Analyzing the role of reoperation in recurrent glioblastoma: a 15-year retrospective study in a single institution.

BACKGROUND: Multiple treatment options at glioblastoma progression exist, including reintervention, reirradiation, additional systemic therapy, and novel strategies. No alternative has been proven to be superior in terms of postprogression survival (PPS). A second surgery has shown conflicting evidence in the literature regarding its prognostic impact, possibly affected by selection bias, and might benefit a sparse subset of patients with recurrent glioblastoma. The present study aims to determine the prognostic influence of salvage procedures in a cohort of patients treated in the same institution over 15 years. METHODS: Three hundred and fifty patients with confirmed primary glioblastoma diagnosed and treated between 2005 and 2019 were selected. To examine the role of reoperation, we intended to create comparable groups, previously excluding all diagnostic biopsies and patients who were not actively treated after the first surgery or at disease progression. Uni- and multivariate Cox proportional hazards regression models were employed, considering reintervention as a time-fixed or time-dependent covariate. The endpoints of the study were overall survival (OS) and PPS. RESULTS: At progression, 33 patients received a second surgery and 84 were treated with chemotherapy only. Clinical variables were similar among groups. OS, but not PPS, was superior in the reintervention group. Treatment modality had no impact in our multivariate Cox regression models considering OS or PPS as the endpoint. CONCLUSIONS: The association of reoperation with improved prognosis in recurrent glioblastoma is unclear and may be influenced by selection bias. Regardless of our selective indications and high gross total resection rates in second procedures, we could not observe a survival advantage.

"Intrasellar Balloon Technique" in intraoperative MRI guided transsphenoidal endoscopic surgery for sellar region tumors. Usefulness on image interpretation and extent of resection evaluation. Technical note.

BACKGROUND: Intraoperative magnetic resonance imaging (iMRI) is an effective and proven tool in transsphenoidal endoscopic surgery. However, image interpretation is not always easy and can be hindered by the presence of blood, tumor remains or the displacement of surrounding structures. In this article we present a novel technique based on using intrasellar ballons to reduce these difficulties and facilitate the surgeon's intraoperative assessment by iMRI. METHODS: Eighteen patients with pituitary macroadenomas underwent transsphenoidal surgery during 2013-2014 under low-field iMRI control (PoleStar N20, 0.15 T). Intrasellar balloons were used in all of them to assess the presence of tumoral remnants. We compared the findings in iMRI and postoperative high-field MRI control scans and also analyzed the number of intermediate imaging controls needed during surgery using this technique. RESULTS: In total, of the 18 patients, 14 underwent a complete resection. In the remaining four patients, a safe maximal resection was performed, leaving a remnant because of cavernous sinus invasion. In all cases, the balloons were a major help in distinguishing the anatomical structures from the tumoral remnants. Fewer imaging controls were required, and there were no false-positives or negative intraoperative findings. No complications related to the technique were registered. CONCLUSION: The "intrasellar balloon technique" is a useful tool that facilitates surgeons' intraoperative decision making. It is an important contribution to overcome the limitations of low-field iMRI as it provides a precise delineation of the resection margins, reduces false-positives and -negatives, and decreases the number of intermediate imaging controls required.

Full kinetic modeling analysis of [18F]fluorocholine Positron Emission Tomography (PET) at initial diagnosis of high-grade glioma.

PURPOSE: The main objective was to characterize the tracer uptake kinetics of [18F]fluoromethylcholine ([18F]F-CHO) in high-grade gliomas (HGG) through a full PET kinetic modeling approach. Secondarily, we aimed to explore the relationship between the PET uptake measures and the HGG molecular features. MATERIALS AND METHODS: Twenty-four patients with a suspected diagnosis of HGG were prospectively included. They underwent a dynamic brain [18F]F-CHO-PET/CT, from which a tumoral time-activity curve was extracted. The plasma input function was obtained through arterial blood sampling with metabolite correction. These data were fitted to 1- and 2-tissue-compartment models, the best of which was selected through the Akaike information criterion. We assessed the correlation between the kinetic parameters and the conventional static PET metrics (SUVmax, SUVmean and tumor-to-background ratio TBR). We explored the association between the [18F]F-CHO-PET quantitative parameters and relevant molecular biomarkers in HGG. RESULTS: Tumoral time-activity curves in all patients showed a rapid rise of [18F]F-CHO uptake followed by a plateau-like shape. Best fits were obtained with near-irreversible 2-tissue-compartment models. The perfusion-transport constant K1 and the net influx rate Ki showed strong correlation with SUVmax (r = 0.808-0.861), SUVmean (r = 0.794-0.851) and TBR (r = 0.643-0.784), p < 0.002. HGG was confirmed in 21 patients, of which those with methylation of the O-6-methylguanine-DNA methyltransferase (MGMT) gene promoter showed higher mean Ki (p = 0.020), K1 (p = 0.025) and TBR (p = 0.001) than the unmethylated ones. CONCLUSION: [18F]F-CHO uptake kinetics in HGG is best explained by a 2-tissue-compartment model. The conventional static [18F]F-CHO-PET measures have been validated against the perfusion-transport constant (K1) and the net influx rate (Ki) derived from kinetic modeling. A relationship between [18F]F-CHO uptake rate and MGMT methylation is suggested but needs further confirmation.

[First intraoperative magnetic resonance imaging in a Spanish hospital of the public healthcare system: initial experience, feasibility and difficulties in our environment]. / Implantación de la primera resonancia magnética intraoperatoria en un hospital de la red sanitaria pública española: experiencia inicial, viabilidad y dificultades en nuestro entorno.

OBJECTIVE: Intraoperative MRI is considered the gold standard among all intraoperative imaging technologies currently available. Its main indication is in the intraoperative detection of residual disease during tumour resections. We present our initial experience with the first intraoperative low-field MRI in a Spanish hospital of the public healthcare system. We evaluate its usefulness and accuracy to detect residual tumours and compare its intraoperative results with images obtained postoperatively using conventional high-field devices. MATERIAL AND METHODS: We retrospectively reviewed the first 21 patients operated on the aid of this technology. Maximal safe resection was the surgical goal in all cases. Surgeries were performed using conventional instrumentation and the required assistance in each case. RESULTS: The mean number of intraoperative studies was 2.3 per procedure (range: 2 to 4). Intraoperative studies proved that the surgical goal had been achieved in 15 patients (71.4%), and detected residual tumour in 6 cases (28.5%). After comparing the last intraoperative image and the postoperative study, 2 cases (9.5%) were considered as "false negatives". CONCLUSIONS: Intraoperative MRI is a safe, reliable and useful tool for guided resection of brain tumours. Low-field devices provide images of sufficient quality at a lower cost; therefore their universalisation seems feasible.

[Vagal nerve stimulation treatment in patients with drug resistant epilepsy: Son Espases University Hospital experience]. / Tratamiento con estimulación del nervio vago en pacientes con epilepsia resistente a los fármacos: experiencia en el Hospital Universitario Son Espases.

OBJECTIVE: To present our experience in treating drug-resistant epilepsy with vagal nerve stimulation in our centre, evaluating its impact on disease control and on different aspects related to the patients and main caretakers' quality of life. MATERIALS AND METHODS: This was a retrospective analysis of patients operated from January 2004 until December 2012. Interviews and tests completed by outpatients and principle caretakers were evaluated. RESULTS: Fifteen patients were included, with a mean postoperative follow-up of 4.41 (0.5-8) years. Mean age at implantation was 25 (10-50) years. Over 66% of the patients perceived a reduction greater than 25% of their crisis intensity. Forty-seven percent of the patients experienced a decrease greater than 50% in the number of crises. As undesired adverse events, one patient presented persistent dysphonia, another self-limited cough and cervical discomfort and another, persistent cervical discomfort. The device had to be removed in 2 patients due to refractory headaches. There were no complications derived from the surgical procedure. CONCLUSIONS: Vagal nerve stimulation is an effective treatment for reducing crisis frequency and intensity. The patients as well as their caretakers experience a subjective improvement in their quality of life. Despite its economic cost, it seems to reduce their care needs to a certain degree and its use may therefore be justified.

Direct observation of human microcirculation during decompressive craniectomy after stroke.

OBJECTIVES: Most knowledge related to the pathophysiology of microcirculation in ischemic stroke comes from experimental research. Unfortunately, data on microcirculation in the human brain are limited, partially as a result of the lack of appropriate investigational techniques. The objective of our study was to test the hypothesis that cortical microcirculatory alterations in the brain, in terms of blood flow and vessel density, occur in patients with stroke who require surgical decompression compared with a control group. DESIGN: Prospective and observational study. SETTING: Third-level university hospital. PATIENTS: Six patients who had undergone decompressive surgery as a result of a space-occupying hemispheric infarction. These patients were compared with five patients who had undergone craniotomy for a disease not affecting the cortex. INTERVENTIONS: Cortical microcirculation in the brain was directly observed using sidestream dark-field imaging. All images were analyzed offline. MEASUREMENTS AND MAIN RESULTS: In patients with stroke with a space-occupying hemispheric infarction, 18 good-quality movie images were compared with 25 control group images. In the control group, cortical vessels showed a continuous flow in small, medium, and large vessels compared with patients with stroke who presented intermittent or no flow in all vessels. The proportion of perfused vessels was near 100% in control subjects and 63.44% in patients with stroke. The perfused vessel density index was also higher in control subjects (6.16 1/mm; interquartile range, 5.65-7.56) than in patients with stroke (2.77 1/mm; interquartile range, 1.75-3.86). CONCLUSION: Sidestream dark-field imaging allowed direct visualization of cerebral microcirculatory alterations in the operating room. This technique allowed the documentation of a significant blood flow reduction in the cortical microvascular and a decreased vascular density in patients with stroke compared with control subjects.

Lack of correlation among intracerebral cytokines, intracranial pressure, and brain tissue oxygenation in patients with traumatic brain injury and diffuse lesions.

OBJECTIVES: To determine the evolution of cytokine patterns using microdialysis in patients with traumatic brain injury with diffuse lesions and to study the relationship between cytokines and intracranial pressure, brain tissue oxygenation and lesion type on the computed cranial tomography scan (patients with and without brain swelling). DESIGN: Prospective and observational study. SETTING: Third-level university hospital. PATIENTS: Patients between 15 and 65 yrs with severe traumatic brain injury and a diffuse lesion requiring intracranial pressure and brain tissue oxygenation monitoring were eligible. INTERVENTIONS: Microdialysis catheters with a high-cutoff membrane of 100 kDa were inserted. RESULTS: Sixteen patients were included in the analysis. There was a substantial interindividual variability between cytokine values. The highest concentrations for the interleukin-1ß, interleukin-6, and interleukin-8 were measured during the first 24 hrs followed by a gradual decline. The average concentration for interleukin-10 did not vary over time. This pattern is the most frequent in patients with traumatic brain injury with diffuse lesions. The intracranial pressure-cytokines correlation coefficients for the 16 patients varied substantially: interleukin-1ß-intracranial pressure (-0.76 to 0.63); interleukin-6-intracranial pressure (-0.83 to 0.78); interleukin-8-intracranial pressure (-0.86 to 0.84); and interleukin-10-intracranial pressure (-0.36 to 0.65). The brain tissue oxygenation-cytokine correlation coefficients, like with intracranial pressure, also varied between patients: interleukin-1ß-brain tissue oxygenation (-0.49 to 0.68), interleukin-6-brain tissue oxygenation (-0.99 to 0.84); interleukin-8-brain tissue oxygenation (-0.65 to 0.74); and interleukin-10-brain tissue oxygenation (-0.34 to 0.52). Similarly, we found no difference in the cytokine values inpatient microdialysis with and without swelling in the computed tomographic scan. CONCLUSIONS: No clear relationship was found between the temporal pattern of cytokines and the behavior of the intracranial pressure, brain tissue oxygenation, and the presence or absence of swelling in the computed tomography scan. This study demonstrates the feasibility of microdialysis in recovering cytokines for a prolonged time, although there may be some nonresolved methodologic problems with this technique when we try to study the inflammation during traumatic brain injury that could affect the results and make interpretation of microdialysis data prone to difficulties.

O6-Methylguanine-DNA methyltransferase protein expression by immunohistochemistry in brain and non-brain systemic tumours: systematic review and meta-analysis of correlation with methylation-specific polymerase chain reaction.

BACKGROUND: The DNA repair protein O6-Methylguanine-DNA methyltransferase (MGMT) confers resistance to alkylating agents. Several methods have been applied to its analysis, with methylation-specific polymerase chain reaction (MSP) the most commonly used for promoter methylation study, while immunohistochemistry (IHC) has become the most frequently used for the detection of MGMT protein expression. Agreement on the best and most reliable technique for evaluating MGMT status remains unsettled. The aim of this study was to perform a systematic review and meta-analysis of the correlation between IHC and MSP. METHODS: A computer-aided search of MEDLINE (1950-October 2009), EBSCO (1966-October 2009) and EMBASE (1974-October 2009) was performed for relevant publications. Studies meeting inclusion criteria were those comparing MGMT protein expression by IHC with MGMT promoter methylation by MSP in the same cohort of patients. Methodological quality was assessed by using the QUADAS and STARD instruments. Previously published guidelines were followed for meta-analysis performance. RESULTS: Of 254 studies identified as eligible for full-text review, 52 (20.5%) met the inclusion criteria. The review showed that results of MGMT protein expression by IHC are not in close agreement with those obtained with MSP. Moreover, type of tumour (primary brain tumour vs others) was an independent covariate of accuracy estimates in the meta-regression analysis beyond the cut-off value. CONCLUSIONS: Protein expression assessed by IHC alone fails to reflect the promoter methylation status of MGMT. Thus, in attempts at clinical diagnosis the two methods seem to select different groups of patients and should not be used interchangeably.

Use of diffusion tensor imaging to assess the vasogenic edema in traumatic pericontusional tissue.

BACKGROUND AND OBJECTIVE: Cerebral edema is a frequent and serious complication of traumatic brain injury (TBI). Diffusion tensor imaging (DTI) is considered a useful technique to assess white matter integrity after TBI. The objective of this prospective, observational study was to assess the characteristics of the vasogenic edema in the traumatic pericontusional tissue and compare it to the vasogenic edema found in brain tumors. We also included a control group. METHODS: Using DTI, the Apparent diffusion coefficient (ADC) and Fractional anisotropy (FA) were measured in the area of vasogenic edema in both TBI and tumor patients. The measurements in the control group were done in the gray and white matter. We included 15 TBI patients, 18 tumor patients and 15 controls. RESULTS: ADC and FA showed no differences between TBI and tumor patients (p=0.27 for AF; p=0.79 for ADC). Compared to healthy controls, TBI and tumor patients presented higher ADC values and lower FA values. The differences between TBI and controls were statistically significant (p<0.05). CONCLUSIONS: In this prospective observational study using DTI-MRI in a selected group of mild and moderate TBI patients with vasogenic pericontusional edema we have shown that there were no significant differences of the ADC and FA values compared to brain tumor patients. Furthermore, healthy controls showed significant lower ADC values and higher FA values compared to TBI and tumor patients. Future studies, using DTI-MRI, should address whether any therapy has a favorable impact on the vasogenic edema of TBI patients with brain contusions.

Loss of cortisol circadian rhythm in patients with traumatic brain injury: a microdialysis evaluation.

BACKGROUND: Traumatic brain injury (TBI) is commonly associated with disturbances of the hypothalamic-pituitary-adrenal axis secretion. Cerebral microdialysis techniques have been recently applied to measure brain interstitial cortisol levels. METHODS: We evaluated for the first time the circadian rhythm of cortisol secretion at 08:00, 16:00, and 24:00 h in the acute phase of TBI by determination of total serum and brain interstitial cortisol levels (microdialysis samples) in 10 patients with TBI. Non-parametric Friedman's two way analysis of variance test was used. RESULTS: Mean age was 29.8 ± 13.6 years. Median Glasgow Coma Scale score after resuscitation was 5 (range 3-10). No differences were found in total serum (P = 0.26) and brain interstitial cortisol (P = 0.77) in the whole sample. Intraindividual analysis showed that circadian variability was lost in all patients, both in serum and brain interstitial cortisol samples in the acute phase after TBI. CONCLUSION: In our series, circadian variability of cortisol evaluated by serum and cerebral microdialysis samples seems to be lost in TBI patients.

Use of diffusion tensor imaging to assess the vasogenic edema in traumatic pericontusional tissue.

BACKGROUND AND OBJECTIVE: Cerebral edema is a frequent and serious complication of traumatic brain injury (TBI). Diffusion tensor imaging (DTI) is considered a useful technique to assess white matter integrity after TBI. The objective of this prospective, observational study was to assess the characteristics of the vasogenic edema in the traumatic pericontusional tissue and compare it to the vasogenic edema found in brain tumors. We also included a control group. METHODS: Using DTI, the Apparent diffusion coefficient (ADC) and Fractional anisotropy (FA) were measured in the area of vasogenic edema in both TBI and tumor patients. The measurements in the control group were done in the gray and white matter. We included 15 TBI patients, 18 tumor patients and 15 controls. RESULTS: ADC and FA showed no differences between TBI and tumor patients (p=0.27 for AF; p=0.79 for ADC). Compared to healthy controls, TBI and tumor patients presented higher ADC values and lower FA values. The differences between TBI and controls were statistically significant (p<0.05). CONCLUSIONS: In this prospective observational study using DTI-MRI in a selected group of mild and moderate TBI patients with vasogenic pericontusional edema we have shown that there were no significant differences of the ADC and FA values compared to brain tumor patients. Furthermore, healthy controls showed significant lower ADC values and higher FA values compared to TBI and tumor patients. Future studies, using DTI-MRI, should address whether any therapy has a favorable impact on the vasogenic edema of TBI patients with brain contusions.

Variability of Clinical and Angiographic Results Based on the Treatment Preference (Endovascular or Surgical) of Centers Participating in the Subarachnoid Hemorrhage Database of the Working Group of the Spanish Society of Neurosurgery.

OBJECTIVES: Since the introduction of endovascular treatment for cerebral aneurysms, hospitals in which subarachnoid hemorrhage is treated show different availability and/or preferences towards both treatment modalities. The main aim is to evaluate the clinical and angiographic results according to the hospital's treatment preferences applied. METHODS: This study was conducted based on use of the subarachnoid hemorrhage database of the Vascular Pathology Group of the Spanish Neurosurgery Society. Centers were classified into 3 subtypes according to an index in the relationship between endovascular and surgical treatment as: endovascular preference, high endovascular preference, and elevated surgical preference. The clinical results and angiographic results were evaluated among the 3 treatment strategies. RESULTS: From November 2004 to December 2017, 4282 subarachnoid hemorrhage patients were selected for the study: 630 (14.7%) patients from centers with surgical preference, 2766 (64.6%) from centers with endovascular preference, and 886 (20.7%) from centers with high endovascular preference. The surgical preference group obtained the best angiographic results associated with a greater complete exclusion (odds ratio: 1.359; 95% confidence interval: 1.025-1.801; P = 0.033). The surgical preference subgroup obtained the best outcome at discharge (65.45%), followed by the high endovascular preference group (61.5%) and the endovascular preference group (57.8%) (odds ratio: 1.359; 95% confidence interval: 1.025-1.801; P = 0.033). CONCLUSIONS: In Spain, there is significant variability in aneurysm exclusion treatment in aneurysmal subarachnoid hemorrhage. Surgical centers offer better results for both surgical and endovascular patients. A multidisciplinary approach and the maintenance of an elevated quality of surgical competence could be responsible for these results.

The tumor suppressor FOXO3a mediates the response to EGFR inhibition in glioblastoma cells.

PURPOSE: Although EGFR activation is a hallmark of glioblastoma (GBM), anti-EGFR therapy has so far not yielded the desired effects. Targeting PI3K/Akt has been proposed as a strategy to increase the cellular sensitivity to EGFR inhibitors. Here we evaluated the contribution of FOXO3a, a key Akt target, in the response of GBM cells to EGFR inhibition. METHODS: FOXO3a activation was assessed by immunofluorescence and gene reporter assays, and by evaluating target gene expression using Western blotting and qRT-PCR. Cellular effects were evaluated using cell viability and apoptosis assays, i.e., Annexin V/PI staining and caspase 3/7 activity measurements. Drug synergism was evaluated by performing isobolographic analyses. Gene silencing experiments were performed using stable shRNA transfections. RESULTS: We found that EGFR inhibition in GBM cells led to FOXO3a activation and to transcriptional modulation of its key targets, including repression of the oncogene FOXM1. In addition, we found that specific FOXO3a activation recapitulated the molecular effects of EGFR inhibition, and that the FOXO3a activator trifluoperazine, a FDA-approved antipsychotic agent, reduced GBM cell growth. Subsequent isobolographic analyses of combination experiments indicated that trifluoperazine and erlotinib cooperated synergistically and that their concomitant treatment induced a robust activation of FOXO3a, leading to apoptosis in GBM cells. Using gene silencing, we found that FOXO3a is essential for the response of GBM cells to EGFR inhibition. CONCLUSIONS: Our data indicate that FOXO3a activation is a crucial event in the response of GBM cells to EGFR inhibition, suggesting that FOXO3a may serve as an actionable therapeutic target that can be modulated using FDA-approved drugs.

Differences in mitochondrial function and antioxidant systems between regions of human glioma.

Metabolic features and oxidative stress have been extensively studied in cancer cells. However, comparative studies between cancer cell populations that coexist in human neoplastic tissue are not frequently available. The aim of the present study was to characterize markers of oxidative status and mitochondrial function in center vs. periphery of human fresh glioma samples; therefore, antioxidant systems, oxidative stress and mitochondrial parameters were assessed in gross total resections of gliomas. Mitochondrial protein and mitochondrial DNA content, enzymatic activities of mitochondrial oxidative and phosphorylative system, antioxidant mechanisms, mitochondrial H(2)O(2) production, oxygen consumption and cellular oxidative damage were measured in human gliomas. Concentric regions of human glioma tissue showed similar mitochondrial structural markers; conversely, the functionality of their isolated mitochondria was significantly different. In this way, the tumor periphery exhibited higher respiratory rate and fewer antioxidant systems than tumor center. Our results have expanded previous investigations, which report the presence of cell populations with different oxidative susceptibility in human brain tumor samples. This is, to our knowledge, the first study to investigate metabolic differences in concentric regions of gross total resections of glioma. Interestingly, the cancer cell population that exhibits an increased antioxidant capacity within the tumor mass might be responsible for tumor resistance to chemotherapy and radiotherapy.

Pentobarbital versus thiopental in the treatment of refractory intracranial hypertension in patients with traumatic brain injury: a randomized controlled trial.

INTRODUCTION: Experimental research has demonstrated that the level of neuroprotection conferred by the various barbiturates is not equal. Until now no controlled studies have been conducted to compare their effectiveness, even though the Brain Trauma Foundation Guidelines recommend that such studies be undertaken. The objectives of the present study were to assess the effectiveness of pentobarbital and thiopental in terms of controlling refractory intracranial hypertension in patients with severe traumatic brain injury, and to evaluate the adverse effects of treatment. METHODS: This was a prospective, randomized, cohort study comparing two treatments: pentobarbital and thiopental. Patients who had suffered a severe traumatic brain injury (Glasgow Coma Scale score after resuscitation < or = 8 points or neurological deterioration during the first week after trauma) and with refractory intracranial hypertension (intracranial pressure > 20 mmHg) first-tier measures, in accordance with the Brain Trauma Foundation Guidelines. RESULTS: A total of 44 patients (22 in each group) were included over a 5-year period. There were no statistically significant differences in ' baseline characteristics, except for admission computed cranial tomography characteristics, using the Traumatic Coma Data Bank classification. Uncontrollable intracranial pressure occurred in 11 patients (50%) in the thiopental treatment group and in 18 patients (82%) in the pentobarbital group (P = 0.03). Under logistic regression analysis--undertaken in an effort to adjust for the cranial tomography characteristics, which were unfavourable for pentobarbital--thiopental was more effective than pentobarbital in terms of controlling intracranial pressure (odds ratio = 5.1, 95% confidence interval 1.2 to 21.9; P = 0.027). There were no significant differences between the two groups with respect to the incidence of arterial hypotension or infection. CONCLUSIONS: Thiopental appeared to be more effective than pentobarbital in controlling intracranial hypertension refractory to first-tier measures. These findings should be interpreted with caution because of the imbalance in cranial tomography characteristics and the different dosages employed in the two arms of the study. The incidence of adverse effects was similar in both groups. TRIAL REGISTRATION: (Trial registration: US Clinical Trials registry NCT00622570.).

[Analysis of early prognostic factors for risk of treatment failure in Cushing's disease treated by trans-sphenoidal pituitary surgery]. / Estudio de factores pronósticos precoces de riesgo de fallo del tratamiento en la enfermedad de Cushing tras la cirugía hipofisaria transesfenoidal.

BACKGROUND AND OBJECTIVE: We performed an analysis of early factors influencing the outcome of Cushing's disease treated by transsphenoidal pituitary surgery. PATIENTS AND METHOD: Prospective study of 29 patients who underwent transsphenoidal pituitary surgery for Cushing's disease. The prognostic value of preoperative and operative variables, histological findings and serum cortisol (measured at 8:00 a.m. the day after surgery) were analyzed. RESULTS: Of the 29 patients included in this study, 26 achieved postoperative remission while in 3 patients treatment failed. Tumor was identified at histology in 92.3% patients in the remission group and in 33.3% in the failure group, this difference being significant (p = 0.03). Median postoperative cortisol levels were 95.8 nmol/l in the remission group and 676 nmol/l in the failure group, this difference being significant (p = 0.024). Serum cortisol of 600 nmol/l correctly classified the remission and failure groups with a sensitivity of 100% and a specificity of 96%. CONCLUSIONS: In our experience, no identification of an adenoma at histology and an early postoperative cortisol level higher than 600 nmol/l after transsphenoidal pituitary surgery for Cushing's disease was associated with a high risk of failed treatment.

Prognostic significance of O6-methylguanine-DNA methyltransferase determined by promoter hypermethylation and immunohistochemical expression in anaplastic gliomas.

PURPOSE: Anaplastic gliomas constitute a heterogeneous group of tumors with different therapeutic responses to adjuvant chemotherapy with alkylating agents. O6-Methylguanine-DNA methyltransferase (MGMT), a DNA repair protein, is one of the implicated factors in glioma chemoresistance. The prognostic value of MGMT remains controversial due in part to the fact that previous published studies included heterogeneous groups of patients with different tumor grades. The aim of this study was to evaluate the prognostic significance of MGMT in patients with anaplastic glioma. EXPERIMENTAL DESIGN: Ninety-three patients with anaplastic glioma were analyzed for MGMT protein expression by immunohistochemistry. In addition, for those patients from whom a good yield of DNA was obtained (n = 40), MGMT promoter methylation profile was analyzed by methylation-specific PCR. MGMT prognostic significance was evaluated together with other well-known prognostic factors. RESULTS: Fifty-one tumors (54.8%) showed nuclear staining of MGMT. There was a trend towards longer overall survival for those patients with negative MGMT immunostaining (hazard ratio, 1.66; P = 0.066). In a secondary analysis including those patients who actually received chemotherapy (n = 72), the absence of MGMT expression was independently associated with better survival (hazard ratio, 2.12; P = 0.027). MGMT promoter methylation was observed in 50% of the analyzed tumors. No statistical correlation between MGMT expression and MGMT promoter hypermethylation was observed. CONCLUSIONS: Unlike previous studies, we did not find a correlation between MGMT promoter methylation and survival. However, we observed a correlation between MGMT protein expression and survival in those patients who received chemotherapy thus suggesting that the absence of MGMT expression is a positive predictive marker in patients with anaplastic glioma.

Fractionated stereotactic radiotherapy in the treatment of exclusive cavernous sinus meningioma: functional outcome, local control, and tolerance.

BACKGROUND: Fractionated stereotactic radiotherapy (FSRT) combines the precision of stereotactic positioning with the radiobiologic advantage of dose fractionation. METHODS: From June 1997 to June 2001, 30 patients with cavernous sinus meningiomas were treated with FSRT using fixed noncoplanar conformal fields. Patient skull fixation was achieved using the BrainLAB mask (20 patients) or Beverly frame (10 patients). The Cosman-Roberts-Wells coordinate frame was used for stereotactic space definition. In selected cases before 1999, and in all cases afterward, gadolinium-enhanced MRI for image fusion was performed. The median radiation dose was 52 Gy, with a daily fraction of 2 Gy. Patients were regularly followed up analyzing symptoms, tumor progression, and side effects. Neurocognitive function was evaluated retrospectively for 26 patients using Mini-Mental State Examination. RESULTS: Median follow-up period was 50 months (range, 28.2-74.5 months). Preexisting neurologic symptoms improved in 50% of the patients and worsened in 2 patients. Only 2 patients progressed and the actuarial local progression free survival was 93% at 4 years. Tolerance was good with 2 cases of late radiation toxicity which consisted of moderate short-term memory loss and dysphasia in one case and neuropsychologic deficit with seizures in the other. Postradiotherapy Mini-Mental State Examination results showed a median score of 28 (range, 16-30). CONCLUSIONS: Fractionated stereotactic radiotherapy is a high-precision technique. It is safe and feasible in the primary and adjuvant treatment of cavernous sinus meningiomas. Fractionated stereotactic radiotherapy allowed local control in more than 90% of patients.

Direct observation during surgery shows preservation of cerebral microcirculation in patients with traumatic brain injury.

OBJECTIVE: To describe the alterations of the cortical microcirculation of the brain (blood flow and vessel density) in TBI patients who and compare them with a control group. METHODS: Prospective and observational study in a third-level university hospital. Cortical microcirculation in the brain was directly observed using sidestream dark-field (SDF) imaging in 14 patients who underwent surgery: 5 subdural hematomas (SDH) and 9 parenchymal lesions (contusions/hematomas). In this last set of patients, images were recorded in the "pericontusional" areas and in the "surrounding" brain (areas that were as far from the lesion as the craniotomy allowed). These patients were compared to five patients who underwent craniotomy for a disease that did not affect the cortex. RESULTS: There were fewer "pericontusional" images that could be analyzed due to the presence of subarachnoid hemorrhage. The proportion or perfused vessels was similar in all groups: control 99.5% ± 1.3%; SDH 98.6% ± 2.4%; "pericontusional" area 98.2% ± 2.4%; "surrounding" area 98.4% ± 2.5% (p = 0.145). The perfused vessel density index was smaller in the "pericontusional" area: control 6.5 ± 1.6 l/mm; SDH 6.5 ± 2.5 l/mm; "pericontusional" area 5.4 ± 2.6 l/mm; "surrounding" 6.6 ± 2.1 l/mm (p = 0.07). CONCLUSIONS: Although the analysis of pericontusional zone was difficult, there were fewer vessels than in the controls and there was no change in the flow. In the surrounding zone and in patients with SDH, we did not document alterations in the microcirculation. Direct imaging of cerebral microcirculation in TBI patients showed that despite serious brain injury the cerebral microcirculation was remarkably well preserved.