Gilles Guy

Local and sustained delivery of 5‐fluorouracil from biodegradable microspheres for the radiosensitization of glioblastoma

The authors have developed a new method of drug delivery into the brain using implantable biodegradable microspheres. In this study, this method was used to provide localized and sustained delivery of 5‐fluorouracil (5‐FU) after the surgical resection of glioblastoma. This antimetabolite and radiosensitizing drug was selected in an attempt to decrease the rate of local recurrence of the tumor.

Effect of Stereotactic Implantation of Biodegradable 5-Fluorouracil-loaded Microspheres in Healthy and C6 Glioma-bearing Rats

OBJECTIVE Poly(lactic acid-co-glycolic acid) (PLAGA) microspheres are promising systems for interstitial chemotherapy of brain tumors. They can be readily implanted by stereotaxy and are biocompatible with the brain, in which they are totally biodegraded within 2 months. 5-Fluorouracil (5-FU) was selected for encapsulation, because this hydrophilic and antimetabolic drug is not directly neurotoxic and does not readily cross the blood-brain barrier. Also, its anticancer activity may be improved by sustained administration. Furthermore, it is a potent radiosensitizer. METHODS To study their fate and toxicity, two types of 5-FU-loaded PLAGA microspheres were implanted in healthy rats by stereotaxy. One type presented a fast in vitro release profile (FR), and the second exhibited a slow in vitro release pattern (SR) (100% of the encapsulated 5-FU is released within 72 hours and 18 days, respectively). Periodically, rats were killed for microscopic examination. The efficacy of these microspheres on rat glioma was then evaluated. Seven days after stereotactic implantation of C6 malignant glioma cells in the brain, the rats were treated by intratumoral injection of 5-FU solution, blank microspheres, or 5-FU-loaded microspheres (FR and SR types). The mortality of these treated groups was compared by the log-rank test with that of an untreated group. RESULTS After implantation of two types of 5-FU-loaded PLAGA microspheres, no sign of clinical or histological toxicity was observed. Entrapped 5-FU crystals were observed until Days 12 and 20 postimplantation within FR and SR microspheres, respectively, which suggests a longer releasing period in vivo than in vitro. In the therapeutic evaluation, only intratumoral implantation of SR-type 5-FU-loaded microspheres significantly decreased the mortality (P = 0.017). CONCLUSION 5-FU-loaded PLAGA microspheres were implanted in rat brains without evident toxicity. Histological examination suggested a longer sustained delivery period in vivo than in vitro. Intratumoral implantation of SR-type 5-FU-loaded microspheres decreased the mortality of C6 tumor-bearing rats. This effect can be related to the local and the sustained delivery of the drug, because 5-FU administered systemically is ineffective against brain tumors.

Drug Targeting into the Central Nervous System by Stereotactic Implantation of Biodegradable Microspheres

Controlled drug release in the central nervous system through an implantable polymeric vector has been developed in recent years. For this purpose, different polymeric devices composed primarily of synthetic biocompatible and biodegradable polymers have been investigated. The first polymeric devices developed were macroscopic implants (monolithic devices), which required open surgery for implantation. Microencapsulation methods, however, allow the production of microparticles or nanoparticles loaded with neuroactive drugs. Because of their size, these micro- or nanoparticles may be easily implanted by stereotaxy in discrete, precise, and functional areas of the brain without causing damage to the surrounding tissue. Presently, this method is most frequently applied in the fields of neuro-oncology and neurodegenerative diseases, but neurologically, the potential applications of drug targeting by stereotactic implantation of drug-loaded particles are legion.

Recurrent intrinsic brain stem epidermoid cyst

The authors report the case of a 14-month-old baby boy with an epidermoid cyst located entirely within the pons and medulla, without an exophytic component. The lesion was examined by computed tomography and magnetic resonance imaging. The child was operated upon three times after two recurrences of the lesion. A suboccipital, subtonsillar approach was used for the first and second procedures and a transtemporal approach for the last one. Excision was thought to be complete the first time, since a solid tumor was found and removed in a large cyst. The cyst wall was not identified. No tumor was found during the second procedure despite recurrence of the cyst, which was drained without an attempt to remove the cyst wall. Finally the cyst recurred with a large tumor in the cyst wall which was again totally removed. Consistent with the high mortality of brain stem epidermoid cysts in the literature, the child eventually died. The therapeutic problems, surgical options, and consequences are discussed.

Intramedullary epidermoid cyst evaluated by computed tomographic scan and magnetic resonance imaging: case report

The authors have treated a 20-year-old man with a dorsal intramedullary epidermoid cyst in whom magnetic resonance imaging was performed both before evacuation of the cyst and 3 months later. Intraspinal epidermoid tumors are rare, and the intramedullary location is quite uncommon. To our knowledge, this is the first description of magnetic resonance imaging of an intramedullary epidermoid cyst. The frequency, possibilities, and limits of surgical treatment of such intraspinal benign tumors are reviewed.

Are the calcium antagonists really useful in cerebral aneurysmal surgery? A retrospective study.

From 1983 to 1990, 234 patients with one or several cerebral arterial aneurysms were surgically treated in our department. Since 1983, we have been performing surgery as early as possible. As soon as the subarachnoid hemorrhage diagnosis is confirmed by computed tomography (or if unconfirmed, by lumbar puncture), we assume that each patient may have an aneurysm. Between 1987 and 1990, 111 patients were treated by vascular volume expansion (maintenance of central venous pressure above 5 cm H2O with 4% albumin or Ringer-lactate or, if necessary, with 20% albumin), which we supplemented with calcium antagonists (nimodipine in 60 patients and nicardipine in 51 patients). Two months after being discharged, each patient is examined by a neurosurgeon and, on the same day, is subjected to a neuropsychological evaluation and a computed tomographic scan of the brain. A few months after this consultation, a working-position/family-activities questionnaire is issued to the patient. All of the results studied on the basis of postoperative mortality, second-month computed tomographic scan ischemia, neuropsychological evaluation, and return to work show no significant difference between the groups with or without calcium antagonists or between the nimodipine and nicardipine subgroups.

Cavernomas of the spinal cord: Report of two patients

Two operated cases of spinal cord cavernomas are presented. Since spinal angiography is usually normal and myelography not specific, the contribution of magnetic resonance imaging to the diagnosis is emphasized. Surgical considerations of treatment are discussed.

Invasive character of an intradural spinal meningioma in early childhood

The authors report the case of a 2-year-old baby girl with an intradural meningotheliomatous meningioma of the cauda equina which recurred three times. Despite four operative procedures and localized radiotherapy, the lesion kept on growing to reach the retroperitoneal space. Extensive laminectomy and associated radiotherapy were probably responsible for a spinal dislocation which had to be operated on. The child was left paraplegic with major bladder dysfunction after all procedures. This is the first reported case of well-documented “malignant” evolution of a spinal meningioma.

Vertebral hemangioma. Spontaneous spinal canal remodeling after fracture.

Study Design. The patient in this report had a fracture of a hemangiomatous vertebra with a fragment protruded into the canal and without neurological signs. There was a 12 month follow-up. Results. After conservative treatment, there were no neurologic signs, a good fusion, and natural remodeling of the spinal canal. Conclusions. The risk of a hemangiomatous vertebra fracture with a fragment retropulsed into the spinal canal and without neurologic signs is low. Also, a remodeling of the spinal canal can occur, as after a burst fracture.

Neuroepithelial Tumors of the Brain Stem

Summary:We review 86 brain stem tumors that are classified into three groups according to strict pathological criteria [World Health Organization (WHO) classification] to give the elements of diagnosis and prognosis. Group I gathers 39 cases of benign tumors, usually WHO grade I pilocytic astrocytoma, involving the cervicomedullary junction, the medulla oblongata, the mesencephalon, or the 4th ventricle (with dorsal exophytosis). The duration of symptoms before diagnosis is usually >6 months. Magnetic resonance imaging (MRI) scan shows well-delimited lesions with hyposignal in Tl-weighted sequences, with signal enhancement after gadolinium injection and sometimes with intratumoral cysts. Total surgical resection is the treatment of choice. The outcome is favorable because the Group I patients have a 2-year survival rate of 70%. Group II is composed of 30 malignant tumors (WHO grades III and IV anaplastic astrocytoma and glioblastoma) that mainly involve the pons, with possible cranial and caudal extensions. The duration of symptoms before diagnosis is usually <3 months. MRI shows poorly delimited tumors with iso- and hyposignals in Tl-weighted sequences. Surgery is not considered helpful. The outcome is poor: The 2-year survival rate is ˜12%. Group III includes intermediate tumors, i.e., 17 patients with WHO grade II fibrillary astrocytoma. Depending on their location, duration of symptoms, and radiological features, these tumors behave differently. The prognosis is part of their behavior as tumors of Group I or Group II.