14, 52%) were common. Seven patients (26%) reported post-vaccination symptoms potentially attributable to vaccination; 6 experienced only local soreness or redness at the injection site and 1 suffered headache, nausea, vomiting. All symptoms were transient and resolved completely. At baseline, 8 patients (30%) had absolute CD4 < 300. Serum samples for HAI assay are being collected. Seroconversion and seroprotection rates are forthcoming. CONCLUSION: Studies have shown that populations known to respond poorly to standard yearly influenza vaccination (e.g. the elderly) can mount an effective immunologic response to the high-dose vaccine. This prospective cohort study will provide preliminary data regarding the immunologic response to high-dose vaccination in patients with primary CNS malignancy. Funding: The Fluzone® High Dose vaccine and HAI titer measurements were provided by Sanofi Pasteur. Acknowledgement: This research was supported by the Clinical Research Unit of the Wake Forest Translational Science Institute.

IB-06 * THE ROLE OF TGF IN NK CELL-MEDIATED CYTOTOXICITY IN MEDULLOBLASTOMA

Medulloblastoma is the most common pediatric central nervous system (CNS) malignancy, with generally favorable outcomes depending on the molecular subtype. However, recurrent/relapsed disease portends a dismal prognosis. Therefore, novel, innovative, and safe therapies are needed to treat such tumors and to minimize treatment-related morbidities. Immune cell therapy is an appealing, targeted approach for CNS tumors. Natural killer (NK) cells are CD56 + /CD3- cytotoxic lymphocytes that possess the ability to target tumor cells without prior exposure to the tumor. Previous limitations on the use of NK cells in adoptive cell therapy included obtaining sufficient cell numbers for clinical use. We developed a robust expansion platform that enables the growth of large numbers of NK cells that are effective for clinical use. We show that expanded NK cells can induce cytotoxicity of medulloblastoma. However, there is evidence that tumor derived factors could dampen NK cell cytotoxicity in a clinical setting. One mechanism by which medulloblastoma cells may evade NK cell-mediated killing is secretion of transforming growth factor beta (TGFβ), by the tumor itself as well as by the surrounding milieu. We show that NK cells express TGFβ receptor family members, and that NK cell-mediated cytotoxicity is diminished in the presence of soluble TGFβ. This suggests a possible role of TGFβ in immune suppression. We have identified populations of NK cells that variably express the TGFβ receptor and will overcome resistance to TGFβ-induced immunosuppression. Further studies will explore the mechanisms by which NK cells can escape immunosuppression. An understanding of how NK cells can overcome immunosuppression by medulloblastoma may lead to a pre-clinical model of NK cell cytotoxicity in medulloblastoma, as well as shed light on the use of NK cell adoptive therapy in other pediatric CNS malignancies.

Abstract PL04-01: Developing therapies for Ras driven cancers.

Abstract The Ras pathway is one of the most commonly deregulated pathways in cancer. However Ras-driven tumors are often refractory to conventional therapies and a clinically effective targeted therapy has not yet been developed. Moreover, in some cancers KRAS mutations are used to exclude patients from being treated with specific targeted agents. As such, developing an effective targeted therapy for Ras-driven tumors is an important endeavor. We have been focusing on developing therapies for distinct Ras-driven cancers: Nf1-mutant cancers (nervous system malignancies and melanoma) as well KRas/p53-mutant non-small cell lung cancer (NSCLC). We have been using PI3K/mTOR inhibitors as a platform to develop novel combination therapies and have identified several new combinations, a subset of which are being evaluated in the clinic. We have also been deconstructing the mechanism by which these agents cooperate, which is providing insight into developing useful biomarkers and additional drug combinations. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):PL04-01. Citation Format: Karen Cichowski. Developing therapies for Ras driven cancers. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr PL04-01.

Cost-effectiveness analysis of proton versus photon therapy with respect to risk of growth hormone deficiency.

e17553 Background: Proton therapy has been endorsed as a radiotherapy (RT) modality with the potential to avert many RT associated comorbidities. Currently, few proton centers exist, and no evidence-based data as yet adequately informs allotment of care. Childhood cancer survivors of central nervous system (CNS) malignancies have high prevalences of growth hormone deficiency (GHD) after hypothalamic exposure, notable for its cost of treatment greater than $10,000/year. We propose methodology to help guide proton referral of pediatric patients with CNS tumors through cost-effective analysis comparisons for proton and photon hypothalamic received dose. Methods: A Markov cohort model was designed to assess the expected costs and effectiveness for specific RT doses to the hypothalamus. Patients entered the model receiving proton or photon RT for CNS tumors at four and twelve years of age and were followed for 60 more years of life. Patients could experience two health states: GHD or healthy. Risk of GHD was based on data by Merchant et al. Costs were measured in USD and captured cost of GHD and cost of RT. Cost of proton course relative to photon was estimated at $160K. Effectiveness was measured in quality-adjusted life years (QALYs). The main outcome measure used for comparison was the incremental cost-effectiveness ratio (ICER). We assumed a societal willingness to pay threshold of $50,000/QALY. Results: Data were used to generate tables incorporating the differential cost of proton RT to project ICERs for different combinations of hypothalamic RT dose as displayed in the Table below. Conclusions: Despite the high cost of proton therapy, the cost of GHD alone can yield proton RT a cost-effective (even cost-minimizing) strategy when compared to photon RT. This work provides a guide for identifying a set of patients for which proton therapy is particularly cost-effective. [Table: see text]

Management of Intractable Hiccups

Often thought of as a benign and self-limited condition, hiccups can become persistent or intractable, and thus be associated with substantial morbidity and distress. In such cases, an underlying etiology is often present, and may be overlooked. Debilitating hiccups can present a major challenge to optimal symptom management. Various causes of protracted hiccups have been identified including metabolic abnormalities, central nervous system pathology, malignancy, medications, and disorders attributed to cardiac, pulmonary and gastrointestinal etiologies. We present a case of intractable hiccups in a patient with an advanced hematological malignancy and review specific therapies for the management of persistent hiccups.

The Therapeutic Management of Bleeding and Thrombotic Disorders Complicating CNS Malignancies

Patients with central nervous system (CNS) malignancies have a substantial risk for developing both thrombotic and bleeding disorders. The risk of venous thromboembolism (VTE) is substantially higher in these patients, both in the perioperative period and throughout their disease course. Patients with CNS malignancy harbor a latent hypercoagulability, which predisposes to VTE, as do postoperative immobility, hemiparesis, and other factors. The management of VTE in these patients is complex, given the significant morbidity and mortality associated with intratumoral hemorrhage. In the past, the perceived risk of intracranial hemorrhage limited the use of anticoagulation for the management of VTE with many favoring nonpharmacologic methods for prophylaxis and treatment. Inferior vena cava (IVC) filters have since lost favor at many centers given significant complications, which appear to be more frequent in patients with CNS malignancy. Recent studies have demonstrated safe and efficacious use of anticoagulation in these patients with a low incidence of intracranial hemorrhage. Treatment of established VTE is now recommended in this population with many centers favoring low-molecular-weight heparin (LMWH) versus oral warfarin for short- or long-term treatment. We advocate a multimodality approach utilizing compression stockings, intermittent compression devices, and heparin in the perioperative setting as the best proven method to reduce the risk of VTE. In the absence of a strict contraindication to systemic anticoagulation, such as previous intracranial hemorrhage or profound thrombocytopenia, we recommend LMWH in patients with newly diagnosed VTE and a CNS malignancy.

The oncogenic RNA-binding protein Musashi1 is regulated by tumor suppressor miRNAs

Musashi1 (Msi1) is an evolutionarily conserved RNA-binding protein that has been implicated in processes like stem cell fate, nervous system development, and tumorigenesis via its activities as a specific regulator of translation. While Msi1 is barely detected in normal adult tissue, it has been observed to be highly expressed in numerous tumor types (e.g. breast, colon, medulloblastoma, glioblastoma, and et cetera). Unfortunately, the molecular cues that are responsible for Msi1 upregulation in cancer cells are largely unknown. Tumor suppressor microRNAs (miRNAs) are known for targeting genes with oncogenic properties like Msi1 and for being either downregulated or deleted in tumor tissue. We observed that Msi1 long 3’UTR region is potentially targeted by several tumor suppressor miRNAs (miR-34a, -101, -128, -137, and -138). Western blotting of endogenous Msi1 protein as well as luciferase assays confirmed Msi1 regulation by these tumor suppressor miRNAs. Furthermore, we observed when examining different cellular states that these miRNAs and Msi1 have opposite expression profiles. Cell proliferation inhibition induced by the tumor suppressor miRNAs was partially rescued by Msi1 transgenic expression. We conclude that tumor suppressor miRNAs are direct and influential regulators of Msi1, affecting its expression pattern during tumorigenesis of malignant nervous system tumors.

Spectrum of brain abnormalities detected on whole body F-18 FDG PET/CT in patients undergoing evaluation for non-CNS malignancies

We present the pattern of metabolic brain abnormalities detected in patients undergoing whole body (WB) F-18 flurodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) examination for non-central nervous system (CNS) malignancies. Knowledge of the PET/CT appearance of various intracranial metabolic abnormalities enables correct interpretation of PET scans in oncological patients where differentiation of metastasis from benign intracranial pathologies is important and improves specificity of the PET study. A complete clinical history and correlation with CT and MRI greatly helps in arriving at a correct imaging diagnosis.

Death during hospitalization in patients on chronic hemodialysis

Mortality from various causes is higher in patients on chronic hemodialysis (HD) than in the general population. There is evidence suggesting that some of the deaths in HD patients are preventable. To identify potentially preventable causes of death, we analyzed deaths that occurred in HD patients during hospitalization over a period of 15 years. We performed a retrospective cohort analysis of 410 patients on HD for at least 6 months between 1995 and 2009 (included), who had all their hospitalizations in the same hospital. The patients were classified into 3 groups: Those who died during hospitalization (group A, n=120), those who died away from the hospital (group B, n=135), and those who were alive at the end of the observation period (group C, n=155). Continuous variables were compared between groups by the Kruskall-Wallis statistic. Logistic regression was used to identify predictors of dying during the observation period and predictors of death in the hospital. For the whole HD group of 410 patients, only 9 (2.2%) were women. 59% of the patients had diabetes mellitus. Age at the onset of HD was 65.8 ± 11.5 years and the duration of HD was 34.4 ± 27.9 months. Group A patients had a higher annual rate and duration of hospitalization and a higher Charlson comorbidity index than either of the other 2 groups, and, in comparison with patients in group C, were older at the end of observation and had a shorter duration of HD. Cardiac disease (19.2%), vascular access complications (18.3%), peripheral vascular disease (16.7%), infections (15.8%), trauma (11.7%), central nervous system disease (7.5%), respiratory failure (4.2%), malignancy (3.3%), and gastrointestinal disease (3.3%) were the causes of the last hospitalization in group A. Compared with the patients who died during hospitalization without discontinuing HD, group A patients who discontinued HD had a longer duration of their last hospitalization (52.7 ± 77.7 vs. 14.3 ± 23.8 days, P<0.001). Discontinuation of HD occurred in 80% of the hospitalizations for respiratory failure, 75% of the hospitalizations for malignancy, 57% of the hospitalizations for trauma, and 56% of the hospitalizations for central nervous system disease. Logistic regression identified a high Charlson index, advanced age, and short duration of HD as predictors of death, and an absence of diabetes, high Charlson index, prolonged annual duration of hospitalization, and short distance of the patient's domicile from the dialysis unit as predictors of death in the hospital. A substantial number of hospitalizations leading to the death of HD patients are caused by potentially preventable conditions, including vascular access complications, peripheral vascular disease, and trauma. Implementation of measures preventing these hospitalizations is a worthwhile undertaking.

Monozygotic twins with Neurofibromatosis type 1, concordant phenotype and synchronous development of MPNST and metastasis

BackgroundNeurofibromatosis type 1 is a common autosomal dominant disorder with full penetrance and variable expression. The condition predisposes individuals to the development of malignant nervous system tumours, most frequently Malignant Peripheral Nerve Sheath Tumours (MPNSTs). Previous studies indicate that genetic factors other than mutations in NF1 may be responsible for the condition's variable expression.Case reportHere we present data from a pair of monozygotic twins affected by Neurofibromatosis type 1 resulting from a de novo mutation. Both twins developed a left sciatic plexiform neurofibroma that evolved into MPNST at a similar age and they also developed pulmonary metastasis at the same age. Other concordant traits between the twins were: macrocephaly, psychomotor delay, café-au-lait spots, cutaneous neurofibromas, retroperitoneal, pleural and paraspinal neurofibromas. The main discordant features observed were tibial pseudoarthrosis, pectus carinatum, osteoporosis and thymus hyperplasia.ConclusionsThis is the first report of monozygotic twins with Neurofibromatosis type 1 that develop MPNSTs, the localization and chronological evolution of which, and its metastasis, is concordant in both twins. These cases suggest that the events involved in the transformation of benign plexiform neurofibromas to MPNSTs in Neurofibromatosis type 1, follow a spatiotemporally programme that is influenced by heritable factors other than NF1 mutations.

Abstract 4194: Interrogation of glioma ontogeny using mouse models

Abstract Gliomas are a group of primary brain tumours that comprise almost 60% of total human central nervous system (CNS) malignancies. The malignant Grade IV Glioblastoma Multiforme (GBM) being the most common, is associated with a median survival of ∼16mths. Gliomas are recognized as highly heterogeneous tumors, however, the phenotypic differences between types and grades of gliomas have not been explained solely on the grounds of an oncogenic stimuli, thus it is possible that this variability might reflect inherent characteristics of the tumour cell of origin. For several decades it was widely assumed that differentiated glia were the only cells capable of transformation as the adult brain was thought to be mitotically inactive, however demonstration of functional neurogenesis in the adult brain provided new possibilities for the candidate cell of origin of CNS neoplasms. Currently, controversy exits on whether the initial transformed cell is a differentiated astrocyte, progenitor or neural stem cell. Putative Cancer stem cells (CSCs), which have features of normal stem cell (self-renewal, multi-potent differentiation) plus the ability to recapitulate the tumor phenotype in vivo in small numbers, have been identified from a variety of solid human cancers including GBMs. However, it is still to be determined whether the appearance of brain tumor stem cells is the cause or consequence of tumor initiation and progression. Using a novel mouse model we will study the gliomagenic potential of different glial precursors at different developmental stages. Towards this objective, a conditional transgenic system which integrates Cre-Loxp mediated and Tet- regulated expression, will be utilized to drive expression of K-Ras to Nestin, BLBP and GFAP positive cells, which target Neural Stem cells, Radial glial cells and terminally differentiated astrocytes, respectively. Specifically, our interests are in the similarities or differences in the incidence, location, subtype, grade, proliferation, apoptosis and angiogenic status of the expected gliomas that result amongst these different transgenics. All of the transgenics have been derived, and control experiments confirm that expression of Kras is dependent on both Cre excision and Dox administration, as shown by Reverse Transcriptase-PCR and Ras GTP pull-downs. If astroglial progenitors are more gliomagenic, we would expect the Blbp-Cre or Nestin-Cre transgenics to result in increased number, more periventricular and potentially different glioma subtypes. These series of experiments will allow us to determine the gliomagenic potential (incidence, subtype, grade) in mature vs. glial progenitor cell compartments at different developmental time-points. The ability to manipulate GEMs developmentally and spatially will allow us to directly interrogate the ontogeny of gliomas. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4194.

The paradoxical effect of targeted antivascular agents in the therapy of CNS malignancies

2013 Background: The rationale of vascular targeted agents (i.e., inhibitors of vascular endothelial growth factors [VEGF] or endothelial intergrins) in the therapy of central nervous system (CNS) malignancies is based upon the concept that normalization of tumor vasculature, with a decrease in tumor interstitial pressure, will improve access of cytoreductive drugs. However, previous studies in our laboratory have raised the serious concern that these agents rapidly normalize the blood-brain barrier (BBB) and therefore may result in restoration of the low permeability characteristics of the BBB. Methods: To evaluate this, we studied the effects of bevacizumab, an anti-VEGF agent on tumor vasculature by MRI, using gadolinium-enhanced T1 weighted sequences to assess permeability and the blood pool agent ferumoxytol to assess blood volume. Patient imaging studies were done on IRB approved protocols. Results: Utilizing two rat brain tumor models, we documented that bevacizumab rapidly decreases tumor enhancement, a pattern equivalent to administration of high dose steroid therapy. Correlative studies in rats and humans exploiting T2 weighted imaging, demonstrated resolution of tumor enhancement with occasional concomitant increase in tumor volume. In a parallel evaluation, pseudo-progression was seen in 9 of 14 glioblastoma patients treated with combined chemo-radiation. These inflammatory responses to treatment, when examined by dynamic MRI, were associated with a transient increase in tumor permeability and decreased cerebral blood volume. This increase could be blocked or reduced by decreasing vascular permeability with bevacizumab. Conclusions: These animal and human studies provide evidence that anti-vascular agents have a steroid-like effect; and in the CNS, may result in reduced delivery of cytoreductive agents to the tumor, thereby compromising standard chemo-radiotherapy. [Table: see text]

Cancer stem cells

The Sixteenth International Symposium of the Hiroshima Cancer Seminar (HCS) Foundation was held on October 22 2006 at the International Conference Center, Hiroshima. The symposium consisted of 10 special lectures and 23 free paper presentations for a poster session. About 230 people were present and actively discussed cancer stem cells. Prior to this symposium, an Open Lecture to the public by HCS and the Japan Society for Dying with Dignity was held on October 21 where Shigehito Yamawaki (Hiroshima University, Hiroshima) and Kazuko Hamanaka (Hamanaka Dermatological Clinic, Hiroshisma) spoke about Psycho-oncology and Breast Cancer to more than 260 people. Eiichi Tahara (Hiroshima Cancer Seminar Foundation), Chairman of the Organizing Committee of the Sixteenth International Symposium, and Chairman of the HCS Foundation, gave an opening address. Tahara introduced a brief background and the purpose of this series of symposia. Since the establishment of the HCS Foundation in 1992, annual international symposia are organized to create an opportunity for basic scientists and clinical researchers to exchange ideas for cancer research, cancer prevention and cancer therapy. This year, the organizing committee planned to explore the important issue of cancer stem cells. Stem cells have a critical role not only in the generation of new populations of normal cells but also in the development of tumors. The balance between self-renewal and differentiation is strictly regulated to maintain normal stem cell pools and to generate the required supply of fully differentiated cells. Recent evidence has suggested that a subset of cancer cells within the tumor, so-called cancer stem cells, may drive the growth and progression of the tumor. Eradication of cancer stem cells may be essential to a cure for cancer. Advances in our knowledge that regulate proliferation, self-renewal, survival and differentiation of cancer stem cells and normal stem cells may shed light on the mechanism that leads to cancer and perhaps improve cancer treatment. The participants will be able to profit by exchanging ideas and learning from the informative presentations and discussions, and will contribute to our understanding of stem cells in relation to cancer development and treatment.

Primitive neuroectodermal tumor presenting as a neck mass

Summary Primitive neuroectodermal tumors (PNET) comprise a family of the small blue round cell tumors. These neural crest origin tumors affect central nervous system (CNS) or peripheral tissues and are characterized by the set of unique chromosomal translocations and MIC-2 antigenic expression. PNET of the CNS are the most common malignant nervous system tumors of childhood. Reports of the peripheral PNET, which can present in the head and neck region are extremely limited. We present a case of the pediatric peripheral primitive neuroectodermal tumor manifested as an acute onset of neck swelling and ascending flaccid paralysis after routine first year immunizations.

Predictors of Mortality in Acute Renal Failure in a Developing Country: A Prospective Study

Acute renal failure (ARF) occurs in wide range of conditions, making the evaluation of its prognosis a difficult task. Data regarding prognostic factors in ARF in a general population in developing countries are scarce. The objective of the study was to describe predictors of mortality in ARF that are relevant in the developing world. This prospective study was carried out over a one-year period; all hospitalized adults with ARF were included in the study. Predictors of mortality studied included causes of ARF, pre-existing diseases, and severity as well as complications of ARF. Of 33,301 patients admitted during the study period, 294 (0.88%) were either admitted with or developed ARF after hospitalization. Mean age was 43.9 ± 16.9 (18–86 yrs). Sepsis was the most common cause (63.26%). Pre-existing diseases like cardiovascular disease (CVSD), respiratory system disease (RSD), central nervous system disease (CNSD), hypertension, diabetet mellitus (DM), and malignancy were significantly higher in elderly as compared to younger patients. On univariate analysis sepsis, hypoperfusion as a cause of ARF and hospital-acquired ARF were associated with higher mortality. Pre-existing diseases viz. RSD, CVSD, CNSD, and DM had higher mortality. Among the severity and complications of ARF, oliguria, bleeding and infection during the course of ARF and critical illness were predictors of poor outcome. Age >60 yrs was associated with significantly higher mortality. However, on multivariate analysis, only critical illness (odds ratio 37.3), age > 60 years (odds ratio of 5.6), and sepsis as cause of ARF (odds ratio of 2.6) were found to be independent predictors of mortality.

Sperm protein 17 is expressed in human nervous system tumours

BackgroundHuman sperm protein 17 (Sp17) is a highly conserved protein that was originally isolated from a rabbit epididymal sperm membrane and testis membrane pellet. It has recently been included in the cancer/testis (CT) antigen family, and shown to be expressed in multiple myeloma and ovarian cancer. We investigated its immunolocalisation in specimens of nervous system (NS) malignancies, in order to establish its usefulness as a target for tumour-vaccine strategies.MethodsThe expression of Sp17 was assessed by means of a standardised immunohistochemical procedure [(mAb/antigen) MF1/Sp17] in formalin-fixed and paraffin embedded surgical specimens of NS malignancies, including 28 neuroectodermal primary tumours (6 astrocytomas, 16 glioblastoma multiforme, 5 oligodendrogliomas, and 1 ependymoma), 25 meningeal tumours, and five peripheral nerve sheath tumours (4 schwannomas, and 1 neurofibroma),.ResultsA number of neuroectodermal (21%) and meningeal tumours (4%) were found heterogeneously immunopositive for Sp17. None of the peripheral nerve sheath tumours was immunopositive for Sp17. The expression pattern was heterogeneous in all of the positive samples, and did not correlate with the degree of malignancy.ConclusionThe frequency of expression and non-uniform cell distribution of Sp17 suggest that it cannot be used as a unique immunotherapeutic target in NS cancer. However, our results do show the immunolocalisation of Sp17 in a proportion of NS tumour cells, but not in their non-pathological counterparts. The emerging complex function of Sp17 makes further studies necessary to clarify the link between it and immunopositive cells.

Neurofibromatosis type 1 — a model for nervous system tumour formation?

Neurofibromatosis type 1 (NF1) is a common genetic condition in which affected individuals develop benign and malignant nervous system tumours. Genetically engineered mouse (GEM) models of these NF1-associated nervous system tumours recapitulate several of the unique clinical aspects of the disease. Moreover, these Nf1 GEM models allow for a direct examination of the earliest stages of tumour evolution, including the contributions that Nf1(+/-) cellular elements and cooperating genetic changes make to facilitate the transition from the pre-neoplastic to the neoplastic state and, in some cases, to promote malignant progression.

The role of protein kinase C-α in malignancies of the nervous system and implications for the clinical development of the specific PKC-α inhibitor aprinocarsen (Review)

Antisense oligonucleotide (ASO) technology offers a novel approach for the development of anti-cancer drugs. For example, the ASO aprinocarsen has been developed to specifically inhibit the intracellular signal transduction protein, protein kinase C-alpha (PKC-alpha). The clinical development of such specific or "new targeted" agents in cancer requires a comprehensive understanding of the target protein. This understanding is expected to improve the identification of patients who most likely will benefit from treatment with a specific inhibitor, such as aprinocarsen. In order to better understand the role of PKC-alpha in nervous system malignancies we here review the published literature on PKC-alpha expression in nervous system tumors, including glioblastoma multiforme. In pre-clinical experiments aprinocarsen had demonstrated anti-tumor activity, in particular in animal models of glioblastoma. Thus, clinical study CS10 with aprinocarsen was undertaken in patients with central nervous system (CNS) malignancies. The results of this study and considerations for future clinical studies in CNS tumors are reviewed.

Determination of HER-2/Neu Overexpression and Clinical Predictors of Survival in a Cohort of 347 Patients with Primary Malignant Brain Tumors

Introduction. HER-2/neu overexpression has been associated with poor prognosis in a variety of malignancies. The extent and relevance of HER-2/neu overexpression in human central nervous system (CNS) malignancies is unclear. We retrospectively analyzed a large cohort of patients with primary malignant brain tumors to evaluate the role of HER-2/neu overexpression, clinical characteristics at presentation, and other predisposing factors as predictors of survival. Materials and Methods. Records of 347 adult patients (193 males, 154 females) diagnosed and followed between 1986 and 2001 with a biopsy-proven diagnosis of a primary malignant brain tumor at a tertiary care oncology center were reviewed. Archival pathologic samples were analyzed for HER-2/neu overexpression using the Hercep immunohistochemical (IHC) assay (DAKO). A score of 2 + or greater on the assay was considered positive for HER-2/neu overexpression. Mortality and its predictors were evaluated using multiple logistic regression. (This study was approved and reviewed by the Institutional Review Board Committee [IRB] of University of North Dakota School of Medicine and Health Sciences.) Results. Among the 347 adult patients with a mean age of 53 years (range; 41–73 years), overall mean survival was 23 months (range; 0–151 months). It was found that 10.4% of the archival pathologic samples showed presence of HER-2/neu overexpression by IHC. The HER-2/neu overexpression predicted significantly increased mortality [p = 0.01, analysis of variance (ANOVA)]. Other clinical predictors associated with increased mortality included site of tumor (occipital and parietal lobes) (p = 0.02, ANOVA), tumor histology (glioblastoma) (p < 0.01, ANOVA), and presenting symptom (nausea/vomiting) (p < 0.01, ANOVA). Also, there was a higher incidence of associated primary malignancies (outside the CNS) in the HER-2/neu overexpression group (30% vs. 7%). Conclusions. HER-2/neu overexpression seen in 10.4 % appears to predict a slight increased mortality in patients with primary malignant brain tumors, especially glioblastoma multiforme, and is associated with a high incidence of a second primary malignancy outside the CNS. Additionally, our data suggests that other clinical variables were predictive of increased mortality, including tumor location (occipital), histology (glioblastoma), and presenting symptoms (nausea/vomiting). The large, heterogeneous sample employed in our study allows more definitive conclusions to be made with regard to the usefulness of HER-2/neu and other clinical predictors of survival in patients with primary brain tumors.

CpG island methylation status and mutation analysis of the RB1 gene essential promoter region and protein-binding pocket domain in nervous system tumours.

A series of 136 nervous system tumours were studied to determine the methylation status of the CpG island contained within the promoter region of the RB1 gene, as well as mutation analysis of the essential promoter region and exons 20–24 (and surrounding intronic regions) coding for the protein-binding pocket domain. Methylation of the RB1 CpG island was detected in 26 samples corresponding to nine glioblastomas, three anaplastic astrocytomas, one mixed oligo-astrocytoma, one ependymoma, two medulloblastomas, two primary central nervous system lymphomas, two neurofibrosarcomas, and six brain metastasis from solid tumours. No inactivating mutations were found within the RB1 promoter region, whereas one glioblastoma and one oligodendroglioma displayed similar sequence variations consisting of 12 and 8 base pair deletions at intron 21. These results suggest that RB1 CpG island hypermethylation is a common epigenetic event that is associated with the development of malignant nervous system tumours.