[Unruptured intracranial saccular aneurysms less than 20 mm in diameter in adults. Radical surgery in 89 cases]. / Les anévrysmes artériels sacculaires intracrâniens non rompus de l'adulte d'un diamètre inférieur à 20 mm. Chirurgie radicale dans 89 cas.

Between 1972 and 1989, 131 unruptured intracranial saccular aneurysms were clipped in the Neurosurgical Department of La Pitié Hospital, Paris. Only 89 of these are considered here, the remaining 42 aneurysms having been discovered and clipped during surgery for a ruptured aneurysm. All isolated unruptured aneurysms were detected by angiography, computerized tomography or magnetic resonance imaging. Twenty out of the 89 aneurysms were asymptomatic ("incidental") while 69 were accompanied by clinical symptoms indicating radiological examination. It is generally accepted that in ruptured aneurysms the mortality rate during 3 days following the rupture is about 50 percent, and for this reason many neurosurgeons are in favour of unruptured aneurysms being treated either by open surgery with clipping of the aneurysmal neck or by inserting a balloon into the aneurysmal sac. The results obtained in 377 published cases, including ours, justify this approach: no recurrent bleeding was observed after open surgery and the mortality rate was nil when the contra-indications of surgery were respected. There was a permanent morbidity of less than 2 per cent directly related to the surgeon's experience.

Steroid receptor status difference in recurrent intracranial meningioma and breast cancer in the same patient.

The authors report a case of multiple recurrent intracranial meningioma associated with breast cancer in a menopausal woman. High affinity estrogen (ER) and progestin receptors (PR) were assayed independently in the meningioma and the tumor. ER were found to be very low in the meningioma and high in the breast tumor. On the contrary PR were found to be high in the meningioma and could be not detected in the breast tumor. This unique case suggests that meningioma and breast cancer are not under the same type of hormonal influence.

[Necrosis of the optic tract, hypothalamus and brain stem after irradiation of a pituitary adenoma with conventional doses]. / Nécrose des voies optiques, de l'hypothalamus et du tronc cérébral après irradiation d'un adénome hypophysaire a doses conventionnelles.

A 56-year-old man had radiation necrosis of the optic pathways, hypothalamus and brainstem following irradiation of a pituitary adenoma at a conventional dose. Factors which predispose to this complication are discussed. Vascular risk factors appear to facilitate radiation induced necrosis, and a reduction of doses is suggested in these cases.

[Early manifestations of neuromeningeal syphilis. Review of the literature apropos of 3 severe forms]. / Manifestations précoces de la syphilis neuro-méningée. Revue de la littérature à propos de 3 formes graves.

We report 3 cases of severe syphilitic neuro-meningitis during the secondary stage: acute transverse dorsal myelitis with permanent paraplegia in a 17 year old teenager (case no. 1), uveo-meningitis with intracranial hypertension and diminished vision in a 52 year old woman (case no. 2), lower medulla lesion in a 46 year old man (case no. 3). The diagnosis was based upon highly positive serological tests for syphilis, associated with a compatible clinical context and meningitis in CSF specimens. Treatment was successful in cases nos. 2 and 3, unsuccessful in case no. 1 due to the irreversible character of the medullar lesions. Based on these 3 cases, the following points are discussed: the relatively atypical clinical character in the current context, the difficulties of the diagnosis, and the treatment regimens recommended for neurological syphilis. Despite the rarity of such cases, their extreme severity early in the secondary stage strongly implies the necessity for prevention by detecting and treating early syphilis. Attention is drawn upon the importance of doing serological tests for syphilis when presented with any atypical neurological situation.

Phase II evaluation of diaziquone (CI-904, AZQ) in the treatment of human malignant glioma.

Diaziquone, a new alkylating agent which crosses the blood brain barrier, has shown a 20% response rate in phase II studies in heavily pretreated patients. We have treated 23 patients at our institution as part of a multicentric phase II European trial of diaziquone. All had histologically proven malignant glioma unequivocally progressing on CT scan. Prior therapy had consisted of surgical excision (13 patients), cobalt radiotherapy to CNS (13 patients), and chemotherapy with nitrosourea derivatives (11 patients). Six patients had no prior therapy. Median age was 42 years (range 22-69) and performance status was 3+ or better. They were treated with monthly courses of diaziquone 5.5 mg/m2 I.V. (10 min.) X 5 days. Dosage adjustments were made according to leucocyte and platelet nadirs. Thrombocytopenia was the dose limiting toxicity. Very mild gastrointestinal toxicity was observed. One patient developed hemolytic anemia. One complete response (clinical and CT scan), 7 partial clinical responses (3: greater than 50%, 4: 25-50%), and 1 disease stabilization (less than 25%) were documented. The longest response has now lasted over 26 months. These preliminary results show that chemotherapy with diaziquone can achieve a response rate as high as 35% in malignant glioma even in patients previously treated with a chemotherapy regimen including a nitrosourea (four of the seven objective responses were seen in such patients). Diaziquone is well tolerated and deserves further study in the management of malignant glioma.

[Hypoglycorrhachia and postpartum aseptic cerebral thrombophlebitis with meningeal hemorrhage]. / Hypoglycorachie et thrombophlébite cérébrale aseptique du post-partum avec hémorragie méningée.

A 42-year-old woman had a puerperal aseptic cerebral thrombophlebitis with repeated episodes of subarachnoid hemorrhage. Cerebrospinal fluid studies revealed a delayed, severe and lasting low sugar and high protein levels. The possible mechanisms of low sugar levels are discussed.

Cerebral edema associated with meningiomas: possible role of a secretory-excretory phenomenon.

A retrospective study of cerebral edema in 40 patients with intracranial meningiomas seems to demonstrate that the extent of edema is not related to anatomical factors such as location. Histological type is more significant; cerebral edema is usually observed with meningothelial forms. Furthermore, the study of tumor cells by electron microscopic methods indicates that secretory-excretory activity is closely associated with with the production of peritumoral edema. The ultrastructural aspects of this secreted material are described, but further biochemical studies are necessary to determine its exact nature. The possible role of tumoral steroid receptors in the secretory-excretory phenomenon is discussed.

[Steroid receptors in the central nervous system. Implications in neurology]. / Les récepteurs de stéroides du sytème nerveux central. Implications en neurologie.

This review deals with steroid hormones and receptors in relation to the physiology and the pathology of the central nervous system (CNS) and meninges. In recent years experiments performed in animals showed that: 1) endogenous steroid hormones cross the blood brain barrier: 2) radiolabelled steroid hormones bind in specific areas of the CNS; 3) all five classes of steroid receptors, i.e. oestrogen, progesterone, androgen, glucocorticoid and mineralocorticoid receptors (OR, PR, AR, GR, MR), are present in brain tissues, especially in the hypothalamus and the limbic system; 4) the interaction of steroid hormones and specific receptors induces the synthesis of proteins in the CNS; 5) finally, in situ metabolism of steroid hormones has been evidenced by the presence of specific enzymes. A few studies in human brain tissues have shown the presence of GR and OR as well as enzymes involved in the metabolism of sex steroid hormones. In neurology, some epidemiological and clinical data suggest the implication of steroid hormones and receptors in human CNS: 1) the influence of oestrogens in tardive dyskinesia; 2) the relevance of hormonal changes in benign intracranial hypertension; 3) the usefulness of glucocorticoid therapy in many patients with intracranial tumors and/or edema. Due to feasibility, most researches have concerned tumors: meningioma, neurinoma and glioma. Firstly, a reappraisal of biochemical and histochemical technics used to detect and characterize the receptors in tumors is presented. Then results from the recent literature are reviewed. In meningioma, PR was found in 89 p. 100 (152/177) of the cases, usually at moderate to high levels (up to 33 000 fmol/gT). In addition, PR has been fully characterized from a biochemical point of view. Furthermore, it has been hypothesized that PR may be a marker of leptomeningeal cells since it was detected at high levels in well differentiated tumors provided they had no or few psammoma. This was further supported by the discovery of PR in normal leptomeninges in human adults. OR was detected in 48 p. 100 (87/177) of the meningioma, at low levels. This is in contrast with PR but the percentage of cases with OR raises to 70 p. 100 (42/60) if one considers only tumors assayed for both cytosolic and nuclear receptors. Therefore it has been suggested that OR had translocated into the nucleus, at least in some cases, and subsequently the hypothesis of functional OR in meningioma was raised. AR was also detected in meningioma. Furthermore AR levels were found to correlate well with PR levels.(ABSTRACT TRUNCATED AT 400 WORDS)

Cytosolic and nuclear sex steroid receptors in meningioma.

To determine the nature of the hormone dependency of meningioma, particularly whether progestin receptor (PR) and tumor growth are estrogen-dependent, we measured the cytosol estrogen receptor (ER) and PR separately by an exchange assay with [3H]R 2858 (for ER) and [3H]RU 27987 (for PR) in 21 meningiomas. We correlated these receptors with age, plasma estradiol and progesterone concentrations, histological subtypes, clinical data such as uterine fibromas, and finally preoperative glucocorticoid therapy. ER was detected at low levels in the cytosol and in the nucleus of a few tumors whereas PR was found in 20 of 21 cases at moderate to high levels, usually with higher concentrations in the cytosol than in the nucleus. No clear relation could be drawn between either cytosol or nuclear ER and PR levels and estradiol and progesterone plasma concentrations, or with the other parameters. On the contrary, a clear correlation could be drawn between cytosolic PR and androgen receptor (AR) concentrations (measured with [3H]R 1881 in the presence of triamcinolone acetonide), leading to several hypotheses of hormonal regulation in meningioma.

[Progesterone receptors in normal human leptomeninges in adults]. / Récepteurs de la progestérone de la leptoméninge humaine normale chez l'adulte.

Cytosolic and/or nuclear 3H-R 5020 binding sites were detected in 6/6 samples of normal leptomeninges obtained at the time of operation in human adults. The levels of binding sites were higher in leptomeninges samples (range of values: 140-1780 fmol/gT) than in the corresponding intracranial tumors (one meningioma, two neurinomas, one metastasis) in 3 out of the 4 cases that were simultaneously studied. The 3H-R 5020 binding systems were characterized in 2 groups, A and B, of pooled samples representing respectively 4 and 17 samples of normal leptomeninges. The study of A (cytosolic and nuclear binding sites) and B (cytosolic binding sites) groups showed that binding systems had a limited capacity and a high affinity (Kd were respectively 2 X 10(-9) and 5.3 10(-10) M) as previously noted for the progestin receptor in human meningioma. Biochemical data and ultrastructural pictures obtained in the present study as well as in previous works, allow to consider the presence of the progestin receptor in normal leptomeninges.

[Kinetics of multicellular spheroids developed from a human glioblastoma, and effect of 1,3-bis (2-chloroethyl)-1-nitrosourea]. / Cinétique de sphéroïdes multicellulaires développés a partir d'un glioblastome humain et action de la 1,3 bis (2-chloroethyl)-1-nitrosourée.

Multicellular spheroids (MCS) were yielded in vitro by early stages of human glioblastoma cell cultures. The spheroids were grown in suspension in the culture medium in agarose-coated (0.65%) dishes. The volume doubling time during the exponential growth phase was longer (13 days) than the population doubling time of monolayer cultures (2-3 days). Pathological examination of MCS showed a thin proliferative outer layer and areas of necrosis in the center. In two experiments BCNU caused a growth delay of MCS which was dose-related. The cells were sensitive to BCNU in monolayer cultures (CFE's assay), whereas the tumor was resistant in vivo. The usefulness and pitfalls of studies using MCS cultured from early passages of human malignant gliomas are discussed.

Stem cell studies of human malignant brain tumors. Part 1: Development of the stem cell assay and its potential.

A stem cell assay for human malignant gliomas has been developed. Cells obtained from tumor biopsies grew into colonies composed of malignant glial cells, as documented by histochemical, immunohistochemical, and immunobiological techniques. Studies suggest that the disaggregated cells are representative of the cells within the solid tumor. Clonogenic cells were obtained from 48 tumors and analyzed for their in vitro sensitivity to graded doses of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). The in vitro anti-tumor activity of BCNU at clinically achievable doses was compared to clinical response to the agent based on changes in computerized tomographic scan, radionuclide brain scan, and neurological examinations. Twenty-two patients received nitrosoureas before or after tumor specimen analysis, and were eligible for in vitro-in situ correlations. Clinical tumor sensitivity to nitrosoureas was predicted by culture results in 42% of all evaluable patients, and clinical resistance was predicted in 100%. The capability of the assay can be appreciated best for the 13 patients not treated with BCNU prior to culture; the in vitro prediction of clinical sensitivity and resistance was 71% and 100%, respectively. Preliminary findings show that clinical tumor resistance to BCNU may result from "intrinsic" cell resistance in some patients and from inadequate delivery of drug to tumor cells in other cases. The potential utility of this method to study the reason(s) for tumor cell resistance to drugs, to screen new chemotherapeutic agents, to individualize patient treatment, and to investigate tumor biology is discussed.

[Spontaneous dissecting aneurysms of the cerebral arteries]. / Les anévrysmes disséquants spontanés des artères cérébrales.

A review of the literature on Spontaneous Dissecting Aneurysms (DA's) of cerebral arteries is presented with 3 personal cases of DA's of the Internal Carotid Artery (ICA). Patients with spontaneous DA's of the extracranial ICA are of middle age (30 to 60 year old) and present with an ipsilateral pain in the neck or face and/or with TIAs (45 p. 100 and 50 p. 100 of the cases respectively). Claude Bernard-Horner's sign is frequent. The clinical, radiological and pathological data suggest that in most cases, if not all, neurological deficits are due to embolism and/or anterograde thrombus. This has led to recommend anticoagulant therapy. Nevertheless, surgery may be indicated is some situations such as in DA's on kinking arteries. The treatment of spontaneous DA's of extracranial vertebral arteries is still a detectable matter, though they have common features with DA's of the extracranial ICA. The DA's of the basilar and intracranial vertebral arteries are often associated with a subarachnoid haemorrhage and most of them have a severe outcome. Lesions of the arterial wall such as cystic medial necrosis and fibromuscular dysplasia play a role in the extent, and presumably in the initiation, of the so-called spontaneous DA's at least in some cases. Minor trauma, high blood pressure (20 p. 100 of the cases), oral contraceptives and coughing have been as well suspected.

Steroid hormone receptors in human meningiomas, gliomas and brain metastases.

Progestin, estrogen, androgen, glucocorticoid as well as mineralocorticoid receptors (PR, ER, AR, GR and MR, respectively) were all evaluated with specific synthetic radioligands (biochemical assays) in 25 meningiomas, 9 gliomas and 4 brain metastases. In meningiomas the main steroid hormone receptors appeared to be the progestin receptor, present in 24/25 cases (mean level: 7 105 fmol/gT) and the androgen receptor, present in 23/25 cases (mean level: 2 265 fmol/gT). Progestin receptor levels were found to be significantly lower in meningiomas of the fibroblastic subtype whereas none of the steroid hormone receptors were detected in the anaplastic case. On the other hand, glucocorticoid receptor levels were related to the preoperative glucocorticoid therapy. In gliomas only estrogen receptors (2/9 cases) and especially androgen receptors (8/9 cases) were noticeable: the latter seemed to be related to the histological types and to the sex of patients. No receptors were found in any of the four studied metastases, including one from breast cancer. The biochemical characterization of the receptors as well as their relevance to tumor biology and to the physiology of the normal tissues where tumors arise, were discussed, and biochemical data were compared with those previously reported.

Progestin and oestrogen receptors in meningiomas. Biochemical characterization, clinical and pathological correlations in 42 cases.

Progestin receptors (PR) were evaluated in 40 intracranial and 2 spinal meningiomas. PR measured with radiolabelled R 5020 were found in 93% of cases (39/42). PR levels were significantly higher (p = 0.05) in females (mean: 5,720 fmol/gmT) than in males (mean: 3,120 fmol/gmT). Biochemical characterization of the R 5020 saturable binding sites showed that they were mainly cytosolic, had a high affinity constant (Kd approximately equal to 1 nM) and were progestin specific. Correlation with sex suggested some biological activity of PR in meningiomas. Oestrogen receptors (OR) were evaluated in 36 intracranial and 2 spinal meningiomas. OR measured with radiolabelled R 2858 were present in 79% of cases (30/38). OR mean levels were equal in females (mean: 285 fmol/gmT) and in males (mean: 330 fmol/gmT). The relevance of PR and possibly OR in the biology of meningiomas and of leptomeninges was suggested by the presence of receptors in a sample of normal leptomeninges.

[Malignant gliomas treated by combination chemotherapy and delayed radiation therapy (author's transl)]. / Traitement des gliomes malins par chimothérapie d'association et irradiation retardée.

The authors present the therapeutical results of two clinical and histological homogeneous series of malignant gliomas. The first group includes 46 patients operated upon and treated successively by chemotherapy associating VM26 and CCNU, a conventional delayed radiotherapy 6 months after surgery and again chemotherapy. In this group, the mean survival is 17 months and 46% of patients were surviving at 18 months. The second group includes 28 patients operated upon and treated with the same associated chemotherapy without radiation therapy. The mean survival was 11 months and 24% of patients were surviving at 18 months. The comparison of results shows that after surgery, the association of a chemotherapy and delayed radiotherapy is more efficient than chemotherapy alone. However, the systematic study of nervous system tolerance to irradiation post-chemotherapy suggests that, in some cases, the chemotherapy is able of increasing the pathogenic effect of irradiation on the brain.