KCa3.1 channels are involved in the infiltrative behavior of glioblastoma in vivo.

Glioblastoma multiforme (GBM) is a diffuse brain tumor characterized by high infiltration in the brain parenchyma rendering the tumor difficult to eradicate by neurosurgery. Efforts to identify molecular targets involved in the invasive behavior of GBM suggested ion channel inhibition as a promising therapeutic approach. To determine if the Ca(2+)-dependent K(+) channel KCa3.1 could represent a key element for GBM brain infiltration, human GL-15 cells were xenografted into the brain of SCID mice that were then treated with the specific KCa3.1 blocker TRAM-34 (1-((2-chlorophenyl) (diphenyl)methyl)-1H-pyrazole). After 5 weeks of treatment, immunofluorescence analyses of cerebral slices revealed reduced tumor infiltration and astrogliosis surrounding the tumor, compared with untreated mice. Significant reduction of tumor infiltration was also observed in the brain of mice transplanted with KCa3.1-silenced GL-15 cells, indicating a direct effect of TRAM-34 on GBM-expressed KCa3.1 channels. As KCa3.1 channels are also expressed on microglia, we investigated the effects of TRAM-34 on microglia activation in GL-15 transplanted mice and found a reduction of CD68 staining in treated mice. Similar results were observed in vitro where TRAM-34 reduced both phagocytosis and chemotactic activity of primary microglia exposed to GBM-conditioned medium. Taken together, these results indicate that KCa3.1 activity has an important role in GBM invasiveness in vivo and that its inhibition directly affects glioma cell migration and reduces astrocytosis and microglia activation in response to tumor-released factors. KCa3.1 channel inhibition therefore constitutes a potential novel therapeutic approach to reduce GBM spreading into the surrounding tissue.

Stop-event-related potentials from intracranial electrodes reveal a key role of premotor and motor cortices in stopping ongoing movements.

In humans, the ability to withhold manual motor responses seems to rely on a right-lateralized frontal-basal ganglia-thalamic network, including the pre-supplementary motor area and the inferior frontal gyrus (IFG). These areas should drive subthalamic nuclei to implement movement inhibition via the hyperdirect pathway. The output of this network is expected to influence those cortical areas underlying limb movement preparation and initiation, i.e., premotor (PMA) and primary motor (M1) cortices. Electroencephalographic (EEG) studies have shown an enhancement of the N200/P300 complex in the event-related potentials (ERPs) when a planned reaching movement is successfully stopped after the presentation of an infrequent stop-signal. PMA and M1 have been suggested as possible neural sources of this ERP complex but, due to the limited spatial resolution of scalp EEG, it is not yet clear which cortical areas contribute to its generation. To elucidate the role of motor cortices, we recorded epicortical ERPs from the lateral surface of the fronto-temporal lobes of five pharmacoresistant epileptic patients performing a reaching version of the countermanding task while undergoing presurgical monitoring. We consistently found a stereotyped ERP complex on a single-trial level when a movement was successfully cancelled. These ERPs were selectively expressed in M1, PMA, and Brodmann's area (BA) 9 and their onsets preceded the end of the stop process, suggesting a causal involvement in this executive function. Such ERPs also occurred in unsuccessful-stop (US) trials, that is, when subjects moved despite the occurrence of a stop-signal, mostly when they had long reaction times (RTs). These findings support the hypothesis that motor cortices are the final target of the inhibitory command elaborated by the frontal-basal ganglia-thalamic network.

Deep brain stimulation of subthalamic nuclei affects arm response inhibition in Parkinson's patients.

The precise localizations of the neural substrates of voluntary inhibition are still debated. It has been hypothesized that, in humans, this executive function relies upon a right-lateralized pathway comprising the inferior frontal gyrus and the presupplementary motor area, which would control the neural processes for movement inhibition acting through the right subthalamic nucleus (STN). We assessed the role of the right STN, via a countermanding reaching task, in 10 Parkinson's patients receiving high-frequency electrical stimulation of the STN of both hemispheres (deep brain stimulation, DBS) and in 13 healthy subjects. We compared the performance of Parkinson's patients in 4 experimental conditions: DBS-ON, DBS-OFF, DBS-OFF right, and DBS-OFF left. We found that 1) inhibitory control is improved only when both DBS are active, that is, the reaction time to the stop signal is significantly shorter in the DBS-ON condition than in all the others, 2) bilateral stimulation of STN restores the inhibitory control to a near-normal level, and 3) DBS does not cause a general improvement in task-related motor function as it does not affect the length of the reaction times of arm movements, that is, in our experimental context, STN seems to play a selective role in response inhibition.

Hypofractionated radiotherapy followed by adjuvant chemotherapy with temozolomide in elderly patients with glioblastoma.

OBJECTIVES: The optimal treatment for elderly patients (age >70 years) with glioblastoma (GBM) remains controversial. We conducted a prospective trial in 43 consecutive elderly patients with GBM treated with hypofractionated radiotherapy (RT) followed by adjuvant temozolomide. PATIENTS AND METHODS: Forty-three patients 70 years of age or older with a newly diagnosed GBM and a Karnofsky performance status (KPS) > or = 60 were treated with hypofractionated RT (6 fractions of 5 Gy each for a total of 30 Gy over 2 weeks) followed by up to 12 cycles of adjuvant temozolomide (150-200 mg/m(2) for 5 days during each 28 day cycle). The HRQOL was assessed with the EORTC Quality of Life Questionnaire C30. The primary endpoint was overall survival (OS). Secondary endpoints included progression free survival (PFS), toxicity and quality of life. RESULTS: The median OS was 9.3 months and the median PFS was 6.3 months. The 6 and 12 month survival rates were 86% and 35%, respectively. The 6 and 12 month PFS rates were 55% and 12%, respectively. In multivariate analysis KPS was the only significant independent predictive factor of survival (P = 0.008). Neurological deterioration occurred during or after RT in 16% of patients and was resolved in most cases with the use of steroids. Grade 3-4 hematologic toxicity occurred in 28% of patients during the adjuvant chemotherapy treatment with temozolomide. The treatment had no negative effect on HRQOL, however, fatigue (P = 0.02) and constipation (P = 0.01) scales worsened over time. CONCLUSIONS: Hypofractionated RT followed by temozolomide may provide survival benefit maintaining a good quality of life in elderly patients with GBM. It may represent a reasonable therapeutic approach especially in patients with less favourably prognostic factors.

How to set up a microsurgical laboratory on small animal models: organization, techniques, and impact on residency training.

Microsurgical training is mandatory for the optimal education of modern neurosurgeons. Even though this is a widely acknowledged statement and a lot of institutions around the world practice training in laboratory, the recent literature lacks tip and tricks on how to start a laboratory from scratch, what would be a convenient anesthesia, and what kind of exercises are appropriate. We present our experience in 16 microsurgical training courses settled up at our institutions. Two hundred eleven rodents were dissected. We will describe the organization of the laboratory and of the training courses and we will discuss its practical impact on the residency program.

Intraoperative localization of subcortical brain lesions.

BACKGROUND: Some brain tumors may grow immediately beneath the cortical surface without distorting its appearance. Intraoperative image guidance promotes safe resection. We have developed MRI-based corticotopography (MRI-bct), to localize lesions during surgery, using simple, non-dedicated equipment, to match a three-dimensional reconstruction with the corresponding appearance of the brain cortex. METHODS: Forty-six patients underwent resection of subcortical brain lesions, aided by MRI-bct. The lesions had a maximum diameter less than 3 cm, were subcortical but no deeper than the floor of the nearest cerebral sulcus. Each patient had a volumetric MRI scan with and without contrast administration. Data sets were transferred to a laptop personal computer and processed using a rendering software. At operation, the three-dimensional model of the brain, including a surface overlay of the lesion, was matched to the exposed brain surface. After its exact relationship with the overlying sulcal pattern was defined, the lesion was localized and resected. In selected patients, the procedure was coupled with functional brain mapping. RESULTS: Data processing took from 10 to 15 min and could be done whenever convenient before operation. Surface matching between the surgical field and the reformatted MRI always required less than 5 min and was done near the operating table. In all patients, the lesion was identified at the first attempt, through a small corticotomy, regardless of the brain shift after dural opening. CONCLUSIONS: MRI-bct is a practical, time-saving neuronavigational aid ideal for localizing superficial lesions underlying the cerebral cortex because it unmistakably characterizes the adjacent sulcal anatomy.

Differential expression of neurogenins and NeuroD1 in human pituitary tumours.

Basic helix-loop-helix (bHLH) transcription factors are involved in neuroendocrine cell growth and differentiation. Though NeuroD1 is viewed as corticotroph specific, its overexpression in non-corticotroph pituitary adenomas (PAs) may reflect the activation of molecular pathways involving other bHLH factors, like neurogenins. To search for neurogenin-NeuroD1 molecular pathways in the human normal and tumoural pituitary. Fifty-one PAs--22 clinically non-secreting (CNS) and 29 secreting respectively--and normal human pituitaries (NP) were studied for NeuroD1 and neurogenins (Ngn1, Ngn2 and Ngn3) gene expression by RT-PCR and quantitative real-time RT-PCR (qRT-PCR). Immunohistochemistry for Ngn2/3 was performed in some cases. NeuroD1, Ngn2, Ngn3 and Ngn1 were observed in up to 84.3, 76.5, 30.4 and 9.1% of PA respectively, only NeuroD1 and Ngn2 being frequently overexpressed when compared with NP. Whereas NeuroD1 expression was higher in corticotroph and CNS adenomas (P=0.0001 versus Pit-1-dependent PA), Ngn2 expression was higher in secreting PA, especially in Pit-1-dependent PA (P=0.007 and P=0.0006 versus CNS respectively). Pit-1-dependent PA which received pre-operative pharmacological treatment expressed higher Ngn2 levels than untreated cases (P=0.025). Nuclear Ngn2 was observed in NP and in most PA, especially ACTH- and GH-secreting adenomas. Nuclear Ngn3 was observed in a minority of secreting PA. Ngn2 is normally expressed in the anterior pituitary and frequently expressed in PA, but does not account for NeuroD1 overexpression where present. Owing to their low and inconstant expression, the biological significance of Ngn1/3 in the adult pituitary is uncertain.

A rapid and reliable procedure to localize subdural electrodes in presurgical evaluation of patients with drug-resistant focal epilepsy.

OBJECTIVES: To evaluate a novel method for localization of subdural electrodes in presurgical assessment of patients with drug-resistant focal epilepsy. METHODS: We studied eight consecutive patients with posterior epilepsy in whom subdural electrodes were implanted for presurgical evaluation. Electrodes were detected on post-implantation brain CT scans through a semiautomated procedure based on a MATLAB routine. Then, post-implantation CT scans were fused with pre-implantation MRI to localize the electrodes in relation to the underlying cortical structures. The reliability of this procedure was tested by comparing 3D-rendered MR images of the electrodes with electrode position as determined by intraoperative digital photography. RESULTS: In each patient, all electrodes could be correctly localized and visualized in a stereotactic space, thus allowing optimal surgery planning. The agreement between the procedure-generated images and the digital photographs was good according to two independent raters. The mean mismatch between the 3D images and the photographs was 2 mm. CONCLUSIONS: While our findings need confirmation on larger samples including patients with anterior epilepsy, this procedure allowed to localize subdural electrodes and to establish the spatial relationship of each electrode to the underlying brain structure, either normal or damaged, on brain convessity, basal and medial cortex. SIGNIFICANCE: Being simple, rapid, unexpensive, and reliable, this procedure holds promise to be useful to optimize epilepsy surgery planning.

Vasospasm of venous grafts in extra-intracranial by-pass. Report of two cases.

Two patients are described, the first with a giant aneurysm of the left carotid bifurcation previously treated by endovascular technique, the second with a bilateral intracavernous aneurysm: both were submitted to high-flow by-pass operation. The first patient was a 40 year-old woman who had presented subarachnoid hemorrhage 6 months before operation. She had been treated by means of a high-flow by-pass between the external carotid artery and the middle cerebral artery. Control angiograms performed 12 hours later showed a stenosis above the suture between the external carotid artery and the venous graft. Angioplasty was performed by endovascular route: new angiograms showed occlusion of the graft while dopplersonography demonstrated the presence of flow within the graft. Angiograms performed 1 week later showed marked vasospasm of the venous graft, of the internal carotid artery, the anterior cerebral artery and the middle cerebral artery. The evolution of spasm of the graft and of the intracranial arterial flow was monitored by dopplersonography and MR-angiography: the latter was performed 20 days after the last angiography and confirmed patency of the graft, while dopplersonography showed resolution of vasospasm. Finally, the aneurysm was embolized. The second patient was a 49 year-old woman with mild left palpebral ptosis and retro-orbital pain. She had already been submitted to high-flow by-pass operation 7 months earlier to treat a right intracavernous aneurysm; the left by-pass was necessary because the intracavernous aneurysm had become symptomatic. One week after surgery, spasm of the venous graft was documented by MR-angiography. In both cases, treatment consisted of calcium antagonists as well as hypertensive and hypervolemic medication, which was successful in treating vasospasm of the venous graft and its symptoms. Spasm of the venous graft, a well-known occurrence in cardiac revascularization, can also be observed in cerebral revascularization.

Rundown of GABA type A receptors is a dysfunction associated with human drug-resistant mesial temporal lobe epilepsy.

Pharmacotherapeutic strategies have been difficult to develop for several forms of temporal lobe epilepsy, which are consequently treated by surgical resection. To examine this problem, we have studied the properties of transmitter receptors of tissues removed during surgical treatment. We find that when cell membranes, isolated from the temporal neocortex of patients afflicted with drug-resistant mesial temporal lobe epilepsy (TLE), are injected into frog oocytes they acquire GABA type A receptors (GABA(A)-receptors) that display a marked rundown during repetitive applications of GABA. In contrast, GABA(A)-receptor function is stable in oocytes injected with cell membranes isolated from the temporal lobe of TLE patients afflicted with neoplastic, dysgenetic, traumatic, or ischemic temporal lesions (lesional TLE, LTLE). Use-dependent GABA(A)-receptor rundown is also found in the pyramidal neurons of TLE neocortical slices and is antagonized by BDNF. Pyramidal neurons in cortical slices of a traumatic LTLE patient did not show GABA(A)-receptor rundown. However, the apparent affinity of GABA(A)-receptor in oocytes microtransplanted with membranes from all of the epileptic patients studied was smaller than the affinity of receptors transplanted from the nonepileptic brain. We conclude that the use-dependent rundown of neocortical GABA(A)-receptor represents a TLE-specific dysfunction, whereas the reduced affinity may be a general feature of brains of both TLE and LTLE patients, and we speculate that our findings may help to develop new treatments for TLE and LTLE.

La influencia de la permeabilidad manual en el porcentaje de separación de los instrumentos rotatorios de NiTi / The influence of a manual glide path on the separation rate of Niti rotary instruments

El propósito doble de este estudio fue evaluar el porcentaje de fracturas de los instrumentos rotatorios de Ni-ti al seguir una permeabilidad preparada manualmente con limas manuales de acero inoxidable antes de la instrumentación con limas rotatorias y comparar los resultados en este estudio con los obtenidos en dos análisis previos en que no se empleó la técnica de permeabilidad manual. Se dividieron un total de 208 conductos radiculares obtenidos de una muestra de molares humanos superiores e inferiores recientemente extraídos en tres grupos que correspondieron a K3, ProFile y ProTaper. Se emplearon los 2/3 coronales de cada diente. En los tres grupos la porción apical de las muestras se preparó con limas manuales K de acero inoxidable de calibres 10-20. Los topes apicales se prepararon con instrumentos rotatorios K3, ProFile y ProTaper. El análisis del modelo de regresión logística indicó que la rotura estaba significativamente asociada con el ángulo de curvatura del conducto (OR= 1.078; 95% CI= 1.032-1.12; p= 0,001) y con el número de usos clínicos (las limas empleadas más de ocho veces se rompieron más frecuentemente que las empleadas de 1 a 2 veces; OR= 22.686; CI 95%: 2,6-191.3; p= 0,004). El porcentaje de rotura obtenido en este estudio es significativamente menor que en nuestros estudios previos, en que el ángulo de curvatura era también mayor de 30° y la velocidad constante de rotación de 350 rpm, pero en que los conductos no se prepararon inicialmente con limas manuales (25/205= 12% frente a l6/6l = 26%, p= 0,007). Basándose en los resultados de este estudio, recomendamos el uso de limas manuales de acero inoxidable para preparar el tercio apical de los conductos curvados antes de emplear las limas rotatorias

The dual purpose of this study was, to evaluate the fracture rate of Ni-Ti rotary instruments when following a manual glide path and using stainless steel band files before carrying out instrumentation by means of rotary files and, to compare the results in this study with those obtained in two previous analyses, in which the glide path technique was not used. A total of 208 canals obtained from a pool of freshly extracted human mandibular and maxillary molars was divided into three groups corresponding to; K3, ProFile and ProTaper. The coronal 2/3 of each tooth were used. In all three groups the apical portion of the samples was prepared with size 10-20 stainless steel K-type hand files. The apical stops were prepared using K3, ProFile and ProTaper rotary instruments. Logistic regression model analysis indicated that breakage was significantly associated with the angle of curvature of the canal (OR = 1.078; 95% Cl= 1.032-1.12;p = 0.001), and with the number of clinical uses (files used more than eight times broke more frequently that those used 1 o 2 times; OR: 22.686; 95% Cl: 2.6-191.3; p= 0.004). The breakage rate obtained in the present study is significantly lower than in our previous studies, in which the angle of curvature was also greated than 30° and rotational speed a constant 350 rpm, but in which the canals were not first prepared with hand files (25/205 = 12% versus 16/61 = 26%, p = 0.007). Based on the results of this study, were recommend the use of stainless steel band files to prepare the apical 1/3 of curved canals before introducing rotary files

Temporal lobe epilepsy surgery: different surgical strategies after a non-invasive diagnostic protocol.

AIM: To test a non-invasive presurgical protocol for temporal lobe epilepsy (TLE) based on "anatomo-electro-clinical correlations". METHODS: All consecutive patients with suspected TLE and seizure history <2 years were entered into the protocol, which included video-electroencephalographic (EEG) monitoring and magnetic resonance imaging (MRI). Three different TLE subsyndromes (mesial, lateral, mesiolateral) were identified by combined anatomical, electrical, and clinical criteria. "Tailored" surgery for each subsyndrome was offered. Patients with seizure history <2 years, MRI evidence of temporal mass lesion, and concordant interictal EEG and clinical data bypassed video-EEG monitoring and were directly scheduled for surgery. RESULTS: Lesionectomy was performed without video-EEG recording in 11 patients with tumorous TLE. Of 146 patients studied with video-EEG, 133 received a TLE diagnosis. Four were excluded for neuropsychological risks, eight refused surgery, and 121 underwent surgery. Of 132 consecutive patients who underwent surgery, 101 had at least one year of follow up. They were divided into a "hippocampal sclerosis/cryptogenic" group (n = 57) and a "tumours/cortical organisation disorders" group (n = 44). In the first group, extensive temporal lobectomy (ETL) was performed in 40 patients, anteromesial temporal lobectomy (AMTL) in 17 patients. At follow up, 47 patients were seizure free. In the second group, lesionectomy plus ETL was performed in 23 patients, lesionectomy plus AMTL in six patients, and lesionectomy alone in 15 patients. Thirty nine patients were seizure free. CONCLUSIONS: These findings suggest that different TLE subsyndromes can be identified accurately using non-invasive anatomo-electro-clinical data and can be treated effectively and safely with tailored surgery.

BDNF modulates GABAA receptors microtransplanted from the human epileptic brain to Xenopus oocytes.

Cell membranes isolated from brain tissues, obtained surgically from six patients afflicted with drug-resistant temporal lobe epilepsy and from one nonepileptic patient afflicted with a cerebral oligodendroglioma, were injected into frog oocytes. By using this approach, the oocytes acquire human GABAA receptors, and we have shown previously that the "epileptic receptors" (receptors transplanted from epileptic brains) display a marked run-down during repetitive applications of GABA. It was found that exposure to the neurotrophin BDNF increased the amplitude of the "GABA currents" (currents elicited by GABA) generated by the epileptic receptors and decreased their run-down; both events being blocked by K252A, a neurotrophin tyrosine kinase receptor B inhibitor. These effects of BDNF were not mimicked by nerve growth factor. In contrast, the GABAA receptors transplanted from the nonepileptic human hippocampal uncus (obtained during surgical resection as part of the nontumoral tissue from the oligodendroglioma margins) or receptors expressed by injecting rat recombinant alpha1beta2gamma2 GABAA receptor subunit cDNAs generated GABA currents whose time-course and run-down were not altered by BDNF. Loading the oocytes with the Ca2+ chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetate-acetoxymethyl ester (BAPTA-AM), or treating them with Rp-8-Br-cAMP, an inhibitor of the cAMP-dependent PKA, did not alter the GABA currents. However, staurosporine (a broad spectrum PK inhibitor), bisindolylmaleimide I (a PKC inhibitor), and U73122 (a phospholipase C inhibitor) blocked the BDNF-induced effects on the epileptic GABA currents. Our results indicate that BDNF potentiates the epileptic GABAA currents and antagonizes their use-dependent run-down, thus strengthening GABAergic inhibition, probably by means of activation of tyrosine kinase receptor B receptors and of both PLC and PKC.

Transsphenoidal adenomectomy for GH-, PRL- and ACTH-secreting pituitary tumours: outcome analysis in a series of 125 patients.

Transsphenoidal surgery (TSS) is a well recognised treatment for secreting pituitary adenomas, however a very wide variation of clinical outcomes and recurrence rates has been reported, depending on the different criteria used to define the cure. We reported the clinical outcome of a large series of patients operated on for a secreting pituitary adenoma according to the most recent stringent criteria of biochemical remission nowadays accepted. One hundred and twenty-five consecutive patients with a secreting pituitary adenoma (42 PRL-, 67 GH- and 16 ACTH-secreting adenomas) who were operated on by the two same neurosurgeons were considered for the study. Biochemical remission of disease was achieved in 56% of patients; 78% for patients with microadenoma and 47% for patients with macroadenomas, respectively. No cases of mortality or major immediate postoperative complications were observed. Tumour size, high hormone levels and dural invasion were significantly correlated to a poor surgical outcome. The recurrence rates ranged between 0 and 24%, being higher for PRL-secreting tumours. In conclusion, TSS is safe and effective in secreting pituitary tumours. It is still the first treatment for GH- and ACTH-secreting adenomas, whereas in patients with prolactinomas, surgery should be reserved for cases of resistance or intolerance to dopamine agonists.

Postoperative spondylodiscitis from Aspergillus fumigatus in immunocompetent subjects.

The authors describe a case of spondylodiscitis from Aspergillus fumigatus which occurred subsequent to surgery for lumbar disc herniation in a non-immunodepressed patient. The results obtained by combined medical and surgical treatment are discussed.

Phosphatase inhibitors remove the run-down of gamma-aminobutyric acid type A receptors in the human epileptic brain.

The properties of gamma-aminobutyric acid (GABA) type A receptors (GABA(A) receptors) microtransplanted from the human epileptic brain to the plasma membrane of Xenopus oocytes were compared with those recorded directly from neurons, or glial cells, in human brains slices. Cell membranes isolated from brain specimens, surgically obtained from six patients afflicted with drug-resistant temporal lobe epilepsy (TLE) were injected into frog oocytes. Within a few hours, these oocytes acquired GABA(A) receptors that generated GABA currents with an unusual run-down, which was inhibited by orthovanadate and okadaic acid. In contrast, receptors derived from membranes of a nonepileptic hippocampal uncus, membranes from mouse brain, or recombinant rat alpha 1 beta 2 gamma 2-GABA receptors exhibited a much less pronounced GABA-current run-down. Moreover, the GABA(A) receptors of pyramidal neurons in temporal neocortex slices from the same six epileptic patients exhibited a stronger run-down than the receptors of rat pyramidal neurons. Interestingly, the GABA(A) receptors of neighboring glial cells remained substantially stable after repetitive activation. Therefore, the excessive GABA-current run-down observed in the membrane-injected oocytes recapitulates essentially what occurs in neurons, rather than in glial cells. Quantitative RT-PCR analyses from the same TLE neocortex specimens revealed that GABA(A)-receptor beta 1, beta 2, beta 3, and gamma 2 subunit mRNAs were significantly overexpressed (8- to 33-fold) compared with control autopsy tissues. Our results suggest that an abnormal GABA-receptor subunit transcription in the TLE brain leads to the expression of run-down-enhanced GABA(A) receptors. Blockage of phosphatases stabilizes the TLE GABA(A) receptors and strengthens GABAergic inhibition. It may be that this process can be targeted to develop new treatments for intractable epilepsy.

Fronto-temporo-orbito-zygomatic approach and variants. Surgical technique and indications.

AIM: In the last decade, development and refìnement of skull base surgery have widened the surgical options available for treatment of mtracramal lesions. Despite the enormous advances made m microsurgical technique, the bony phase is still extremely important for achievmg optimal exposure of vascular and tumoral skull base lesions. The role of anterolateral approaches for such lesions is discussed. METHODS: We collected 87 consecutive patients with 74 neoplasms and 13 vascular lesions involving the floor of the antenor and/or middle cranial fossae, cavernous sinus, orbit, petrous bone, clivus, parasellar region and infratemporal fossa operated throughout 8 and a half years by means of an anterolateral approach and we evaluated the results obtained employing different craniotomies. RESULTS: To simplify the parameters for evaluation of outcome, we considered 2 main aspects: comparison between pre- and postoperative neurological status and the extent of tumour removal on MR imaging. For vascular lesions, we took into consideration the neurological outcome and the successful clipping of the aneurysm or disappearance of the AVM (l case) on postoperative angiography. Satisfactory surgical results were obtained with each type of craniotomy employed (fronto-teniporo-orbito-zygomatic, fronto-temporo-orbital, fronto-temporo-zygomatic, fronto-orbito-zygomatic). CONCLUSION: On the whole, surgical results were satisfactory. By deliberately excluding the microsurgical aspects of the lesions treated, we can observe that the fronto-temporo-orbito-zygomatic approach is principally indicated for lesions requiring a multidirectional approach such as spheno-petro-clival tumours, aneurysms of the basilar tip and intracavemous lesions while the fronto-temporo-orbital approach proved excellent for more medial lesions such as meningiomas of the luberculum sellae and cramopharyngiomas. The fronto-temporo-zygomatic approach is our 1(st) choice for neoplasms involving the Gassenan ganglion and the intratemporal fossa. For lesions of the orbital apex, a fronto-orbito-zygomatic approach can be successfully employed. Introduction of these approaches is relatively recent but promises a further refinement of their indications and surgical technique aimed at mimmismg postoperative morbidity.

Evolving criteria for post-operative biochemical remission of acromegaly: can we achieve a definitive cure? An audit of surgical results on a large series and a review of the literature.

Criteria to define the biochemical remission of acromegaly following surgery have changed over the years, and the current use of stringent criteria needs a critical re-evaluation of the surgical results. On the other hand, few data are currently available concerning the possible impact of pituitary surgery on the quality of life of operated acromegalic patients. In this prospective study, we wished to evaluate the initial outcome and long-term recurrence rate in a large series of acromegalic patients operated on by transsphenoidal surgery (TSS), to carefully analyse predictive factors for surgical outcome and to point out possible additional effects of surgery in these patients. Ninety-two out of 98 operated patients could be considered for follow-up. Biochemical remission was strictly defined as plasma GH levels <1 ng/ml during an oral glucose tolerance test (OGTT) and normalisation of age-related IGF-I levels. Hormonal assessment, including an OGTT, was performed 6 months following surgery and then annually to evaluate pituitary function. Fifty-five per cent of patients achieved a biochemical remission of acromegaly. The remission rate at 6 months was 80% for patients with microadenoma and 50% for macroadenoma. Univariate analysis showed that a large extrasellar extension, preoperative high GH levels and dural invasion were correlated with a poor outcome of surgery while, according to multivariate analysis, only invasion of cavernous sinus and preoperative GH levels > 10 ng/ml were independent negative predictors. Mortality was 0% and the overall complication rate was about 10%. Pituitary function worsened in five patients but improved in 16 out of 30 patients with preoperative pituitary defects. No recurrence was observed during a median follow-up of about 8 years. We conclude that TSS is able to achieve a biochemical remission in more than half of acromegalic patients, and that the current criteria for remission seem to indicate a cure in most cases.

Human pituitary tumours express the bHLH transcription factors NeuroD1 and ASH1.

Among the transcription factors involved in pituitary ontogenesis and physiology, basic helix-loop-helix (bHLH) have been poorly studied. Members of bHLH family include NeuroD1 and ASH1, both involved in neuroendocrine differentiation. We evaluated their mRNA expression patterns, by semi-quantitative RT-PCR analysis (sq-RT-PCR) and/or Northern blot, in a series of 33 pituitary adenomas (PA), anterior pituitaries, and pituitary cell lines. Immunohistochemistry for NeuroD1 was also performed in 25 PA. Low levels of NeuroD1 were observed in normal pituitaries and in the somatomammotroph cell lines GH3/GH4C1, contrasting with high levels in corticotroph AtT20 cells. NeuroD1 mRNA was widely expressed in PA (82%), with measurable levels found especially in those derived from Pit-1 independent lineages, i.e. corticotroph (5/5) and clinically non-secreting (CNS) adenomas (9/11). According to sq-RT-PCR analysis, overexpression of NeuroD1 compared to normal pituitaries was frequent. Variable nuclear NeuroD1 immunopositivity was also present in about 70% of studied cases. ASH1 mRNA was widely detected in normal pituitaries, in all tumour cell lines and in most PA (84%), with measurable levels in corticotroph (5/5) and CNS (9/11) adenomas, and in a significant subset of PA derived from Pit-1 dependent lineages (9/16). We conclude that: a) NeuroD1 is differentially expressed in PA and its possible ontogenetic and/or pathogenetic implications in non-corticotroph PA are discussed; b) ASH1 is a neuroendocrine marker whose expression is largely conserved in normal and neoplastic pituitary cells.

Surgical approaches to tumours of the lateral ventricles in the dominant hemisphere.

BACKGROUND: Intraventricular neoplasms are rare tumours (1% of the tumours of the central nervous system). The surgical approach sometimes is quite difficult, particularly in the dominant hemisphere. The best choice of surgical approach is discussed. METHODS: The authors describe a series of 25 patients who underwent surgical treatment for tumours situated in the lateral ventricles of the dominant hemisphere. They discuss the most influential factors in the choice of surgical approach, which must allow maximum exposure of the lesion and vascular feeding branches without damaging highly functional areas (motor, visual and language areas). In particular, they report their experience using a low transtemporal route, between the middle and inferior gyri, for removing tumours localized in the temporal horn and/or trigone which made it possible to keep postoperative visual and phasic deficits to a minimum. RESULTS: In 5 patients the approach was transfrontal, in 10 temporal, in 6 superior parieto-occipital and in 4 transcallosal. Three patients died. Only 5 patients presented permanent deficits (anomia, apraxia and visual fields alterations). CONCLUSIONS: The size, site, hemisphere and vascularization of intraventricular tumours influence the choice of surgical approach. The basal transtemporal approach is particularly indicated to remove tumours of the temporal horn and trigone and it seems to reduce the risk of speech disturbances and alterations of posture.