A Pathophysiological Approach to Reduce Peritumoral Edema with Gamma Knife Radiosurgery for Large Incidental Meningiomas.

BACKGROUND: Peritumoral edema may be a prohibitive side effect in treating large incidental meningiomas with stereotactic radiosurgery. An approach that limits peritumoral edema and achieves tumor control with SRS would be an attractive management option for large incidental meningiomas. METHODS: This is a retrospective cohort study of patients with large incidental meningiomas (≥2 mL in volume and/or 2 cm in diameter) treated with gamma knife radiosurgery (GKRS) between 2000 and 2019 in Taiwan and followed up for 5 years. The outcomes of a pathophysiological approach targeting the dural feeding artery site with a higher marginal dose (18-20 Gy) to enhance vascular damage and the parenchymal margin of the tumor with a lower dose (9-11 Gy) to reduce parenchymal damage were compared with those of a conventional approach targeting the tumor center with a higher dose and tumor margin with a lower dose (12-14 Gy). RESULTS: A total of 53 incidental meningiomas were identified, of which 23 (43.4%) were treated with a pathophysiological approach (4 cases underwent a two-stage approach) and 30 (56.7%) were treated with a conventional approach. During a median follow-up of 3.5 (range 1-5) years, tumor control was achieved in 19 (100%) incidental meningiomas that underwent a single-stage pathophysiological approach compared with 29 (96.7%) incidental meningiomas that underwent a conventional approach (log-rank test: p = 0.426). Peritumoral edema developed in zero (0%) incidental meningiomas that underwent a single stage pathophysiological approach compared to seven (23.3%) incidental meningiomas that underwent a conventional approach (log-rank test: p = 0.023). CONCLUSIONS: Treatment of large incidental meningiomas with a pathophysiological approach with GKRS achieves similar rates of tumor control and reduces the risk of peritumoral edema. GKRS with a pathophysiological approach may be a reasonable management strategy for large incidental meningiomas.

Outcome of Gamma Knife radiosurgery for trigeminal neuralgia associated with neurovascular compression.

We reviewed 130 patients from 1999 to 2012 to evaluate whether neurovascular compression (NVC) has prognostic value for pain relief in idiopathic trigeminal neuralgia (TN) treated by Gamma Knife radiosurgery (GKRS). Patients were assigned to one of the following groups based on NVC identified by MRI: no NVC, small vessel NVC, and large vessel (defined as part of the vertebrobasilar arterial system) NVC. Follow-up ranged from 4 to 14years. Primary outcome was pain graded by the Barrow Neurological Institute (BNI) pain scale. Successful pain control was defined asa score within Grade I-IIIb. Among the 130 patients, 53 had no neurovascular compression (group 1), 60 had a small vessel NVC (group 2), and 17 had a large vessel NVC (group 3). Successful pain control was 85% in group 1, 75% in group 2, and 88% in group 3 (X2=2.480, p=.289). Secondary outcome was new onset facial numbness which was 21% in group 1, 28% in group 2, and 35% in group 3 (X2=1.683, p=.431). NVC did not affect pain outcome for TN patients treated by GKRS. The lack of poorer response with large vessel NVC that has been reported in literature may be explained by treatment of multiple 4mm shots (as opposed to a single shot in 11/17 patients) to cover a larger compression area of the nerve root by a tortuous vessel.

Gamma Knife radiosurgery for large vestibular schwannomas greater than 3 cm in diameter.

OBJECTIVE Stereotactic radiosurgery (SRS) is an important alternative management option for patients with small- and medium-sized vestibular schwannomas (VSs). Its use in the treatment of large tumors, however, is still being debated. The authors reviewed their recent experience to assess the potential role of SRS in larger-sized VSs. METHODS Between 2000 and 2014, 35 patients with large VSs, defined as having both a single dimension > 3 cm and a volume > 10 cm3, underwent Gamma Knife radiosurgery (GKRS). Nine patients (25.7%) had previously undergone resection. The median total volume covered in this group of patients was 14.8 cm3 (range 10.3-24.5 cm3). The median tumor margin dose was 11 Gy (range 10-12 Gy). RESULTS The median follow-up duration was 48 months (range 6-156 months). All 35 patients had regular MRI follow-up examinations. Twenty tumors (57.1%) had a volume reduction of greater than 50%, 5 (14.3%) had a volume reduction of 15%-50%, 5 (14.3%) were stable in size (volume change < 15%), and 5 (14.3%) had larger volumes (all of these lesions were eventually resected). Four patients (11.4%) underwent resection within 9 months to 6 years because of progressive symptoms. One patient (2.9%) had open surgery for new-onset intractable trigeminal neuralgia at 48 months after GKRS. Two patients (5.7%) who developed a symptomatic cyst underwent placement of a cystoperitoneal shunt. Eight (66%) of 12 patients with pre-GKRS trigeminal sensory dysfunction had hypoesthesia relief. One hemifacial spasm completely resolved 3 years after treatment. Seven patients with facial weakness experienced no deterioration after GKRS. Two of 3 patients with serviceable hearing before GKRS deteriorated while 1 patient retained the same level of hearing. Two patients improved from severe hearing loss to pure tone audiometry less than 50 dB. The authors found borderline statistical significance for post-GKRS tumor enlargement for later resection (p = 0.05, HR 9.97, CI 0.99-100.00). A tumor volume ≥ 15 cm3 was a significant factor predictive of GKRS failure (p = 0.005). No difference in outcome was observed based on indication for GKRS (p = 0.0761). CONCLUSIONS Although microsurgical resection remains the primary management choice in patients with VSs, most VSs that are defined as having both a single dimension > 3 cm and a volume > 10 cm3 and tolerable mass effect can be managed satisfactorily with GKRS. Tumor volume ≥ 15 cm3 is a significant factor predicting poor tumor control following GKRS.

Use of apparent diffusion coefficients in evaluating the response of vestibular schwannomas to Gamma Knife surgery.

OBJECT: Cellular density is a major factor responsible for changes in apparent diffusion coefficients (ADCs). The authors hypothesized that loss of tumor cells after Gamma Knife surgery (GKS) might alter ADC values. Magnetic resonance imaging, including diffusion-weighted (DW) imaging, was performed to detect cellular changes in brain tumors so that the authors could evaluate the tumor response to GKS as well as the efficacy of the procedure. METHODS: The authors conducted a prospective trial involving 31 patients harboring solid or cystic vestibular schwannomas (VSs) that were treated with GKS. The patients underwent serial MR imaging, including DW imaging, before GKS and at multiple intervals following the procedure. The authors observed the patients over time, evaluating MR imaging findings and clinical outcomes at 6-month intervals. The ADCs were calculated from echo-planar DW images, and mean ADC values were compared at each follow-up. RESULTS: The mean follow-up period was 36.5 months (range 18-60 months). Imaging studies showed a reduction in tumor volume in 19 patients (61.3%) and tumor growth arrest in 9 patients (29%). In the remaining 3 patients (9.7%), tumor enlargement was documented at 18, 36, and 42 months. The mean ADC value before GKS for all solid VSs was 1.06 ± 0.17 × 10(-3) mm(2)/second, which significantly increased 6 months after GKS and continued to increase with time (p = 0.0086). The mean ADC value for treated solid tumors as of the last mean follow-up of 36 months (range 18-60 months) was 1.72 ± 0.26 × 10(-3) mm(2)/second (range 1.50-2.09 × 10(-3) mm(2)/second), which was significantly higher than that before GKS (p = 0.0001). Tumor volumes were positively related to ADC values (p = 0.03). The mean ADC value before GKS for all cystic VSs was 2.09 ± 0.24 × 10(-3) mm(2)/second (range 1.80-2.58 × 10(-3) mm(2)/second). The mean ADC value for treated cystic tumors as of the last mean follow-up of 38 months (range 18-48 months) was 1.89 ± 0.22 × 10(-3) mm(2)/second. In 3 patients harboring solid VSs, the tumor enlarged after GKS but the ADC values were higher than those before GKS. The authors considered these tumors to be controlled and continued follow-up in the patients. CONCLUSIONS: Apparent diffusion coefficient values may be useful for evaluating treatment results before any definite volume change is detected on imaging studies and for distinguishing radiation-induced necrosis from tumor recurrence in cases in which other imaging results are not definitive, as in cases of increased tumor volume or no volume change. The authors suggest that ADC measurements be included during routine MR imaging examinations for the evaluation of GKS results.

Gamma Knife surgery for hemifacial spasm related to cerebellopontine angle tumors.

OBJECT: Most cases of tumor-related hemifacial spasm (HFS) are treated by open surgery. The authors report the effects of Gamma Knife surgery (GKS) on benign tumor-related HFS at a mean follow-up time of 84 months. METHODS: Between 2000 and 2011, 6 patients (5 women and 1 man) harboring single tumors of the cerebellopontine angle (4 meningiomas and 2 vestibular schwannomas [VSs]) and experiencing HFS underwent GKS as a primary treatment. The mean age of the patients at the time of radiosurgery was 52.7 years (range 45-60 years). The patients' tumors lay within the radiosurgical target area. In the 4 cases of meningioma, the mean radiosurgical treatment volume was 5.3 cm(3) (range 1.2-9.6 cm(3)), and the mean radiosurgical tumor margin dose was 14.1 Gy (range 12-18 Gy); in the 2 cases of VS, the treatment volume was 2.5 cm(3) in 1 patient and 11.2 cm(3) in the other, and the margin doses were 11.5 and 12 Gy, respectively. The mean duration of HFS symptoms was 15.5 months (range 3-36 months). RESULTS: The mean follow-up period was 84 months (range 40-110 months). Overall, 4 (66%) of the 6 patients experienced complete relief from HFS without medication after GKS and 1 patient obtained a good outcome. The mean time for improvement to be realized was 12.6 months (range 3-24 months). Only 1 patient failed to experience relief from HFS, and coincidentally, the tumor did not shrink in that case. In all 6 patients (100%), tumor growth was controlled at a mean follow-up of 56 months after GKS: in 5 patients the tumor had decreased in size and in the other patient the tumor size remained unchanged. No new neurological deficit was noted after GKS, and 1 patient with facial numbness reported improvement after tumor shrinkage. CONCLUSIONS: Gamma Knife surgery appears to be effective in treating benign tumor-related HFS and in controlling tumor growth. A reduction in tumor volume is related to spasm improvement. Although a time latency for spasm relief is associated with GKS, minimal side effects are expected.

Docetaxel and 5-fluorouracil induce human p53 tumor suppressor gene transcription via a short sequence at core promoter element.

The p53 tumor suppressor protein is involved in cellular defense against agents that can cause genetic damage. Induction of p53 gene expression at transcriptional and post-transcriptional levels by such agents results in p53-regulated gene activation or suppression. Docetaxel (DOC), a member of the taxanes family that is widely used in cancer chemotherapy, activates p53 at the transcriptional level. We demonstrated that p53 is induced by low dose DOC treatment, resulting in MDR-1 gene suppression in human lung cancer cells. To identify the cis-element of p53 promoter that responds to DOC, p53 promoter region was cloned and promoter activity was analyzed on luciferase gene reporter assay. Promoter region (-78 to +129) contained the highest basal p53 promoter activity and deletion of +86 to +129 severely reduced basal promoter activity. Basal promoter region included the 21-bp element (PE21) that determines UV-inducible expression of p53 and mediates DOC-inducible p53 expression. On site-specific mutagenesis of PE21 (-78 to -58), with mutation of ATTG (-62 to -59) to CGGT, completely diminished the response to DOC. The same mutations also inhibited 5-fluorouracil (5-FU)-inducible p53 expression. Our data revealed that a sequence located at PE21 of p53 core promoter regulates p53 induction by chemotherapeutic agents.

Gamma Knife surgery for recurrent or residual trigeminal neuralgia after a failed initial procedure.

OBJECT: The purpose of this study was to assess outcomes of Gamma Knife surgery (GKS) as a second treatment for recurrent or residual trigeminal neuralgia (TN) after failure of 3 initial procedures: microvascular decompression (MVD), GKS, and percutaneous radiofrequency rhizotomy (PRR). METHODS: Between 1999 and 2008, 65 patients (31 men [48%] and 34 women [52%]) with recurrent TN were treated with GKS. All 65 patients had undergone previous medical procedures that failed to achieve sufficient pain relief: 27 patients (42%) had undergone MVD, 8 (12%) had undergone PRR, and 30 (46%) had undergone GKS as the initial treatment. The entry zone of the trigeminal nerve was targeted using a 4-mm collimator and treated with 35-90 Gy. The isocenter was positioned so that the brainstem surface was usually irradiated at an isodose no greater than 20% (59 patients) to 30% (6 patients). The median duration of TN symptoms in these patients was 39 months (range 1-192 months). RESULTS: At the clinical evaluation, 42 patients (65%) with idiopathic TN reported successful pain control at a median follow-up point of 64 months (range 18-132 months). Of these patients, 33 (51%) were no longer using medication. At the 1-, 2-, and 3-year follow-up examinations, 74%, 71%, and 66% of patients experienced successful pain control, respectively. There was no significant difference in pain relief in the initial MVD group compared with the initial GKS and initial PRR groups (74% vs 59% and 50%, respectively; p = 0.342). Recurrence of pain was noted in 23 patients. Twelve of these 23 patients underwent another GKS, resulting in pain control in 8 patients (67%); 8 other patients underwent MVD, resulting in pain relief in 7 patients (87.5%). The median time from GKS to pain recurrence was 7 months (range 3-48 months). There was no significant difference in new facial numbness among the 3 groups (p = 0.24); however, in the initial GKS group, facial numbness was significantly associated with freedom from pain (p = 0.0012). There was a significant correlation between the total radiation dose and facial numbness. The cutoff value for facial numbness ranged from 115 to 120 Gy (p = 0.037). CONCLUSIONS: Gamma Knife surgery as a second treatment achieved acceptable levels of pain control in 65% of patients with residual or recurrent TN after long-term follow-up. Initial treatment was not a factor that affected pain control, but salvage surgery may be considered separately for each group.

Quality-of-life outcomes after Gamma Knife surgery for trigeminal neuralgia.

OBJECT: Gamma Knife surgery (GKS) is an important part of the neurosurgical armamentarium for treatment of patients with trigeminal neuralgia (TN) and is regarded as the first-line treatment in patients with TN who have serious medical comorbidities. In this study, the authors investigated the efficacy of GKS on TN in patients with serious medical comorbidities. METHODS: Between May 2004 and September 2007, 52 severely ill patients who also had TN with Barrow Neurological Institute (BNI) facial pain scores of IV or V were entered into this study. The patients' medical records and imaging findings were reviewed by an anesthesiologist and neurosurgeons to determine whether GKS was a reasonable approach to palliate the patient's pain. All patients underwent GKS, in which a maximum dose of 80 Gy was targeted to the trigeminal nerve with or without plugging to keep the dose received by the brainstem at less than 16 Gy. After treatment, every patient had clinical follow-up every 1-3 months and filled out questionnaires designed to assess BNI facial pain and numbness scores, visual analog scale scores, and 36-Item Short Form Health Survey (SF-36) scores every 3 months until the end of the study. Statistical analysis was performed to find favorable prognostic factors related to pain relief and changes in quality of life. RESULTS: The median age of the patients was 71 years, and the male/female ratio was 30:22. The median follow-up period was 54 months (at least 2 years). All patients had a positive initial response to GKS, with BNI facial pain scores at least 1 point less than respective pre-GKS scores. Three patients (5.7%) obtained BNI facial pain Score I. Twenty-three patients (44.2%) experienced pain recurrence at a median follow-up of 33 months. One patient suffered from angina and required time in an intensive care unit; another patient had bleeding from a pin wound that required suturing. Alterations in BNI scores were highly correlated to visual analog scale scores (R(2) = 0.978). In both univariate and multivariate analyses, a decreased BNI facial pain score at different time points was significantly (p < 0.05) related to younger patient age, no previous treatment, evidence of vessel compression on MR imaging, time of first GKS ≤ 24 months, physical function (SF-36), role limitation due to a physical problem (SF-36), role limitation due to an emotional problem (SF-36), mental health (SF-36), social functioning (SF-36), bodily pain (SF-36), and general health (SF-36), but was not related to vitality (SF-36). Five patients (9.6%) experienced facial numbness at a mean of 13.2 ± 3.1 months after GKS (4 patients with BNI facial numbness Score II and 1 with BNI facial numbness Score III). Post-GKS MR imaging changes, including focal contrast enhancement or T2-weighted signal alterations, were identified in 3 patients (5.7%). CONCLUSIONS: Gamma Knife surgery produced significant pain relief in severely ill patients who had TN without causing appreciable morbidity. The effect of reduced pain significantly paralleled an improvement in SF-36 quality-of-life indices.

Genetic determinants of pemetrexed responsiveness and nonresponsiveness in non-small cell lung cancer cells.

BACKGROUND: Pemetrexed disodium (Alimta), LY231514, is an antifolate that is able to simultaneously inhibit the synthesis of purines and pyrimidines. Pemetrexed has been approved for first- and second-line treatment in patients with non-small cell lung cancer (NSCLC). However, there is still a lack of clinical biomarkers for predicting the therapeutic response to pemetrexed. The aim of this study is to establish new biomarkers for pemetrexed treatment in NSCLC. METHODS: Human NSCLC cell lines were exposed to pemetrexed. The antitumor effect was measured by growth inhibition with MTT assay and expression of cell cycle mediators with immunoblots. Using the Superarray cancer pathway gene array, 482 genes were screened for differential expression in A549 cells that were untreated or treated with pemetrexed. RESULTS: A549 cells exhibited sensitivity but H1355 cells showed resistance to pemetrexed. To investigate the mechanisms of responsiveness and nonresponsiveness to pemetrexed in these cell lines, we measured the expression levels of thymidylate synthase (TS), dihydrofolate reductase (DHFR), reduced folate carrier, and folylpoly-gamma-glutamate synthetase genes. TS, DHFR, and reduced folate carrier gene expressions were significantly reduced in A549 and H1355 cells. Pemetrexed caused cell cycle arrest in the G1 phase and S phase in H1355 and A549 cells, respectively. Significantly higher expressions of many genes, especially lipocalin-2 (Lcn-2) and nm23-H1 proteins, were noted in A549 cells treated with pemetrexed in comparison with untreated cells. Furthermore, reverse transcriptase polymerase chain reaction and Western blot showed that Lcn-2 and nm23-H1 expressions increase in response to pemetrexed treatment in a dose-responsive manner in pemetrexed-sensitive A549 cells but not in resistant H1355 cells. CONCLUSIONS: Our results indicated that downregulation of TS and DHFR genes and upregulation of p21, p27, Lcn-2, and nm23-H1 genes may serve as new biomarkers for predicting responsiveness to pemetrexed.

Apparent diffusion coefficients for evaluation of the response of brain tumors treated by Gamma Knife surgery.

OBJECT: Cellular density is a major factor for change in the apparent diffusion coefficient (ADC). The authors hypothesized that loss of tumor cells after Gamma Knife surgery (GKS) may alter the ADC value and used diffusion weighted MR imaging (DW imaging) to evaluate cellular changes in brain tumors to detect their treatment response and the efficacy of GKS. METHODS: In this paper the authors describe a prospective trial involving 86 patients harboring 38 solid or predominantly solid brain metastases, 30 meningiomas, and 24 acoustic neuromas that were treated by GKS. The patients underwent serial MR imaging examinations, including DW imaging, before treatment and at multiple intervals following GKS. Follow-up MR images and clinical outcomes were reviewed at 3-month intervals for metastatic lesions and at 6-month intervals for benign tumors. Apparent diffusion coefficients were calculated from echo planar DW images, and mean ADC values were compared at each follow-up. RESULTS: The mean ADC value for all meningiomas was 0.82 ± 0.15 × 10-3 mm2/sec before GKS. The mean ADC value as of the last mean follow-up of 42 months was 1.36 ± 0.19 × 10-3 mm2/sec, a significant increase compared to that before treatment (p < 0.0001). Calcification (p = 0.006) and tumor recurrence (p = 0.025) significantly prevented a rise in the ADC level.The mean ADC value for all solid acoustic neuromas was 1.06 ± 0.17 × 10-3 mm2/sec before GKS. The mean ADC value as of the last mean follow-up of 36 months was 1.72 ± 0.26 × 10-3 mm2/sec, a significant increase (p =0.0002) compared with values before GKS. At the last mean MR imaging follow-up there appeared to be tumor enlargement in 3 patients (12.5%); however, since the ADC values in these patients were significantly higher than the preradiosurgery values, the finding was considered to be a sign of radiation necrosis rather than tumor recurrence. The mean ADC value of metastatic tumors was 1.05 ± 0.12 × 10-3 mm2/sec before GKS. This value rose significantly(p < 0.0001) to 1.64 ± 0.18 × 10-3 mm2/sec after GKS at a mean follow-up of 9.4 months. Magnetic resonance imaging showed that 89% of these tumors had been controlled by GKS. In 2 patients there were enlarged lesions, but the ADC values were the same as pre-GKS levels, and therefore, the lesions were deemed recurrent. CONCLUSIONS: Apparent diffusion coefficient values may be useful in evaluating treatment results before a definitive change in volume is evident on imaging studies. In some patients in whom imaging findings are equivocal, ADC values may also be used to distinguish radiation-induced necrosis from tumor recurrence.(DOI: 10.3171/2010.7.GKS10864)

Synthesis of enantiomers of exo-2-norbornyl-N-n-butylcarbamate and endo-2-norbornyl-N-n-butylcarbamate for stereoselective inhibition of acetylcholinesterase.

The acetylcholinesterase inhibition by enantiomers of exo- and endo-2-norbornyl-N-n-butylcarbamates shows high stereoselelectivity. For the acetylcholinesterase inhibitions by (R)-(+)- and (S)-(-)-exo-2-norbornyl-N-n-butylcarbamates, the R-enantiomer is more potent than the S-enantiomer. But, for the acetylcholinesterase inhibitions by (R)-(+)- and (S)-(-)-endo-2-norbornyl-N-n-butylcarbamates, the S-enantiomer is more potent than the R-enantiomer. Optically pure (R)-(+)-exo-, (S)-(-)-exo-, (R)-(+)-endo-, and (S)-(-)-endo-2-norbornyl-N-n-butylcarbamates are synthesized from condensations of optically pure (R)-(+)-exo-, (S)-(-)-exo-, (R)-(+)-endo-, and (S)-(-)-endo-2-norborneols with n-butyl isocyanate, respectively. Optically pure norborneols are obtained from kinetic resolutions of their racemic esters by lipase catalysis in organic solvent.

Comparison of active sites of butyrylcholinesterase and acetylcholinesterase based on inhibition by geometric isomers of benzene-di-N-substituted carbamates.

We have reported that benzene-1,2-, 1,3-, and 1,4-di-N-substituted carbamates (1-15) are characterized as the conformationally constrained inhibitors of acetylcholinesterase and mimic gauche, eclipsed, and anti-conformations of acetylcholine, respectively (J Biochem Mol Toxicol 2007;21:348-353). We further report the inhibition of butyrylcholinesterase by these inhibitors. Carbamates 1-15 are also characterized as the pseudosubstrate inhibitors of butyrylcholinesterase as in the acetylcholinesterase catalysis. Benzene-1,4-di-N-n-hexylcarbamate (12) and benzene-1,4-di-N-n-octylcarbamate (13) are the two most potent inhibitors of butyrylcholinesterase among inhibitors 1-15. These two para compounds, with the angle of 180 degrees between two C(benzene)--O bonds, mimic the preferable anti C--O/C--N conformers for the choline ethylene backbone of butyrylcholine during the butyrylcholinesterase catalysis. The second n-hexylcarbamyl or n-octylcarbamyl moiety of inhibitors 12 and 13 is proposed to bind tightly to the peripheral anionic site of butyrylcholinesterase from molecular modeling. Butyrylcholinesterase prefers para-carbamates to ortho- and meta-carbamates, whereas acetylcholinesterase prefers para- and meta-carbamates to ortho-carbamates. This result implies that the anionic site of butyrylcholinesterase is relatively smaller than that of acetylcholinesterase because meta-carbamates, which may bind to the anionic sites of both enzymes, are not potent inhibitors of butyrylcholinesterase.

Gamma Knife surgery for trigeminal pain caused by benign brain tumors.

OBJECT: The authors report the effects of Gamma Knife surgery (GKS) on benign tumor-related trigeminal pain in patients who underwent follow-up for a mean 57.8 months. METHODS: From 1999 to 2004, 21 patients with benign tumor-related trigeminal pain (12 meningiomas and 9 schwannomas) underwent GKS as a primary or repeated treatment. These patients harbored tumors within the radiosurgical target area. For meningiomas, the mean radiosurgical treatment volume was 8.2 ml (range 1.1-21 ml), and the mean radiosurgical tumor margin dose was 12.7 Gy (range 12-15 Gy); for schwannomas, the mean volume was 5.6 ml (range 2-9.2 ml), and the mean marginal dose was 13 Gy (range 11.5-16 Gy). Seven patients underwent retreatment for recurrent or persistent pain; the ipsilateral trigeminal nerve or ganglion was identified and a mean maximal dose of 60.7 Gy (range 40-70 Gy) was delivered to these targets. In 1 patient undergoing retreatment, the margin dose was 12 Gy. The mean age at the time of radiosurgery was 54.5 years (range 18-79 years). RESULTS: The mean follow-up period was 57.8 months (range 36-94 months). Overall, 12 (57%) of 21 patients experienced pain relief without medication after the first GKS and the mean time to drug discontinuation was 10.5 months (range 2-24 months). Initial pain improvement was noted in 17 patients (81%) with a mean time of 3.7 months (range 1 week-10 months) after GKS. Eight patients underwent repeated GKS for persistent and recurrent pain. Four patients (50%) had complete pain relief. The final results of the first and repeated GKS were excellent in 16 patients (76%), and in only 1 patient did GKS fail, and this patient later underwent open surgery. For all 21 patients (100%), control of tumor growth was documented at a mean of 46 months after GKS. Three of 6 patients with pre-GKS facial numbness reported improvement, but 4 suffered new facial numbness after repeated GKS. CONCLUSIONS: Gamma Knife surgery appears to be an effective tool to treat benign tumor-related trigeminal pain and control tumor growth. Repeated GKS targeting the trigeminal root or ganglion can be considered a tool to enhance the efficacy of pain management if pain persists or recurs, but the optimum treatment dose needs further investigation.

Gamma Knife surgery used as primary and repeated treatment for idiopathic trigeminal neuralgia.

OBJECT: The purpose of this study was to assess the outcome of idiopathic trigeminal neuralgia (TN) treated with Gamma Knife surgery (GKS) as a primary and repeated treatment modality with a mean follow-up of 5.7 years. METHODS: Between July 1999 and September 2005, a total of 89 patients with idiopathic TN underwent GKS as a primary treatment. The entry zone of the TN was targeted with a 4-mm collimator and treated with a maximal dose of 60-90 Gy (mean 79 Gy). The dose to the pontine margin was always kept < 15 Gy. Twenty patients received repeated GKS for recurrent or residual pain with a maximal dose of 40-76 Gy (mean 52 Gy). For the second procedure, the target was positioned at the same location as the first treatment. RESULTS: The mean follow-up period was 68 months (range 32-104 months). Sixty-nine (77.5%) of the 89 patients experienced a favorable response, as follows: 50 (56%) had excellent, 12 (13.5%) had good, and 7 (7.8%) had fair outcomes. The mean time to pain relief was 1.1 months (range 2 days-6 months). No significant correlation, but more likely a tendency, was found between the dose and pain relief (p = 0.08). Also, no correlation was noted for facial numbness (p = 0.77). The mean follow-up period after repeated GKS was 60 months (range 32-87 months). Outcomes after repeated GKS were excellent in 11 patients (55%) and good in 1 (5%). Seven patients experienced facial numbness. No correlation was found between the additive dose and pain relief (p = 0.24) or facial numbness (p = 0.15). Final outcomes of primary and repeated GKS were excellent in 61 (68.5%), good in 13 (14.6%), and fair in 7 (7.9%). In total, 91% of the patients were successfully treated with this method. There was no statistical significance for efficacy between primary and repeated GKS (p = 0.65), but there was a significant difference for facial numbness (p = 0.007). CONCLUSIONS: Gamma Knife surgery established durable pain relief when used as a primary and repeated surgery. Treatment was successful for a total of 91% of patients at a mean follow-up of 5.7 years, but facial numbness was also relatively higher.

Diffusion magnetic resonance imaging as an evaluation of the response of brain metastases treated by stereotactic radiosurgery.

BACKGROUND: Loss of tumor cell results in a relative increase in extracellular space that may lead to alteration of ADC. Our purpose was to see if the ADC could be used, rather than methods depending on changes in tumor size, to predict treatment success after treatment of brain metastases with SRS. METHODS: In a prospective study, the ADCs of 21 patients with 32 solid or solid-dominated brain metastases were taken before and 1 week, 1 month, and at 3-month intervals after SRS. Mean ADC values at the various time intervals were compared with each other to see whether or not the ADC might be used as an early indicator of treatment success or failure. RESULTS: The mean pretreatment value of the ADC in the metastatic tumors was 1.05 +/- 0.12 x 10(-3) mm2/s (mean +/- SD). This value for the tumors rose significantly (P = .009) 7 days after SRS and continued to rise with time. Magnetic resonance imaging showed that 91% of these tumors had been controlled by the SRS. The ADC values in cystic/necrotic tumor tissue (2.13 +/- 0.18 x 10(-3) mm2/s) were significantly (P < .001) higher than those in noncentral necrotic tumor tissue (1.61 +/- 0.14 x 10(-3) mm2/s). CONCLUSIONS: The ADC values might eventually be useful to evaluate treatment success-and in some patients, detected even at early time points-and to distinguish radiation-induced central necrosis from tumor regrowth in cases where other imagery is not definitive.

Histopathology of radiation necrosis with severe peritumoral edema after gamma knife radiosurgery for parasagittal meningioma. A report of two cases.

BACKGROUND: Gamma knife radiosurgery (GKS) has been an effective treatment for meningiomas. Nevertheless, it still has certain risks. We present 2 cases of parasagittal meningioma after GKS complicated with radiation necrosis and peritumoral edema. The results of histologic examination are discussed. CASE DESCRIPTION: Two cases of parasagittal meningioma received GKS. Symptomatic peritumoral edema developed 3-4 months after GKS. Both of them underwent surgical resection of their tumor afterwards. Histologic examination showed necrotic change inside the tumor and infiltration of inflammatory cells in both cases. Hyalinization of blood vessels was seen in the 2nd case. The patients had improvement of neurologic function after surgical resection. Imaging performed 3 months after surgical resection showed alleviation of brain edema. CONCLUSION: After radiosurgery peritumoral edema tends to occur in meningiomas with a parasagittal position. Radiation necrosis, infiltration of inflammatory cells, and radiation injury to the vasculature causing hyalinization of blood vessels are suggested as the underlying histopathology.

Two consecutive dural arteriovenous fistulae in a child: a case report of successful treatment with gamma knife radiosurgery.

INTRODUCTION: The occurrence of dural arteriovenous fistulae in children is quite rare. Endovascular embolization is typically the first line treatment. In general, Gamma Knife radiosurgery is used as adjuvant treatment and seldom performed as the first line treatment in children. DISCUSSION: We report a case of a 27-month-old girl who presented with an initial dural arteriovenous fistula (AVF) located at anterior base of the left middle cranial fossa. She subsequently developed another dural AVF over the left transverse-sigmoid sinus region 2 years later. CONCLUSION: Both fistulae were successfully obliterated with Gamma Knife radiosurgery.

Repeated Gamma Knife surgery for refractory trigeminal neuralgia.

OBJECT: Repeated Gamma Knife surgery (GKS) for trigeminal neuralgia (TN) is an acceptable method for refractory cases but not well established in terms of dose effect and nerve tolerance. The authors report their experience in 28 patients over 3.5 years of follow up. METHODS: Between 1999 and 2004, a total of 28 patients with recurrent or residual TN underwent repeated GKS. The median follow-up periods were 52 and 43 months after the first and repeated procedures, respectively. The entry zone of the trigeminal nerve was targeted using a 4-mm collimator and treated with 40 to 76 Gy as maximal dose. Additive doses ranged between 110 and 152 Gy. The median duration of symptoms was 4.86 years. There were 12 women (46%) and 16 men (54%). At the last evaluation, a total of 19 patients (68%) reported pain relief. Of these patients, 13 were no longer taking pain medications. Significant recurrent or residual pain was noted in nine patients after a median follow up of 12 months (range 6-48 months). New onset of facial numbness was noted in 10 patients. An additive dose above 115 Gy was found to be associated with facial numbness and nonfacial numbness (p = 0.047). No definite additive dose correlation with pain relief was noted (p = 0.23). CONCLUSIONS: Repeated GKS established durable pain relief in a majority of patients, and a higher additive dose (> 115 Gy) tended to cause facial numbness. However, a prospective trial is needed to fully assess the efficacy and late complications of GKS.

Microsurgical outcomes after failed repeated Gamma Knife surgery for refractory trigeminal neuralgia.

OBJECT: The results of microsurgery in patients with trigeminal neuralgia (TN) after failure of repeated Gamma Knife surgery (GKS) have not previously been examined. The effects of microvascular decompression (MVD) in patients in whom repeated GKS has failed are reported. METHODS: Between 1999 and 2004, eight patients (five women and three men) who underwent repeated GKS and experienced treatment failure subsequently underwent MVD. These patients underwent MVD for recurrent or residual intractable trigeminal pain. The duration of facial pain before MVD ranged from 0.8 to 13 years (mean 5.2 years). The total treatment dose administered ranged from 110 to 140 Gy (mean 129 Gy). The mean age was 59.5 years (range 44-68 years). Seven patients in whom the offending vessel (five arteries and two veins) was located at the nerve entry zone improved with variable pain relief after MVD. One patient in whom the vessel could not be identified did not improve. Intraoperatively, there were no signs in any patient of radiation-induced damage such as thickening of arachnoid membrane. In one patient a segment of atherosclerotic plaque was discovered at the nerve entry zone. Two patients experienced numbness at 1 and 3 months after MVD. CONCLUSIONS: Microvascular decompression is an effective treatment for patients with TN in whom repeated GKS has failed. Previous radiation treatment did not negatively impact operative difficulty or risk to the patient in this small series. Radiosurgery may induce vascular injury and cause pain recurrence.

Radiosurgery for vestibular schwannomas.

BACKGROUND: Radiosurgery has been established as an important alternative to microsurgery. We report our experience with radiosurgery for tumor control and the complications of unilateral vestibular schwannomas. METHODS: We reviewed our early experience regarding clinical presentation, management and outcomes in 45 patients with acoustic schwannomas who underwent gamma knife stereotactic radiosurgery. The median follow-up period was 25 months (range, 6-48 months). Thirteen patients had undergone 1 or more previous resections before radiosurgery; 32 underwent radiosurgery as the first procedure. Median tumor volume was 4.5 mL (range, 0.5-30.0), and median radiotherapy dose was 11.5 Gy (range, 10.5-14.0 Gy). RESULTS: Tumor control was achieved in 43 patients (95.6%). Loss of central contrast enhancement was a characteristic change and was noted in 29 patients (64.4%). Reduction in tumor size was shown in 15 patients (33.3%). Thirteen patients (28.9%) had good or serviceable hearing preoperatively, and in all of these, the preoperative status was retained immediately after radiosurgery. At follow-up, however, 10 patients (76.9%) had preserved hearing and 3 (23.1%) had reduced hearing on the treated side. Hearing in 1 patient that was not serviceable preoperatively later improved to a serviceable level. No patients had delayed facial palsy or lower cranial nerve dysfunction, but one had delayed trigeminal sensory loss. CONCLUSION: Radiosurgery achieved a high tumor control rate and a relatively low post-radiosurgical complication rate for acoustic neuromas.