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Background: ANG1005 consists of three molecules of paclitaxel conjugated via ester bonds to the 19-amino-acid peptide Angiopep-2. The new chemical agent has been shown to cross the blood-brain barrier (BBB) by receptor-mediated transcytosis via low-density lipoprotein receptor-related protein 1 (LRP1). The experiments here examined the role of LRP1 in the subsequent endocytosis of drug into cancer cells., Methods: Localisation of ANG1005 and Angiopep-2 was examined by immunohistochemistry and in-vivo near-infrared fluorescence imaging in mice carrying orthotopic glioma tumours. Transport of ANG1005 and Angiopep-2 was examined in U87 glioblastoma cell lines., Results: Systemically administered ANG1005 and Cy5.5Angiopep-2 localised to orthotopic glioma tumours in mice. The glioma transplants correlated with high expression levels of LRP1. Decreasing LRP1 activity, by RNA silencing or LRP1 competitors, decreased uptake of ANG1005 and Angiopep-2 into U87 glioblastoma cells. Conversely, LRP1 expression and endocytosis rates for ANG1005 and Angiopep-2 increased in U87 cells under conditions that mimicked the microenvironment near aggressive tumours, that is, hypoxic and acidic conditions., Conclusion: ANG1005 might be a particularly effective chemotherapeutic agent for the wide array of known LRP1-expressing brain and non-brain cancers, in particular those with an aggressive phenotype.

Background and Purpose: Paclitaxel is highly efficacious in the treatment of breast, head and neck, non-small cell lung cancers and ovarian carcinoma. For malignant gliomas, paclitaxel is prevented from reaching its target by the presence of the efflux pump P-glycoprotein (P-gp) at the blood-brain barrier. We investigated the utilization of a new drug delivery system to increase brain delivery of paclitaxel., Experimental Approach: Paclitaxel molecules were conjugated to a brain peptide vector, Angiopep-2, to provide a paclitaxel-Angiopep-2 conjugate named ANG1005. We determined the brain uptake capacity, intracellular effects and antitumour properties of ANG1005 in vitro against human tumour cell lines and in vivo in human xenografts. We then determined ANG1005 activity on brain tumours with intracerebral human tumour models in nude mice., Key Results: We show by in situ brain perfusion that ANG1005 enters the brain to a greater extent than paclitaxel and bypasses the P-gp. ANG1005 has an antineoplastic potency similar to that of paclitaxel against human cancer cell lines. We also demonstrate that ANG1005 caused a more potent inhibition of human tumour xenografts than paclitaxel. Finally, ANG1005 administration led to a significant increase in the survival of mice with intracerebral implantation of U87 MG glioblastoma cells or NCI-H460 lung carcinoma cells., Conclusions and Implications: These results demonstrate the antitumour potential of a new drug, ANG1005, and establish that conjugation of anticancer agents with the Angiopep-2 peptide vector could increase their efficacy in the treatment of brain cancer.

We report two cases of papillary glioneuronal tumour. Both patients underwent gross total resection of their tumour. One of them was also treated by radiotherapy. Neither tumour had recurred, 19 and 2 years after treatment, thus confirming the good prognosis commonly associated with this tumour.

Myopericytoma is a benign tumour generally arising in the subcutaneous and superficial soft tissues of the extremities. Very few cases have been reported in other locations and intracranial examples are exceptional. We now report on three cases of primary intracranial myopericytoma and review the literature on that rare entity. The patients were women in their fifties who presented with decreased visual acuity in two cases and raised intracranial pressure in one case. The tumour involved, respectively, the anterior cranial fossa, the orbital apex and the pineal region. Gross total resection was achieved in all three cases. Histological analysis revealed oval-to-spindle shaped myoid-appearing cells with a striking tendency for concentric perivascular growth. The lesional cells showed apparent differentiation towards perivascular myoid cells as witnessed by smooth muscle actin expression. In one case, an epithelioid differentiation was also present. None of the patients received adjuvant therapy. One patient died of unrelated causes 6 months after surgery. The other two are alive and well at 9 and 12 month follow-up respectively. Myopericytoma is a recently described neoplasm, and it is likely that reappraisal of intracranial haemangiopericytoma with which it shares many histopathologic features will lead to more case reports of primary intracranial myopericytoma.

A cerebellar tumour, first diagnosed as an anaplastic oligodendroglioma, received radiation therapy (45 Gy) following gross total resection. The second histological study revealed a liponeurocytoma, a benign tumour not requiring adjuvant therapy. This case emphasizes the importance of considering this diagnosis to prevent unnecessary irradiation of such rumours.

An intra-cerebral schwannoma, presenting as a cystic, calcified, enhancing frontal mass, arising in a 52-year-old woman was misdiagnosed as a glioma and treated with radiotherapy. This observation emphasizes the importance of careful histological reexamination of all brain tumors when a discrepancy appears between the initial histological diagnosis and the clinical evolution, in order to recognize rare curable entities and to avoid potentially toxic treatment.

Objective: To identify different genetic molecular profiles in oligodendrogliomas and to evaluate their prognostic significance., Methods: The main genetic alterations reported in glial tumors were investigated in 26 oligodendrogliomas (10 World Health Organization grade II and 16 World Health Organization grade III). Correlation between identified molecular changes and pathologic grade or clinical course was subsequently analyzed using univariate and multivariate statistical analyses., Results: Loss of heterozygosity (LOH) on chromosome 1p, 19q, and 10; P16/CDKN2A homozygous deletion; EGFR (epidermal growth factor receptor) amplification; and TP53 and PTEN mutations were observed in 14 (54%), 15 (58%), 9 (35%), 7 (27%), 5 (19%), 1 (4%), and 0 cases. LOH 1p and 19q were tightly associated (p < 0.0001). A mutual exclusion was found between LOH 1p/19q and EGFR amplification (p = 0.01), P16/CDKN2A deletions (p = 0.001), or LOH on 10q (p = 0.03), suggesting the existence of distinct genetic subsets in oligodendrogliomas. On univariate analysis, age <50 years (p = 0.002) and LOH 1p (p = 0.01) were associated with a longer progression-free survival (PFS) whereas LOH 10q (p = 0.03) and EGFR amplification (p = 0.007) were associated with a worse PFS. In multivariate analyses, age <50 years (p = 0.001) and LOH 1p (p = 0.006) remained independent predictive factors for PFS., Conclusion: These results provide evidence for two alternative molecular pathways of progression in oligodendrogliomas. The first one is associated with loss of 1p and 19q and the second one with P16/CDKN2A deletion, 10q loss, and EGFR amplification. The findings confirm the value of loss of 1p as predictor of longer progression-free survival; in addition, the study demonstrates the unfavorable impact of 10q loss and EGFR amplification on the prognosis.

Glioblastoma (GBM) is considered by the WHO classification to represent the most malignant grade of the astrocytic tumors. However, a subset of GBM includes recognizable areas with oligodendroglial features, suggesting that some GBM may also have an oligodendroglial origin. The aim of this study was to analyze the molecular profile of GBM associated with an oligodendroglial component (GBMO). We analyzed a series of 25 GBMO. Loss of heterozygosity (LOH) on 1p and 19q, known as common markers of oligodendroglial tumors, were observed in 40% and 60% of cases, respectively; 72% of the tumors displayed one or both of these markers. All but 4 tumors (84%) showed alterations known to be preferentially involved in the progression of astrocytic tumors to GBM, such as EGFR amplification (44%), P16 deletion (48%), LOH on 10q (64%), PTEN (20%), and TP53 (24%) mutations. Therefore, GBMO displayed all the genetic aberrations found in "standard" GBM with a comparable incidence, but differed from GBM by having a higher rate of LOH on 1p and 19q. These results suggest that GBMO might represent a subgroup of tumors of oligodendroglial origin that is distinct from the "standard" GBM in terms of tumorigenesis pathway.

OLIG2 is a recently identified transcription factor involved in the specification of cells in the oligodendroglial lineage. We investigated the expression of OLIG2 by in-situ hybridisation in 21 brain tumours: nine grade II and III oligodendrogliomas, three grade II oligoastrocytomas, and nine non-oligodendroglial tumours (four grade IV astrocytomas, two meningiomas, a dysembryoplastic neuroepithelial tumour, and two metastases). OLIG2-positive cells corresponding to neoplastic oligodendrocytes were present in all oligodendrogliomas and oligoastrocytomas. By contrast, OLIG2 expression was not detected in the non-oligodendroglial tumours. Thus, oligodendroglioma probably arise from oligodendrocyte precursor cells. OLIG2 should prove a useful marker for the diagnosis of oligodendroglial tumours.

Although the current radiological imaging is really performing, histologic examination remains essential in as much regarding the diagnosis as the pronostical assessment of cerebral tumors pronostic. The difficulties of histological diagnosis are not the same according to the various processes such as cerebral biopsy, extemporaneous examination or routine examination. Grading of gliomatous tumors is one among all the components that might enable pronostical assessment. Predictivity of meningiomas and pituitary adenomas recurrences remain unreliable despite numerous histological techniques that can be used (proliferative markers, bromodeoxyuridine incorporation, nucleolar organizers, flow cytometry).

A 50 y.o. male presented with a right parietal tumor which was a glioblastoma on stereotactic biopsy. He was treated by radiation and steroids, with clinical improvement. Four months later, he presented with a left preauricular mass and cervical lymphadenopathy. CT scan showed destruction of the left mastoid and filling of the left tympanic cavity. One month later, he suffered progressive dyspnea. Chest X ray showed a mediastinal mass on the right side and numerous bilateral interstitial opacities in the lungs. A bronchial biopsy was inconclusive. His general condition worsened, and he died. Postmortem showed continuous neoplastic infiltration of the left part of the base of skull, extending into the neck. Numerous metastases were present in mediastinal lymph nodes, lung parenchyma, pleura and pleural aspect of the diaphragm. There were no subdiaphragmatic metastases. Neuropathological examination confirmed a poorly differentiated highly malignant glioblastoma with severe necrosis involving the internal part of the parietal lobe extending to the dura mater of the convexity and falx cerebri with invasion of the superior longitudinal sinus which was entirely occluded. The biopsy scar was not infiltrated. Visceral tumors were morphologically identical to the brain tumor. They were strongly GFAP positive and cytokeratin negative. Extraneural metastases of glioblastoma in the absence of surgery are uncommon in adults. Involvement of the dura mater and/or superior longitudinal sinus is an almost constant feature. In our case, this may have led to invasion of the base of skull and secondary regional, lymphatic, and hematogenous spread.

We report two cases of oligodendroglioma-like meningioma revealed by symptoms of increased intracranial pressure, progressive hemiparesia and partial epileptic seizures. Brain CT-scan or scintigraphy and carotid arteriography were suggestive of a convexity meningioma. One patient had received radiation treatment for scalp tinea capitis 25 years previously. In spite of complete surgical removal, the tumor recurred in both cases respectively 17 years and 18 months later. The two patients were operated again, and one underwent a complementary radiotherapy. Pathologic diagnosis was particularly difficult in the first case where the pattern at conventional histologic technics was that of oligodendroglioma. On the occasion of recurrence, immuno-histochemistry and ultrastructural studies were performed. The tumor was positive for epithelial membrane antigen (E.M.A) and cytokeratin, but was negative for glial fibrillary acidic (G.F.A.) protein, S 100 protein (S 100), neuron-specific enolase (N.S.E.), vimentin, anti-LEU-7 (N.H.K.1), and neurofilaments (N.F.). Electron microscopy showed closely adjacent cells with tonofilaments and numerous desmosomes. These findings permitted to establish the diagnosis of oligodendroglioma-like meningioma instead of oligodendroglioma. In the second case, the histologic pattern was also reminiscent of oligodendroglioma, but presence of few cellular whorls in some part of the tumor permitted the correct diagnosis. The pathogenesis of this atypical form of meningioma, its tendency for recurrence, and usefulness of radiotherapy are discussed and literature is reviewed.

We have developed a method for creating brain slices in the same plane and intervals as pre-mortem CT scan images. Our experience with this very simple technique on 20 brains confirms the practicality, reliability and usefulness of this tool for correlating complex CT images with the pathologic anatomy. Corresponding case-material of cerebral astrocytomas with be presented.

The clinical history and postmortem neuropathologic findings of a case of cerebral lymphoma revealed by a typical parkinsonian syndrome are reported. The clinical symptoms initially improved with dopa therapy. The tumor was classified as a diffuse, non-cleaved, large-cell lymphoma of B-cell origin producing monoclonal lambda light chains. The substantia nigra was infiltrated by the tumor and showed neuronal loss and extraneuronal pigment. The most striking histological feature was the presence of neuronophagic-like nodules composed of lymphomatous cells both in the locus niger and in the left thalamus. No tumoral mass effect and no histological stigmata of other etiologies of parkinsonian syndromes were observed. A hypothesis is that the neuronophagic-like nodules may reflect a neuronotoxic activity of the lymphoma and may be considered at the origin of parkinsonism.

Preliminary electron microprobe studies of a small number of meningiomas, oligodendrogliomas, glioblastoma multiformae, craniopharyngiomas, and metastatic epithelioma of the breast suggest that the elemental composition of the deposits associated with these tumors is characteristic for each type of tumor.

A 30-year-old woman, who, since the age of 20, had epileptic seizures, was hospitalized in 1972 because of frontal headaches, nausea, and vomiting. Clinical examination revealed a right cerebellar syndrome; gamma-encephalogram showed a focus of subtentorial hyperactivity; iodoventriculography showed a deformation of the aqueduct. At surgery, a posterior fossa tumor implanted on the dura mater and tentorium of the right cerebellar fossa was enucleated. The histologic features were those of giant lymph node hyperplasia. Postoperative craniospinal radiotherapy was administered. Ten years later the patient was in good health and neurogically normal.

A case of high-grade malignant extramedullary plasmacytoma (EMP), unusual in its initial cutaneous localization and major involvement in the central nervous system rapidly resulting in death, is reported. Light- and electron-microscopic studies of a skin nodule revealed a high proportion of immature and mature plasmacytes. Immunohistological study revealed that both cells synthesized different amounts of a monotypic cytoplasmic kappa light chain. Neuropathological study revealed extensive infiltration of the leptomeninges and perivascular spaces as far as the deep parenchyma. In several places, effraction of vessels resulted in parenchymatous, tumor-like, plasmacytic infiltration. The findings of this case were compared with those of the few previously reported cases of EMP with initial cutaneous or intracranial localization, and with those of immunoblastic sarcoma occurring in some cases of myeloma.

A 24 year-old man experienced a left retrobulbar neuritis which improved completely after 2 months of non-steroid antiinflammatory therapy. One month after the end of the treatment he developed a Korsakoff-like amnestic syndrome. Three months later he complained of horizontal diplopia. A CT Scan showed a diffuse enhancement of the periventricular areas, corpus callosum and fornix. Diplopia and CT scan abnormalities disappeared after the administration of tetracosactide. Subsequently a progressive worsening of the neurological condition developed, including a 1 1/2 syndrome of Fisher. In C.S.F. proteins ranged from 35 to 66 mg/dl, gammaglobulins from 4 to 5 per cent, cells from 2.2 to 6.8 per mm3 without abnormal cells. Rounded areas of enhancement were observed on CT scan in pons and right occipital lobe. Usual biological tests, abdominal echography and lymphography were normal. Death occurred 15 months after the onset of symptoms. Neuropathological examination showed: 1) a cerebral lymphoma of probable B origin with distinct masses in right occipital lobe and pontine tegmentum and a more diffuse perivascular infiltration on the left side in the amygdaloid nucleus, fourth temporal gyrus, sublenticular area, hypothalamus and in the right internal capsule; 2) multiple small clear-cut foci of demyelination with myelin-axonal dissociation bilaterally in the optic pathways, periventricular regions, corona radiata, cerebral and cerebellar white matter, sublenticular areas, temporal lobes, splenium of the corpus callosum and fornices with secondary atrophy of the mamillary bodies. Both recent and old plaques were observed. Inflammatory perivascular cuffing, when present, consisted of small nontumoral lymphocytes.(ABSTRACT TRUNCATED AT 250 WORDS)

A man of 32 years was admitted with a 3-month history of temporal lobe epilepsy. CT-Scan showed a well-circumscribed area of heterogenous contrast enhancement in the right temporal lobe. Gross total resection was performed but the tumor recurred: the patient died 6 months after the onset of symptoms. There was no autopsy. Histology revealed a highly pleomorphic neoplasm with extensive zones of necrosis. Monster cells, up to several hundred micrometers in diameter, with multiple and/or multi-lobed nuclei were numerous and showed emperipolesis for polymorphonuclear, mononuclear, and small tumor cells. Abundant mitoses were observed. Tumor cells of all sizes had ground-glass or vacuolated cytoplasm which obscured their glial nature. GFAP was demonstrated in some neoplastic cells. Reticulin fibers were confined to perivascular areas where mononuclear inflammatory cells were sometimes noted. Vascular proliferation was mild. Electromicroscopic study revealed that the cytoplasms of the tumor cells contained abundant lipid droplets, numerous mitochondria, and glio-filaments. Such a tumor has been reported recently as "malignant glioma with heavily lipidized tumor cells". This rare entity, previously reported as xanthosarcoma of the brain, represents a subgroup of primitive monstrocellular cerebral tumors.