[show abstract][hide abstract] ABSTRACT: To assess the safety and efficacy of fractionated stereotactic radiotherapy (FSRT) for large skull base meningiomas.
Fifty-two patients with large skull base meningiomas aged 34-74 years (median age 56 years) were treated with FSRT between June 2004 and August 2009. All patients received FSRT for residual or progressive meningiomas more than 4 centimeters in greatest dimension. The median GTV was 35.4 cm3 (range 24.1-94.9 cm3), and the median PTV was 47.6 cm3 (range 33.5-142.7 cm3). Treatment volumes were achieved with 5-8 noncoplanar beams shaped using a micromultileaf collimator (MLC). Treatment was delivered in 30 daily fractions over 6 weeks to a total dose of 50 Gy using 6 MV photons. Outcome was assessed prospectively.
At a median follow-up of 42 months (range 9-72 months) the 3-year and 5-year progression-free survival (PFS) rates were 96% and 93%, respectively, and survival was 100%. Three patients required further debulking surgery for progressive disease. Hypopituitarism was the most commonly reported late complication, with a new hormone pituitary deficit occurring in 10 (19%) of patients. Clinically significant late neurological toxicity was observed in 3 (5.5%) patients consisting of worsening of pre-existing cranial deficits.
FSRT as a high-precision technique of localized RT is suitable for the treatment of large skull base meningiomas. The local control is comparable to that reported following conventional external beam RT. Longer follow-up is required to assess long term efficacy and toxicity, particularly in terms of potential reduction of treatment-related late toxicity.
[show abstract][hide abstract] ABSTRACT: We previously found that the endogenous anticonvulsant adenosine, acting through A(2A) and A(3) adenosine receptors (ARs), alters the stability of currents (I(GABA)) generated by GABA(A) receptors expressed in the epileptic human mesial temporal lobe (MTLE). Here we examined whether ARs alter the stability (desensitization) of I(GABA) expressed in focal cortical dysplasia (FCD) and in periglioma epileptic tissues. The experiments were performed with tissues from 23 patients, using voltage-clamp recordings in Xenopus oocytes microinjected with membranes isolated from human MTLE and FCD tissues or using patch-clamp recordings of pyramidal neurons in epileptic tissue slices. On repetitive activation, the epileptic GABA(A) receptors revealed instability, manifested by a large I(GABA) rundown, which in most of the oocytes (approximately 70%) was obviously impaired by the new A(2A) antagonists ANR82, ANR94, and ANR152. In most MTLE tissue-microtransplanted oocytes, a new A(3) receptor antagonist (ANR235) significantly improved I(GABA) stability. Moreover, patch-clamped pyramidal neurons from human neocortical slices of periglioma epileptic tissues exhibited altered I(GABA) rundown on ANR94 treatment. Our findings indicate that antagonizing A(2A) and A(3) receptors increases the I(GABA) stability in different epileptic tissues and suggest that adenosine derivatives may offer therapeutic opportunities in various forms of human epilepsy.
Proceedings of the National Academy of Sciences 09/2009; 106(37):15927-31. · 9.74 Impact Factor
[show abstract][hide abstract] ABSTRACT: We examined how the endogenous anticonvulsant adenosine might influence gamma-aminobutyric acid type A (GABA(A)) receptor stability and which adenosine receptors (ARs) were involved. Upon repetitive activation (GABA 500 microM), GABA(A) receptors, microtransplanted into Xenopus oocytes from neurosurgically resected epileptic human nervous tissues, exhibited an obvious GABA(A)-current (I(GABA)) run-down, which was consistently and significantly reduced by treatment with the nonselective adenosine receptor antagonist CGS15943 (100 nM) or with adenosine deaminase (ADA) (1 units/ml), that inactivates adenosine. It was also found that selective antagonists of A2B (MRS1706, 10 nM) or A3 (MRS1334, 30 nM) receptors reduced I(GABA) run-down, whereas treatment with the specific A1 receptor antagonist DPCPX (10 nM) was ineffective. The selective A2A receptor antagonist SCH58261 (10 nM) reduced or potentiated I(GABA) run-down in approximately 40% and approximately 20% of tested oocytes, respectively. The ADA-resistant, AR agonist 2-chloroadenosine (2-CA) (10 microM) potentiated I(GABA) run-down but only in approximately 20% of tested oocytes. CGS15943 administration again decreased I(GABA) run-down in patch-clamped neurons from either human or rat neocortex slices. I(GABA) run-down in pyramidal neurons was equivalent in A1 receptor-deficient and wt neurons but much larger in neurons from A2A receptor-deficient mice, indicating that, in mouse cortex, GABA(A)-receptor stability is tonically influenced by A2A but not by A1 receptors. I(GABA) run-down from wt mice was not affected by 2-CA, suggesting maximal ARs activity by endogenous adenosine. Our findings strongly suggest that cortical A2-A3 receptors alter the stability of GABA(A) receptors, which could offer therapeutic opportunities.
Proceedings of the National Academy of Sciences 10/2008; 105(39):15118-23. · 9.74 Impact Factor
[show abstract][hide abstract] ABSTRACT: A study was made of the "rundown" of GABA(A) receptors, microtransplanted to Xenopus oocytes from surgically resected brain tissues of patients afflicted with drug-resistant human mesial temporal lobe epilepsy (mTLE). Cell membranes, isolated from mTLE neocortex specimens, were injected into frog oocytes that rapidly incorporated functional GABA(A) receptors. Upon repetitive activation with GABA (1 mM), "epileptic" GABA(A) receptors exhibited a GABA(A)-current (I(GABA)) rundown that was significantly enhanced by Zn(2+) (</=250 microM), and practically abolished by the high-affinity GABA(A) receptor inverse agonist SR95531 (gabazine; 2.5-25 microM). Conversely, I(GABA) generated by "control" GABA(A) receptors microtransplanted from nonepileptic temporal lobe, lesional TLE, or authoptic disease-free tissues remained stable during repetitive stimulation, even in oocytes treated with Zn(2+). We conclude that rundown of mTLE epileptic receptors depends on the presence of "phasic GABA(A) receptors" that have low sensitivity to antagonism by Zn(2+). Additionally, we found that GABA(A) receptors, microtransplanted from the cerebral cortex of adult rats exhibiting recurrent seizures, caused by pilocarpine-induced status epilepticus, showed greater rundown than control tissue, an event also occurring in patch-clamped rat pyramidal neurons. Rundown of epileptic rat receptors resembled that of human mTLE receptors, being enhanced by Zn(2+) (40 microM) and sensitive to the antiepileptic agent levetiracetam, the neurotrophin brain-derived neurotrophic factor, and the phosphatase blocker okadaic acid. Our findings point to the rundown of GABA(A) receptors as a hallmark of TLE and suggest that modulating tonic and phasic mTLE GABA(A) receptor activity may represent a useful therapeutic approach to the disease.
Proceedings of the National Academy of Sciences 12/2007; 104(52):20944-8. · 9.74 Impact Factor
[show abstract][hide abstract] ABSTRACT: We studied a new procedure of BOLD/fMRI acquisition in epilepsy. They use the benzodiazepine effect to achieve a more reliable baseline for statistical analysis. The method works only in the MR domain without EEG correlation. It compares the EPI images during interictal epileptic discharges and the images "inactivated" by benzodiazepine. The results in five out of eight patients show that this procedure in comparison with the EEG/fMRI method gives a net improvement of spatial definition of BOLD areas. These preliminary results seem to confirm the hypothesis that the better BOLD/fMRI procedure in epilepsy is to make use of physical features of MR that, unlike EEG, is not influenced by the distance of intercerebral sources and consequently allows a more complete and undistorted display of BOLD areas.
Magnetic Resonance Imaging 01/2005; 22(10):1487-92. · 2.06 Impact Factor
[show abstract][hide abstract] ABSTRACT: The primary aim of surgical treatment for falcotentorial meningiomas is gross total excision. The vital surrounding brain structures make this a complex task. Seeking elements that might facilitate presurgical planning we reviewed our surgical records of falcotentorial meningiomas treated during the past 20 years.
Between 1975 and 1996, in the Neurosurgical Unit at the University of Rome, "La Sapienza," 13 consecutive patients underwent surgery for falcotentorial meningiomas that had been localized on preoperative imaging and confirmed by histology. The surgical approach varied according to the site of the tumor.
Nine meningiomas were totally removed and 4 subtotally. Three patients (23.0%), all treated early in the series, died after the operation. Ten patients (76.9%) survived: 3 (23.0%) had postoperative neurologic complications necessitating reintervention, and 7 patients (53.8%) had an uneventful postoperative course. Two of the 4 patients who had subtotal resections had regrowth at 1 year that responded to radiosurgery.
The ideal surgical approach to falcotentorial meningiomas should allow gross total removal and minimum brain retraction while safeguarding the galenic system and other vital neighboring structures. Toward achieving this aim we propose detailed preoperative imaging studies to classify falcotentorial meningiomas according to their site and direction of growth-craniocaudal or anteroposterior-in relation to the cerebellar tentorium.