Purpose The extent of resection (EOR) is an independent prognostic factor for overall survival (O... more Purpose The extent of resection (EOR) is an independent prognostic factor for overall survival (OS) in adult patients with Glioma Grade 4 (GG4). The aim of the neuro-oncology section of the Italian Society of Neurosurgery (SINch®) was to provide a general overview of the current trends and technical tools to reach this goal. Methods A systematic review was performed. The results were divided and ordered, by an expert team of surgeons, to assess the Class of Evidence (CE) and Strength of Recommendation (SR) of perioperative drugs management, imaging, surgery, intraoperative imaging, estimation of EOR, surgery at tumor progression and surgery in elderly patients. Results A total of 352 studies were identified, including 299 retrospective studies and 53 reviews/meta-analysis. The use of Dexamethasone and the avoidance of prophylaxis with anti-seizure medications reached a CE I and SR A. A preoperative imaging standard protocol was defined with CE II and SR B and usefulness of an early ...
International Journal of Radiation Oncology*Biology*Physics, 2016
To investigate the local control and radiation-induced brain necrosis in patients with brain meta... more To investigate the local control and radiation-induced brain necrosis in patients with brain metastases >2 cm in size who received single-fraction or multifraction stereotactic radiosurgery (SRS); factors associated with clinical outcomes and the development of brain radionecrosis were assessed. Two hundred eighty-nine consecutive patients with brain metastases >2.0 cm who received SRS as primary treatment at Sant'Andrea Hospital, University of Rome Sapienza, Rome, Italy, were analyzed. Cumulative incidence analysis was used to compare local control and radiation-induced brain necrosis between groups from the time of SRS. To achieve a balanced distribution of baseline covariates between treatment groups, a propensity score analysis was used. The 1-year cumulative local control rates were 77% in the single-fraction SRS (SF-SRS) group and 91% in the multifraction SRS (MF-SRS) group (P=.01). Recurrences occurred in 25 and 11 patients who received SF-SRS or MF-SRS (P=.03), respectively. Thirty-one patients (20%) undergoing SF-SRS and 11 (8%) subjected to MF-SRS experienced brain radionecrosis (P=.004); the 1-year cumulative incidence rate of radionecrosis was 18% and 9% (P=.01), respectively. Significant differences between the 2 groups in terms of local control and risk of radionecrosis were maintained after propensity score adjustment. Multifraction SRS at a dose of 27 Gy in 3 daily fractions seems to be an effective treatment modality for large brain metastases, associated with better local control and a reduced risk of radiation-induced radionecrosis as compared with SF-SRS.
Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is viewed by many as the ultimate t... more Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is viewed by many as the ultimate therapy targeting severe advanced stages of Parkinson's disease (PD). A fundamental constituent of the mechanisms underlying the therapeutic effects of DBS is clearly the functional organization of the STN; however, there is limited understanding of the organization of this structure in humans. Data from primates suggest that different domains can be identified in the STN, including a sensorimotor area with a segregated body map, as well as nonmotor areas. Recent clinical studies have used microelectrode recording to investigate the presence of a body map in the sensorimotor STN of PD patients. This paper will review and compare experimental and clinical data regarding the functional organization of the STN and discuss the clinical implications for PD patients undergoing STN DBS.
Treatment targets in functional neurosurgery usually consist of selected structures within the th... more Treatment targets in functional neurosurgery usually consist of selected structures within the thalamus and basal ganglia, which can be stimulated in order to affect specific brain pathways. Chronic electrical stimulation of these structures is a widely used approach for selected patients with advanced movement disorders. An alternative therapeutic solution consists of producing a lesion in the target nucleus, for example by means of radiosurgery, a noninvasive procedure, and this prevents the use of intraoperative microelectrode recording as a method for accurate target definition. The need to have accurate noninvasive localization of the target motivated our previous work on atlas-based identification; the aim of this present work is to provide additional validation of this approach based on the identification of the red nuclei (RN), which are located near the subthalamic nucleus (STN). Coordinates of RN were obtained from the Talairach and Tournoux (TT) atlas and transformed into the coordinates of the Montreal Neurological Institute (MNI) atlas, creating a mask representation of RN. The MNI atlas volume was nonrigidly registered onto the patient magnetic resonance imaging (MRI). This deformation field was then applied to the RN mask, providing its location on the patient MRI. Because RN are easily identifiable on 1.5 T T2-MRI images, they were manually delineated; the coordinates of the centers of mass of the manually and automatically identified structures were compared. Additionally, volumetric overlapping indices were calculated. Ten patients were examined by this technique. All indices indicated a high level of agreement between manually and automatically identified structures. These results not only confirm the accuracy of the method but also allow fine tuning of the automatic identification method to be performed.
Proceedings of the National Academy of Sciences, 2005
Cell membranes isolated from brain tissues, obtained surgically from six patients afflicted with ... more 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 GABA A 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 GABA A receptors transplanted from the nonepileptic human hippocampal uncus (obtained during surgical resection as part of the nontumoral tissue ...
Proceedings of the National Academy of Sciences, 2004
The properties of γ-aminobutyric acid (GABA) type A receptors (GABA A receptors) microtransplante... more The properties of γ-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 α1β2γ2-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 ...
Intracranial hypotension syndrome as a complication of diagnostic lumbar puncture is a rarely obs... more Intracranial hypotension syndrome as a complication of diagnostic lumbar puncture is a rarely observed entity. Intracranial hypotension syndrome is characterized by postural headache, neck pain/stiffness, blurred vision, nausea, vomiting, clouding of consciousness, dizziness and vertigo. The majority of cases resolve spontaneously with conservative treatment. Rarely, epidural blood patch is required. We report a 41-year-old man with multiple sclerosis, who developed intracranial hypotension syndrome after diagnostic lumbar puncture and who did not respond to conservative treatment. A subdural hematoma was subsequently found, when the patient showed considerable worsening of clinical conditions with life-threatening symptoms. Surgical evacuation of the subdural hematoma was not sufficient to improve significantly the patient's conditions, while complete symptoms remission was achieved 12 hours after epidural blood patch. We stress the need for epidural blood patch in any case of post-diagnostic lumbar puncture postural headache which does not resolve with conservative therapy.
Several molecular markers have been proposed as predictors of outcome in patients with high grade... more Several molecular markers have been proposed as predictors of outcome in patients with high grade gliomas. We report a retrospective multicenter study of 97 consecutive adult patients with anaplastic astrocytoma (AA) treated with radiation therapy (RT) plus concomitant and adjuvant temozolomide (TMZ) between October 2004 and March 2012. Correlations between the isocitrate dehydrogenase 1 (IDH1) mutation and O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation with survival outcomes have been analyzed. At a median follow-up time of 46 months (range 12-89 months), median and 5-year overall survival rates were 50.5 months (95 % CI, 37.8-63.2) and 38% (95 % CI, 25.7-50.7%), and median and 5-year progression-free survival rates were 36 months (95% CI, 28.5-44.0) and 22 % (95 % CI, 10-34%), respectively. IDH1 mutation and MGMT promoter methylation were present in 54 and 60% of evaluable patients, respectively. Multivariate Cox proportional hazards regression analysis showed that IDH1 mutation (P = 0.001), MGMT methylation (P = 0.01), age < 50 years (P = 0.02), and extent of resection (P = 0.04) were significantly associated with longer survival. Our study confirms the favorable prognostic value of IDH1 mutation and MGMT methylation in patients with AA treated with RT plus concomitant and adjuvant TMZ. The superiority of combined radiochemotherapy over other treatment modalities remains to be demonstrated.
International Journal of Radiation Oncology*Biology*Physics, 2010
To determine the maximum tolerated dose (MTD) of fractionated intensity-modulated radiotherapy (I... more To determine the maximum tolerated dose (MTD) of fractionated intensity-modulated radiotherapy (IMRT) with temozolomide (TMZ) in patients with glioblastoma. A Phase I clinical trial was performed. Eligible patients had surgically resected or biopsy-proven glioblastoma. Patients started TMZ (75 mg/day) during IMRT and continued for 1 year (150-200 mg/day, Days 1-5 every 28 days) or until disease progression. Clinical target volume 1 (CTV1) was the tumor bed +/- enhancing lesion with a 10-mm margin; CTV2 was the area of perifocal edema with a 20-mm margin. Planning target volume 1 (PTV1) and PTV2 were defined as the corresponding CTV plus a 5-mm margin. IMRT was delivered in 25 fractions over 5 weeks. Only the dose for PTV1 was escalated (planned dose escalation: 60 Gy, 62.5 Gy, 65 Gy) while maintaining the dose for PTV2 (45 Gy, 1.8 Gy/fraction). Dose limiting toxicities (DLT) were defined as any treatment-related nonhematological adverse effects rated as Grade >or=3 or any hematological toxicity rated as >or=4 by Radiation Therapy Oncology Group (RTOG) criteria. Nineteen consecutive glioblastoma were treated with step-and-shoot IMRT, planned with the inverse approach (dose to the PTV1: 7 patients, 60 Gy; 6 patients, 62.5 Gy; 6 patients, 65 Gy). Five coplanar beams were used to cover at least 95% of the target volume with the 95% isodose line. Median follow-up time was 23 months (range, 8-40 months). No patient experienced DLT. Grade 1-2 treatment-related neurologic and skin toxicity were common (11 and 19 patients, respectively). No Grade >2 late neurologic toxicities were noted. Accelerated IMRT to a dose of 65 Gy in 25 fractions is well tolerated with TMZ at a daily dose of 75 mg.
Purpose The extent of resection (EOR) is an independent prognostic factor for overall survival (O... more Purpose The extent of resection (EOR) is an independent prognostic factor for overall survival (OS) in adult patients with Glioma Grade 4 (GG4). The aim of the neuro-oncology section of the Italian Society of Neurosurgery (SINch®) was to provide a general overview of the current trends and technical tools to reach this goal. Methods A systematic review was performed. The results were divided and ordered, by an expert team of surgeons, to assess the Class of Evidence (CE) and Strength of Recommendation (SR) of perioperative drugs management, imaging, surgery, intraoperative imaging, estimation of EOR, surgery at tumor progression and surgery in elderly patients. Results A total of 352 studies were identified, including 299 retrospective studies and 53 reviews/meta-analysis. The use of Dexamethasone and the avoidance of prophylaxis with anti-seizure medications reached a CE I and SR A. A preoperative imaging standard protocol was defined with CE II and SR B and usefulness of an early ...
International Journal of Radiation Oncology*Biology*Physics, 2016
To investigate the local control and radiation-induced brain necrosis in patients with brain meta... more To investigate the local control and radiation-induced brain necrosis in patients with brain metastases >2 cm in size who received single-fraction or multifraction stereotactic radiosurgery (SRS); factors associated with clinical outcomes and the development of brain radionecrosis were assessed. Two hundred eighty-nine consecutive patients with brain metastases >2.0 cm who received SRS as primary treatment at Sant'Andrea Hospital, University of Rome Sapienza, Rome, Italy, were analyzed. Cumulative incidence analysis was used to compare local control and radiation-induced brain necrosis between groups from the time of SRS. To achieve a balanced distribution of baseline covariates between treatment groups, a propensity score analysis was used. The 1-year cumulative local control rates were 77% in the single-fraction SRS (SF-SRS) group and 91% in the multifraction SRS (MF-SRS) group (P=.01). Recurrences occurred in 25 and 11 patients who received SF-SRS or MF-SRS (P=.03), respectively. Thirty-one patients (20%) undergoing SF-SRS and 11 (8%) subjected to MF-SRS experienced brain radionecrosis (P=.004); the 1-year cumulative incidence rate of radionecrosis was 18% and 9% (P=.01), respectively. Significant differences between the 2 groups in terms of local control and risk of radionecrosis were maintained after propensity score adjustment. Multifraction SRS at a dose of 27 Gy in 3 daily fractions seems to be an effective treatment modality for large brain metastases, associated with better local control and a reduced risk of radiation-induced radionecrosis as compared with SF-SRS.
Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is viewed by many as the ultimate t... more Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is viewed by many as the ultimate therapy targeting severe advanced stages of Parkinson's disease (PD). A fundamental constituent of the mechanisms underlying the therapeutic effects of DBS is clearly the functional organization of the STN; however, there is limited understanding of the organization of this structure in humans. Data from primates suggest that different domains can be identified in the STN, including a sensorimotor area with a segregated body map, as well as nonmotor areas. Recent clinical studies have used microelectrode recording to investigate the presence of a body map in the sensorimotor STN of PD patients. This paper will review and compare experimental and clinical data regarding the functional organization of the STN and discuss the clinical implications for PD patients undergoing STN DBS.
Treatment targets in functional neurosurgery usually consist of selected structures within the th... more Treatment targets in functional neurosurgery usually consist of selected structures within the thalamus and basal ganglia, which can be stimulated in order to affect specific brain pathways. Chronic electrical stimulation of these structures is a widely used approach for selected patients with advanced movement disorders. An alternative therapeutic solution consists of producing a lesion in the target nucleus, for example by means of radiosurgery, a noninvasive procedure, and this prevents the use of intraoperative microelectrode recording as a method for accurate target definition. The need to have accurate noninvasive localization of the target motivated our previous work on atlas-based identification; the aim of this present work is to provide additional validation of this approach based on the identification of the red nuclei (RN), which are located near the subthalamic nucleus (STN). Coordinates of RN were obtained from the Talairach and Tournoux (TT) atlas and transformed into the coordinates of the Montreal Neurological Institute (MNI) atlas, creating a mask representation of RN. The MNI atlas volume was nonrigidly registered onto the patient magnetic resonance imaging (MRI). This deformation field was then applied to the RN mask, providing its location on the patient MRI. Because RN are easily identifiable on 1.5 T T2-MRI images, they were manually delineated; the coordinates of the centers of mass of the manually and automatically identified structures were compared. Additionally, volumetric overlapping indices were calculated. Ten patients were examined by this technique. All indices indicated a high level of agreement between manually and automatically identified structures. These results not only confirm the accuracy of the method but also allow fine tuning of the automatic identification method to be performed.
Proceedings of the National Academy of Sciences, 2005
Cell membranes isolated from brain tissues, obtained surgically from six patients afflicted with ... more 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 GABA A 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 GABA A receptors transplanted from the nonepileptic human hippocampal uncus (obtained during surgical resection as part of the nontumoral tissue ...
Proceedings of the National Academy of Sciences, 2004
The properties of γ-aminobutyric acid (GABA) type A receptors (GABA A receptors) microtransplante... more The properties of γ-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 α1β2γ2-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 ...
Intracranial hypotension syndrome as a complication of diagnostic lumbar puncture is a rarely obs... more Intracranial hypotension syndrome as a complication of diagnostic lumbar puncture is a rarely observed entity. Intracranial hypotension syndrome is characterized by postural headache, neck pain/stiffness, blurred vision, nausea, vomiting, clouding of consciousness, dizziness and vertigo. The majority of cases resolve spontaneously with conservative treatment. Rarely, epidural blood patch is required. We report a 41-year-old man with multiple sclerosis, who developed intracranial hypotension syndrome after diagnostic lumbar puncture and who did not respond to conservative treatment. A subdural hematoma was subsequently found, when the patient showed considerable worsening of clinical conditions with life-threatening symptoms. Surgical evacuation of the subdural hematoma was not sufficient to improve significantly the patient's conditions, while complete symptoms remission was achieved 12 hours after epidural blood patch. We stress the need for epidural blood patch in any case of post-diagnostic lumbar puncture postural headache which does not resolve with conservative therapy.
Several molecular markers have been proposed as predictors of outcome in patients with high grade... more Several molecular markers have been proposed as predictors of outcome in patients with high grade gliomas. We report a retrospective multicenter study of 97 consecutive adult patients with anaplastic astrocytoma (AA) treated with radiation therapy (RT) plus concomitant and adjuvant temozolomide (TMZ) between October 2004 and March 2012. Correlations between the isocitrate dehydrogenase 1 (IDH1) mutation and O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation with survival outcomes have been analyzed. At a median follow-up time of 46 months (range 12-89 months), median and 5-year overall survival rates were 50.5 months (95 % CI, 37.8-63.2) and 38% (95 % CI, 25.7-50.7%), and median and 5-year progression-free survival rates were 36 months (95% CI, 28.5-44.0) and 22 % (95 % CI, 10-34%), respectively. IDH1 mutation and MGMT promoter methylation were present in 54 and 60% of evaluable patients, respectively. Multivariate Cox proportional hazards regression analysis showed that IDH1 mutation (P = 0.001), MGMT methylation (P = 0.01), age < 50 years (P = 0.02), and extent of resection (P = 0.04) were significantly associated with longer survival. Our study confirms the favorable prognostic value of IDH1 mutation and MGMT methylation in patients with AA treated with RT plus concomitant and adjuvant TMZ. The superiority of combined radiochemotherapy over other treatment modalities remains to be demonstrated.
International Journal of Radiation Oncology*Biology*Physics, 2010
To determine the maximum tolerated dose (MTD) of fractionated intensity-modulated radiotherapy (I... more To determine the maximum tolerated dose (MTD) of fractionated intensity-modulated radiotherapy (IMRT) with temozolomide (TMZ) in patients with glioblastoma. A Phase I clinical trial was performed. Eligible patients had surgically resected or biopsy-proven glioblastoma. Patients started TMZ (75 mg/day) during IMRT and continued for 1 year (150-200 mg/day, Days 1-5 every 28 days) or until disease progression. Clinical target volume 1 (CTV1) was the tumor bed +/- enhancing lesion with a 10-mm margin; CTV2 was the area of perifocal edema with a 20-mm margin. Planning target volume 1 (PTV1) and PTV2 were defined as the corresponding CTV plus a 5-mm margin. IMRT was delivered in 25 fractions over 5 weeks. Only the dose for PTV1 was escalated (planned dose escalation: 60 Gy, 62.5 Gy, 65 Gy) while maintaining the dose for PTV2 (45 Gy, 1.8 Gy/fraction). Dose limiting toxicities (DLT) were defined as any treatment-related nonhematological adverse effects rated as Grade >or=3 or any hematological toxicity rated as >or=4 by Radiation Therapy Oncology Group (RTOG) criteria. Nineteen consecutive glioblastoma were treated with step-and-shoot IMRT, planned with the inverse approach (dose to the PTV1: 7 patients, 60 Gy; 6 patients, 62.5 Gy; 6 patients, 65 Gy). Five coplanar beams were used to cover at least 95% of the target volume with the 95% isodose line. Median follow-up time was 23 months (range, 8-40 months). No patient experienced DLT. Grade 1-2 treatment-related neurologic and skin toxicity were common (11 and 19 patients, respectively). No Grade >2 late neurologic toxicities were noted. Accelerated IMRT to a dose of 65 Gy in 25 fractions is well tolerated with TMZ at a daily dose of 75 mg.
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Papers by Vincenzo Esposito