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.

Fetal brain MR imaging.

In the past 10 years, improvements in MR imaging and faster imaging techniques have dramatically increased the use of in-utero fetal brain MR imaging. Challenging abnormalities now can be diagnosed prenatally through a careful analysis of morphology and signal changes. Using illustrations of normal brain development as a starting point, this article illustrates and discusses major brain malformations and specific morphologic changes, destructive lesions, and isolated ventriculomegalies, and the advantages and disadvantages of T1 and T2 sequences are provided.

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.

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.

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.

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.

Contribution of cytogenetics and FISH in the diagnosis of meningiomas. A study of 189 tumors.

The correlation between cytogenetic and histopathological findings were analysed in 189 meningiomas. The tumors were classified according to increasing degrees of anaplasia. We observed normal karyotype or only monosomy 22 in grade 1 (benign) tumors, while in grade 3 (anaplastic) only 1.5% of karyotypes were normal. Grade 2 (atypical) and 3 (anaplastic) tumors showed complex structural abnormalities. Loss of chromosome 14 were only found in grade 3. In cases with complex structural rearrangements, fluorescence in situ hybridization technique (FISH) has been realized and permitted a best identification of abnormalities. In our series, five patients recurred. They presented chromosomal abnormalities. These complex karyotypes in recurrent meningiomas might indicate aggressive tumor characteristics. Our results indicate histolopathological and cytogenetics correlations might represent a prognostic factor in meningiomas.

Prenatal ultrasonographic findings in Proteus syndrome.

Proteus syndrome, a disorder which consists of skeletal, hamartomatous and other mesodermal malformations proves to be tremendously variable. Although most of the patients show deformities at birth, the diagnosis is usually made later in life as the phenotype develops over time. We report on the case of a fetus presenting in utero, with a cystic abdominal mass and malposition of the fingers, which was found to have additional features of Proteus syndrome after termination of pregnancy. This case demonstrates that severe cases of Proteus syndrome can be detected prenatally.

Prognostic significance of Ki67, p53 and epidermal growth factor receptor immunostaining in human glioblastomas.

Since glioblastomas in adults are uniformly fatal, evaluation of easily reproducible prognostic criteria which would attempt to define groups of patients is required. However, there is lack of a clear consensus regarding the expression of some markers in the literature. Therefore, an immunohistochemical study was performed to determine the prognostic significance of Ki67, p53, and epidermal growth factor receptor (EGFR) in a retrospective series of 63 glioblastomas. Image analysis was carried out in positive specimens to quantify the immunoprecipitates. p53 and EGFR expression were specifically addressed in the 36 primary glioblastomas reported in this series. In all cases, clinical data (age, Karnofsky performance scale index [KPS] before surgery, extent of surgery) and immunohistochemical features were analysed using univariate and multivariate analysis to ascertain whether any significant correlation exists between [1] EGFR expression [2], p53 accumulation [3], Ki67 labelling index and prognosis (survival time and disease-free survival time, DFST). The results showed that in this series of glioblastomas, none of these markers had any prognostic value. Among the clinical parameters, a high KPS before surgery was found to be indicative of a shorter DFST and survival time (P < 0.05), whereas a younger age at onset and total or subtotal surgical excision were associated with a longer survival (P < 0.001 and 0.05, respectively). EGFR protein accumulation was inversely correlated with p53 accumulation (P = 0.01). The percentage of the primary glioblastomas expressing EGFR was much lower in our study (33%) than in the literature suggesting that the molecular distinction between primary and secondary glioblastomas is not so clear-cut.

Devic's neuromyelitis optica: a clinicopathological review of the literature in connection with a case showing fatal dysautonomia.

A new clinicopathological case of Devic's neuromyelitis optica, including unusual predominant clinical features (fatal dysautonomia) is described herein: pathological examination showed extensive and severe demyelination mainly involving the optic nerves, the medulla, and spinal cord, which was particularly pronounced in the thoracic segments, and thus explained the unusual vegetative symptomatology. In a review of 45 clinicopathological cases described in the literature as Devic's disease (DD), it turned out that only 22 cases, including the patient described here, fulfilled the recently defined diagnostic criteria [Devic 1980]. Among the other 23 cases, 15 did not fulfill the criteria because of the occurrence of relapses, 3 others had 2 separate pathological locations within the spinal cord, and the remaining 5 showed evidence that a disease other than DD was involved. Among the 22 cases which were definitely taken to be DD, the mean age at clinical onset was 39 years (+/- 14); it was characterized by acute bilateral visual loss and transversal myelitis which gradually led either to death or to partial or complete recovery. The pathological lesions, which mostly were located along the optic tracts and the spinal cord, were characterized by demyelination with inflammation and necrosis; in some cases the pathological process diffused into the medulla (8/22 cases) or the whole brainstem (4/22 cases). The cavitation of the spinal cord was not a key feature of the diagnosis, since it was observed on only 9/22 cases. Devic's neuromyelitis optica may be a separate nosological entity which differs from multiple sclerosis.

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.

A permanent pure amnestic syndrome of insidious onset related to Alzheimer's disease.

A 55-year-old patient experienced a pure amnestic syndrome of insidious onset that worsened progressively. Subsequently, her memory disorder stabilized and remained her only cognitive impairment for several years. She ultimately developed more widespread cognitive decline and terminal dementia. Postmortem examination 18 years after the onset revealed numerous senile plaques and neurofibrillary tangles consistent with Alzheimer's disease. A permanent pure amnestic syndrome of insidious onset may represent a further type of focal cerebral degeneration.

[Neurosyphilis with multiple gummas and AIDS. Report of a case]. / Neurosyphilis à gommes multiples et SIDA. A propos d'un cas.

The incidence of neurosyphilis has been increasing since AIDS has appeared but acute gummatous necrotizing progression is so far exceptional. We report a second case of "quaternary neurosyphilis" in a 29-year-old patient without serologic nor CT scan evidence of treponema. Diagnosing neurosyphilis is particularly difficult in HIV-1 infected patients, specially in spirochetes-poor injuries.

[Acute Weston Hurst necrotizing hemorrhagic leukoencephalitis]. / Leucoencéphalite aiguë hémorragique et nécrosante de Weston Hurst.

The clinical and pathological findings of a 43-year-old woman, diagnosed as having acute hemorrhagic leukoencephalitis at postmortem examination, are presented. The acute hemorrhagic leukoencephalitis affects mainly young adults and is the most fulminant from of demyelinating disease. It is frequently preceded by a respiratory infection. Diagnosis is facilitated by CT scanning and MRI, which reveal the massive lesion in the cerebral white matter. Many cases terminate fatally in 2 or 4 days, but in others survival is longer. The pathological findings are distinctive.

[2 cases of frontal dementia with non-specific histological lesions: clinico-pathological and nosological discussion]. / Deux cas de démence frontale avec lésions histologiques non spécifiques: discussion clinico-pathologique et nosologique.

We report two cases of "frontal lobe dementia", patho-anatomically defined by non-specific as neuronal loss, gliosis and spongosis. The review of the literature permit to discuss the clinical picture of "fronto-temporal dementia" in regard to neuropathological basis. Further, the boundaries with Pick's disease, Kraepelin disease, subcortical gliosis and the "prions diseases" are considered. Without more precise nosological status, tacking in count the great variability of the clinical signs, we can concluded that, at present time, the term of frontal type dementia with "non-specific histological features", that underlines the neuropathological characteristics is the most appropriate to define this clinico-pathological entity.

The contribution of cytogenetics to the histogenesis of meningeal hemangiopericytoma.

Some controversy has existed regarding the nosology of meningeal hemangiopericytoma. In the WHO's classification of 1979 these tumours were included as a subgroup of meningiomas, but for some authors, they should not be classified as meningiomas. Cytogenetic studies on meningioma demonstrate monosomy or partial deletion of chromosome 22 in 60% of these tumors. There have been few cytogenetic studies about meningeal hemangiopericytoma. We present here the results of cytogenetic studies and fluorescence in situ hybridization in six cases of meningeal hemangiopericytoma. In these tumours we have never found monosomy 22, but all six cases were hyperdiploid. These cytogenetic data might provide additional evidence to differenciate the meningeal hemangiopericytoma from the meningioma.

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.

[An anatomo-clinical case of dementia in endovascular large-cell lymphoma]. / Un cas anatomo-clinique de démence au couors d'un lymphome endovasculaire à grandes cellules.

Cerebral angiotropic large cell lymphoma is a rare fatal neurologic disorder characterized by multifocal intravascular proliferation of large pleomorphic cells within vessels of all caliber, predominantly skin and nervous system. Clinical manifestations in previously reported cases were dominated by focal neurologic signs, epilepsia and progressive dementia. We report a case of a 70 year-old man with subacute dementia, epileptic seizures and cerebrovascular events. There was no evidence of a systemic disease outside the nervous system. Cerebrospinal fluid contained 13 leukocytes/mm3 (49% of lymphocytic cells) and more than 100 mg/dl of protein. Cytology was negative. Cranial MRI demonstrated cerebral atrophy and an increased paraventricular signal in T 2 weighted images. A frontal brain biopsy revealed only neuronal dystrophy and astrocytic gliosis. Despite treatment with corticosteroids the patient died 18 months after the onset of the first symptoms. Autopsy was performed and revealed B cell lymphoma.

Expression of Flt3 tyrosine kinase receptor gene in mouse hematopoietic and nervous tissues.

The Flt3 gene encodes a tyrosine kinase receptor highly related to the Kit and Fms gene products. We have studied the expression of Flt3 by using in situ hybridization of mouse tissue sections. The results show that Flt3 RNAs are present in certain regions of lymphohematopoietic organs, placenta and nervous system. Flt3 is expressed in the medullary area of fetal and newborn thymus, in the paracortical regions of lymph nodes and in the red pulp of spleen. In placenta, labyrinthine trophoblasts express Flt3. Finally, Flt3 RNAs are found in several regions of the brain and in cerebellar Purkinje cells. Western-blot analysis showed that the FLT3 protein is present in the tissues positive for Flt3 RNA expression. Our observations allow for a comparison with the distribution of the Kit gene and analysis of a possible redundancy between KIT and FLT3 receptors.

[Cognition disorders and parkinsonian syndrome: diffuse Lewy body disease?]. / Troubles cognitifs et syndrome parkinsonien: maladie a corps de Lewy diffus?.

A 68 year old man developed progressive cognitive impairment with an akinetic-rigid syndrome which was atypically responsive to levodopa. The patient died after 18 months and the postmortem examination showed typical Lewy bodies in the substantia nigra and pale bodies in the cortex which were unlabelled by ubiquitin antibodies. This case is particular by the neuropathological examination (no immunoreactivity to antibodies against ubiquitin) and by the abnormal response to treatment (dystonia). These two aspects are discussed.