Insulin-like growth factor type I biology and targeting in malignant gliomas.

Growth factors such as insulin-like growth factor type I (IGF-I), epidermal growth factor (EGF), vascular-endothelial growth factor (VEGF) and transforming growth factor beta (TGF-beta) are present during the development of the CNS. When they reappear in the mature brain they are overexpressed in neoplastic glia, participating in the development of the most common human brain malignant tumor, glioblastoma multiforme, which is invariably fatal. Progress in treatment of this disease involves an increase in median survival from 8 to 11 months to an average of 15 months, rarely to 18 months. We do not know any therapy, which can make a complete stop of this neoplasm. To inhibit this process various anti-growth factor therapies have been proposed. We describe actual applications of growth factor inhibitors and antisense approaches. The review highlights results obtained with the promising treatment of glioblastoma multiforme: using inhibitors and antisense targeting growth factors, including IGF-I, their receptors, and their downstream signaling effectors including glycogenesis and oncogenes. The antisense strategies have been the subject of many clinical trials, especially the IGF-I antisense approach. Such antisense therapies, already introduced in clinical trial in the USA, Europe and Asia, will soon become the preferred alternative treatment for human glioblastoma multiforme. The inhibition of signal transduction pathways common to growth factors and glycogenesis appears as a parallel challenge to glioblastoma multiforme inhibition studies.

[Homocysteinemia and thrombophilic factors in unexplained decompression sickness]. / Homocystéinémie et facteurs de thrombophilie dans des accidents de décompression immérités chez des plongeurs.

INTRODUCTION: Decompression sickness with cerebral ischemic lesions occurs even in divers who have not committed any technical error. This study sought to determine whether an acquired or inborn thrombophilic factor might be involved. METHODS: 44 divers with ischemic medullar lesions (36 men, 8 women, mean age 39.9+/-4.7 yr) were compared with 44 controls (34 men, 10 women, mean age 38.2+/-5.1 yr). Coagulation screening included proteins S, C, and thrombin III and Factor VIII assays and circulating antibodies, Factor V Leiden, and mutation G20210A in Factor II gene research. Total plasma homocysteine (Hcy), an atherosclerosis factor (assayed by FPIA), folate and vitamin B12, (by microbiology), the cofactors of its metabolism, were assayed, and subjects were genotyped for mutation C677T on the MTHFR gene. RESULTS: Coagulation screening--protein C, protein S, or antithrombin III deficit or mutation G20210A--was negative in all divers. 3/44 divers were heterozygous for Factor V Leiden, 1/44 had IgG antiphospholipid antibodies (9p.cent). While not found in controls, these percentages were not greater than those reported in the general population. 3/44 divers had elevated Factor VIII levels, but repeat assays on Day 2 were much lower. 11/44 divers had a moderate increase in Hcy value (20p.cent): in 7 divers, Hcy values were>15 micromol/L, and in 4 others>12, vs. 2.3p.cent of the controls; 2/11 had normal vitamin levels and 11 divers had folate or vitamin B12 deficiency or both, vs 2.3p.cent controls with a vitamin B12 deficit (percentage significantly different). 7/26 divers were homozygous for the C677T mutation, i.e. 27p.cent vs 12p.cent of 98 healthy controls (laboratory technicians). CONCLUSIONS: A high percentage of unexplained diving accident victims had moderate HHC, a folate or vitamin B12 deficiency or both, that are easy to detect, plus a genetic predisposition to HHC or to coagulation abnormality. Easy-to-perform homocysteine, vitamin B12, and folate assays might prove helpful for primary prevention of diving accidents.

Epidermal growth factor receptor and labeling index are independent prognostic factors in glial tumor outcome.

The aim of this study was to perform a multivariate analysis including clinical and biological prognostic factors on glial tumor outcome. Seventy-nine patients were analyzed (48 men and 31 women; mean age = 56 years, range = 16-77 years): 7 had a benign glial tumor (grades 1 and 2), 21 had an anaplastic glial tumor (grade 3), and 51 had a glioblastoma (grade 4). Median follow-up was 17.9 months for patients who survived (50 patients died). Biopsies were obtained at time of diagnosis (complete tumor resection in 62 patients and stereotaxic biopsies in 17 patients). Epidermal growth factor receptor (EGFR) was measured by a binding assay, and labeling index (LI) was measured by tritiated thymidine incorporation. EGFR varied from 4 to 73,110 fmol/mg protein (mean = 3912 fmol/mg protein; median = 374 fmol/mg protein; n = 79). LI varied between 0.1 and 16.5% (mean = 6.2%; median = 5.2%; n = 40). Log10 EGFR was significantly and positively correlated with patient age. LI was significantly different according to tumor histology. Univariate Cox analysis (end point was cancer death) showed that age (P = 0.027), log10 EGFR (P = 0.025), and LI (P = 0.0019) were significant continuous variables, the survival being shortened when the covariable increased; tumor resection (P = 0.015, relative risk = 0.45) and histology (P = 0.0009) were significant categorical factors. A multivariate Cox analysis (forward selection) including age, histology, tumor resection, log10 EGFR, and LI revealed that log10 EGFR, LI, and tumor resection were the only independent significant predictors of survival. This multivariate approach reveals that the clinical prognostic factors of glial tumors, namely age and tumor histology, disappear, to the benefit of intrinsic characteristics of the tumor, i.e., EGFR expression and LI, suggesting that coupled EGFR and LI determination could be a useful tool for better evaluation of glial tumor outcome.

[Relapsing remitting multiple sclerosis or multiphasic disseminated encephalomyelitis?]. / Sclérose en plaques rémittente ou encéphalomyélite multiphasique disséminée?

INTRODUCTION: The imaging presentation of some forms of multiple sclerosis may be misleading. In patients with a history of recent infection or vaccination, especially for adolescents or young adults, the differential diagnosis with acute disseminated encephalomyelitis can be difficult. CASE REPORT: We report an unusual clinical and radiological presentation of multiple sclerosis, mimicking acute disseminated encephalomyelitis. We discuss clinical and radiological differential diagnosis, and the outcome after immunosuppressive treatment. CONCLUSION: Distinguishing between acute disseminated encephalomyelitis and the first relapse of multiple sclerosis can be difficult. Brain imaging is a precious tool for differentiating between the two diseases.

The intranuclear filamentous inclusions of a human glioma. Their relation with nuclear bodies.

The intranuclear filamentous inclusions of a human glioma were analysed with an electron microscope equipped with a goniometer stage. The inclusions consist of 6 to 8 filaments. Considering the organization of the constituent filaments we distinguish three basic types: 1. Filamentous bundles of more or less parallel filaments, forming a cigarshaped inclusion. 2. Crystalloid inclusions: a. Prisms. They consist of stacked layers of strictly parallel filaments. The angle formed by the filaments of adjacent layers if 60 degrees. b. Cylinders. The layers of filaments are bent up and may form either a circle or a spiral, when the inclusion is seen in cross-section. 3. Partially crystalloid or "intermediate" inclusions. We consider them to be transitional forms between types 1 and 2 inclusions. The crystalloid layers of such intermediate inclusions may form either prisms or cylinders. Finally, the similarity between the granulo-fibrillar capsules surrounding granular nuclear bodies and filamentous inclusions, as well as the existence of granular material dispersed between the filaments of some inclusions led us to investigate a relationship between these two structures.

Expression of vascular endothelial growth factor-b in human astrocytoma.

Growth of human malignant gliomas is stringently dependent on an angiogenic process that probably involves vascular endothelial growth factor (VEGF). Expressions of mRNA coding for the different forms of VEGF were analyzed in surgical specimens from human astrocytomas. Low levels of placental growth factor (PGF) and VEGFC mRNA were observed in polymerase chain reaction, but not in Northern blot experiments. VEGF mRNA was found in some but not all grade and grade IV astrocytomas. VEGFB mRNA was observed in all tissue samples analyzed irrespective of the tumor grade. A new splice variant of VEGFB (VEGFB155) that lacks exons 5 and 6 is described. Expressions of VEGF mRNA in cultured glioblastomas cells were upregulated by hypoxia, but the sensitivity of the cells to hypoxia was reduced as compared with normal rat astrocytes. VEGF expression was depressed by dexamethasone. Expressions of VEGFB mRNA were affected neither by hypoxia nor by dexamethasone. The results indicate a coexpression of VEGF mRNA and VEGFB mRNA in human astrocytomas. Expression of VEGFB is markedly different from that of VEGF. Possible roles of VEGFB as a cofactor for hypoxia-induced angiogenesis in human astrocytomas are discussed.

Complex partial status epilepticus of extratemporal origin: report of a case.

A 28-year-old woman with no history of seizure was 7 months pregnant when she developed a prolonged complex partial status epilepticus (CPSE) organized in recurrent complex partial seizures of occipital origin, which was ascertained by the presence of elementary visual hallucinations and nystagmus heralding the attacks. EEG demonstrated recurrent seizures starting from the right occipital area. This especially refractory case of CPSE resolved after treatment with antiepileptic drugs and termination of pregnancy by cesarean section.

Ictal asomatognosia with hemiparesis.

A 69-year-old woman presented with an ictal Anton-Babinski syndrome (asomatognosia with hemiparesis). Except for head and eye deviation to the side of the paralyzed limb, epileptic nystagmus, brief episodes of impaired consciousness, and automatisms, clinical symptomatology was identical to Anton-Babinski syndrome of vascular origin. Results of MRI imaging were normal. EEG showed a simple partial nonconvulsive status epilepticus of right parieto-temporal origin. Anton-Babinski syndrome may thus be a functional expression of focal status epilepticus.

'De novo' absence status of late onset: report of 11 cases.

Absence status (AS) is a heterogenous epileptic syndrome that can occur at any age, usually in a context of prior epilepsy. Eleven cases of AS occurring in middle-aged patients who had no history of epilepsy were retrospectively collected over a 10-year period (10 women and one man; mean age, 58.6 years). Eight patients were receiving high doses of psychotropic drugs. Clinical and EEG presentation was similar to AS occurring in patients with prior epilepsy. Evaluation of precipitating factors revealed that AS coincided with benzodiazepine withdrawal in eight cases. Cofactors included excessive use of other psychotropic drugs, nonpsychotropic treatment, hypocalcemia, hyponatremia, and chronic alcoholism. CT demonstrated mild cerebral atrophy in six cases. There was no recurrence, even without chronic antiepileptic treatment. These data indicate that (1) most cases of "de novo" AS of middle age or late onset result from the addition of various epileptogenic factors; (2) AS can be considered a new and uncommon complication of benzodiazepine withdrawal, and (3) long-term administration of anticonvulsant medication may not be required.

Ehlers-Danlos syndrome with subependymal periventricular heterotopias.

A 24-year-old woman with Ehlers-Danlos syndrome had complex partial and right sensory motor seizures. MRI showed periventricular subependymal heterotopias, agenesis of the posterior part of the corpus callosum, mega cisterna magna, and aneurysms of the sinuses of Valsalva. This may constitute a new subtype of type 1 Ehlers-Danlos syndrome characterized by X-linked periventricular subependymal heterotopias and epilepsy.

Up-front chemotherapy with fotemustine (F) / cisplatin (CDDP) / etoposide (VP16) regimen in the treatment of 33 non-removable glioblastomas.

Despite combinations of surgery, radiotherapy (RT) and chemotherapy used in the treatment of glioblastomas, mean and median survival rates in most patients remain 12 months or less after diagnosis. RT and nitrosourea after surgery are the standard combination for glioblastomas. They may induce acquired resistance and, consequently, non-operable glioblastomas is a unique biological and clinical situation allowing evaluation of intrinsic chemosensitivity. We assess the fotemustine (F) (100 mg/m2 day 1)/ cisplatin (CDDP) (33 mg/m2 days 1-3)/etoposide (VP16) (75 mg/m2 days 1-3) monthly regimen for efficacy in non-removable glioblastomas at presentation. Between 1995 and 1998, 33 consecutive patients with symptomatic non-removable histologically proven glioblastomas were treated: none of them had previously received chemotherapy, irradiation or surgical debulking. Objective response was evaluated by contrast enhancement with magnetic resonance imaging (MRI) scan after each treatment. Toxicity was moderate and mainly haematological (grade III-IV thrombopenia = 20/171 cycles; leucopenia = 25/171). Neutropenic fever was rare and no intracranial haemorrhages or treatment-related deaths were noted. Nausea and vomiting (grade 1), and asymptomatic hearing loss were common. Peripheral neuropathy occurred in 3 patients. Objective response rates were 9/33 (27%) (stabilisation = 17/33). Mean survival time was 14.4 (11.2 months in the 26 deceased patients) with a median survival of 10 months. Median survival rates at 6 and 12 months were 88% and 42%, respectively. 7/33 patients are still alive with median survival of 34.6 months. 7/33 (4/7 alive) were long-term survivors (range: 19-67 months). Neoadjuvant chemotherapy in non-resectable patients is safe allowing delayed RT. Phase II chemotherapy trials should include studies with a subgroup of non-resectable tumours.

Fluorescence in situ hybridization study of aneuploidy of chromosomes 7, 10, X, and Y in primary and secondary glioblastomas.

The aneuploidy of autosomes 7, 10, and sex chromosomes (X and Y) was analyzed in a series of 44 primary (de novo) and 20 secondary glioblastomas using fluorescence in situ hybridization (FISH) on smear preparations of glioma tissue. The tumors were screened for trisomy 7, monosomy 10, as well as loss of the Y chromosome and disomy of the X chromosome in male subjects, and monosomy of the X chromosome in female subjects. We found that taken alone or in combination, these chromosomal abnormalities do not appear to be characteristic of a glioblastoma subtype; therefore, they do not allow the differentiation between primary and secondary glioblastomas. Also, the loss of a chromosome 10 appears to be an earlier event than a gain of a chromosome 7 for the genesis of a secondary glioblastoma.

Cytogenetics of malignant gliomas: I. The autosomes with reference to rearrangements.

Autosomal chromosome abnormalities are far from always detectable and, when detected, far from fully consistent in malignant gliomas. In 15 of 41 malignant gliomas, we found autosomal chromosome aberrations ranging from solitary trisomy to a wildly abnormal polyploid complement. The sequence of chromosome events appears to proceed from the normal to the near-diploid state (via structural and numerical changes) to near-tetraploidy (via polyploidization), and finally toward near-triploidy (via chromosome loss and additional rearrangements). Characteristic chromosome changes of trisomy 7 and monosomy 10 were repeatedly found, usually together in the same cell clones. In only one case was trisomy 7 an isolated change. We observed structural rearrangements of chromosomes 7 and 10 which may be of some use in mapping specific genes duplicated or deleted by the whole-chromosome changes of chromosomes 7 and 10. Nonrandom structural changes of other autosomes, including chromosomes 1, 5, and 11, fit with the model of malignant glioma as a process involving multiple genes. An unusual concentration of breakpoints in 12q13, juxtaposing it to at least five other regions, reflects the presence of genetic information in 12q13 important to the development of malignant gliomas.

Cytogenetics of malignant gliomas. II. The sex chromosomes with reference to X isodisomy and the role of numerical X/Y changes.

Sex chromosomal monosomy with total loss of an X or Y is frequently observed in malignant gliomas. Beyond that, not much is known about the behavior of the sex chromosomes in these tumors. We noted loss of the X from 3 of 13 gliomas from women (23%) compared to loss of the Y from 16 of 28 gliomas from men (57%). There were two structural rearrangements of the Y (an inversion and a translocation with chromosome 4). Most unexpectedly, clones with sex chromosome reversal were encountered in 3 cases. These XX clones in gliomas from men are perforce the consequence of Y loss coupled with X isodisomy, a nonrandom sequence of sex chromosome changes. We examined the company kept by numerical X and Y changes in clones and found that clones with numerical sex chromosome changes had fewer autosomal abnormalities, reflecting a distinct tendency to clonal separation of sex chromosome from autosomal abnormalities. We conclude that the sex chromosome changes are not a necessary part of the neoplastic process in malignant gliomas but that they must be of biologic significance to the brain since they are highly nonrandom in frequency, type, and sequence in brain cells.

[A case of bilateral lesions in the temporal convexity: attempt to define symptoms]. / Un cas de lesions bilaterales de la convexite temporale: tentative de definition des symptomes

The case is reported of a boy aged 15 who suffered a bilateral lesion of the temporal convexity after a brain traumatism; he died 5 years later and the symptoms during that period are described. The clinical picture is adequately described neither under the title of dementia, nor under that of aphasia. The concept of an abolition involving the systems of cultural mediation (linguistic, technical) is introduced. The status of echolalia and echo-praxia is discussed.

[11C]L-methionine uptake in gliomas.

Treatment of gliomas remains disappointing in spite of a great number of experimental biological data and of randomized therapeutic studies. This could be partly explained by the inefficiency of our conventional methods to assess the regional metabolism of these tumors. The use of positron emission tomography (PET) brings encouraging possibilities in this field. We report our preliminary experience of measuring regional cerebral methionine uptake with PET after intravenous injection of [11C]L-methionine. Twenty-two patients with histologically confirmed gliomas were studied. An ECAT II positron emission tomograph was used for scanning. The position of the plane was chosen to include a major section of the tumor in the reconstructed brain slice. The protocol required a two-step examination: 1) after injection of 15 to 25 mCi of [11C]L-methionine, 12 scans were performed over a period of 46 minutes; and 2) 18 hours later, regional cerebral blood volume was measured in the same slice after intravenous injection of 2 to 4 mCi of 68GaCl3. The tumoral region of interest was determined as being the area of maximum activity. For each patient we calculated the ratio, R, between the activity in this tumor region of interest and the activity in the contralateral healthy symmetric region of interest which was used as an "internal standard" for the same patient. We correlated the ratio R with the histological grading. In 22 patients, mean values of R were calculated for each tumor: Grade II (n = 5): R = 1.04 +/- 0.27; Grade III (n = 5): R = 1.68 +/- 0.22; and Grade IV (n = 12): R = 2.33 +/- 0.86.(ABSTRACT TRUNCATED AT 250 WORDS)

The antitumoral action of polyamine linked cyclophosphazenes on human malignant glioma heterografts in nu/nu mice.

Since the polyamine metabolism system is very active in proliferative glioma cells, polyamine linked drugs are to be considered as potential antineoplastic agents against malignant gliomas. This study reports the trial of a new compound lineage, the Polyamine Linked Cyclophosphazenes, on human glioblastoma heterografts in nu-nu mice. Two agents are tested: DIAM 3 and DIAM 4. Both show an important antineoplastic action either on a chronic treatment schedule or as single dose. Systemic tolerance is satisfactory.

Red blood cell polyamines as biochemical markers of supratentorial malignant gliomas.

Data obtained during post-surgical monitoring (2 to 28 months) of 32 histologically confirmed malignant supratentorial glioma patients, are reported here. It was observed that: whatever the grade of malignancy, 100% of the patients whose tumor recurred showed, on at least one occasion, abnormal red blood cell (RBC) spermidine (SPD) (greater than 14 nmoles/8.10(9) RBC) or spermine (SPM) (less than 2 nmoles/8.10(9) RBC) levels. 30% of the patients whose tumor recurred had abnormal RBC polyamine concentrations, one to six months before any other sign of tumor progression. In patients with normal RBC polyamine values, clinical and tomodensitometric indications of tumor progression have to be reconsidered. During individual follow-up, RBC SPD levels of each patient were generally significantly correlated to those of SPM, and the slopes of their straight regression lines (SRL) appeared to be related to the importance of the intracranial cell proliferation. In such conditions we established the regression equation of the group of all recurring patients taken together. We propose a graphic model, including a space corresponding to RBC SPD and SPM levels observed in case of tumor recurrence, which can be utilized routinely in neuro-oncology during the monitoring of post-operative malignant supratentorial glioma patients.

[Status epilepticus with aphasic manifestation]. / Etat de mal épileptique à expression aphasique.

Aphasia as the sole manifestation of focal status epilepticus in adult is rarely described. Such a case is reported here. Two separate episodes were studied: 1) prolonged mixed aphasia with continuous epileptic patterns; 2) Epileptic aphasia organized in shortly spaced temporal seizures marked by total suspension of speech, paraphasic utterances characterizing the interictal period. The clinical and EEG criteria and nosographic situation of this syndrome are reviewed. We conclude that epileptic aphasia exists if a fixed and lasting epileptic condition is created, even if a post-ictal phenomenon accounts for the symptomatology.

[Pain in multiple sclerosis]. / Les douleurs dans la sclérose en plaques.

Pain is a major issue in the care of Multiple Sclerosis patients. It is present in more than half of the cases and it adopts many aspects, which frequently ruin the patients quality of life. Most of them do not receive appropriate treatments, as clinicians are more oriented towards controlling the immuno-pathogenic process of the disease than coping with symptomatic consequences of the lesions. Any clinical form of the disease may include pain and no clinical criteria have been correlated with the occurrence of pain: neither age, nor gender, nor MS subtypes nor severity of the handicap; almost all MS cases will complain of pain at a time or another of their evolution. A key issue is to make a precise diagnosis of the type or types of pain that any patient reports: is pain due to a central neuropathic or a nociceptive pathogenesis. Treatments will depend upon these two main pain mechanisms and will use different agents according to each type: antispastic, antiepileptic, anti-inflammatory, opioids.... Pain has to be taken in consideration in every MS patient and adapted treatment strategy must be prescribed.