Postoperative chemotherapy without irradiation for ependymoma in children under 5 years of age: a multicenter trial of the French Society of Pediatric Oncology.

PURPOSE: To evaluate a strategy that avoids radiotherapy in first-line treatment in children under 5 years of age with brain or posterior fossa ependymoma, by exclusively administering 16 months of adjuvant multiagent chemotherapy after surgery. PATIENTS AND METHODS: Between June 1990 and October 1998, 73 children with ependymoma (82% with high-grade tumors) were enrolled onto this multicenter trial. Children received adjuvant conventional chemotherapy after surgery consisting of seven cycles of three courses alternating two drugs at each course (procarbazine and carboplatin, etoposide and cisplatin, vincristine and cyclophosphamide) over a year and a half. Systematic irradiation was not envisaged at the end of chemotherapy. In the event of relapse or progression, salvage treatment consisted of a second surgical procedure followed by local irradiation with or without second-line chemotherapy. RESULTS: Conventional chemotherapy was well tolerated and could be administered in outpatient clinics. No radiologically documented response to chemotherapy more than 50% was observed. With a median follow-up of 4.7 years (range, 5 months to 8 years), the 4-year progression-free survival rate in this series was 22% (95% confidence interval [CI], 13% to 43%) and the overall survival rate was 59% (95% CI, 47% to 71%). Overall, 40% (95% CI, 29% to 51%) of the patients were alive having never received radiotherapy 2 years after the initiation of chemotherapy and 23% (95% CI, 14% to 35%) were still alive at 4 years without recourse to this modality. In the multivariate analysis, the two factors associated with a favorable outcome were a supratentorial tumor location (P =.0004) and complete surgery (P =.0009). Overall survival at 4 years was 74% (95% CI, 59% to 86%) for the patients in whom resection was radiologically complete and 35% (95% CI, 18% to 56%) for the patients with incomplete resection. CONCLUSION: A significant proportion of children with ependymoma can avoid radiotherapy with prolonged adjuvant chemotherapy. Deferring irradiation at the time of relapse did not compromise overall survival of the entire patient population.

Central neurocytoma: a synopsis of clinical and histological features.

The central neurocytoma is a supratentorial, often calcified brain tumour affecting young adults and is typically located in the lateral ventricles in the region of the foramen of Monro. Clinically, the tumour causes signs of increased intracranial pressure, visual and mental disturbances and, occasionally, pyramidal or endocrine symptoms. By light microscopy, the tumour is composed of small round cells in a delicate fibrillary matrix. Tumour cells consistently show features of neuronal differentiation by electron microscopy (synapses, dense-core vesicles, presynaptic clear vesicles, specialized synaptic junctions) and immunoreactivity for synaptophysin and other neuronal marker proteins. The tumour can be totally removed in nearly half of the cases. After incomplete surgical resection neurocytomas may recur but because of their low proliferation potential, radio- or chemotherapy are not generally recommended. Postoperative recurrence-free survival times of up to 19 years have been reported. Neurocytomas constitute nearly one half of supratentorial intraventricular tumours in adults but amount to less than 1% of all tumours of the central nervous system and its coverings.

Lithostathine and pancreatitis-associated protein are involved in the very early stages of Alzheimer's disease.

According to one of the theories formulated to explain the etiology of Alzheimer's disease (AD), amylosis may reflect a specific inflammatory response. Two inflammatory proteins, lithostathine and PAP, were evidenced by immunohistochemistry in senile plaques and neurofibrillary tangles of patients with AD. In addition, lithostathine and PAP were significantly increased in the cerebrospinal fluid of patients with AD when compared to patients with multiple sclerosis, another inflammatory disease, and to normal control subjects. However, no correlation was observed with age of occurrence. Furthermore, lithostathine and PAP were increased even at the very early stages of AD, and their level remained elevated during the course of the AD unlike TNFalpha whose level, very high at very early stages, regularly decreased. Finally, if part of lithostathine and PAP are synthesized in the brain, a large part comes from serum by passage over the blood-brain barrier. These results indicate (i) the existence of an acute phase response followed by a chronic inflammation in AD, and (ii) that lithostathine and PAP are involved even at the first pre-clinical biochemical events of AD. In addition, because lithostathine undergoes an autolytic cleavage leading to its precipitation and the formation of fibrils, we believe that it may be involved in amyloidosis and tangles by allowing heterogeneous precipitation of other proteins.

Isolated, chronic, epilepsia partialis continua in an HIV-infected patient.

BACKGROUND: The characteristic clinical feature of epilepsia partialis continua (EPC) is chronic focal myoclonus, usually involving the distal part of one extremity. A variety of pathogenetic factors have been implicated in EPC. In children, the most common cause is Rasmussen encephalitis; in adults, it is vascular disease or tumor involving the sensorimotor cortex. Epileptic seizures are a relatively common manifestation of central nervous system involvement in patients infected with human immunodeficiency virus (HIV), but, to our knowledge, isolated, chronic EPC has not been previously reported. OBJECTIVE: To describe a case of typical EPC in a patient infected with HIV. DESIGN AND SETTING: Case report from an epilepsy center. PATIENT: A 58-year-old man infected with HIV had continuous myoclonus that involved the right arm and was associated with intermittent motor seizures. The electroencephalographic findings were normal at the onset of the symptoms, but left central theta rhythm appeared later. Serial magnetic resonance imaging scans obtained over a 3-month period showed a progressively increasing left rolandic T2-weighted hypersignal. Histologic study of a stereotactic biopsy specimen demonstrated inflammation characterized by perivascular mononuclear cell infiltration. The only detectable cause was HIV infection. Immunocytochemical tests ruled out JC virus. Neuropsychological testing showed no evidence of cognitive impairment. An electroencephalographic-electromyographic "back-averaging" study showed a reproducible transient left biphasic complex preceding the bursts by about 30 milliseconds on the C3 and F3 electrodes, thus demonstrating that the myoclonus was of cortical origin. High-dose corticosteroid (prednisone, 100 mg/d) and anti-HIV- 1 therapy led to marked radiological and clinical improvement. Infection with HIV enhances the risk of seizures, but, to our knowledge, this is the first reported case of "inflammatory" EPC. CONCLUSIONS: The present case suggests that the possibility of central nervous system involvement by HIV-1 should be taken into account in the diagnostic workup of patients with EPC. This case also indicates that treatment can be effective.

Atypical inflammatory histiocytic tumor of the cerebellum. A histological, immunohistochemical, and ultrastructural study.

We report a primary histiocytic tumor involving the cerebellum. Microscopically, the tumor was composed of nests of pleomorphic cells surrounded by thin vascular septa invaded by lymphocytes. Immunocytochemistry and electron microscopy confirmed the histiocytic origin of the tumor. Although we considered several diagnoses, we ultimately concluded that "atypical inflammatory histiocytic tumor of the cerebellum" best characterized the lesion. This case represents another example of the diversity of histiocytic tumors and shows that they can occur in the central nervous system.

Central neurocytomas. Critical evaluation of a small-cell neuronal tumor.

We report herein the clinical and pathological features of 20 patients with central neurocytomas. Investigations for various differentiation antigens and cell type-specific markers were performed by immunohistochemistry using paraffin-embedded tissue. In addition, the expression of L1 adhesion molecule and of the various N.CAM (neural cell adhesion molecule) isoforms were investigated by immunoblotting studies in two frozen specimens. Central neurocytomas are clinically characterized by their intraventricular localization, occurrence in young adults, and good prognosis. It rarely occurs in patients over 50, but such cases have a poor prognosis. Total surgical excision is the best treatment. Radiotherapy is appropriate if surgery is incomplete or contraindicated. Histologically, central neurocytomas display the following features: an oligo-like pattern, usually associated with large fibrillary rosettes or perivascular arrangement, and a rich endocrine-type vasculature. Central neurocytomas have a remarkably homogeneous antigenic profile. GFAP expression is only found in scattered reactive astrocytes, S100 protein in reactive astrocytes and rare tumor cells. Among the pan-neuroendocrine markers, central neurocytomas always express neuron-specific enolase; they frequently express synaptophysin but never chromogranin A. Synaptophysin is the most reliable immunohistological marker for central neurocytomas; however, immunoreactivity could be lost with long formalin fixation. In these cases, electron microscopy is used to support the neuronal nature of the tumor cells. The expression of L1 adhesion molecule and the isoform 180 of N.CAM, indicates that central neurocytomas are formed by cells committed to neuronal phenotype. Nevertheless, advanced neuronal differentiation may be absent, as suggested by the persistence of embryonic N.CAM, the nonexpression of neurofilament proteins, and the absence of mature synapses in numerous cases. Central neurocytomas and neuroblastomas share some biochemical properties, but their respective clinicopathological features and biological behavior are dramatically different.

Development of lymphoid hyperplasia in transgenic mice expressing the HIV tat gene.

During HIV infection, individuals experience multiorgan disorders such as adenopathy, splenomegaly, and lung and brain diseases. There is an increasing body of evidence that the HIV trans-activating tat gene product possesses multiple activities. First, it can activate several cellular genes; second, in its extracellular soluble form, it plays the role of growth factor in some cells such as Kaposi's sarcoma cells. Thus, we introduced the HIV tat gene, under the control of the cellular proteolipoprotein promoter, into the germline of mice and demonstrate that, when expressed, the tat gene product induces lymphoid hyperplasia in spleen, lymph nodes, and lung, as is observed in AIDS patients, but not in the brain or testes. Our findings indicate that HIV, through some of its genes, directly participates in the pathogenesis of AIDS.

Macrophagic activity in intracerebral germinoma: ultrastructural study of a case.

This report presents the ultrastructural study of a germinoma of the third ventricle occurring in a 13 year old boy. The electron microscopic data showed similarities linking this tumor to gonadal and mediastinal germinomas and emphasized the exceptional glycogenic storage in tumor and stroma cells. Another morphological analogy was the intense macrophagic activity that led to tumor cell phagocytosis. The authors discuss the meaning of such an immune response, which is usually not observed in cerebral tumors.

A defective control of small-amplitude movements in monkeys with globus pallidus lesions: an experimental study on one component of pallidal bradykinesia.

The effects of globus pallidus (GP) lesion were examined in two monkeys trained to perform a visually guided pointing movement in simple and choice reaction time tasks involving small and large amplitude movements. The reaction time (RT) and the movement time (MT) were measured. The Y-axis error (EY) was also analyzed in order to assess the movement accuracy. Unilateral GP lesion was made by locally injecting an excitatory amino acid, quisqualic acid. GP lesion led to little change in the RTs (simple and choice RTs) and in the EY, whereas a large increase in the MT occurred. The MT impairments seem to have been correlated with the movement amplitude, since they were larger in the case of small-amplitude than large-amplitude movements. These results suggest that the GP may be involved in the control of small-amplitude rather than large-amplitude movements. As various studies have shown that proprioceptive cues are more strongly involved in the control of discrete than large-amplitude movements, the MT deficit, i.e., the bradykinesia observed here, may reflect a defective integration of proprioceptive information occurring after GP lesion.

Detection of i(17q) chromosome by fluorescent in situ hybridization (FISH) with interphase nuclei in medulloblastoma.

Medulloblastomas are the most frequent primitive neurectodermal tumors in children. An isochromosome for the long arm of 17, i(17q), is found in 30% of medulloblastomas. For some authors, this abnormality is observed in cases with a shorter survival time. In our cytogenetic studies of 30 medulloblastomas, we observed i(17q) in only three cases, a monosomy 17 in two cases, a monosomy 22 in four cases, nonspecific numerical or structural abnormalities in five cases, and normal karyotypes in 12 cases. We compared the results of karyotypic analysis after culture and FISH with a chromosome 17 alpha satellite DNA probe on interphase nuclei in five cases of medulloblastoma. In one case, i(17q) was only observed in four cells in karyotypic analysis, in three cases a normal karyotype was found, and in one case karyotypic analysis was impossible. In all of these cases, i(17q) was observed in a great number of nuclei by FISH on interphase nuclei. Our study shows that the FISH on interphase nuclei permitted us to observe i(17q) in the cases where it was not or could not be completely detected by karyotypic analysis. The association of these two techniques is required to detect i(17q), an abnormality whose prognosis value in medulloblastomas is now recognized.

Are juvenile pilocytic astrocytomas benign tumors? A cytogenetic study in 24 cases.

We performed a cytogenetic study on 24 pilocytic astrocytomas: 23 in children and 1 in a young adult. We observed 12 normal karyotypes. In 12 karyotypes with structural and/or numerical abnormalities, chromosomes 7, 8, and 11 were most frequently involved. One case recurred and presented chromosomal abnormalities (hyperdiploidy) in the first tumor and additional structural abnormalities in the second tumor. We believe that chromosomal abnormalities in pilocytic astrocytomas are frequent and indicate tumoral progression.

Cytogenetic study of 33 ependymomas.

Ependymomas are glial tumors. They constitute approximately 5-10% of intracranial tumors. Ependymomas are tumors which can recur. Predictive factors of outcome in ependymomas are not well-established. Karyotypic studies on ependymomas are relatively scarce, and no specific chromosomal change has been described in these neoplasms. We performed a cytogenetic study of 33 ependymomas, of which eight were recurrent tumors, to determine the type and incidence of cytogenetic changes.

Apomorphine-induced circling behaviour in hamsters following unilateral injection of scrapie gent in the striatum.

Twenty golden hamsters received a microinjection of scrapie agent into the left striatum. At different times after inoculation animals were injected intraperitoneally with apomorphine, a direct dopamine receptor agonist. Two types of effects developed simultaneously, starting at about 80 days after infection. First, apomorphine induced a rotational behaviour which showed a progressive destruction of the striatal neurones at the site of injection. This suggest a local spread of scrapie agent by cell to cell transfer in the striatum. Secondly, the clinical signs of scrapie developed, indicating a more widespread distribution of agent throughout the brain.

[Cerebral hemangiopericytoma. Ultrastructural study of one case]. / Hémangiopéricytome cérébral. Etude ultrastructurale d'un cas

The authors report electron-microscopic observations upon a primitive cerebral haemangiopericytoma. The vascular appearance of the tumour is due to the presence of abundant extracellular material which has a structure like that of vascular basement membranes. The fact that the tumour cells are pericytes is confirmed by the existence of intracytoplasmic microfilaments of 60-80 A in diameter, sometimes gathered into osmiophilic aggregations and forming simple cellular junctions (zonulae adherentes). Stress is laid upon the importance of differentiating this rare tumour from an angioblastic meningioma; the haemangiopericytoma is more rapidly growing and carries a more serious prognosis.

Correlation between cytogenetic and histopathological findings in 75 human meningiomas.

The correlations between cytogenetic and histopathological findings were analyzed in 75 human meningiomas. The tumors were classified according to increasing degrees of anaplasia into three grades: Grade I, benign; Grade II, atypical; Grade III, anaplastic. In 45 tumors of Grade I (benign), we more often observed a normal karyotype or monosomy 22. In 23 tumors of Grade II (atypical), we observed karyotypes with structural and/or numerical abnormalities with the presence of telomeric associations in 8 of them. These last tumors were fibroblastic. In seven Grade III tumors (anaplastic), we also observed complex abnormalities, and in one case, we observed telomeric associations. Our observations show that complex chromosome abnormalities and telomeric associations are observed in tumors that histologically display a certain degree of anaplasia. It is possible that the result of histopathological and cytogenetic correlations might represent a prognostic factor in meningiomas.

Primary intracerebral plasma cell granuloma: a light, immunocytochemical, and ultrastructural study of one case.

A case of primary intracerebral plasma cell granuloma without meningeal attachment is presented. Histologically, the lesion showed two different patterns. At the center, it displayed the features of a benign fibrous histiocytoma. At the periphery, a mixture of polyclonal plasma cells, lymphocytes, and "epithelial-like" cells was observed. Electron microscopy and immunocytochemistry confirmed the histiocytic nature of the "epithelial-like cells." The differential diagnosis and histogenesis of such a lesion are discussed.

Choristoma of the intracranial maxillary nerve in a child. Case report.

This report describes what the authors believe to be the first reported case of choristoma of the intracranial maxillary nerve. This 12-year-old girl presented with a 5-year history of severe isolated left-sided trigeminal neuralgia. Computerized tomography and magnetic resonance imaging revealed a mass below the anterior portion of the left cavernous sinus, enlarging the foramen rotundum. Total resection was achieved via a pterional extradural approach. Histological examination revealed a choristoma composed of smooth-muscle fibers. The histogenesis of these tumors when they develop in a nerve remains unclear. They may represent abnormal migration or proliferation of neuroectodermal tissue in or close to a peripheral nerve. Total removal of these tumors should be attempted at initial diagnosis.

Malignant transformation of an osteoblastoma of the skull: an exceptional occurrence. Case report.

What is apparently the first reported case of spontaneous malignant transformation of a benign osteoblastoma of the skull is described. The initial lesion was completely removed surgically and showed the histological features typical of a benign osteoblastoma. No radiotherapy was performed. Eleven years later the patient developed an osteosarcoma of the skull. Review of the literature showed that malignant transformation of benign osteoblastomas is extremely rare and could take place spontaneously. However, the risk of this occurring seems higher after inadequate initial treatment (curettage or partial excision). Follow-up monitoring of patients with osteoblastoma of the cranial vault is suggested.

Prognostic factors in intracranial ependymomas in children.

OBJECT: The occurrence of intracranial ependymomas in children is relatively infrequent, and their prognostic factors are still controversial, especially regarding histological composition. METHODS: A retrospective study was conducted of 37 children treated during the last 20 years for intracranial ependymomas at the Hôpital de la Timone. Both univariate and multivariate statistical analyses were performed to assess the prognostic relevance of patient age and sex, extent of tumor removal, location of the tumor (supratentorial compared with infratentorial, median compared with lateral), tumor histological composition, and adjuvant therapies in affecting the 5-year progression-free survival (PFS) rate and overall survival (OS) rate. The following histopathological features, either alone or in combination, were analyzed: endothelial proliferation, necrosis, loss of differentiating structures (present compared with absent), the number of mitotic figures per 10 hpf, and cellularity (number of nuclei/5 hpf). In addition, immunohistochemical detection of Ki-67 antigen was performed and the Ki-67 labeling index (LI) evaluated in all cases. The 5-year OS and PFS rates were 45% and 25%, respectively (median follow up 34 months). Four patients died of disease without remission (median 163 days) and disease in 21 patients relapsed: 18 in situ and three both in situ and distantly. On univariate analysis total surgical resection and median infratentorial location were associated with a better outcome (p < 0.002) for both OS and PFS. Loss of differentiating structures was associated with poor prognosis (p < 0.008) and the combination of necrosis, endothelial proliferation, and mitotic index greater than 5 was also a negative predictive factor for both OS (p < 0.002) and PFS (p = 0.02). The PFS time was shorter in patients younger than 4 years of age and in patients in whom a Ki-67 LI greater than 1 was found (p = 0.03 and 0.006, respectively). Adjuvant radiotherapy and chemotherapy were not relevant to prognosis. Moreover, among the 15 patients in whom total excision was achieved, OS was better in those who did not receive adjuvant therapies. In contrast, adjuvant therapies significantly enhanced PFS time in patients in whom tumor excision was incomplete. CONCLUSIONS: This study and analysis of the literature further highlight that total tumor removal is the treatment of choice for ependymomas in children. Postoperative measurement of residual tumor is required, especially because a subgroup of patients might be treated by surgery alone. Median infratentorial ependymomas have to be distinguished from the lateral type. Appropriate and reproducible histological parameters and Ki-67 LI are of interest as predictors of outcome.

What's new in primary central nervous system lymphomas?

Primary central nervous system lymphomas (CNSL) are uncommon neoplasms accounting for about 1% of primary brain tumors. Patients with congenital or acquired immunodeficiencies including AIDS patients and transplant recipients represent the main high-risk population for CNSL occurrence. An important point emerging from the literature is that CNSL incidence has dramatically increased during the last years not only in HIV infected patients by virtue of the AIDS epidemic spread, but also for unclear reasons in immunologically normal persons. Although c-myc oncogene activation and Epstein-Barr virus infection are considered to play a role in CNSL development, the peculiar tendency of these lymphomas to occur and remain inside the CNS is not well understood and may involve putative CNS binding molecules carried by lymphocytes. The clinical presentation is characterized by a great variety of neurological disorders. Radiological features consist of hyperdense homogeneous deposits within the subcortical white matter with a pattern of marked enhancement after injection of contrast material. The tumor masses are usually ill-defined and multicentric. Although all cytological types can be observed, the most common types belong to the high-grade category of non-Hodgkin's lymphoma. Monoclonal antibodies reactive with formalin-fixed, paraffin-embedded sections can be used in conjunction with stereotactic needle biopsy to provide accurate immunological characterization of CNSL. The large majority of CNSL is of B-cell origin but T-cell lymphomas seem at the present time less exceptional than previously thought. Although radiotherapy and chemotherapy can increase length of survival, the prognosis of CNS remains dramatically poor, the shortest survival being observed in AIDS patients.