Tumors Of Neuroectodermal Origin Research Articles

Co-Expression of an IL-15 Superagonist Facilitates Self-Enrichment of GD2-Targeted CAR-NK Cells and Mediates Potent Cell Killing in the Absence of IL-2.

In contrast to T lymphocytes, natural killer (NK) cells do not require prior sensitization but are rapidly activated upon encountering virally infected or neoplastic cells. In addition, NK cells can be safely applied in an allogeneic setting, making them important effector cells for the development of off-the-shelf therapeutics for adoptive cancer immunotherapy. To further enhance their therapeutic potential, here, we engineered continuously expanding NK-92 cells as a clinically relevant model to express a humanized second-generation chimeric antigen receptor (CAR) with a composite CD28-CD3ζ signaling domain (hu14.18.28.z) that targets the disialoganglioside GD2, which is expressed at high levels by neuroblastoma cells and other tumors of neuroectodermal origin. In a separate approach, we fused an IL-15 superagonist (RD-IL15) to the GD2-CAR via a P2A processing site. Lentivirally transduced NK-92/hu14.18.28.z and NK-92/hu14.18.28.z_RD-IL15 cells both displayed high and stable CAR surface expression and specific cytotoxicity toward GD2-positive tumor cells. GD2-CAR NK cells carrying the RD-IL15 construct in addition expressed the IL-15 superagonist, resulting in self-enrichment and targeted cell killing in the absence of exogenous IL-2. Furthermore, co-culture with RD-IL15-secreting GD2-CAR NK cells markedly enhanced proliferation and cytotoxicity of bystander immune cells in a paracrine manner. Our results demonstrate that GD2-CAR NK cells co-expressing the IL-15 superagonist mediate potent direct and indirect antitumor effects, suggesting this strategy as a promising approach for the further development of functionally enhanced cellular therapeutics.

전정수도관 확장 증후군 환자에서 발견된 내림프낭 종양 1예

An endolymphatic sac tumor (ELST) is a tumor of neuroectodermal origin. Although several cases have been reported in Korea, it is known to be very rare. Clinically, it grows slowly but shows an aggressive pattern accompanied by bone destruction pathologically. As the tumor grows, it shows symptoms due to endolymphatic hydrops such as hearing loss, tinnitus, and dizziness. In this paper, we report a case in which an ELST was found in a patient suffering from profound sensorineural hearing loss, tinnitus, and dizziness, who turned out to be an enlarged vestibular aqueduct syn-drome.

T CELLS ENGINEERED TO EXPRESS A CAR ANTI-GD2 AND THE COSTIMULATORY MOLECULE GITRL ERADICATE GLIOBLASTOMA CELLS AND ARE IFNY PRODUCERS

The adoptive transfer of T lymphocytes expressing chimeric antigen receptors (CAR) has resulted in impressive complete remission rates in B-cell malignancies. However, the therapeutic efficacy of CAR-T cells is still low or non-existent against solid tumors, which make up the vast majority of neoplasms. One of the main reasons for this failure is the presence of ligands and immunosuppressive cells in the tumor microenvironment. The complete activation of T cells requires the engagement of costimulatory molecules whose expression is temporally segregated and whose nature of biochemical signals are complementary. This is the case of CD28, expressed constitutively, and GITR, expressed right after the initial activation of T cells. Therefore, our hypothesis is that the combined expression of a CAR containing the costimulatory domain CD28 and the GITR ligand (GITRL) will potentiate the antineoplastic action of CAR-T cells. In addition to providing complementary costimulatory signals for effector CAR-T cells, GITRL can suppress the action of regulatory T cells in the tumor microenvironment, thus possibly reducing local immunosuppression. Then, the aim of this study is to evaluate the therapeutic efficiency of anti-GD2 CAR-T cells coexpressing GITRL in a preclinical model of glioblastoma multiforme. In this project, we used as a model a CAR against the ganglioside GD2, which is highly immunogenic and expressed in tumors of neuroectodermal origin, such as glioblastoma. To test our hypothesis, we generated two lentiviral vectors to express CAR anti-GD2 and another one coexpressing GITRL as a costimulatory domain. After that, we produced lentiviral particles to transduced human T lymphocytes and we detected CAR expression in the T cells transduced with both vectors. To verify the functional activity of these CAR-T cells, we performed a coculture assay against T98G cell line, which express high levels of GD2, and HCT-166 cell, that dont express. These cell lines were previously modified to express luciferase to enable the analysis through bioluminescence imaging. We tested two ratios of effector:target cells (E:T) and we observed that both CAR.GD2 and CAR.GD2-GITRL T cells demonstrated powerful capacity of lysis only against cells that express GD2. Then, we interrogated whether these CAR-T cells could keep their lysis capacity after additional rechallenges. So, another two rounds of coculture were performed and the cells showed persistence of cytotoxicity. In addition, tumor cell killing was associated with secretion of IFNy as evaluated by ELISA quantification of coculture supernatants. These data encouraged us to compare the antineoplastic activity and persistence of CAR-T cells anti-GD2 in an orthotopic pre-clinical model of glioblastoma multiforme, which is under way. We expect that the potential results of this project will foster the development of a new advanced cellular immunotherapy strategy for the treatment of solid GD2+ neoplasms and will pave the way to increase the antineoplastic efficiency of CAR-T cells against other malignancies.

EWING SARCOMA OF MAXILLA IN A CHILD: CASE REPORT OF A RARE TUMOR IN THE HEAD AND NECK REGION

Ewing sarcoma (ES) is a tumor of neuroectodermal origin. ES mainly affects children and adolescents and is rare in head and neck region. A 3-year-old boy was referred for investigation of swelling in the maxilla. According to his mother, 8 days prior to our consultation, the patient was evaluated by a doctor who prescribed amoxicillin-clavulanate. However, the lesion did not regress and increased over time. Intraoral examination revealed a mass in the right posterior region of the maxilla, extending to the hard palate and tuber. Indefinite limits, softened consistency, and painful symptoms were observed. Panoramic radiography revealed bone destruction with ill-defined limits in the right maxilla. The diagnostic hypotheses included lymphoma and sarcoma. A biopsy was performed, and microscopic evaluation showed a malignant neoplasm composed by small, round, and blue cells. Immunohistochemistry staining was positive for CD99. Clinical and immunohistochemical features favored the diagnosis of ES. The patient was referred for oncological treatment.

Expression Analysis of GD2 by Immunohistochemistry in Invasive Breast Carcinoma: Clinical and Pathologic Correlation.

The glycosphingolipid disialoganglioside GD2 is a cell surface-associated antigen expressed on tumors of neuroectodermal origin that serves as a target of immunotherapy in select cancer types. Information about the expression of GD2 in breast cancer is limited. In the present study, we investigate the utility of GD2 as a potential biomarker for targeted treatment. The study cohort consists of 386 breast carcinomas of several histologic types. GD2 expression was assessed in both whole tumor sections and tissue microarrays with anti-GD2 3F8 monoclonal antibody immunohistochemistry and correlated with clinicopathologic features and survival outcomes. A total of 134 (35%) breast carcinomas were positive for GD2, with a median H-score of 100. 3F8 staining displayed granular and predominantly cytoplasmic or perinuclear patterns, which was confined to the neoplastic tissue in nearly all cases. GD2 positivity was significantly associated with tumor histologic type (P=0.0015), low grade (P<0.0001), estrogen receptor positivity (P<0.0001), low stage (P=0.0014), and multifocality (P=0.022). Event-free survival and overall survival of patients with GD2-positive and GD2-negative tumors were not significantly different. Our results support further assessment of GD2 using the 3F8 antibody as a predictive and prognostic biomarker in breast cancer.

Phase I/II trial of intratumoral administration of hu14.18-IL2, with local radiation, nivolumab, and ipilimumab in subjects with advanced melanoma.

TPS9591 Background: We are studying an intratumoral (IT) in situ vaccine strategy using the GD2-reactive hu14.18-IL2 immunocytokine (hu-IC) to convert the injected tumor into a site of enhanced tumor antigen presentation, as has been shown in mice. Hu-IC is a humanized monoclonal antibody (mAb) covalently linked to two molecules of IL-2 at the Fc region. The hu14.18 mAb recognizes GD2, a disialoganglioside found in tumors of neuroectodermal origin. We previously studied intravenous (IV) hu-IC and reported immune activation and reversible toxicities (1). Surgery to resect recurrent stage III or stage IV melanoma combined with 3 courses of IV hu-IC resulted in prolonged tumor-free survival in some patients (2). Murine GD2+ tumor models showed enhanced antitumor activity and recruitment of T cells using hu-IC IT versus IV (3). In these models, the combination of radiation therapy (RT) followed by IT hu-IC dramatically potentiates the antitumor response and enhanced response to immune checkpoint blockade (4). Biological samples (blood and tumor) will be interrogated to identify biological mechanisms and develop biomarkers for future testing. Methods: This outpatient phase I/II trial uses a 3 + 3 design to determine maximum tolerated or maximum administered dose of IT hu-IC (planned dose level: 2 mg/m2/day; de-escalation dose level: 1 mg/m2/day) when given alone (Phase 1A: 3-12 patients), after RT (Phase 1B: 6-12 patients), after RT and in combination with nivolumab (Phase 1C: 6-12 patients), and after RT and in combination with nivolumab and ipilimumab (Phase 1D: 31-34 patients). The trial will evaluate safety, antitumor activity, and immunologic endpoints and includes an expanded Phase II cohort (Phase 1D). The IT injections (once daily x 3 days) are delivered every 21 days for 4 cycles and can then continue every 28 days for up to 13 cycles if there is response/stable disease and residual injectable tumor. Key inclusion criteria: 1) histologically proven, malignant melanoma that is advanced (Stage IV) or surgically incurable; 2) at least 1 (preferably 2) sites of disease amenable to safe repeated IT injections; and 3) must have received or declined at least one FDA approved therapy, either in the adjuvant setting or for metastatic disease, with an impact on survival. Two subjects have been accrued into Phase IA as of 2-4-2021.

MAGNETIC RESONANCE IMAGING FEATURES OF PEDIATRIC MEDULLOBLASTOMA IN RELATION TO PATHOLOGICAL SUBTYPES

Medulloblastma (MB) is a highly malignant (WHO grade IV), primitive cerebellar tumor of neuroectodermal origin. Medulloblastomas have been classified, based on histopathological, biological, and clinical characteristics, into classic medulloblastoma (CMB), desmoplastic nodular medulloblastoma (DNMB), medulloblastoma with extensive nodularity and anaplastic/large cell medulloblastoma.Medulloblastoma shows heterogenous tumor features in each subtype. Based on these heterogeneity, magnetic resonance imaging (MRI) could differentiate pathological subtypes according to each imaging features. This study aimed to assess the relation between Magnetic Resonance imaging features of pediatric medulloblastoma and pathological subtypes to improve treatment outcomes of the disease.All patients were subjected to the following:o History taking.o Thorough clinical examination.o Conventional MRI study of the brain.o Susceptibility-weighted imaging of the brain with post processing phase image. The study was applied on a 1.5 Tesla Magnetom Avanto Siemens (left handed system) machine using conventional MRI sequences in addition to DWI. Imaging evaluation depended on tumor location, tumor enhancement and degree of tumor restriction on DWI. Histo-pathology remains the gold standard in differentiating subtypes, however we can use MRI in early prediction of the subtypes and early planning for their management, regardless MRI very important role in post-surgical assessment and follow up.

Targeting glycosphingolipids for cancer immunotherapy.

Aberrant expression of glycosphingolipids (GSLs) is a unique feature of cancer and stromal cells in tumor microenvironments. Although the impact of GSLs on tumor progression remains largely unclear, anticancer immunotherapies directed against GSLs are attracting growing attention. Here, we focus on GD2, a disialoganglioside expressed in tumors of neuroectodermal origin, and Globo H ceramide (GHCer), the most prevalent cancer-associated GSL overexpressed in a variety of epithelial cancers. We first summarize recent advances on our understanding of GD2 and GHCer biology and then discuss the clinical development of the first immunotherapeutic agent targeting a glycolipid, the GD2-specific antibody dinutuximab, its approved indications, and new strategies to improve its efficacy for neuroblastoma. Next, we review ongoing clinical trials on Globo H-targeted immunotherapeutics. We end with highlighting how these studies provide sound scientific rationales for targeting GSLs in cancer and may facilitate a rational design of new GSL-targeted anticancer therapeutics.

Characterization of New Human Glioblastoma Cell Lines

Glioblastomas are tumors of neuroectodermal origin with a high degree of diversity. Tumor cells isolated from the surgical material of patients with glioblastomas are heterogeneous populations varying in morphology, phenotype, and genetic characteristics. This paper presents a description of two new glioblastoma cell lines, R1 and T2, isolated from tumor tissue of patients in 2010. We investigated their morphological and cytochemical cell characteristics and the expression of neuronal, mesenchymal, and endothelial markers, as well as the activity of genes encoding a number of growth factors, extracellular matrix proteins, and intracellular proteins typical for cells of mesenchymal origin. R1 and T2 cell lines are morphologically different. T2 cell line was characterized by the presence of multinuclear cells. In terms of the expression of β-tubulin III, MGMT, and p53 protein, R1 cell line was more heterogeneous than T2. R1 and T2 glioblastoma cell lines also differed in the presence and ratio of cell populations with mesenchymal, neuronal, and endothelial markers. Thus, neuronal markers CD133/2 and CD56 were detected only on R1 cells. Both lines were characterized by high activity of growth factor genes TGFβ1, VEGF, and FGF2(b), lower activity of EGF, and high expression of THBS1 and αSMA genes. However, the activity of most of the genes under study in R1 cells was higher than in T2 cells. The greatest difference lay in the expression of HGF, FAP, and TNC. Comparison of two new glioblastoma cell lines, R1 and T2, with the continuously cultivated lines А172 and T98G showed that R1 line had remarkable similarity with A172, while T2 glioblastoma resembled T98G cells. Apparently, the differences between R1 and T2 cell lines are determined by the properties of the initial tumors rather than the time of the cell cultivation.

ФУНКЦІОНАЛЬНІ ХАРАКТЕРИСТИКИ ЦИРКУЛЮЮЧИХ ФАГОЦИТІВ ЩУРІВ ІЗ ГЛІОМОЮ С6

Gliomas, tumors of the central nervous system, are a heterogeneous group of neoplasms of neuroectodermal origin. Gliomas are the most common primary brain tumors and cmprise about 80% of all malignant neoplasms of this location. The growth of malignant glioma is accompanied by the development of local and systemic immunosuppression that is a distinctive characteristics of the disease. At the early stages of tumor growth, glioma cells secrete numerous chemokines, cytokines and other biologically active mediators that contribute to the infiltration of tumor tissue by immune cells: resident microglial cells, as well as monocytes, granulocytes, T-cells, B-cells etc. Tumor-associated phagocytes comprise most significant part of the immunocytes in the microenvironment of malignant gliomas. These cells play a leading role in the development of local immunosuppression. The triggers of systemic immunosuppression, as well as the relationship between local and systemic immunosuppression is virtually unexplored and requires an in-depth study of the functional characteristics of circulating cells of the immune system. The aim of this work was to determine the phenotypic and functional characteristics of circulating phagocytes in rats with C6 glioma. Metabolic and phenotypic indices of circulating phagocytes were examined at different time point of tumor growth. It has been established that the late stages of C6 glioma growth in rats are associated with changes in the functional characteristics of peripheral blood mono- and polymorphonuclear phagocytes: a decrease in oxidative metabolism, an increase in phagocytic activity along with an increase CD206 expression. Taken together these alteration are characteristic for alternatively activated phagocytes that can participate in the development of glioma-associated systemic immunosupression. Keywords.

Supratentorial primitive neuroectodermal tumor with thoracic metastasis: Case report

Primary intracranial primitive neuroectodermal tumors are rare malignant small cell embryonal neoplasms of neuroectodermal origin, accounting for approximately 2.5% of childhood brain tumors and 0.46% of those in adults. There are very few reported cases of extracranial metastases from these tumors. We report a very rare case of primary intracranial primitive neuroectodermal tumor with metastasis to the lungs.

Primitive Neuroectodermal Tumor of Ovary in a Young Lady, Confirmed with Molecular and Cytogenetic Results—A Rare Case Report with a Diagnostic and Therapeutic Challenge

Primitive neuroectodermal tumor (PNET) is a small round cell tumor of neuroectodermal origin. It is the most differentiated form of PNET/Ewing’s family of tumors (EFT) [1]. It is the second most common sarcoma among children and usually occurs in the bone and soft tissues [2]. Ewing’s sarcoma/ PNET is characterized by a t (11; 22) (q24; q12) chromosomal translocation that leads to formation of a chimeric transcript EWS-FLI1 in 85% cases, presence of which confirms its diagnosis, especially at non-conventional sites [3]. It has been uncommonly documented at sites other than musculoskeletal system, such as kidneys [4]. PNET has been rarely documented in the female genital system, including ovary, with only few cases confirmed by molecular and / or molecular cytogenetic analysis [5–12]. Herein, we present an uncommon case of PNET involving ovary in a young lady, who presented with a pelvic mass. The diagnostic and therapeutic implications are discussed herewith.

Cribriform neuroepithelial tumour: novel clinicopathological, ultrastructural and cytogenetic findings

Cribriform neuroepithelial tumour (CRINET) is a recently described tumour of neuroectodermal origin with distinct cribriform non-rhabdoid histological features and loss of INI1 protein expression [2]. The INI protein is encoded by the hSNF/INI1/BAF47 (SMARCB1) tumour suppressor gene, which is located on chromosome 22q.11.2 [4]. The gene product is a subunit of the adenosine triphosphate (ATP)-dependent SWI/SNF chromatin-remodelling complex, which normally regulates cell proliferation [7, 8]. Biallelic loss of SMARCB1 is seen in peripheral rhabdoid tumours, atypical teratoid/rhabdoid tumours (AT/RTs) of the central nervous system as well as familial schwannomatosis [1, 3, 10]. In contrast to AT/RTs, CRINETs lack rhabdoid tumour cells, and may be associated with a more favourable prognosis [2]. Here, we present a third case of CRINET with complete clinicopathological, ultrastructural and cytogenetic features. A 21-month-old boy presented with a 1-week history of imbalance, discoordination, recurrent falls and torticollis, as well as progressive nausea, vomiting and irritability. The family history was significant for possible ependymomas in the maternal great uncle and two maternal second cousins. Computed tomography (CT) and magnetic resonance (MR) imaging demonstrated a large heterogeneously enhancing mass within the fourth ventricle extending into the left cerebellopontine angle and associated with mild hydrocephalus and brainstem compression (Fig. 1a). The patient experienced an acute neurological deterioration and an urgent CT scan demonstrated haemorrhage into the tumour causing obliteration of the fourth ventricle and acute obstructive hydrocephalus (Fig. 1b). The patient underwent an urgent posterior fossa decompression and gross total tumour resection. Post-operatively, he underwent chemotherapy according to the Children’s Oncology Group (COG) 99703 protocol, which includes cisplatin, cyclophosphamide, etoposide and vincristine with stem cell rescue followed by the maintenance chemotherapy with tamoxifen and cis-retinoic acid. Fourteen months following the presentation, he remains in remission. On histology, the specimen showed a cellular neoplasm, in which mitotic activity was scattered and MIB-1 index was high. Cells were found to have oval nuclei with occasional notable nucleoli (Fig. 2a). Cuboidal to polygonal cells were arranged in sheets and chords occasionally forming tubule-like or rosette-like structures. The specimen contained punched out foci of necrosis. Typical rhabdoid cells were not appreciated. Immunohistochemistry showed neoplastic cells to be non-reactive for BAF47 (Fig. 2b). These cells were reactive for Vimentin, S100, beta-catenin (nucleus and cytoplasm), c-erbB2 and MAP2. Isolated cells reacted for p53, GFAP, cytokeratin (rare), EMA (scattered foci) and SMA (usually vasocentric). Studies for synaptophysin were negative. A summary of the current and previous immunohistochemical findings is presented in Table 1. Electron G. M. Ibrahim P. B. Dirks Division of Neurosurgery, The Hospital for Sick Children, Toronto, ON, Canada

Annexin A2 Is a Molecular Target for TM601, a Peptide with Tumor-targeting and Anti-angiogenic Effects

TM601 is a synthetic form of chlorotoxin, a 36-amino acid peptide derived from the venom of the Israeli scorpion, Leirius quinquestriatus, initially found to specifically bind and inhibit the migration of glioma cells in culture. Subsequent studies demonstrated specific in vitro binding to additional tumor cell lines. Recently, we demonstrated that proliferating human vascular endothelial cells are the only normal cell line tested that exhibits specific binding to TM601. Here, we identify annexin A2 as a novel binding partner for TM601 in multiple human tumor cell lines and human umbilical vein endothelial cell (HUVEC). We demonstrate that the surface binding of TM601 to the pancreatic tumor cell line Panc-1 is dependent on the expression of annexin A2. Identification of annexin A2 as a binding partner for TM601 is also consistent with the anti-angiogenic effects of TM601. Annexin A2 functions in angiogenesis by binding to tissue plasminogen activator and regulating plasminogen activation on vascular endothelial cells. We demonstrate that in HUVECs, TM601 inhibits both vascular endothelial growth factor- and basic fibroblast growth factor-induced tissue plasminogen activator activation, which is required for activation of plasminogen to plasmin. Consistent with inhibition of cell surface protease activity, TM601 also inhibits platelet-derived growth factor-C induced trans-well migration of both HUVEC and U373-MG glioma cells.

Nestin expression in human tumors and tumor cell lines.

The aim of this review is to summarize current knowledge on nestin expression in human tumors and corresponding tumor cell lines. Nestin belongs to class VI of the intermediate filaments and it is expressed primarily in mammalian nervous tissue during embryonic development. In adults, nestin occurs only in a small subset of cells and tissues. This protein has been observed in the subventricular zone of the adult mammalian brain, where neurogenesis is localized. Nestin expression has also been detected in various types of human solid tumors, as well as in the corresponding established cell lines. This article provides an up-to-date overview of tumors in which nestin has been found. Another aim of this review is to summarize recent findings on the intracellular localization of nestin in human tumor cells, especially with regard to the possible correlation between nestin expression and the malignant phenotype of transformed cells. Nestin expression in vascular endothelial cells during angiogenesis is also reviewed. Special attention is paid to the detection of nestin in cancer stem cells because this protein, together with the CD133 surface molecule, is considered to be a possible marker of cancer stem cells, especially in tumors of neuroectodermal origin.

Inhibition of Tumor‐Cell Invasion with Chlorotoxin‐Bound Superparamagnetic Nanoparticles

Nanoparticles have been investigated as drug delivery vehicles, contrast agents, and multifunctional devices for patient care. Current nanoparticle-based therapeutic strategies for cancer treatment are mainly based on delivery of chemotherapeutic agents to induce apoptosis or DNA/siRNA to regulate oncogene expression. Here, a nanoparticle system that demonstrates an alternative approach to the treatment of cancers through the inhibition of cell invasion, while serving as a magnetic resonance and optical imaging contrast agent, is presented. The nanoparticle comprises an iron oxide nanoparticle core conjugated with an amine-functionalized poly(ethylene glycol) silane and a small peptide, chlorotoxin (CTX), which enables the tumor cell-specific binding of the nanoparticle. It is shown that the nanoparticle exhibits substantially enhanced cellular uptake and an invasion inhibition rate of approximately 98% compared to unbound CTX ( approximately 45%). Significantly, the investigation from flow cytometry analysis, transmission electron microscopy, and fluorescent imaging reveals that the CTX-enabled nanoparticles deactivated the membrane-bound matrix metalloproteinase 2 (MMP-2) and induced increased internalization of lipid rafts that contain surface-expressed MMP-2 and volume-regulating ion channels through receptor-mediated endocytosis, leading to enhanced prohibitory effects. Since upregulation and activity of MMP-2 have been observed in tumors of neuroectodermal origin, and in cancers of the breast, colon, skin, lung, prostate, ovaries, and a host of others, this nanoparticle system can be potentially used for non-invasive diagnosis and treatment of a variety of cancer types.

Intrapancreatic schwannoma diagnosed by endoscopic ultrasound‐guided fine‐needle aspiration cytology

Schwannoma is a tumor of neuro-ectodermal origin, usually occuring in the head and neck and extremities. A retroperitoneal, and particularly intra-pancreatic presentation is very rare, and poses a clinical and diagnostic challenge. We report a case of a male patient who underwent an Endoscopic Ultrasound-guided Fine Needle Aspiration (EUS-FNA) biopsy of a hypoechoic, intra-pancreatic mass. The onsite cytological evaluation was consistent with a spindle cell neoplasm. Further evaluation, aided by immunohistochemical stains, defined the mass as a Schwannoma. The patient then underwent a pancreaticoduodenectomy and the histopathological diagnosis of the surgical specimen confirmed the cytological diagnosis. To our knowledge, this is the first report of intra-pancreatic Schwannoma diagnosed preoperatively by EUS-FNA cytology.

Chemotherapy in patients with brain metastases

The development of brain metastases is still considered as a "terminal complication" of a cancer disease. The potential for CNS metastases appears to be greatest in tumours of neuroectodermal origin like melanoma or SCLC, very high in patients with tumours of ectodermal origin like breast cancer and NSCLC, whereas tumours arising from other embryonic origin develop brain metastases less often. Neovacularisation with upregulated VEGF Expression by the tumour cells facilitates their transmigration through the BBB. Temozolomide and "small molecules" are currently under investigation in solid tumours as farnesyltransferase inhibitors and tyrosin kinase inhibitors are able to cross BBB and thus should be active within the brain. Although studies on chemotherapy of brain metastases are usually small and include mostly a small number of patients, responses and prolongations of survival have been recorded. More studies are needed to evaluate the potential of the new therapeutics agents which increased therapeutic ratio and reduced side effects from chemotherapy.

In vivo MRI detection of gliomas by chlorotoxin-conjugated superparamagnetic nanoprobes.

Converging advances in the development of nanoparticle-based imaging probes and improved understanding of the molecular biology of brain tumors offer the potential to provide physicians with new tools for the diagnosis and treatment of these deadly diseases. However, the effectiveness of promising nanoparticle technologies is currently limited by insufficient accumulation of these contrast agents within tumors. Here a biocompatible nanoprobe composed of a poly(ethylene glycol) (PEG) coated iron oxide nanoparticle that is capable of specifically targeting glioma tumors via the surface-bound targeting peptide, chlorotoxin (CTX), is presented. The preferential accumulation of the nanoprobe within gliomas and subsequent magnetic resonance imaging (MRI) contrast enhancement are demonstrated in vitro in 9L cells and in vivo in tumors of a xenograft mouse model. TEM imaging reveals that the nanoprobes are internalized into the cytoplasm of 9L cells and histological analysis of selected tissues indicates that there are no acute toxic effects of these nanoprobes. High targeting specificity and benign biological response establish this nanoprobe as a potential platform to aid in the diagnosis and treatment of gliomas and other tumors of neuroectodermal origin.

Tumor antigen precursor protein profiles of adult and pediatric brain tumors identify potential targets for immunotherapy

We evaluated and compared tumor antigen precursor protein (TAPP) profiles in adult and pediatric brain tumors of 31 genes related to tumor associated antigens (TAA) for possible use in immunotherapy. Antigens were selected based on their potential to stimulate T cell responses against tumors of neuroectodermal origin. Thirty-seven brain tumor specimens from 11 adult and 26 pediatric patients were analyzed by quantitative real-time PCR for the relative expression of 31 TAPP mRNAs. The age range of adults (4F:7M) was 27-77 years (median 51.5 +/- 14.5 years) and for pediatrics (12F:14M) was 0.9-19 years (median 8.3 +/- 5.5 years). Histological diagnoses consisted of 16 glioblastomas, 4 low grade astrocytomas, 10 juvenile pilocytic astrocytomas, and 7 ependymomas. The adult gliomas expressed 94% (29 of 31) of the TAPP mRNAs evaluated compared with pediatric brain tumors that expressed 55-74% of the TAPP mRNAs, dependent on tumor histological subtype. Four types of TAPP expression patterns were observed: (1) equal expression among adult and pediatric cases, (2) greater expression in adult than pediatric cases, (3) expression restricted to adult GBM and (4) a random distribution. The pediatric brain tumors lacked expression of some genes associated with engendering tumor survival, such as hTert and Survivin. The potential TAA targets identified from the TAPP profiles of 31 genes associated with adult and pediatric brain tumors may help investigators select specific target antigens for developing dendritic cell- or peptide-based vaccines or T cell-based immunotherapeutic approaches against brain tumors.