Multiple protonation states in ligand-free SARS-CoV-2 main protease revealed by large-scale quantum molecular dynamics simulations.

The main protease (Mpro) in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) catalyzes the cleavage of polyproteins for viral replication. Here, large-scale quantum molecular dynamics and metadynamics simulations for ligand-free Mpro were performed, where all the atoms were treated quantum-mechanically, focusing on elucidation of the controversial active-site protonation state. The simulations clarified that the interconverting multiple protonation states exist in unliganded Mpro, and the catalytically relevant ion-pair state is more stable than the neutral state, which is consistent with neutron crystallography. The results highlight the importance of the ion-pair state for repurposing or discovering antiviral drugs that target Mpro.

Sagittal splitting of the temporalis muscle for encephalo-myo-synangiosis to prevent ischemic complications due to a swollen temporalis muscle without inhibiting collateral developments in patients with moyamoya disease.

OBJECTIVEEncephalo-myo-synangiosis (EMS) is an effective revascularization procedure for the treatment of moyamoya disease (MMD). However, the temporalis muscle used for EMS sometimes swells and causes ischemic complications by compressing the underlying brain. This study aimed to elucidate the effect of sagittal splitting (SS) of the muscle for prevention of ischemic complications and its impact on the postoperative development of collateral vessels.METHODSIn this historical case-control study, we analyzed 60 hemispheres in adult patients with MMD who underwent EMS using the temporalis muscle from December 1998 to November 2017. The muscle was divided anteroposteriorly by coronal splitting, and the anterior, posterior, or both parts of the muscle were used for EMS in 17, 4, and 39 hemispheres, respectively. In cases performed after 2006, the muscle was halved by SS, and the medial half was used for EMS to reduce the muscle volume (n = 47). The degree of postoperative muscle swelling was evaluated by measuring the maximum thickness of the muscle on CT scans obtained 3 to 7 days after surgery. The collateral developments of the anterior deep temporal artery (aDTA), posterior deep temporal artery (pDTA), and middle temporal artery (MTA) were assessed using digital subtraction angiography and MR angiography performed 6 months or more after surgery.RESULTSSS significantly reduced the temporalis muscle thickness from 12.1 ± 5.0 mm to 7.1 ± 3.0 mm (p < 0.01). Neurological deterioration due to the swollen temporalis muscle developed in 4 of the 13 hemispheres without SS (cerebral infarction in 1, reversible neurological deficit in 2, and convulsion in 1) but in none with SS. There were no significant differences in the postoperative collateral developments of the aDTA, pDTA, and MTA between hemispheres with and without SS. The MTA more frequently developed in hemispheres with EMS in which the posterior part of the muscle was used (30/37) than those in which this part was not used (4/16) (p < 0.01).CONCLUSIONSSS of the temporalis muscle might prevent neurological deterioration caused by the swollen temporalis muscle by reducing its volume without inhibiting the development of the collateral vessels.

Cortical Venous Redness Represents Tissue Circulation Status in Patients With Moyamoya Disease.

BACKGROUND AND PURPOSE: Venous oxygen saturation (SO2) is measured in medical fields to assess tissue circulation insufficiency. This study aimed to elucidate the use of a cortical venous redness measurement to evaluate hemodynamic changes during revascularization surgery for patients with moyamoya disease. METHODS: In this retrospective case-series analysis, we first quantitatively measured and correlated SO2 and R intensity of 24-bit color digital red-green-blue pictures of blood samples from 3 volunteers. Subsequently, based on intraoperative digital pictures of 29 patients with moyamoya disease, we measured the R intensities of a cortical vein near the anastomosis site before and after anastomosis. Cerebral blood flow (CBF) at the site was measured using a single-photon emission computed tomography before and 1 to 3 days after surgery. Venous R intensity and CBF were measured twice by 4 raters, and their correlations were examined using generalized linear mixed effect model and linear regression analysis. RESULTS: A strong linear correlation was found between blood R intensity and its SO2 (coefficients, 0.522; 95% confidence interval, 0.364-0.680, using generalized linear mixed effect model). Venous R intensity before the anastomosis was not correlated with preoperative CBF (coefficients, 0.000352; 95% confidence interval, -0.000369 to 0.00107, by generalized linear mixed effect); however, the increases in venous R intensity after anastomosis were correlated with postoperative increases in CBF (R2, 0.367; 95% confidence interval, 0.116-0.618 to 0.548; 95% confidence interval, 0.331-0.764, by linear regression analysis). CONCLUSIONS: Cortical venous redness represented impaired CBF and could be a useful parameter for assessing hemodynamic changes during revascularization surgery.

Development and validation of a score for evaluating comprehensive stroke care capabilities: J-ASPECT Study.

BACKGROUND: Although the Brain Attack Coalition recommended establishing centers of comprehensive care for stroke and cerebrovascular disease patients, a scoring system for such centers was lacking. We created and validated a comprehensive stroke center (CSC) score, adapted to Japanese circumstances. METHODS: Of the selected 1369 certified training institutions in Japan, 749 completed an acute stroke care capabilities survey. Hospital performance was determined using a 25-item score, evaluating 5 subcategories: personnel, diagnostic techniques, specific expertise, infrastructure, and education. Consistency and validity were examined using correlation coefficients and factorial analysis. RESULTS: The CSC score (median, 14; interquartile range, 11-18) varied according to hospital volume. The five subcategories showed moderate consistency (Cronbach's α = 0.765). A strong correlation existed between types of available personnel and specific expertise. Using the 2011 Japanese Diagnosis Procedure Combination database for patients hospitalized with stroke, four constructs were identified by factorial analysis (neurovascular surgery and intervention, vascular neurology, diagnostic neuroradiology, and neurocritical care and rehabilitation) that affected in-hospital mortality from ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage. The total CSC score was related to in-hospital mortality from ischemic stroke (odds ratio [OR], 0.973; 95% confidence interval [CI], 0.958-0.989), intracerebral hemorrhage (OR, 0.970; 95% CI, 0.950-0.990), and subarachnoid hemorrhage (OR, 0.951; 95% CI, 0.925-0.977), with varying contributions from the four constructs. CONCLUSIONS: The CSC score is a valid measure for assessing CSC capabilities, based on the availability of neurovascular surgery and intervention, vascular neurology, diagnostic neuroradiology, and critical care and rehabilitation services.

Subcortical Low-Intensity Lesions on Fluid-Attenuated Inversion Recovery Images After Revascularization Surgery for Moyamoya Disease.

OBJECTIVE: Although uncommon, subcortical low-intensity (SCLI) changes on fluid-attenuated inversion recovery images are observed in various diseases, including cerebral ischemia. Here, we aimed to clarify the incidence and clinical implications of SCLI changes after revascularization surgery for moyamoya disease, focusing on the correlation with postoperative transient neurologic events (TNEs). METHODS: In this retrospective case series analysis, we included 10 hemispheres from 9 adults with moyamoya disease who underwent revascularization surgery. Subcortical signal intensity at the 5 gyri around the anastomosis point was quantitatively measured at 1 week and 3 months postoperatively. Changes in cerebral blood flow (CBF) were assessed using single-photon emission computed tomography. RESULTS: Images taken 1 week after surgery showed widespread SCLI changes below the operative fields in all 10 cases, but these changes normalized by 3 months. In addition, the changes in signal intensity at anastomoses negatively correlated with the changes in CBF (R2 = 0.36; P = 0.039). Postoperative TNEs occurred in 6 cases (60%) but were resolved within 17 days after surgery. Postoperative CBF increased in 9 of the 10 cases, with a median of 23%; however, these increases were not associated with the development of TNEs. The SCLI changes at the anastomosis points did not differ by the experience of TNEs. CONCLUSIONS: Early after surgery, SCLI changes are common findings below the operative fields but negatively correlate with increases in CBF. Although no significant association was found between TNEs and the SCLI changes, the synchronized development of these phenomena may suggest a common underlying pathogenesis.

Robustness of the neurological prognostic score in brain metastasis patients treated with Gamma Knife radiosurgery.

OBJECTIVE The neurological prognostic score (NPS) was recently proposed as a means for predicting neurological outcomes, such as the preservation of neurological function and the prevention of neurological death, in brain metastasis patients treated with Gamma Knife radiosurgery (GKRS). NPS consists of 2 groups: Group A patients were expected to have better neurological outcomes, and Group B patients were expected to have poorer outcomes. NPS robustness was tested in various situations. METHODS In total, 3040 patients with brain metastases that were treated with GKRS were analyzed. The cumulative incidence of the loss of neurological function independence (i.e., neurological deterioration) was estimated using competing risk analysis, and NPS was compared between Groups A and B by employing Gray's model. NPS was tested to determine if it can be applied to 5 cancer categories-non-small cell lung cancer, small cell lung cancer, gastrointestinal tract cancer, breast cancer, and other cancers-as well as if it can be incorporated into the 5 major grading systems: recursive partitioning analysis (RPA), score index for stereotactic radiosurgery (SIR), basic score for brain metastases (BSBM), graded prognostic assessment (GPA), and modified-RPA (M-RPA). RESULTS There were 2263 patients in NPS Group A and 777 patients in Group B. Neurological deterioration was observed in 586 patients (19.2%). The cumulative incidences of neurological deterioration were 9.5% versus 21.0%, 14.1% versus 25.4%, and 17.6% versus 27.8% in NPS Groups A and B at 1, 2, and 5 years, respectively. Significant differences were detected between the NPS groups in all cancer categories. There were significant differences between NPS Groups A and B for all classes in terms of the BSBM, GPA, and M-RPA systems, but the differences failed to reach statistical significance in terms of RPA Class I and SIR Class 0 to 3. CONCLUSIONS The NPS was verified as being highly applicable to all cancer categories and almost all classes for the 5 grading systems in terms of neurological function independence. This NPS system appears to be quite robust in various situations for brain metastasis patients treated with GKRS.

A new grading system focusing on neurological outcomes for brain metastases treated with stereotactic radiosurgery: the modified Basic Score for Brain Metastases.

OBJECT: The Basic Score for Brain Metastases (BSBM) proposed by Lorenzoni and colleagues is one of the best grading systems for predicting survival periods after stereotactic radiosurgery (SRS) for brain metastases. However, it includes no brain factors and cannot predict neurological outcomes, such as preservation of neurological function and prevention of neurological death. Herein, the authors propose a modified BSBM, adding 4 brain factors to the original BSBM, enabling prediction of neurological outcomes, as well as of overall survival, in patients undergoing SRS. METHODS: To serve as neurological prognostic scores (NPSs), the authors scored 4 significant brain factors for both preservation of neurological function (qualitative survival) and prevention of neurological death (neurological survival) as 0 or 1 as described in the following: > 10 brain tumors = 0 or ≤ 10 = 1, total tumor volume > 15 cm(3) = 0 or ≤ 15 cm(3) = 1, MRI findings of localized meningeal dissemination (yes = 0 or no = 1), and neurological symptoms (yes = 0 or no = 1). According to the sum of NPSs, patients were classified into 2 subgroups: Subgroup A with a total NPS of 3 or 4 and Subgroup B with an NPS of 0, 1, or 2. The authors defined the modified BSBM according to the NPS subgroup classification applied to the original BSBM groups. The validity of this modified BSBM in 2838 consecutive patients with brain metastases treated with SRS was verified. RESULTS: Patients included 1868 with cancer of the lung (including 1604 with non-small cell lung cancer), 355 of the gastrointestinal tract, 305 of the breast, 176 of the urogenital tract, and 134 with other cancers. Subgroup A had 2089 patients and Subgroup B 749. Median overall survival times were 2.6 months in BSBM 0 (382 patients), 5.7 in BSBM 1 (1143), 11.4 in BSBM 2 (1011) and 21.7 in BSBM 3 (302), and pairwise differences between the BSBM groups were statistically significant (all p < 0.0001). One-year qualitative survival rates were 64.6% (modified BSBM 0A, 204 patients), 45.0% (0B, 178), 82.5% (1A, 825), 63.3% (1B, 318), 86.4% (2A, 792), 73.7% (2B, 219), 91.4% (3A, 268), and 73.5% (3B, 34). One-year neurological survival rates were 82.6% (0A), 52.4% (0B), 90.5% (1A), 78.1% (1B), 91.1% (2A), 83.2% (2B), 93.9% (3A), and 76.3% (3B), where A and B identify the subgroup. Statistically significant differences in both qualitative and neurological survivals between Subgroups A and B were detected in all BSBM groups. CONCLUSIONS: The authors' new index, the modified BSBM, was found to be excellent for predicting neurological outcomes, independently of life expectancy, in SRS-treated patients with brain metastases.

Risk factors in chronic subdural hematoma: comparison of irrigation with artificial cerebrospinal fluid and normal saline in a cohort analysis.

BACKGROUND: Chronic subdural hematoma (CSDH) is known to have a substantial recurrence rate. Artificial cerebrospinal fluid (ACF) is an effective irrigation solution in general open craniotomy and endoneurosurgery, but no evidence of its use in burr-hole surgery exists. OBJECTIVE: To identify the potential of ACF irrigation to prevent CSDH recurrence. More specifically, to investigate the perioperative and intraoperative prognostic factors, and to identify controllable ones. METHODS: To examine various prognostic factors, 120 consecutive patients with unilateral CSDH treated with burr-hole drainage between September 2007 and March 2013 were analyzed. Intraoperative irrigation was performed with one of two irrigation solutions: normal saline (NS; n = 60) or ACF (n = 60). All patients were followed-up for at least 6 months postoperatively. We also examined the morphological alternations of the hematoma outer membranes after incubation with different solutions. RESULTS: Eleven patients (9.2%) had recurrence. Nine patients (15%) required additional surgery in the NS group, whereas only 2 patients (3.3%) in the ACF group required additional surgery. Among preoperative and intraoperative data, age (<80 years old, P = .044), thrombocyte (>22.0, P = .037), laterality (right, P = .03), and irrigation solution (ACF, P = .027) were related to smaller recurrence rates by log-rank tests. Only the type of irrigation solution used significantly correlated with recurrence in favor of ACF in both Cox proportional hazards (relative hazard: 0.20, 95% confidence interval (CI): 0.04-0.99; P = .049) and logistic regression models (odds ratio, 0.17, 95% CI: 0.03-0.92; P = .04) using these factors. Histological examinations of the hematoma membranes showed that the membranes incubated with NS were loose and infiltrated by inflammatory cells compared with those incubated with ACF. CONCLUSION: Irrigation with ACF decreased the rate of CSDH recurrence.

Influence of antiplatelet therapy on postoperative recurrence of chronic subdural hematoma: a multicenter retrospective study in 719 patients.

OBJECTIVE: The present study tested the hypothesis of whether antiplatelet agents (APA) induce chronic subdural hematoma (CSDH) recurrence via a platelet aggregation inhibitory effect. METHOD: We examined risk factors for CSDH recurrence, focusing on APA, in 719 consecutive patients who admitted to three tertiary hospitals and underwent burr-hole craniostomy and irrigation for CSDH. This was a multicenter, retrospective, observational study. RESULTS: Age, sex, history of diabetes mellitus, hypertension, chronic renal failure, alcohol consumption habits, consciousness disturbance on admission, or preoperative CT density was not associated with recurrence. Subdural drainage was significantly associated with less recurrence. Preoperative oral APA administration was significantly associated with more recurrence. The recurrence rate of CSDH in non-APA group was 11% if surgery was performed on admission. However, if surgery was performed immediately after discontinuation of oral APA administration, the recurrence rate in APA group significantly increased to 32% (p value<0.0001; odds ratio, 3.77; 95% confidence interval, 1.72-8.28). The effect of APA on CSDH recurrence gradually diminished as the number of days until initial surgery, after stopping APA, increased. CONCLUSION: Antiplatelet therapy significantly influences the recurrence of CSDH.

Validity of two recently-proposed prognostic grading indices for lung, gastro-intestinal, breast and renal cell cancer patients with radiosurgically-treated brain metastases.

We tested the validity of two prognostic indices for stereotactic radiosurgically (SRS)-treated patients with brain metastases (BMs) from five major original cancer categories. The two indices are Diagnosis-Specific Graded Prognostic Assessment (DS-GPA) and our Modified Recursive Partitioning Analysis (RPA). Forty-six hundred and eight BM patients underwent gamma knife SRS during the 1998-2011 period. Primary cancer categories were non-small cell lung cancer (NSCLC, 2827 patients), small cell lung cancer (SCLC, 460), gastro-intestinal cancer (GIC, 582), breast cancer (BC, 547) and renal cell cancer (RCC, 192). There were statistically significant survival differences among patients stratified into four groups based on the DS-GPA systems (p < 0.001) in all five original cancer categories. In the NSCLC category, there were statistically significant mean survival time (MST) differences (p < 0.001) among the four groups without overlapping of 95 % confidence intervals (CIs) between any two pairs of groups with the DS-GPA system. However, among the SCLC, GIC, BC and RCC categories, MST differences between some pairs of groups failed to reach statistical significance with this system. There were, however, statistically significant MST differences (p < 0.001) among the three groups without overlapping of 95 % CIs between any two pairs of groups with the Modified RPA system in all five categories. The DS-GPA system is applicable to our set of patients with NSCLC only. However, the Modified RPA system was shown to be applicable to patients with five primary cancer categories. This index should be considered when designing future clinical trials involving BM patients.

Testing different brain metastasis grading systems in stereotactic radiosurgery: Radiation Therapy Oncology Group's RPA, SIR, BSBM, GPA, and modified RPA.

OBJECT: The authors conducted validity testing of the 5 major reported indices for radiosurgically treated brain metastases- the original Radiation Therapy Oncology Group's Recursive Partitioning Analysis (RPA), the Score Index for Radiosurgery in Brain Metastases (SIR), the Basic Score for Brain Metastases (BSBM), the Graded Prognostic Assessment (GPA), and the subclassification of RPA Class II proposed by Yamamoto-in nearly 2500 cases treated with Gamma Knife surgery (GKS), focusing on the preservation of neurological function as well as the traditional endpoint of overall survival. METHODS: The authors analyzed data from 2445 cases treated with GKS by the first author (T.S.), the primary surgeon. The patient group consisted of 1716 patients treated between January 1998 and March 2008 (the Chiba series) and 729 patients treated between April 2008 and December 2011 (the Tokyo series). The interval from the date of GKS until the date of the patient's death (overall survival) and impaired activities of daily living (qualitative survival) were calculated using the Kaplan-Meier method, while the absolute risk for two adjacent classes of each grading system and both hazard ratios and 95% confidence intervals were estimated using the Cox proportional hazards model. RESULTS: For overall survival, there were highly statistically significant differences between each two adjacent patient groups characterized by class or score (all p values < 0.001), except for GPA Scores 3.5-4.0 and 3.0. The SIR showed the best statistical results for predicting preservation of neurological function. Although no other grading systems yielded statistically significant differences in qualitative survival, the BSBM and the modified RPA appeared to be better than the original RPA and GPA. CONCLUSIONS: The modified RPA subclassification, proposed by Yamamoto, is well balanced in scoring simplicity with respect to case number distribution and statistical results for overall survival. However, a new or revised grading system is necessary for predicting qualitative survival and for selecting the optimal treatment for patients with brain metastasis treated by GKS.

Subclassification of recursive partitioning analysis Class II patients with brain metastases treated radiosurgically.

PURPOSE: Although the recursive partitioning analysis (RPA) class is generally used for predicting survival periods of patients with brain metastases (METs), the majority of such patients are Class II and clinical factors vary quite widely within this category. This prompted us to divide RPA Class II patients into three subclasses. METHODS AND MATERIALS: This was a two-institution, institutional review board-approved, retrospective cohort study using two databases: the Mito series (2,000 consecutive patients, comprising 787 women and 1,213 men; mean age, 65 years [range, 19-96 years]) and the Chiba series (1,753 patients, comprising 673 female and 1,080 male patients; mean age, 65 years [range, 7-94 years]). Both patient series underwent Gamma Knife radiosurgery alone, without whole-brain radiotherapy, for brain METs during the same 10-year period, July 1998 through June 2008. The Cox proportional hazard model with a step-wise selection procedure was used for multivariate analysis. RESULTS: In the Mito series, four factors were identified as favoring longer survival: Karnofsky Performance Status (90% to 100% vs. 70% to 80%), tumor numbers (solitary vs. multiple), primary tumor status (controlled vs. not controlled), and non-brain METs (no vs. yes). This new index is the sum of scores (0 and 1) of these four factors: RPA Class II-a, score of 0 or 1; RPA Class II-b, score of 2; and RPA Class II-c, score of 3 or 4. Next, using the Chiba series, we tested whether our index is valid for a different patient group. This new system showed highly statistically significant differences among subclasses in both the Mito series and the Chiba series (p < 0.001 for all subclasses). In addition, this new index was confirmed to be applicable to Class II patients with four major primary tumor sites, that is, lung, breast, alimentary tract, and urogenital organs. CONCLUSIONS: Our new grading system should be considered when designing future clinical trials involving brain MET patients.

Analysis of 2000 cases treated with gamma knife surgery: validating eligibility criteria for a prospective multi-institutional study of stereotactic radiosurgery alone for treatment of patients with 1-10 brain metastases (JLGK0901) in Japan.

OBJECTIVE: The Japan Leksell Gamma Knife (JLGK) Society has conducted a prospective multi-institute study (JLGK0901, UNIN000001812) for selected patients in order to prove the effectiveness of stereotactic radiosurgery (SRS) alone using the gamma knife (GK) for 1-10 brain lesions. Herein, we verify the validity of 5 major patient selection criteria for the JLGK0901 trial. MATERIALS AND METHODS: Between 1998 and 2010, 2246 consecutive cases with 10352 brain metastases treated with GK were analyzed to determine the validity of the following 5 major JLGK0901 criteria; 1) 1-10 brain lesions, 2) less than 10 cm3 volume of the largest tumor, 3) no more than 15 cm3 total tumor volume, 4) no cerebrospinal fluid (CSF) dissemination, 5) Karnofsky performance status (KPS) score ≥70. RESULTS: For cases with >10 brain metastases, salvage treatments for new lesions were needed more frequently. The tumor control rate for lesions larger than 10 cm3 was significantly lower than that of tumors <10 cm3. Overall, neurological and qualitative survivals (OS, NS, QS) of cases with >15 cm3 total tumor volume or positive magnetic resonance imaging findings of CSF were significantly poorer. Outcomes in cases with KPS <70 were significantly poorer in terms of OS. CONCLUSION: Our retrospective results of 2246 GK-treated cases verified the validity of the 5 major JLGK0901 criteria. The inclusion criteria for the JLGK0901 study are appearently good indications for SRS.

Gamma Knife surgery as sole treatment for multiple brain metastases: 2-center retrospective review of 1508 cases meeting the inclusion criteria of the JLGK0901 multi-institutional prospective study.

OBJECT: The authors retrospectively reviewed the results of Gamma Knife surgery (GKS) used as the sole treatment for brain metastases in patients who met the eligibility criteria for the ongoing JLGK0901 multi-institutional prospective trial. They also discuss the anticipated results of the JLGK0901 study. METHODS: Data from 1508 consecutive cases were analyzed. All of the patients were treated at the Gamma Knife House of Chiba Cardiovascular Center or the Mito Gamma House of Katsuta Hospital between 1998 and 2007 and met the following JLGK0901 inclusion criteria: 1) newly diagnosed brain metastases, 2) 1-10 brain lesions, 3) less than 10 cm(3) volume of the largest tumor, 4) no more than 15 cm(3) total tumor volume, 5) no findings of CSF dissemination, and 6) no impairment of activities of daily living (Karnofsky Performance Scale score < 70) due to extracranial disease. At the initial treatment, all visible lesions were irradiated with GKS without upfront whole-brain radiation therapy. Thereafter, gadolinium-enhanced MR imaging was performed every 2-3 months, and new distant lesions were appropriately retreated with GKS. Patients were divided into groups according to numbers of tumors: Group A, single lesions (565 cases); Group B, 2-4 tumors (577 cases); and Group C, 5-10 tumors (366 cases). The differences in overall survival (OS) were compared between groups. RESULTS: The median age of the patients was 66 years (range 19-96 years). There were 963 men and 545 women. The primary tumors were in the lung in 1114 patients, gastrointestinal tract in 179, breast in 105, urinary tract in 66, and other sites in 44. The overall mean survival time was 0.78 years (0.99 years for Group A, 0.68 years for Group B, and 0.62 years for Group C). The differences between Groups A and B (p < 0.0001) and between Groups B and C (p = 0.0312) were statistically significant. Multivariate analysis revealed significant prognostic factors for OS to be sex (poor prognostic factor: male, p < 0.0001), recursive partitioning analysis class (Class I vs Class II and Class II vs III, both p < 0.0001), primary site (lung vs breast, p = 0.0047), and number of tumors (Group A vs Group B, p < 0.0001). However, no statistically difference was detected between Groups B and C (p = 0.1027, hazard ratio 1.124, 95% CI 0.999-1.265). CONCLUSIONS: The results of this retrospective analysis revealed an upper CI of 1.265 for the hazard ratio, which was lower than the 1.3 initially set by the JLGK0901 study. The JLGK0901 study is anticipated to show noninferiority of GKS as sole treatment for patients with 5-10 brain metastases compared with those with 2-4 in terms of OS.

Trigeminal nerve dysfunction after Gamma Knife surgery for trigeminal neuralgia: a detailed analysis.

OBJECT: Gamma Knife surgery (GKS) is an effective treatment option for intractable trigeminal neuralgia (TN). The incidence of trigeminal nerve dysfunction, such as facial numbness or dysesthesia, has been reported to be higher than previously published, and the degree and prognosis of trigeminal nerve dysfunction has not been well evaluated. The authors evaluated the incidence, timing, degree, and outcome of trigeminal nerve dysfunction after GKS for TN. METHODS: One hundred four patients with medically refractory TN were treated by GKS. Thirty-nine patients were men and 65 were women; their median age at GKS was 74 years. Using a single isocenter and a 4-mm collimator, 80 or 90 Gy was directed to the trigeminal nerve root. Follow-up data were obtained at clinical examinations every 3-6 months after GKS. Each patient's pain-control status and degree of trigeminal nerve dysfunction were recorded. The incidence, timing, and degree of dysfunction (assessed using the Barrow Neurological Institute facial numbness scale [BNI-N]) and the prognosis and factors related to trigeminal nerve dysfunction were analyzed. RESULTS: The median duration of follow-up in these patients was 37 months (range 6-121 months). At the final clinical visit, a pain-free status was still observed in 71 patients (68.3%). In 51 patients (49.0%), new or increased trigeminal nerve dysfunction developed at a median of 10.5 months (range 4-68 months) after GKS. In 24 patients (23.1%), this dysfunction was categorized as BNI-N Score II, in 20 patients (19.2%) as BNI-N Score III, and in 7 patients (6.7%) as BNI-N Score IV. Among those patients, 18 patients, including 3 patients with BNI-N Score IV, experienced improvement in nerve dysfunction between 24 and 108 months after GKS (median 52.5 months). At the final clinical visit, 43 patients (41.3%) reported having some trigeminal nerve dysfunction: in 26 patients (25.0%) this was categorized as BNI-N Score II, in 13 patients (12.5%) as BNI-N Score III, and in 4 patients (3.8%) as BNI-N Score IV. The only independent factor that was correlated to all trigeminal nerve dysfunction and also specifically to bothersome trigeminal nerve dysfunction was pain-free status at the final clinic visit. CONCLUSIONS: The incidence of trigeminal nerve dysfunction after GKS for TN was 49%. The severity of the dysfunction improved in one-third of the afflicted patients, even in those with severe dysesthesia at long-term follow-up. A strong relationship between TN and good pain control was identified.

Gamma knife surgery for 1-10 brain metastases without prophylactic whole-brain radiation therapy: analysis of cases meeting the Japanese prospective multi-institute study (JLGK0901) inclusion criteria.

We evaluated the results of stereotactic radiosurgery (SRS) alone using gamma knife (GK) for selected patients with 1-10 brain metastases without prophylactic whole-brain radiation therapy (WBRT) among JLGK0901-eligible cases. Seven hundred seventy-eight consecutive cases meeting the following JLGK0901 study inclusion criteria were analyzed: (1) newly diagnosed brain metastases, (2) 1-10 brain lesions, (3) less than 10 cm(3) volume of the largest tumor, (4) less than 15 cm(3) total tumor volume, (5) no magnetic resonance (MR) findings of cerebrospinal fluid (CSF) dissemination, and (6) no impaired activity of daily living [<70 Karnofsky Performance Score (KPS)] due to extracranial disease. At initial treatment, all lesions were irradiated with SRS without upfront WBRT. Thereafter, enhanced magnetic resonance imaging (MRI) was applied every 2-3 months, and new distant lesions were appropriately retreated with SRS or WBRT. We divided patients according to tumor number: single lesion for group A (280 cases), 2 for group B (135), 3-4 for group C (148), 5-6 for group D (93), and 7-10 for group E (122). Differences among groups were compared in terms of overall, neurological, qualitative, and new-lesion-free survival (NLFS). Median age was 65 years (range 26-92 years). There were 505 men and 273 women. The primary organ was lung in 579 patients, gastrointestinal tract in 79, breast in 48, urinary tract in 34, and others/unknown in 38. Mean survival time was 0.72 years (0.83 years for 1, 0.69 years for 2, 0.69 years for 3-4, 0.59 years for 5-6, and 0.62 years for 7-10 metastases). On multivariate analysis, significant poor prognostic factors for overall survival (OS) were active systemic disease, poor (<70) initial KPS, and male gender. Neurological survival and qualitative survival at 1 year were 92.7% and 88.2%, respectively. NLFS at 6 months and 1 year were 69.8% and 43.8%, respectively. There were statistically significant differences in new lesion emergence between groups A and B and between groups B and C. SRS using GK provides excellent results in selected patients with 1-10 brain lesions, without prophylactic WBRT. This study revealed that brain lesion number has no effect on any of the four types of survivals, which is anticipated to be confirmed by the JLGK0901 study.

Tumor shrinkage of vestibular schwannomas after Gamma Knife surgery: results after more than 5 years of follow-up.

OBJECT: The authors prospectively analyzed volume changes in vestibular schwannomas (VSs) after Gamma Knife surgery (GKS). METHODS: Among 104 VSs treated by GKS at the Chiba Cardiovascular Center between 1998 and 2004, 87 consecutively treated unilateral VSs observed on follow-up MR imaging for at least 5 years were analyzed. These lesions were harbored by 31 men and 56 women, with a mean age of 58.6 years (range 29­80 years). The Gd-enhanced volume of each lesion was measured serially every 3 months during the 1st year and every 6 months thereafter using Gamma Plan or SurgiPlan. The frequency and degree of volume shrinkage were documented and possible prognostic factors were analyzed. RESULTS: The mean tumor volume at GKS was 2.5 cm3 (range 0.1­13.2 cm3). The lesions were irradiated by directing a mean dose of 12.0 Gy (range 10.5­13.0 Gy) to the tumor margin, which was located at the mean 52.2% isodose line (range 50%­67% isodose line). The mean follow-up period was 7.5 years (range 5.0­11.1 years). Peak tumor volume expansion was most frequently observed at 8.6 months after GKS and averaged 58% (range 0%­613%). Five years after GKS, the mean reduction in tumor volume was 31%, and 9 tumors still remained larger than their initial volumes. Tumors that homogeneously enhanced on MR images displayed less shrinkage than other tumors. CONCLUSIONS: Most VSs exhibit shrinkage 5 years after GKS. The mean volume reduction in this series was 31%. These results indicate that careful serial follow-up is necessary for patients who harbor tumors that display homogeneous enhancement on MR images and patients whose tumors continue to expand in size after GKS. (DOI: 10.3171/2010.8.GKS10960)

Three-staged stereotactic radiotherapy without whole brain irradiation for large metastatic brain tumors.

PURPOSE: To evaluate the efficacy and toxicity of staged stereotactic radiotherapy with a 2-week interfraction interval for unresectable brain metastases more than 10 cm(3) in volume. PATIENTS AND METHODS: Subjects included 43 patients (24 men and 19 women), ranging in age from 41 to 84 years, who had large brain metastases (> 10 cc in volume). Primary tumors were in the colon in 14 patients, lung in 12, breast in 11, and other in 6. The peripheral dose was 10 Gy in three fractions. The interval between fractions was 2 weeks. The mean tumor volume before treatment was 17.6 +/- 6.3 cm(3) (mean +/- SD). Mean follow-up interval was 7.8 months. The local tumor control rate, as well as overall, neurological, and qualitative survivals, were calculated using the Kaplan-Meier method. RESULTS: At the time of the second and third fractions, mean tumor volumes were 14.3 +/- 6.5 (18.8% reduction) and 10.6 +/- 6.1 cm(3) (39.8% reduction), respectively, showing significant reductions. The median overall survival period was 8.8 months. Neurological and qualitative survivals at 12 months were 81.8% and 76.2%, respectively. Local tumor control rates were 89.8% and 75.9% at 6 and 12 months, respectively. Tumor recurrence-free and symptomatic edema-free rates at 12 months were 80.7% and 84.4%, respectively. CONCLUSIONS: The 2-week interval allowed significant reduction of the treatment volume. Our results suggest staged stereotactic radiotherapy using our protocol to be a possible alternative for treating large brain metastases.

Transient expansion of vestibular schwannoma following stereotactic radiosurgery.

OBJECT: The authors prospectively analyzed volume changes in vestibular schwannomas (VSs) after stereotactic radiosurgery. METHODS: One hundred consecutive patients with unilateral VS treated with Gamma Knife surgery (GKS) at Chiba Cardiovascular Center between 1998 and 2006 were analyzed in this study. For each lesion the Gd-enhanced volume was measured serially every 3 months in the 1st year, then every 6 months thereafter, using volumetric software. The frequency and degree of transient tumor expansion were documented and possible prognostic factors were analyzed. Concurrently, neurological deterioration involving trigeminal, facial, and cochlear nerve functions were also assessed. RESULTS: The mean observation period was 65 months (range 25-100 months). There were 32 men and 68 women, whose mean age was 59.1 years (range 29-80 years). Tumor volumes at GKS averaged 2.7 cm3 (range 0.1-13.2 cm3), and the lesions were irradiated at the mean 52.2% isodose line for the tumor margin (range 50-67%), with a mean dose of 12.2 Gy (range 10.5-13 Gy) at the periphery. The tumor volume was increased by 23% at 3 months and 27% at 6 months. Tumors shrank to their initial size over a mean period of 12 months. The maximum volume increase was < 10% (no significant increase) in 26 patients, 10-30% in 23, 30-50% in 22, 50-100% in 16, and > 100% in 13. The peak tumor expansion averaged 47% (range 0-613%). A high-dose (> or = 3.5 Gy/min) treatment appears to be the greatest risk factor for transient tumor expansion, although the difference did not reach statistical significance. Transient facial palsy and facial dysesthesia correlated strongly with tumor expansion, but only half of the hearing loss was coincident with this phenomenon. CONCLUSIONS: Transient expansion of VSs after GKS was found to be much more frequent than previously reported, strongly suggesting a correlation with deterioration of facial and trigeminal nerve functions.

Gamma Knife surgery for metastatic brain tumors.

OBJECT: The authors compared results of Gamma Knife surgery (GKS) for brain metastases obtained at 2 institutions in Japan. METHODS: They analyzed a consecutive series of 2390 patients with brain metastases who underwent GKS from 1998 through 2005 in 2 institutes (1,181 patients in Chiba; 1,209 in Mito). In the 2 facilities, 1 neurosurgeon each was responsible for diagnosis, patient selection, GKS procedures, and follow-up (T.S. in Chiba, M.Y. in Mito). Even if tumor numbers exceeded 4, all visible lesions were irradiated with a total skull integral dose (TSID) of