Massimo Scerrati

Poly(ADP-ribose) polymerase inhibitor increases growth inhibition and reduces G2/M cell accumulation induced by temozolomide in malignant glioma cells

Temozolomide (TZM) is a novel methylating agent currently under investigation for treatment of recurrent high‐grade gliomas. Although TZM generates a wide spectrum of methyl adducts, its cytotoxicity has been attributed to mismatch repair (MR)‐mediated processing of O6‐methylguanine:T mispairs. N3‐methyladenine and N7‐methylguanine adducts are promptly repaired by the base excision repair system, unless a poly(ADP‐ribose) polymerase (PARP) inhibitor is combined to TZM. In this case, the repair process of N‐methylpurines cannot be completed and the deriving DNA strand breaks contribute to cytotoxicity. In this study, we investigated the influence on cell growth and cell cycle of treatment with TZM + PARP inhibitor in glioma cells characterized by different susceptibility to TZM. The results indicated that PARP inhibitor increases growth inhibition induced by TZM in either p53–wild‐type or p53‐mutant glioblastoma cells, as early as 24 h after drug exposure. The enhancing effect exerted by PARP inhibitor was particularly evident in glioma cells characterized by a defective expression of MR, since these cells are tolerant to O6‐methylguanine damage and show low sensitivity to TZM. In O6‐alkylguanine‐DNA alkyltransferase (OGAT)‐deficient and MR‐proficient tumor cells bearing wild‐type p53, the drug combination markedly reduced cell accumulation in the G2/M phase of cell cycle and induction of the G2 checkpoint regulator Chk1 kinase. In short‐term cultures of glioma cells derived from surgical specimens, PARP inhibitor enhanced chemosensitivity to TZM and this effect was especially evident in OGAT‐proficient tumors. Thus, a pharmacological strategy based on the interruption of N‐methylpurine repair might represent a novel strategy to restore or increase glioma sensitivity to TZM. GLIA 40:44–54, 2002.

Epileptogenic Cerebral Low-Grade Tumors: Effect of Interstitial Stereotactic Irradiation on Seizures

15 patients with various types of surgically inaccessible epileptogenic cerebral neuroepithelial tumors were treated with stereotactic interstitial irradiation. Epilepsy was improved in all cases, being abolished in 6 and markedly reduced in another 7. The effects which became apparent soon after the radioisotope implant persisted. Possible mechanisms of the phenomenon are discussed.

Interstitial brachytherapy for low-grade cerebral gliomas: analysis of results in a series of 36 cases.

SummaryThe results obtained with interstitial brachytherapy in thirty-six low-grade cerebral gliomas (2 pilocytic astrocytomas, 23 astrocytomas and 11 oligodendrogliomas) are reported (mean follow-up: 75 months, range 37–159). All tumours were situated in locations which did not call for surgical removal as the treatment of choice. Their volume ranged from 4 to 82 cc (m=32); the Karnofsky performance status (KPS) of the treated patients lay between 0.60 and 0.90.The sources utilized (Iridium-192 in 32 cases and Iodine-125 in 4) were implanted permanently in 22 patients and temporarily in 14, using the Talairach stereotactic apparatus. The mean peripheral dose was 89.7 Gy for the permanent implants and and 42.8 Gy with a rate of 32.05 cGy/h for the temporary implants. External beam irradiation was added for tumour volumes greater than 35 cc (19 cases) on a second target volume extending 2 cm beyond the tumoural borders treated with interstitial irradiation.The survival estimates for the entire group showed a probability of 82.9% at 60 months, of 56.8% at 96, 39.4% at 120 (m.s.t.: 112 months). The quality of life in the treated patients was satisfactory, KPS never falling below a mean score of 0.70. The extent of the target volume turned out to be the most significant factor influencing survival at the multivariate analysis. Severe neurological impairment due to radionecrosis occurred in 4 patients (11%), three of them requiring surgical decompression. Target volume and radiation dose showed a direct correlation with the risk of radionecrosis at the regression analysis, the critical values being 35 cc and 100 Gy (permanent implants) or 50 Gy (42 cGy/h, temporary implants) respectively. The analysis of the results indicates that, even though many questions still remain open, brachytherapy can represent a valid alternative to surgery for tumours not suitable for surgical removal.

Factors of surgical outcome in tumoural epilepsy.

Summary Objectives. The purposes of the study were the assessment of the role of surgery in the suppression of epilepsy due to low-grade primitive cerebral tumours and the search for factors relevant to the surgical outcome. Patients and Methods. Forty-eight patients with epilepsy due to low-grade supratentorial cerebral tumours were considered. They presented drug-resistant daily to monthly seizures since for least one year (mean 7 yrs). Twenty-four patients underwent a combined tumour and epileptogenic zone resection (“epilepsy surgery”) and 24 tumour resection alone (“lesionectomy”). The surgical outcome was evaluated two years after surgery. Several variables related to the characteristics of the epilepsy, the tumour and surgery, were considered for a possible association with the outcome. Statistical analyses were performed. Results. Seizure freedom, including aura, was obtained in 35 patients (72.9%). Mild permanent complications occurred in 6 cases. Seizure suppression was significantly associated with complete tumour resection (post-surgical CT or MRI) and relatively low presurgical seizure frequency; it was also related, though not significantly, to small tumour size and histological grade I. The surgical outcome was only slightly better following “epilepsy surgery” than “lesionectomy”. However: i) the extent of tumour resection was not relevant regarding the “epilepsy surgery” outcome, while significantly influencing the outcome after “lesionectomy”; ii) the presurgical frequency of seizures and, to a less extent, the tumour size, had a higher influence on the outcome after “lesionectomy”. Conclusion. Long-lasting and drug-resistant epilepsy due to cerebral tumours can be suppressed surgically in the majority of cases. The extent of tumour resection and the frequency of the seizures are the most relevant prognostic factors. Both “epilepsy surgery” and “lesionectomy” can provide good results. However, the two approaches should not be regarded as interchangeable: a choice of the approach based on the characteristics of seizures and of the tumour appears relevant to improve the surgical prognosis.

Resection surgery for partial epilepsy. Relation of surgical outcome with some aspects of the epileptogenic process and surgical approach

SummaryIn spite of the progressive improvement of the results of resective surgery for epilepsy, the number of not significantly benefited patients remains high. An attempt was made to find out a relation between outcome and some aspects of the pathophysiological organization of the epileptogenic process and of the surgical procedure. Chi-square and logistic regression statistic analyses were utilized. The study was retrospectively performed on 138 surgically treated patients having a minimum follow-up of three years. Three classes of surgical outcome were considered: completely seizure free (including aura; 86 cases, 62.3%), significant seizure reduction (31 cases, 22.5%), and no significant improvement (21 cases, 15.2%). What follows was brought into evidence by the study. 1) On the diagnostic side, the spatial arrangement (focal, unilateral, multifocal) of both the interictal and the ictal epileptic electrocerebral activities are significantly associated with the surgical outcome. Their relative impact on outcome is related to the presence of a structural lesion: when a lesion is documented, the interictal activity has the higher value; vice versa, when no lesion is apparent, the role of the ictal activity is prevalent. However, the presence, as well as the nature of the lesion, per se, are not significantly associated with outcome. 2) On the surgical side, the extent of resection of both the structural lesion and of the epileptogenic zone are highly associated with the surgical result; the extent of lesion resection prevails on that of the epileptogenic zone. The type of surgical approach (hemispherectomy: 17 cases; temporal lobectomy: 67 cases; extratemporal resection: 54 cases) has no significant relation to the outcome. The value and the limits of the results obtained are discussed.

Callosotomy for generalized seizures associated with hypothalamic hamartoma

A case is reported of intractable epilepsy associated with a hypothalamic hamartoma in an 18 year old man. The patient underwent a two-third anterior callsotomy and, subsequently, removal of the hamartoma. Callosotomy did not affect the generalized seizure pattern. The authors believe this to be the first documented case of hypothalamic hamartoma in which callosotomy for seizure control was attempted. The poor response to callosotomy suggests the extracallosal diffusion of the generalized seizures from hypothalamic hamartomas.

Discussion on the causes of failure of surgical treatment of partial epilepsies.

Despite continuous improvement in diagnosis and surgery, persistence of seizures following surgical treatment of partial epilepsies still occurs in a relevant number of cases (30--40%). The analysis of personal material and of data from the literature appears to indicate that relevant causes of surgical failure are difficulties in delimitation of the epileptogenic zone and therefore of complete surgical removal. These difficulties are illustrated and discussed.

Comments on brachycurie therapy of cerebral tumours.

Between 1980 and 1987 thirty patients harbouring cerebral neuroepithelial tumours have been treated with stereotactic brachycurie therapy (18 males, 12 females), either alone (n = 16) or combined with surgery (n = 7) and/or external radiotherapy (n = 10). There were 25 slowly growing tumours (grade I n = 1; grade II n = 24). The remaining 5 were malignant tumours (grade III n = 3; grade IV n = 2). The radioactive sources utilized were 192Ir in 26 cases and 125I in 4. Twenty-eight patients underwent permanent implantation, the other two received temporary irradiation with removable after-loaded catheters. Target volume was less than 15 cm3 in 6 cases, between 16-60 cm3 in 17 and more than 60 cm3 in 7. Tumour dose at the periphery of the target volume was: 70-100 Gy in 19 and 100-130 Gy in 9 of the cases treated with permanent implantation; the patients irradiated with removable implants received 40-60 Gy in 5-7 days. General follow-up ranged between 0.3 and 6.9 years (mean = 2.5 years). The results are analyzed with reference to the following aspects: 1) natural history of the disease; 2) modalities and goal of the treatment; 3) place of brachy therapy as sole treatment and combined with the other available therapeutical means.

Natural History of Neuroepithelial Tumours: Contribution of Stereotactic Biopsy

Quantitative tumour growth into the brain (stage of the disease) and qualitative tumour evolution in the time (progression) are the two basic aspects of the natural history of the cerebral neoplastic disease. Recently the development of neuroradiological imaging (CT and MR) and the progress in biopathology of the nervous system tumours introduced new concepts like heterogeneity of neuroepithelial tumours or evolution to anaplasia. The findings obtained in 159 neuroepithelial tumours studied with stereotactic biopsy from 1980 to 1987 are presented. Most of them were glioblastomas (n = 43; 27%) and astrocytic tumours (n = 81; 50.9%). Twenty-nine cases of fibrillary astrocytomas (35.8% of all astrocytic tumours) showed focal anaplasia (progression). In 10 out of the 43 glioblastomas (23.3%) signs of astrocytic differentiation were clearly evident (secondary glioblastoma?). Our data confirm that neuroectodermal tumours, particularly of astrocytic series, undergo progression through anaplasia, which may be at the beginning a circumscribed phenomenon (focal anaplasia). The staging of the disease (tumour growth) into cerebral nervous system in some cases can not be correctly expressed through the neuroradiological imaging. Sometime CT scan may underestimate the true extension of the lesion. On the contrary, MR may overrate the extension of the lesion. Such mistakes in evaluation of tumour staging may be corrected through seriate stereotactic biopsy.

Neurosurgery at the Catholic University in Rome.

Neurosurgery at the Catholic University in Rome was initiated by Gian Franco Rossi in 1969 and has gradually expanded since then. From the beginning, research has been regarded as an essential part of training and daily activities in the universitys neurosurgery programs. The professional and research education of all faculty members includes at least 1 year abroad in a reputable neurosurgical center. Subspecialization is encouraged. Today, the faculty is composed of 3 full professors, 4 associate professors, and 16 assistant professors. The universitys neurosurgery programs include the Institute of Neurosurgery, the residency program, and the following clinical units: a Division of General Neurosurgery; three subspecialty sections comprising Neurotraumatology, Pediatric Neurosurgery, and Functional and Spine Surgery; a day hospital; and dedicated laboratories. More than 1700 surgical patients are treated annually. Epilepsy, pain management, parkinsonism, spinal cord and vertebral pathologies, clinical and basic neuro-oncology, cerebrospinal fluid and intracranial pressure dynamics, cerebrovascular disease, neurotrauma, developmental malformations, and peripheral and central nervous system neuroregeneration are the main fields of clinical and research activities. The results of the research performed thus far at the Catholic University in Rome have been reported in more than 900 publications, most of which have appeared in prominent journals and books. Members of the faculty are involved in relevant editorial activities and serve as officers of national and international scientific and professional societies. In 1999, Giulio Maira succeeded Dr. Rossi in directing the Institute of Neurosurgery and the Division of General Neurosurgery. In addition to the history of neurosurgery at the Catholic University in Rome, this article describes present challenges and plans for the future in neurosurgery at the university.