A Practical Grading Scale for Predicting Outcomes of Radiosurgery for Dural Arteriovenous Fistulas: JLGK 1802 Study.

BACKGROUND AND PURPOSE: To assess the long-term outcomes of intracranial dural arteriovenous fistula (DAVF) treated with stereotactic radiosurgery (SRS) alone or embolization and SRS (Emb-SRS) and to develop a grading system for predicting DAVF obliteration. METHODS: This multi-institutional retrospective study included 200 patients with DAVF treated with SRS or Emb-SRS. We investigated the long-term obliteration rate and obliteration-associated factors. We developed a new grading system to estimate the obliteration rate. Additionally, we compared the outcomes of SRS and Emb-SRS by using propensity score matching. RESULTS: The 3- and 4-year obliteration rates were 66.3% and 78.8%, respectively. The post-SRS hemorrhage rate was 2%. In the matched cohort, the SRS and Emb-SRS groups did not differ in the rates of obliteration (P=0.54) or post-SRS hemorrhage (P=0.50). In multivariable analysis, DAVF location and cortical venous reflux (CVR) were independently associated with obliteration. The new grading system assigned 2, 1, and 0 points to DAVFs in the anterior skull base or middle fossa, DAVFs with CVR or DAVFs in the superior sagittal sinus or tentorium, and DAVFs without these factors, respectively. Using the total points, patients were stratified into the highest (0 points), intermediate (1 point), or lowest (≥2 points) obliteration rate groups that exhibited 4-year obliteration rates of 94.4%, 71.3%, and 60.4%, respectively (P<0.01). CONCLUSIONS: SRS-based therapy achieved DAVF obliteration in more than three-quarters of the patients at 4 years of age. Our grading system can stratify the obliteration rate and may guide physicians in treatment selection.

Stereotactic radiosurgery results for brain metastasis patients with renal cancer: A validity study of Renal Graded Prognostic Assessment and proposal of a new grading index (JLGK2101 Study).

BACKGROUND AND PURPOSE: The Renal Graded Prognostic Assessment (GPA) is relatively new and has not been sufficiently validated using a different dataset. We thus developed a new grading index, the Renal Brain Metastasis Score (Renal-BMS). MATERIALS AND METHODS: Using our dataset including 262 renal cancer patients with brain metastases (BMs) undergoing stereotactic radiosurgery (SRS) (test series), we validity tested the Renal-GPA. Next, we applied clinical factor-survival analysis to the test series and thereby developed the Renal-BMS. This system was then validated using another series of 352 patients independently undergoing SRS at nine gamma knife facilities in Japan (verification series). RESULTS: Using the test series, with the Renal-GPA, 95% confidence intervals (CIs) of the post-SRS median survival times (MSTs) overlapped between pairs of neighboring subgroups. Among various pre-SRS clinical factors of the test series, six were highly associated with overall survival. Therefore, we assigned scores for six factors, i.e., "KPS ≥ 80%/<80% (0/3)", "tumor numbers 1-4/≥5 (score; 0/2)", "controlled primary cancer/not (0/2)", "existing extra-cerebral metastases/not (0/3)", "blood hemoglobin ≥ 11.0/<11.0 g/dl (0/1)" and "interval from primary cancer to SRS ≥ 5/<5 years (0/1)". Patients were categorized into three subgroups according to the sum of scores, i.e., 0-4, 5-8 and 9-12. In the test and verification series, post-SRS MSTs differed significantly (p < 0.0001) with no overlaps of 95% CIs among the three subgroups. CONCLUSIONS: The Renal BMS has the potential to be very useful to physicians selecting among aggressive treatment modalities for renal cancer patients with BMs.

Stereotactic Radiosurgery Results for Patients With Brain Metastases From Gastrointestinal Cancer: A Retrospective Cohort Study of 802 Patients With GI-GPA Validity Test.

PURPOSE: The role of stereotactic radiosurgery (SRS) alone for patients with gastrointestinal (GI) cancer has yet to be established based on a large patient series. We analyzed post-SRS treatment results and reappraised whether either the GI graded prognostic assessment (GPA) system or modified-recursive partitioning assessment (M-RPA) system was applicable to our 802 SRS-treated patients with GI cancer with brain metastases. METHODS AND MATERIALS: This was an institutional review board approved retrospective cohort study 2 database comprising 802 patients with GI cancer treated with gamma-knife SRS by 2 experienced neurosurgeons during the 1998 to 2018 period. The Kaplan-Meier method was applied to determine post-SRS survival times, and competing risk analyses were used to estimate cumulative incidences of the secondary endpoints. RESULTS: The median survival time (MST; months) after SRS was 5.7. With the GI GPA system, MSTs were 3.5/6.1/7.7/11.0 in the 4 subgroups, that is, 0 to 1.0/1.5 to 2.0/2.5 to 3.0/3.5 to 4.0, respectively (stratified P < .0001). However, there was no significant MST difference between 2 of the subgroups, GI-GPA 1.5 to 2.0 and 2.5 to 3.0 (P = .073). In contrast, using the M-RPA system, 3 plot lines corresponding to the 3 subgroups showed no overlap and the MST differences between the subgroups with M-RPA were 1 + 2a versus 2b (P < .0001) and 2b versus 2c + 3 (P < .0001). Better Karnofsky performance status score, solitary tumor, well-controlled primary cancer, and the absence of extracerebral metastases were shown by multivariable analysis to be significant predictors of longer survival. The crude and cumulative incidences of neurologic death, neurologic deterioration, local recurrence, salvage whole brain radiation therapy, and SRS-related complications did not differ significantly between the 2 patient groups, with upper and lower GI cancers. CONCLUSIONS: This study clearly demonstrated the usefulness of the GI GPA. Patients with GI GPA 1.5 to 2.0 or better or M-RPA 2b or better are considered to be favorable candidates for treatment with SRS alone.

[A Case of Miliary Brain Metastases Molecularly Diagnosed as Silent Lung Adenocarcinoma Origin].

A 60-year-old woman was referred to our hospital because of possible miliary brain metastases of unknown primary origin. On admission, she was alert and had no apparent motor weakness. Neuroradiological examinations revealed more than 100 small enhancing lesions, some of which had undergone cystic changes, suggesting multiple metastases. However, plain chest and abdominal CT revealed no abnormalities, and fluorodeoxyglucose-positron emission tomography could not reveal the primary origin of the cancer. Blood examination revealed no apparent abnormalities, except for tumor markers, including pro-gastrin-releasing peptide and carcinoembryonic antigen. On day 22, the patient underwent a biopsy through right frontal craniotomy. Histopathological findings indicated metastases from cancer. Immunohistochemistry was positive for cytokeratin(CK)7 and thyroid transcription factor-1 while negative for CK20(-), CK5/6, and p40, resulting in the diagnosis of lung adenocarcinoma. Genetic testing showed negative for EGFR mutation and positive for ALK fusion gene. From the day 48, whole brain radiotherapy was started, and the ALK inhibitor was prescribed from day 64. Metastatic brain tumors of unknown primary are rare. Miliary brain metastases from an unknown primary origin are rare. To our knowledge, this is the first case of military brain metastases of an unknown primary origin, which was later determined to have originated from ALK fusion-positive lung cancer.

Applicability and limitations of a recently-proposed prognostic grading metric, initial brain metastasis velocity, for brain metastasis patients undergoing stereotactic radiosurgery.

PURPOSE: This study, based on our brain metastasis (BM) patients undergoing stereotactic radiosurgery (SRS) procedures, aimed to validate whether the recently-proposed prognostic grading system, initial brain metastasis velocity (iBMV, scoring the cumulative number of BMs at the time of SRS divided by time [years] since the initial primary cancer diagnosis), is generally applicable. METHODS: This was an institutional review board-approved, retrospective cohort study using our prospectively accumulated database including 3498 patients who underwent SRS for BMs during the 19.5-year-period between July, 1998 and December, 2017. We excluded four lost to follow-up, 24 for whom the day of primary cancer diagnosis was not available, 665 with synchronous presentation and 651 with pre-SRS radiotherapy and/or surgery, ultimately studying 2150 patients. Patients were categorized into two classes by iBMV scores, i.e., < 2.00 and ≥ 2.00. RESULTS: In a multivariable model, iBMV was directly associated with a higher risk of death (p < 0.0001). The median survival time of patients with iBMV scores < 2.00, 10.0 (95% CI; 9.2-10.9) months, was longer than that of patients with iBMV scores ≥ 2.00, 6.3 (5.6-6.7) months, showing a significant difference between the two groups (HR 1.599, 95% CI 1.458-1.753, p < 0.0001). The same results were obtained in patients with non-small cell lung, breast, kidney or other cancers. Among 608 patients who underwent repeat SRS for newly-developed BMs, iBMV score categories correlated well with brain metastasis velocity risk groups (p < 0.0001). CONCLUSIONS: Our present results support the validity of iBMV for predicting survival after SRS.

Long-term follow-up results of stereotactic radiosurgery for vestibular schwannomas larger than 8 cc.

BACKGROUND: Accumulated stereotactic radiosurgery (SRS) experience for large vestibular schwannomas (VSs) based on over 5 years of follow-up are as yet insufficient, and chronological volume changes have not been documented. METHOD: Among 402 patients treated between 1990 and 2015, tumor volumes exceeded 8 cc in 30 patients. We studied 19 patients with follow-up for more than 36 post-SRS months or until an event. Median tumor volume was 11.5 cc (range; 8.0 to 30.6). The target volume was basically covered with 12.0 Gy. RESULTS: The median magnetic resonance imaging and clinical follow-up periods were both 98 months (range 49 to 204). Tumor shrinkage was documented in 13 patients (72%), no change in 2 (11%), and growth in the other 3 (17%). Therefore, the crude growth control rate was 83%. All three patients with tumor enlargement needed salvage treatment. Thus, the crude clinical control rate was 84%. Actuarial further procedure-free rates were 91%, 83% and 76%, at the 60th, 120th, and 180th post-SRS month. Among six patients followed chronologically, transient tumor expansion was observed in three (43%) and two cystic VSs showed rapid tumor growth. Transient trigeminal neuropathy occurred in two patients (11%). No patients experienced facial nerve palsy. None of the six patients with useful hearing pre-SRS maintained serviceable hearing. Ventricular-peritoneal shunt placement was required in three patients. CONCLUSIONS: Long-term tumor control with SRS was moderately acceptable in large VSs. In terms of functional outcome, trigeminal neuropathies and facial palsies were rare. However, hearing preservation remains a challenge. In the long term, chronological tumor volumes were generally decreased after SRS. However, caution is required regarding rapid increases in tumor size, especially for cystic type VSs. Further studies are needed to optimize clinical positioning of SRS for large VSs.

Validity of a Recently Proposed Prognostic Grading Index, Brain Metastasis Velocity, for Patients With Brain Metastasis Undergoing Multiple Radiosurgical Procedures.

PURPOSE: This study of our patients with brain metastasis who underwent multiple stereotactic radiosurgery (SRS) procedures aimed to validate whether the recently proposed prognostic grading system, brain metastasis velocity (BMV), is generally applicable. The BMV scores the cumulative number of new brain metastases that developed after the first SRS divided by time (years) since the initial SRS. Patients were categorized into 3 classes by their BMV scores (ie, ≤3, 4-13, and ≥14). METHODS AND MATERIALS: This retrospective cohort study was approved by the Tokyo Women's Medical University Institutional Review Board (number 1981). We used our prospectively accumulated database, which included 833 patients who underwent a second SRS procedure for newly detected lesions, using a gamma knife, for brain metastases. Patients who had whole-brain radiation therapy were excluded. The procedures took place during the 19-year period between July 1998 and June 2017. Furthermore, among the 833 patients, 250 underwent a third SRS procedure, and 88 had a fourth SRS procedure. RESULTS: The median survival times (MSTs) after the second SRS were 12.9 months (95% confidence interval [CI], 10.2-17.1) for the BMV group with a score of ≤3; 7.5 months (CI, 6.5-9.0) for the group scoring 4 to 13, and 5.1 months (CI, 4.0-5.6) for the group scoring ≥14 (P = .0001). The corresponding MSTs after the third SRS were 13.2 months (95% CI, 9.1-21.6), 8.0 months (CI, 6.2-11.2), and 5.7 months (CI, 4.8-7.8; P = .0001). Respective MSTs after the fourth SRS were 13.2 months (95% CI, 9.1-21.6), 8.0 months (CI, 6.2-11.2), and 5.7 months (CI, 4.8-7.8; P < .0001). The mean BMV score of patients with small cell lung cancer, 24.8, was significantly higher than that of patients with non-small cell lung cancer, 17.7 (P = .032). CONCLUSIONS: Our present results support the validity of BMV for predicting survival not only after the second SRS but also after the third and fourth SRS.

Postsurgical Salvage Radiosurgery for Nonfunctioning Pituitary Adenomas Touching/Compressing the Optic Chiasm: Median 13-Year Postirradiation Imaging Follow-up Results.

BACKGROUND: There is little information on long-term outcomes after salvage treatment by either surgery or stereotactic radiosurgery (SRS) for patients with recurrent/residual nonfunctioning pituitary adenomas (NFPAs). OBJECTIVE: To reappraise the efficacy and safety of SRS for patients with NFPAs touching/compressing the optic apparatus (OA). METHODS: We studied 27 patients (14 females, 13 males; mean age: 61 [range, 19-85] yr) who underwent SRS between 1998 and 2008 for NFPAs with such condition. The median tumor volume was 4.9 (range, 1.8-50.8) cc. To avoid excess irradiation to the OA, the lower part of the tumor was covered with a 50% or a 60% isodose gradient, ie 49% to 98% (mean, 84%; median, 88%) of the entire tumor received the selected doses. Median doses at the tumor periphery/OA were 7.6/11.0 (interquartile range [IQR], 5.8-9.1/10.1-11.8) Gy. RESULTS: Seven patients (26%) were confirmed to be deceased due to unrelated diseases at a median post-SRS period of 149 (IQR, 83-158) mo. Follow-up magnetic resonance imaging (MRI) showed tumor growth in 2 patients (7%) at the 11th and 134th post-SRS month; the former underwent surgery and the other SRS. Excluding these 2 patients, the latest follow-up MRI examinations, performed 13 to 238 (median: 168, IQR: 120-180) mo after SRS, showed no size changes in 5 (19%) and shrinkage in 20 (74%) patients. Cumulative incidences of tumor growth control were 96.3% and 91.8% at the 120th and 180th post-SRS month. None of our patients developed subjective symptoms suggesting SRS-induced optic neuropathy or endocrinological impairment. CONCLUSION: In patients with NFPAs touching/compressing the OA, SRS achieves good long-term results.

Three-stage Gamma Knife treatment for metastatic brain tumors larger than 10 cm3: a 2-institute study including re-analyses of earlier results using competing risk analysis.

OBJECTIVEThe results of 3-stage Gamma Knife treatment (3-st-GK-Tx) for relatively large brain metastases have previously been reported for a series of patients in Chiba, Japan (referred to in this study as the C-series). In the current study, the authors reappraised, using a competing risk analysis, the efficacy and safety of 3-st-GK-Tx by comparing their experience with that of the C-series.METHODSThis was a retrospective cohort study. Among 1767 patients undergoing GK radiosurgery for brain metastases at Mito Gamma House during the 2005-2015 period, 78 (34 female, 44 male; mean age 65 years, range 35-86 years) whose largest tumor was > 10 cm3, treated with 3-st-GK-Tx, were studied (referred to in this study as the M-series). The target volumes were covered with a 50% isodose gradient and irradiated with a peripheral dose of 10 Gy at each procedure. The interval between procedures was 2 weeks. Because competing risk analysis had not been employed in the published C-series, the authors reanalyzed the previously published data using this method.RESULTSThe overall median survival time after 3-st-GK-Tx was 8.3 months (95% CI 5.6-12.0 months) in the M-series and 8.6 months (95% CI 5.5-10.6 months) in the C-series (p = 0.41). Actuarial survival rates at the 6th and 12th post-3-st-GK-Tx months were, respectively, 55.1% and 35.2% in the M-series and 62.5% and 26.4% in the C-series (HR 1.175, 95% CI 0.790-1.728, p = 0.42). Cumulative incidences at the 12th post-3-st-GK-Tx, determined by competing risk analyses, of neurological deterioration (14.2% in C-series vs 12.8% in M-series), neurological death (7.2% vs 7.7%), local recurrence (4.8% vs 6.2%), repeat SRS (25.9% vs 18.0%), and SRS-related complications (2.3% vs 5.1%) did not differ significantly between the 2 series.CONCLUSIONSThere were no significant differences in post-3-st-GK-Tx results between the 2 series in terms of overall survival times, neurological death, maintained neurological status, local control, repeat SRS, and SRS-related complications. The previously published results (C-series) are considered to be validated by the M-series results.

Prognostic grading system specifically for elderly patients with brain metastases after stereotactic radiosurgery: a 2-institution study.

OBJECTIVEWith the aging of the population, increasing numbers of elderly patients with brain metastasis (BM) are undergoing stereotactic radiosurgery (SRS). Among recently reported prognostic grading indexes, only the basic score for brain metastases (BSBM) is applicable to patients 65 years or older. However, the major weakness of this system is that no BM-related factors are graded. This prompted the authors to develop a new grading system, the elderly-specific (ES)-BSBM.METHODSFor this IRB-approved, retrospective cohort study, the authors used their prospectively accumulated database comprising 3267 consecutive patients undergoing Gamma Knife SRS for BMs during the 1998-2016 period at the Mito GammaHouse. Among these 3267 patients, 1789 patients ≥ 65 years of age were studied (Yamamoto series [Y-series]). Another series of 1785 patients ≥ 65 years of age in whom Serizawa and colleagues performed Gamma Knife SRS during the same period (Serizawa series [S-series]) was used for validity testing of the ES-BSBM.RESULTSTwo factors were identified as strongly impacting longer survival after SRS by means of multivariable analysis using the Cox proportional hazard model with a stepwise selection procedure. These factors are the number of tumors (solitary vs multiple: HR 1.450, 95% CI 1.299-1.621; p < 0.0001) and cumulative tumor volume (≤ 15 cm3 vs > 15 cm3: HR 1.311, 95% CI 1.078-1.593; p = 0.0067). The new index is the addition of scores 0 and 1 for these 2 factors to the BSBM. The ES-BSBM system is based on categorization into 3 classes by adding these 2 scores to those of the original BSBM. Each ES-BSBM category has 2 possible scores. For the category ES-BSBM 4-5, the score is either 4 or 5; for ES-BSBM 2-3, the score is either 2 or 3; and for ES-BSBM 0-1, the score is either 0 or 1. In the Y-series, the median survival times (MSTs, months) after SRS were 17.5 (95% CI 15.4-19.3) in ES-BSBM 4-5, 6.9 (95% CI 6.4-7.4) in ES-BSBM 2-3, and 2.8 (95% CI 2.5-3.6) in ES-BSBM 0-1 (p < 0.0001). Also, in the S-series, MSTs were, respectively, 20.4 (95% CI 17.2-23.4), 7.9 (95% CI 7.4-8.5), and 3.2 (95% CI 2.8-3.6) (p < 0.0001). The ES-BSBM system was shown to be applicable to patients with all primary tumor types as well as to those 80 years or older.CONCLUSIONSThe authors found that the addition of the number of tumors and cumulative tumor volume as scoring factors to the BSBM system significantly improved the prognostic value of this index. The present study is strengthened by testing the ES-BSBM in a different patient group.

Clinical significance of conformity index and gradient index in patients undergoing stereotactic radiosurgery for a single metastatic tumor.

OBJECTIVEAlthough the conformity index (CI) and the gradient index (GI), which were proposed by Paddick and colleagues, are both logically considered to correlate with good posttreatment results after stereotactic radiosurgery (SRS), this hypothesis has not been confirmed clinically. The authors' aim was to reappraise whether high CI values correlate with reduced tumor progression rates, and whether low GI values correlate with reduced complication incidences.METHODSThis was an institutional review board-approved, retrospective cohort study conducted using a prospectively accumulated database including 3271 patients who underwent Gamma Knife SRS for brain metastases (BMs) during the 1998-2016 period. Among the 3271 patients, 925 with a single BM at the time of SRS (335 women and 590 men, mean age 66 [range 24-93] years) were studied. The mean/median CIs were 0.62/0.66 (interquartile range [IQR] 0.53-0.74, range 0.08-0.88) and the mean/median GIs were 3.20/3.09 (IQR 2.83-3.39, range 2.27-11.4).RESULTSSRS-related complications occurred in 38 patients (4.1%), with a median post-SRS interval of 11.5 (IQR 6.0-25.8, maximum 118.0) months. Cumulative incidences of post-SRS complications determined by a competing risk analysis were 2.2%, 3.2%, 3.6%, 3.8%, and 3.9% at the 12th, 24th, 36th, 48th, and 60th post-SRS month, respectively. Multivariable analyses showed that only two clinical factors (i.e., peripheral doses and brain volume receiving ≥ 12 Gy) correlated with complication rates. However, neither CIs nor GIs impacted the incidences of complications. Among the 925 patients, post-SRS MRI was performed at least once in 716 of them, who were thus eligible for local progression evaluation. Among these 716 patients, local progression was confirmed in 96 (13.4%), with a median post-SRS interval of 10.8 (IQR 6.7-19.5, maximum 59.8) months. Cumulative incidences of local progression determined by a competing risk analysis were 7.7%, 12.6%, 14.2%, 14.8%, and 15.3% at the 12th, 24th, 36th, 48th, and 60th post-SRS month, respectively. Multivariable analyses showed neurological symptoms, extracerebral metastases, repeat SRS, and CIs to correlate with incidences of local progression, whereas GIs had no impact on local tumor progression. Particularly, cumulative incidences of local progression were significantly lower in patients with CIs < 0.65 than in those with CIs ≥ 0.65 (adjusted hazard ratio 1.870, 95% confidence interval 1.299-2.843; p = 0.0034).CONCLUSIONSTo the authors' knowledge, this is the first analysis to focus on the clinical significance of CI and GI based on a large series of patients with BM. Contrary to the majority opinion that dose planning with higher CI and lower GI results in good post-SRS outcomes (i.e., low local progression rates and minimal complications), this study clearly showed that the lower the CIs were, the lower the local progression rates were, and that the GI did not impact complication rates.

Complications after stereotactic radiosurgery for brain metastases: Incidences, correlating factors, treatments and outcomes.

BACKGROUND AND PURPOSE: Complications after stereotactic radiosurgery (SRS) for brain metastases (BMs) were analyzed in detail using our database including nearly 3000 BM patients. MATERIALS AND METHODS: This was an institutional review board-approved, retrospective cohort study using our prospectively accumulated database including 3271 consecutive patients who underwent gamma knife SRS for BMs during the 1998-2016 period. Excluding four patients lost to follow-up, 112 with three-staged treatment and 189 with post-operative irradiation, 2966 who underwent a single-session of SRS only as radical irradiation were studied. RESULTS: The overall median survival time after SRS was 7.8 (95% CI; 7.4-8.1) months. Post-SRS complications occurred in 86 patients (2.9%) 1.9-211.4 (median; 24.0, IQR; 12.0-64.6) months after treatment. RTOG neurotoxicity grades were 2, 3 and 4 in 58, 25 and 3 patients, respectively. Cumulative incidences determined with a competing risk analysis were 1.4%, 2.2%, 2.4%, 2.6% and 2.9% at the 12th, 24th, 36th, 48th and 60th post-SRS month, respectively. Among various pre-SRS clinical factors and radiosurgical parameters, multivariable analyses demonstrated solitary tumor (Adjusted HR; 0.584, 95% CI; 0.381-0.894, p = 0.0133), controlled primary cancer (Adjusted HR; 2.595, 95% CI; 1.646-4.091, p < 0.0001), no extra-cerebral metastases (Adjusted HR; 1.608, 95% CI; 1.028-2.514, p = 0.0374), KPS ≥80% (Adjusted HR; 2.715, 95% CI; 1.245-5.924, p = 0.0121) and largest tumor volume ≥3.3 cc (Adjusted HR; 0.516, 95% CI; 0.318-0.836, p = 0.0072) to be independently significant predictors of a higher incidence of complications. CONCLUSION: The post-SRS complication incidence is acceptably low (2.9%). Meticulous long-term follow-up after SRS is crucial for all patients.

Unusual Presentations of Pediatric Skull Hemangiomas: Report of Two Cases.

BACKGROUND: Intraosseous hemangioma is a rare bone tumor, accounting for 0.7%-1.0% of all bone tumors. It can occur at any age, but only 9% of cases are younger than 10 years old. Although this tumor is usually slow-growing and clinically silent, we experienced 2 pediatric patients undergoing surgery for skull hemangioma who presented with uncommon clinical manifestations. CASE DECRIPTION: Case 1 was a 9-year-old boy who presented with sudden onset of headache and was referred to our hospital. Radiologic images revealed an osteolytic oval lesion in the right parietal bone and acute subdural hemorrhage in the right cerebral hemisphere. The right parietal lesion was removed surgically. The lesion was found to have grown into the dura and to be adherent to the pia matter. The removed lesion was histologically confirmed to be a hemangioma. Case 2 was an 8-year-old girl who was referred to our hospital with an elastic mass that had been slowly enlarging for 7 years. Radiologic images revealed an osteolytic oval lesion in the right parietal bone. Surgical removal was thus planned. The lesion was found to be attached to the dura, and we removed the lesion with the surrounding bone and attached dura. Histologic examination confirmed the lesion to be a hemangioma. CONCLUSIONS: Although skull hemangiomas show clinical heterogeneity, surgical removal is usually diagnostic and leads to good patient outcomes. On occasion, however, this tumor causes secondary changes in the dura, such that dural incision and dural plasty should be planned in advance of lesion removal.

Treatment of a skull-base giant cell tumor with endoscopic endonasal resection and denosumab: case report.

A 34-year-old man with a 1-week history of diplopia was referred to the authors' hospital. Neurological examination revealed left abducens nerve palsy. Computed tomography showed a lesion in the left sphenoid sinus involving the medial wall of the left internal carotid artery (ICA) and osteolytic change at the clivus bordering the lesion. Magnetic resonance imaging demonstrated an extensive soft-tissue mass occupying the left sphenoid sinus. Surgical intervention by the endoscopic transnasal method allowed most of the lesion to be removed. Only the portion attached to the medial wall of the ICA was not removed. Postoperatively, the lesion was diagnosed as a giant cell tumor (GCT) and the patient received 120 mg of subcutaneous denosumab every 4 weeks, with additional doses on Days 8 and 15 during the first month of therapy. MRI a week after starting denosumab revealed shrinkage of the initially fast-growing residual tumor. The patient was discharged upon completion of the third denosumab administration. GCT is an aggressive stromal tumor developing mainly in young adults. Complete resection is recommended for GCT in the literature. However, size and location of the CGT often limit this approach. Various adjuvant treatments for skull base GCTs have been reported, including radiation and chemotherapy. However, the roles of adjuvant therapies have yet to be clearly defined. Denosumab, a monoclonal antibody, was recently approved for GCT in several countries. Denosumab may permit less invasive treatments for patients with GCTs while avoiding deleterious outcomes, and may also limit disease progression and recurrence.

Follow-up results of brain metastasis patients undergoing repeat Gamma Knife radiosurgery.

OBJECTIVE Stereotactic radiosurgery (SRS) without upfront whole-brain radiotherapy (WBRT) has influenced recent treatment recommendations for brain metastasis patients. However, in brain metastasis patients who undergo SRS alone, new brain metastases inevitably appear with relatively high incidences during post-SRS follow-up. However, little is known about the second SRS results. The treatment results of second SRS were retrospectively reviewed, mainly for newly developed or, uncommonly, for recurrent brain metastases in order to reappraise the efficacy of this treatment strategy with a special focus on the maintenance of neurological status and safety. METHODS This was an institutional review board-approved, retrospective cohort study that used a prospectively accumulated database, including 3102 consecutive patients with brain metastases who underwent SRS between July 1998 and June 2015. Among these 3102 patients, 859 (376 female patients; median age 64 years; range 21-88 years) who underwent a second SRS without WBRT were studied with a focus on overall survival, neurological death, neurological deterioration, local recurrence, salvage SRS, and SRS-induced complications after the second SRS. Before the second SRS, the authors also investigated the clinical factors and radiosurgical parameters likely to influence these clinical outcomes. For the statistical analysis, the standard Kaplan-Meier method was used to determine post-second SRS survival and neurological death. A competing risk analysis was applied to estimate post-second SRS cumulative incidences of local recurrence, neurological deterioration, salvage SRS, and SRS-induced complications. RESULTS The post-second SRS median survival time was 7.4 months (95% CI 7.0-8.2 months). The actuarial survival rates were 58.2% and 34.7% at 6 and 12 months after the second SRS, respectively. Among 789 deceased patients, the causes of death could not be determined in 24 patients, but were confirmed in the remaining 765 patients to be nonbrain diseases in 654 (85.5%) patients and brain diseases in 111 (14.5%) patients. The actuarial neurological death-free survival rates were 94.4% and 86.6% at 6 and 12 months following the second SRS. Multivariable analysis revealed female sex, Karnofsky Performance Scale score of 80% or greater, better modified recursive partitioning analysis class, smaller tumor numbers, and higher peripheral dose to be significant predictive factors for longer survival. The cumulative incidences of local recurrence were 11.2% and 14.9% at 12 and 24 months after the second SRS. The crude incidence of neurological deterioration was 7.1%, and the respective cumulative incidences were 4.5%, 5.8%, 6.7%, 7.2%, and 7.5% at 12, 24, 36, 48, and 60 months after the second SRS. SRS-induced complications occurred in 25 patients (2.9%) after a median post-second SRS period of 16.8 months (range 0.6-95.0 months; interquartile range 5.6-29.3 months). The cumulative incidences of complications were 1.4%, 2.0%, 2.4%, 3.0%, and 3.0% at 12, 24, 36, 48, and 60 months after the second SRS, respectively. CONCLUSIONS Carefully selected patients with recurrent tumors-either new or locally recurrent-are favorable candidates for a second SRS, particularly in terms of neurological status maintenance and the safety of this treatment strategy.

Gamma Knife radiosurgery for brain metastases from pulmonary large cell neuroendocrine carcinoma: a Japanese multi-institutional cooperative study (JLGK1401).

OBJECTIVE In 1999, the World Health Organization categorized large cell neuroendocrine carcinoma (LCNEC) of the lung as a variant of large cell carcinoma, and LCNEC now accounts for 3% of all lung cancers. Although LCNEC is categorized among the non-small cell lung cancers, its biological behavior has recently been suggested to be very similar to that of a small cell pulmonary malignancy. The clinical outcome for patients with LCNEC is generally poor, and the optimal treatment for this malignancy has not yet been established. Little information is available regarding management of LCNEC patients with brain metastases (METs). This study aimed to evaluate the efficacy of Gamma Knife radiosurgery (GKRS) for patients with brain METs from LCNEC. METHODS The Japanese Leksell Gamma Knife Society planned this retrospective study in which 21 Gamma Knife centers in Japan participated. Data from 101 patients were reviewed for this study. Most of the patients with LCNEC were men (80%), and the mean age was 67 years (range 39-84 years). Primary lung tumors were reported as well controlled in one-third of the patients. More than half of the patients had extracranial METs. Brain metastasis and lung cancer had been detected simultaneously in 25% of the patients. Before GKRS, brain METs had manifested with neurological symptoms in 37 patients. Additionally, prior to GKRS, resection was performed in 17 patients and radiation therapy in 10. A small cell lung carcinoma-based chemotherapy regimen was chosen for 48 patients. The median lesion number was 3 (range 1-33). The median cumulative tumor volume was 3.5 cm3, and the median radiation dose was 20.0 Gy. For statistical analysis, the standard Kaplan-Meier method was used to determine post-GKRS survival. Competing risk analysis was applied to estimate GKRS cumulative incidences of maintenance of neurological function and death, local recurrence, appearance of new lesions, and complications. RESULTS The overall median survival time (MST) was 9.6 months. MSTs for patients classified according to the modified recursive partitioning analysis (RPA) system were 25.7, 11.0, and 5.9 months for Class 1+2a (20 patients), Class 2b (28), and Class 3 (46), respectively. At 12 months after GKRS, neurological death-free and deterioration-free survival rates were 93% and 87%, respectively. Follow-up imaging studies were available in 78 patients. The tumor control rate was 86% at 12 months after GKRS. CONCLUSIONS The present study suggests that GKRS is an effective treatment for LCNEC patients with brain METs, particularly in terms of maintaining neurological status.

Stereotactic radiosurgery for vestibular schwannomas: average 10-year follow-up results focusing on long-term hearing preservation.

OBJECTIVE The aim of this study was to reappraise long-term treatment outcomes of stereotactic radiosurgery (SRS) for vestibular schwannomas (VSs). The authors used a database that included patients who underwent SRS with a unique dose-planning technique, i.e., partial tumor coverage designed to avoid excess irradiation of the facial and cochlear nerves, focusing on tumor control and hearing preservation. Clinical factors associated with post-SRS tumor control and long-term hearing preservation were also analyzed. METHODS This institutional review board-approved, retrospective cohort study used the authors' prospectively accumulated database. Among 207 patients who underwent Gamma Knife SRS for VSs between 1990 and 2005, 183 (who were followed up for at least 36 post-SRS months) were studied. The median tumor volume was 2.0 cm3 (range 0.05-26.2 cm3). The median prescribed dose at the tumor periphery was 12.0 Gy (range 8.8-15.0 Gy; 12.0 Gy was used in 171 patients [93%]), whereas tumor portions facing the facial and cochlear nerves were irradiated with 10.0 Gy. As a result, 72%-99% of each tumor was irradiated with the prescribed dose. The mean cochlear doses ranged from 2.3 to 5.7 Gy (median 4.1 Gy). RESULTS The median durations of imaging and audiometric follow-up were 114 months (interquartile range 73-144 months) and 59 months (interquartile range 33-109 months), respectively. Tumor shrinkage was documented in 110 (61%), no change in 48 (27%), and enlargement in the other 22 (12%) patients. A further procedure (FP) was required in 15 (8%) patients. Thus, the tumor growth control rate was 88% and the clinical control rate (i.e., no need for an FP) was 92%. The cumulative FP-free rates were 96%, 93%, and 87% at the 60th, 120th, and 180th post-SRS month, respectively. Six (3%) patients experienced facial pain, and 2 developed transient facial palsy. Serviceable hearing was defined as a pure tone audiogram result better than 50 dB. Among the 66 patients with serviceable hearing before SRS who were followed up, hearing acuity was preserved in 23 (35%). Actuarial serviceable hearing preservation rates were 49%, 24%, and 12% at the 60th, 120th, and 180th post-SRS month, respectively. On univariable analysis, only cystic-type tumor (HR 3.36, 95% CI 1.18-9.36; p = 0.02) was shown to have a significantly unfavorable association with FP. Multivariable analysis followed by univariable analysis revealed that higher age (≥ 65 years: HR 2.66, 95% CI 1.16-5.92; p = 0.02), larger tumor volume (≥ 8 cm3: HR 5.36, 95% CI 1.20-17.4; p = 0.03), and higher cochlear dose (mean cochlear dose > 4.2 Gy: HR 2.22, 95% CI 1.07-4.77; p = 0.03) were unfavorable factors for hearing preservation. CONCLUSIONS Stereotactic radiosurgery achieved good long-term results in this series. Tumor control was acceptable, and there were few serious complications in patients with small- to medium-sized VSs. Unfortunately, hearing preservation was not satisfactory. However, the longer the observation period, the more important it becomes to compare post-SRS hearing decreases with the natural decline in untreated cases.

A case-matched study of stereotactic radiosurgery for patients with brain metastases: comparing treatment results for those with versus without neurological symptoms.

We aimed to reappraise whether post-stereotactic radiosurgery (SRS) results for brain metastases differ between patients with and without neurological symptoms. This was an institutional review board-approved, retrospective cohort study using our prospectively accumulated database including 2825 consecutive BM patients undergoing gamma knife SRS alone during the 15-year period since July 1998. The 2825 patients were divided into two groups; neurologically asymptomatic [group A, 1374 patients (48.6 %)] and neurologically symptomatic [group B, 1451 (51.4 %)]. Because there was considerable bias in pre-SRS clinical factors between groups A and B, a case-matched study was conducted. Ultimately, 1644 patients (822 in each group) were selected. The standard Kaplan-Meier method was used to determine post-SRS survival. Competing risk analysis was applied to estimate cumulative incidences of neurological death, neurological deterioration, local recurrence, re-SRS for new lesions and SRS-induced complications. Post-SRS median survival times (MSTs) did not differ between the two groups; 7.8 months in group A versus 7.4 months in group B patients (HR 1.064, 95 % CI 0.963-1.177, p = 0.22). However, cumulative incidences of neurological death (HR 1.637, 95 % CI 1.174-2.281, p = 0.0036) and neurological deterioration (HR 1.425, 95 % CI 1.073-1.894, p = 0.014) were significantly lower in the group A than in the group B patients. Neurologically asymptomatic patients undergoing SRS for BM had better results than symptomatic patients in terms of both maintenance of good neurological state and prolonged neurological survival. Thus, we conclude that screening computed tomography/magnetic resonance imaging is highly beneficial for managing cancer patients.

Does Modern Management of Malignant Extracranial Disease Prolong Survival in Patients with ≥3 Brain Metastases?

OBJECTIVE: To assess if modern management of extracranial malignant diseases has prolonged the survival times for patients with more than 2 brain metastases (BM). METHODS: Data from 2385 patients treated with Gamma Knife surgery (GKS) for ≥3 BM between 1982 and 2011 were retrospectively analyzed. The patients were divided into 6 groups based on the treatment year and the median and 10% survival times were compared with the median and mean treatment dates in each group. RESULTS: The later the treatment date, the longer the median as well as the 10% survival times. The relation between the median treatment date and both the 10% and median survival times could be accurately expressed by a linear as well as an exponential curve fit. The median and 10% survival times increased by around 80% and 150%, respectively, between 1990 and 2010. CONCLUSIONS: Both the median and 10% survival times have increased in recent years among patients with more than 2 BM treated with GKS. Both linear and exponential regressions accurately expressed the increase in both median and 10% survival times during the years 1990-2010. Findings from other published data support the observation of longer survival times among patients treated more recently, independent of the patients being treated with GKS or with whole-brain radiation therapy with or without radiosurgery. Thus, earlier findings of short survival times for patients with multiple BM are no longer valid, at least not for patients deemed suitable for radiosurgery. Aggressive management is thus warranted for these patients.

Hyperfractionated high-dose proton beam radiotherapy for clival chordomas after surgical removal.

OBJECTIVE: To evaluate the hyperfractionated high-dose proton beam therapy (PBT) for patients with clival chordomas. METHODS: Records for 19 patients with pathologically verified clival chordomas treated with surgery followed by hyperfractionated PBT were retrospectively reviewed. The first 9 consecutive patients were treated with 77.44 cobalt gray equivalents (CGEs) in 64 fractions, and the latter 10 patients were treated with 78.4 CGE in 56 fractions. RESULTS: The median follow-up period of all 19 cases was 61.7 months with a range from 31.5 to 115.4 months. At 5 years, the local control, cause-specific and overall survival rates for all 19 cases were 75%, 94% and 83.2%, respectively. Whereas the 5-year local control, cause-specific and over all survival rates of the latter 10 cases were 100%, 100% and 88.9%, respectively, with a median follow-up period of 59.5 months. One of the first nine patients demonstrated bilateral temporal lobe radiation necrosis, who were successfully treated conservatively. In the latter cohort, two cases showed transient neurological symptoms probably due to brain stem ischaemia, but both cases recovered completely with conservative treatment. CONCLUSION: The hyperfractionated high-dose scheme combined with maximum surgical removal was shown to be efficient for patients with clival chordomas. ADVANCES IN KNOWLEDGE: High-dose proton beam radiotherapy using a hyperfractionation scheme yielded a more favourable outcome than previous reports.