Formation of internal carotid artery aneurysms following gamma knife radiosurgery for pituitary adenomas: a case series and literature review.

Only two aneurysm formations in the internal carotid artery after gamma knife radiosurgery (GKRS) for pituitary adenomas are reported so far. Here, out of the 482 patients who underwent GKRS for pituitary adenomas at our institute, at least five developed aneurysms within the area of high single-dose irradiation. Three patients presented with epistaxis due to aneurysmal rupture and one presented with abducens paralysis due to nerve compression, while one was asymptomatic. The interval between irradiation and aneurysmal detection ranged from 14 to 21 years. Aneurysm formation in those conditions may be higher than previously thought.

Risk for Brain Arteriovenous Malformation Rupture During Pregnancy and Puerperium.

BACKGROUND: The hemorrhage risk of unruptured and untreated cerebral arteriovenous malformations (AVMs) has been shown to be higher for female patients than male patients in their child bearing ages. Although it has been neurosurgical practice to advise female patients in their childbearing ages to postpone pregnancy until proven AVM obliteration, there is no literature consensus regarding this potential hemorrhage risk increase. OBJECTIVE: To accurately quantify the risk increase for AVM hemorrhage during pregnancy. METHODS: This study is based on data from previous publications, consisting of known age at the first AVM hemorrhage in 3425 patients. The risk increase during pregnancy could be calculated from the difference in age distribution for the first AVM hemorrhage between male patients and female patients, taking the average pregnancy time per female into account. A comparison was also made with data for all hospital discharges (13 751) in Germany 2008 to 2018 with the diagnosis brain AVM. RESULTS: The average pregnancy and puerperium time was 1.54 years per female in the patient population, which was used to determine the annual AVM hemorrhage risk during pregnancy to be around 9%. The increased risk during pregnancy was further evidenced by analysis of a subgroup of 105 female patients, for which pregnancy status at the time of hemorrhage was known. CONCLUSION: The quantified annual risk for AVM hemorrhage during pregnancy is about 3 times higher than that of male patients at corresponding age. This provides an important basis for advising female patients with patent AVMs about the increased risk for hemorrhage that a pregnancy would entail.

Retiform endothelial hyperplasia mimicking cavernous malformation as a late complication of Gamma Knife radiosurgery.

OBJECTIVE: Gamma Knife radiosurgery (GKRS) is a powerful tool for the management of arteriovenous malformations; however, newly formed mass lesions resembling cavernous malformations are a rare late complication of GKRS. In this retrospective study, the authors tried to clarify the unique histological features of these mass lesions. METHODS: The authors retrospectively reviewed the clinical course of 889 patients who had undergone GKRS for arteriovenous malformations at their institute from 1991 to 2021. Among the 848 patients who had been followed up periodically with neuroradiological imaging, 37 developed a mass lesion mimicking a cavernous malformation and underwent surgical removal of the lesion. The median volume of the original nidus was 3.7 cm3 (range 0.07-30.5 cm3), and the median prescription dose was 21 Gy (range 12-25 Gy). The histological characteristics and radiological and clinical features of the 37 patients were investigated. RESULTS: Histological examination showed an organized hematoma and a structure termed "retiform endothelial hyperplasia" (RFEH) consisting of endothelium forming multiple lumen-like vascular channels mimicking cavernous malformations but lacking the subendothelial connective tissue that forms the typical vascular wall structure found in cavernous angioma and capillary telangiectasia. RFEH was detected a median of 10.8 years (range 3.2-27.4 years) after GKRS. Neuroimaging showed hematoma surrounded by massive brain edema in all 37 patients. Symptoms caused by mass effect of the lesion and perifocal edema worsened relatively rapidly but completely disappeared after surgery. No recurrence or morbidity occurred after the surgery. CONCLUSIONS: The delayed formation of RFEH that is mimicking a cavernous malformation neuroradiologically but is histologically distinct from a vascular malformation is a potential complication of GKRS. Its progressive clinical course suggests that surgical removal should be considered for symptomatic patients and/or patients with an apparent radiological mass sign.

Risk for Hemorrhage the First 2 Years After Gamma Knife Surgery for Arteriovenous Malformations: An Update.

BACKGROUND: Knowledge about the natural course of brain arteriovenous malformations (AVMs) have increased during the past 20 years, as has the number of AVMs treated, especially larger ones. It is thus timely to again analyze the risk for hemorrhage after Gamma Knife Surgery (GKS). OBJECTIVE: To confirm or contradict conclusions drawn 20 years ago regarding factors that affect the risk for post-GKS hemorrhage. METHODS: The outcome after GKS was studied in 5037 AVM patients followed for up to 2 years. The relation between post-treatment hemorrhage rate and a number of patient, AVM, and treatment parameters was analyzed. The results were also compared with the results from our earlier study. RESULTS: The annual post-treatment hemorrhage rate was 2.4% the first 2 years after GKS. Large size, low treatment dose, and old age were independent risk factors for AVM hemorrhage. After having compensated for the factors above, peripheral AVM location and female sex, at least during their child bearing ages, were factors associated with a lower post-GKS hemorrhage rate. CONCLUSION: Large AVMs (>5 cm 3 ) treated with low doses (≤16 Gy) had higher and small AVMs treated with high doses a lower risk for hemorrhage as compared with untreated AVMs. This was detectable within the first 6 months after GKS. No difference in hemorrhage rate could be detected for the other AVMs. Based on our findings, it is advisable to prescribe >16 Gy to larger AVMs, assuming that the risk for radiation-induced complications can be kept at an acceptable level.

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.

Outcomes of Gamma Knife radiosurgery for skull base chondrosarcomas: a multi-institutional retrospective study.

OBJECTIVE: Radiotherapy has an essential role in the management of skull base chondrosarcomas (SBCs) after resection. This multi-institutional study evaluated the outcomes of Gamma Knife radiosurgery (GKRS) for histopathologically proven SBCs. METHODS: Data of patients who underwent GKRS for SBCs at Gamma Knife centers in Japan were retrospectively collected. Patients without a histopathological diagnosis and those who had intracranial metastases from extracranial chondrosarcomas were excluded. Histologically, grade III and some nonconventional variants were identified as aggressive types. The cumulative local control rates (LCRs) and disease-specific survival (DSS) rates were calculated using the Kaplan-Meier method. Factors potentially affecting the LCR were evaluated using the Cox proportional hazards model for bivariate and multivariate analyses. The incidence of radiation-induced adverse effects (RAEs) was calculated as crude rates, and factors associated with RAEs were examined using Fisher's exact test. RESULTS: Fifty-one patients were enrolled, with a median age of 38 years. Thirty patients (59%) were treated with upfront GKRS for residual SBCs after resection (n = 27) or biopsy (n = 3), and 21 (41%) underwent GKRS as a salvage treatment for recurrence. The median tumor volume was 8 cm3. The overall LCRs were 87% at 3 years, 78% at 5 years, and 67% at 10 years after GKRS. A better LCR was associated with a higher prescription dose (p = 0.039) and no history of repeated recurrence before GKRS (p = 0.024). The LCRs among patients with the nonaggressive histological type and treatment with ≥ 16 Gy were 88% at 3 years, 83% at 5 years, and 83% at 10 years. The overall survival rates after GKRS were 96% at 5 years and 83% at 10 years. Although RAEs were observed in 3 patients (6%), no severe RAEs with Common Terminology Criteria for Adverse Events grade 3 or higher were identified. No significant factor was associated with RAEs. CONCLUSIONS: GKRS for SBCs has a favorably low risk of RAEs and could be a reasonable therapeutic option for SBC in multimodality management. A sufficient GKRS prescription dose is necessary for higher LCRs. Histological grading and subtype evaluations are important for excluding exceptional SBCs. Patients with conventional SBCs have a long life expectancy and should be observed for life after treatment.

Midterm prognosis and surgical implication for clival chordomas after extended transsphenoidal tumor removal and gamma knife radiosurgery.

BACKGROUND: Treating chordoma through surgery alone is often ineffective. Thus, surgery often performed with irradiation, with a reported 5-year survival rate of 60-75%. The clinical course varies, and disease rarity prevents larger number of clinical investigations. METHODS: In total, 19 patients with clival chordomas were retrospectively extracted from our institutional database. They were initially treated with maximal tumor removal using the extended transsphenoidal approach between March 2006 and January 2021. When total tumor removal was achieved, prophylactic irradiation was not performed. If tumor remnants or recurrence were confirmed, Gamma Knife (GK) radiosurgery was performed. The mean follow-up period was 106.7 months (ranged 27-224 months). The clinical course and prognostic factors were investigated. RESULTS: Total removal was achieved in 10 patients, whereas 4 patients suffered recurrence and required GK. GK was applied to 11 patients with a 50% isodose of 13-18 Gy (mean: 15.4 Gy), and eight patients remained progression free, whereas three patients suffered repeated local recurrence and died of tumor-related complications. The mean overall progression-free interval was 57.2 months (range: 6-169 months). One male patient died of tumor un-related lung cancer 36 months after the initial treatment, and other patients survived throughout the observational periods. The mean overall survival was 106.7 months (range: 27-224 months). Thus, the 5-year survival rate was 94.7%. Statistical analysis indicated that sex (men), > 15 Gy of 50% isodose by GK, and screening brain examinations as prophylactic medicine were significant favorable prognostic factors. CONCLUSIONS: The favorable outcomes in this investigation suggest the importance of early detection and treatment. Surgery may enable better conditions for sufficient GK doses.

Simultaneous Truth and Performance Level Estimation Method for Evaluation of Target Contouring in Radiosurgery.

BACKGROUND/AIM: The problem of lack of standardisation in target delineation and herewith the variability of target contours in Gamma Knife radiosurgery is as severe as in linac-based radiotherapy in general. The first aim of this study was to quantify the contouring variability for a group of five radiosurgery targets and estimate their true-volume based on multiple delineations using the Simultaneous Truth and Performance Level Estimation (STAPLE) algorithm. The second aim was to assess the robustness of the STAPLE method for the assessment of the true-volume, with respect to the number of contours available as input. PATIENTS AND METHODS: A multicentre analysis of the variability in contouring of five cases was performed. Twelve contours were provided for each case by experienced planners for Gamma Knife. To assess the robustness of the STAPLE method with respect to the number of contours used as input, sets of contours were randomly selected in the analysis. RESULTS: A high similarity was observed between the STAPLE generated true-volume and the 50%-agreement volume when all 12 available contours were used as input (90-100%). Lower similarity was observed with smaller sets of contours (10-70%). CONCLUSION: If a high number of input contours is available, the STAPLE method provides a valuable tool in the estimation of the true volume of a target based on multiple contours as well as the sensitivity and specificity for each input contour relative to the true volume of that structure. The robustness of the STAPLE method for rendering the true target volume depends on the number of contours provided as input and their variability with respect to shape, size and position.

Impact of breast cancer subtype on clinical outcomes after Gamma Knife radiosurgery for brain metastases from breast cancer: a multi-institutional retrospective study (JLGK1702).

INTRODUCTION: Brain metastasis (BM) is one of the most important issues in the management of breast cancer (BC), since BMs are associated with neurological deficits. However, the importance of BC subtypes remains unclear for BM treated with Gamma Knife radiosurgery (GKS). Thus, we conducted a multicenter retrospective study to compare clinical outcomes based on BC subtypes, with the aim of developing an optimal treatment strategy. METHODS: We studied 439 patients with breast cancer and 1-10 BM from 16 GKS facilities in Japan. Overall survival (OS) was analyzed by the Kaplan-Meier method, and cumulative incidences of systemic death (SD), neurologic death (ND), and tumor progression were estimated by competing risk analysis. RESULTS: OS differed among subtypes. The median OS time (months) after GKS was 10.4 in triple-negative (TN), 13.7 in Luminal, 31.4 in HER2, and 35.8 in Luminal-HER2 subtype BC (p < 0.0001). On multivariate analysis, poor control of the primary disease (hazard ratio [HR] = 1.84, p < 0.0001), active extracranial disease (HR = 2.76, p < 0.0001), neurological symptoms (HR 1.44, p = 0.01), and HER2 negativity (HR = 2.66, p < 0.0001) were significantly associated with worse OS. HER2 positivity was an independent risk factor for local recurrence (p = 0.03) but associated with lower rates of ND (p = 0.03). TN histology was associated with higher rates of distant brain failure (p = 0.03). CONCLUSIONS: HER2 positivity is related to the longer OS after SRS; however, we should pay attention to preventing recurrence in Luminal-HER2 patients. Also, TN patients require meticulous follow-up observation to detect distant metastases and/or LMD.

Clinical outcome following cerebral AVM hemorrhage.

BACKGROUND: A significant difference exists between the published results reporting the clinical outcome following brain arteriovenous malformation (AVM) ruptures. Information about the outcome following hemorrhage in an AVM population treated with radiosurgery could provide additional information to assess the risk of mortality and morbidity following an AVM hemorrhage. METHODS: Clinical outcome was studied in 383 patients, the largest patient population yet studied, who suffered from a symptomatic hemorrhage after Gamma Knife® surgery (GKS) but before confirmed AVM obliteration. The impact of different patient, AVM, and treatment parameters on the clinical outcome was analyzed. The aim was to generate outcome predictions by comparing our data to and combining them with earlier published results. RESULTS: No relation was found between clinical outcome and treatment parameters, indicating that the results are applicable also on untreated AVMs. Twenty-one percent of the patients died, 45% developed or experienced worsening of neurological sequelae, and 35% recovered completely after the hemorrhage. Old age was a predictor of poor outcome. Sex, AVM location, AVM volume, and history of prior hemorrhage did not influence the outcome. The mortality rate was comparable to earlier published prospective data, but higher than that found in retrospective studies. CONCLUSIONS: The mortality rates in earlier published retrospective series as well as in studies focusing on clinical outcome following AVM hemorrhage significantly underestimate the risk for a mortal outcome following an AVM hemorrhage. Based on our findings, an AVM rupture has around 20% likelihood to result in mortality, 45% likelihood to result in a minor or major deficit, and 35% likelihood of complete recovery. The findings are probably applicable also for AVM ruptures in general. The cumulative mortality and morbidity rates 25 years after diagnosis were estimated to be around 40% in a patient with a patent AVM.

The impact of EGFR-TKI use on clinical outcomes of lung adenocarcinoma patients with brain metastases after Gamma Knife radiosurgery: a propensity score-matched analysis based on extended JLGK0901 dataset (JLGK0901-EGFR-TKI).

PURPOSE: Recent advances in targeted therapy have prolonged overall survival (OS) for patients with lung cancer. The impact of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) on brain metastases (BM) treated with stereotactic radiosurgery (SRS) has not, however, been fully elucidated. We investigated the influence of post-SRS EGFR-TKI use on the efficacy and toxicity of SRS for BM from lung adenocarcinoma. METHODS: We used the updated dataset of the Japanese Leksell Gamma Knife (JLGK) 0901 study, which proved the efficacy of Gamma Knife SRS in patients with BM. Propensity score matching (PSM) analysis was employed to determine the impact of concurrent or post-SRS EGFR-TKI use on OS, neurological death, intracranial disease recurrence and SRS-related adverse events. RESULTS: Among 1194 patients registered in the JLGK0901 study, 608 eligible lung adenocarcinoma patients were identified and 238 (39%) had received EGFR-TKI concurrently or during the post-SRS clinical course. After PSM, there were 200 patient pairs with/without post-SRS EGFR-TKI use. EGFR-TKI use was associated with longer OS (median 25.5 vs. 11.0 months, HR 0.60, 95% CI 0.48-0.75, p < 0.001), although the long-term OS curves eventually crossed. Distant intracranial recurrence was more likely in patients receiving EGFR-TKI (HR 1.45, 95% CI 1.12-1.89, p = 0.005). Neurological death, local recurrence and SRS-related adverse event rates did not differ significantly between the two groups. CONCLUSIONS: Although patients receiving EGFR-TKI concurrently or after SRS had significantly longer OS, the local treatment efficacy and toxicity of SRS did not differ between patients with/without EGFR-TKI use.

Stereotactic radiosurgery in elderly patients with brain metastases: comparison with non-elderly patients using database of a multi-institutional prospective observational study (JLGK0901-Elderly).

PURPOSE: Stereotactic radiosurgery (SRS) has been increasingly used for elderly patients with brain metastases (BMs). However, no studies based on a large sample size have been reported. To compare SRS treatment results between elderly and non-elderly patients, we performed a subset study of elderly patients using our prospectively-accumulated multi-institution study database (JLGK0901 Study, Lancet Oncol 15:387-395, 2014). METHODS: During the 2009-2011 period, 1194 eligible patients undergoing gamma knife SRS alone for newly diagnosed BMs were enrolled in this study from 23 gamma knife facilities in Japan. Observation was discontinued at the end of 2013. The 1194 patients were divided into the two age groups, 693 elderly ( ≥ 65 years) and 501 non-elderly ( < 65 years) patients. Our study protocol neither set an upper age limit nor required dose de-escalation. RESULTS: Median post-SRS survival time was significantly shorter in the elderly than in the non-elderly patient group (10.3 vs 14.3 months, HR 1.380, 95% CI 1.218-1.563, p < 0.0001). However, regarding all secondary endpoints including neurological death, neurological deterioration, SRS-related complications, leukoencephalopathy, local recurrence, newly-developed tumors, meningeal dissemination, salvage SRS, whole brain radiotherapy and surgery and decreased mini-mental state examination scores, the elderly patient group was not inferior to the non-elderly patient group. In the 693 elderly patients, there was no post-SRS median survival time difference between those with 5-10 versus 2-4 tumors (10.8 vs 8.9 months, HR 0.936, 95% CI 0.744-1.167, p = 0.5601). CONCLUSIONS: We conclude that elderly BM patients are not unfavorable candidates for SRS alone treatment.

Local tumor progression treated with Gamma Knife radiosurgery: differences between patients with 2-4 versus 5-10 brain metastases based on an update of a multi-institutional prospective observational study (JLGK0901).

OBJECTIVE: The Japanese Leksell Gamma Knife (JLGK)0901 study proved the efficacy of Gamma Knife radiosurgery (GKRS) in patients with 5-10 brain metastases (BMs) as compared to those with 2-4, showing noninferiority in overall survival and other secondary endpoints. However, the difference in local tumor progression between patients with 2-4 and those with 5-10 BMs has not been sufficiently examined for this data set. Thus, the authors reappraised this issue, employing the updated JLGK0901 data set with detailed observation via enhanced MRI. They applied sophisticated statistical methods to analyze the data. METHODS: This was a prospective observational study of 1194 patients harboring 1-10 BMs treated with GKRS alone. Patients were categorized into groups A (single BM, 455 cases), B (2-4 BMs, 531 cases), and C (5-10 BMs, 208 cases). Local tumor progression was defined as a 20% increase in the maximum diameter of the enhanced lesion as compared to its smallest documented maximum diameter on enhanced MRI. The authors compared cumulative incidence differences determined by competing risk analysis and also conducted propensity score matching. RESULTS: Local tumor progression was observed in 212 patients (17.8% overall, groups A/B/C: 93/89/30 patients). Cumulative incidences of local tumor progression in groups A, B, and C were 15.2%, 10.6%, and 8.7% at 1 year after GKRS; 20.1%, 16.9%, and 13.5% at 3 years; and 21.4%, 17.4%, and not available at 5 years, respectively. There were no significant differences in local tumor progression between groups B and C. Local tumor progression was classified as tumor recurrence in 139 patients (groups A/B/C: 68/53/18 patients), radiation necrosis in 67 (24/31/12), and mixed/undetermined lesions in 6 (1/5/0). There were no significant differences in tumor recurrence or radiation necrosis between groups B and C. Multivariate analysis using the Fine-Gray proportional hazards model revealed age < 65 years, neurological symptoms, tumor volume ≥ 1 cm3, and prescription dose < 22 Gy to be significant poor prognostic factors for local tumor progression. In the subset of 558 case-matched patients (186 in each group), there were no significant differences between groups B and C in local tumor progression, nor in tumor recurrence or radiation necrosis. CONCLUSIONS: Local tumor progression incidences did not differ between groups B and C. This study proved that tumor progression after GKRS without whole-brain radiation therapy for patients with 5-10 BMs was satisfactorily treated with the doses prescribed according to the JLGK0901 study protocol and that results were not inferior to those in patients with a single or 2-4 BMs.Clinical trial registration no.: UMIN000001812 (umin.ac.jp).

The NASSAU (New ASSessment of cerebral Arteriovenous Malformations yet Unruptured) Analysis: Are the Results From The ARUBA Trial Also Applicable to Unruptured Arteriovenous Malformations Deemed Suitable for Gamma Knife Surgery?

BACKGROUND: The optimal management of unruptured brain arteriovenous malformations (AVMs) is controversial after the ARUBA trial. OBJECTIVE: To confirm or repudiate the ARUBA conclusion that "medical management only is superior to medical management with interventional therapy for unruptured brain arteriovenous malformations." METHODS: Data were collected from 1351 patients treated with Gamma Knife Surgery (GKS; Elekta AB, Stockholm, Sweden) for unruptured and untreated AVMs The follow-up was 8817 yr (median 5.0 and mean 6.5). The results of the analyses were compared to that found in patients randomized to medical management only in the ARUBA trial and extrapolated to a 10-yr time period. Our data were also compared to the natural course in a virtual AVM population for a 25-yr time period. RESULTS: The incidence of stroke was similar among ARUBA and our patients for the first 5 yr. Thereafter, the longer the follow-up, the relatively better outcome following treatment. Both the mortality rate and the incidence of permanent deficits in patients with small AVMs were the same as in untreated patients for the first 2 to 3 yr after GKS, after which GKS patients did better. Patients with large AVMs had a higher incidence of neurological deficits in the first 3 yr following GKS. The difference decreased thereafter, but the time until break even depended on the analysis method used and the assumed risk for hemorrhage in patent AVMs. CONCLUSION: The ARUBA trial conclusion that medical management is superior to medical management with interventional therapy for all unruptured AVMs could be repudiated.

Multiinstitutional prospective observational study of stereotactic radiosurgery for patients with multiple brain metastases from non-small cell lung cancer (JLGK0901 study-NSCLC).

OBJECTIVEPrevious Japanese Leksell Gamma Knife Society studies (JLGK0901) demonstrated the noninferiority of stereotactic radiosurgery (SRS) alone as the initial treatment for patients with 5-10 brain metastases (BMs) compared with those with 2-4 BMs in terms of overall survival and most secondary endpoints. The authors studied the aforementioned treatment outcomes in a subset of patients with BMs from non-small cell lung cancer (NSCLC).METHODSPatients with initially diagnosed BMs treated with SRS alone were enrolled in this prospective observational study. Major inclusion criteria were the existence of up to 10 tumors with a maximum diameter of less than 3 cm each, a cumulative tumor volume of less than 15 cm3, and no leptomeningeal dissemination in patients with a Karnofsky Performance Scale score of 70% or better.RESULTSAmong 1194 eligible patients, 784 with NSCLC were categorized into 3 groups: group A (1 tumor, n = 299), group B (2-4 tumors, n = 342), and group C (5-10 tumors, n = 143). The median survival times were 13.9 months in group A, 12.3 months in group B, and 12.8 months in group C. The survival curves of groups B and C were very similar (hazard ratio [HR] 1.037; 95% CI 0.842-1.277; p < 0.0001, noninferiority test). The crude and cumulative incidence rates of neurological death, deterioration of neurological function, newly appearing lesions, and leptomeningeal dissemination did not differ significantly between groups B and C. SRS-induced complications occurred in 145 (12.1%) patients during the median post-SRS period of 9.3 months (IQR 4.1-17.4 months), including 46, 54, 29, 11, and 5 patients with a Common Terminology Criteria for Adverse Events v3.0 grade 1, 2, 3, 4, or 5 complication, respectively. The cumulative incidence rates of adverse effects in groups A, B, and C 60 months after SRS were 13.5%, 10.0%, and 12.6%, respectively (group B vs C: HR 1.344; 95% CI 0.768-2.352; p = 0.299). The 60-month post-SRS rates of neurocognitive function preservation were 85.7% or higher, and no significant differences among the 3 groups were found.CONCLUSIONSIn this subset analysis of patients with NSCLC, the noninferiority of SRS alone for the treatment of 5-10 versus 2-4 BMs was confirmed again in terms of overall survival and secondary endpoints. In particular, the incidence of neither post-SRS complications nor neurocognitive function preservation differed significantly between groups B and C. These findings further strengthen the already-reported noninferiority hypothesis of SRS alone for the treatment of patients with 5-10 BMs.

A novel method to determine the natural course of unruptured brain arteriovenous malformations without the need for follow-up information.

OBJECTIVEThere is a strong clinical need to accurately determine the average annual hemorrhage risk in unruptured brain arteriovenous malformations (AVMs). This need motivated the present initiative to use data from a uniquely large patient population and design a novel methodology to achieve a risk determination with unprecedented accuracy. The authors also aimed to determine the impact of sex, pregnancy, AVM volume, and location on the risk for AVM rupture.METHODSThe present study does not consider any specific management of the AVMs, but only uses the age distribution for the first hemorrhage, the shape of which becomes universal for a sufficiently large set of patients. For this purpose, the authors collected observations, including age at first hemorrhage and AVM size and location, in 3425 patients. The average annual risk for hemorrhage could then be determined from the simple relation that the number of patients with their first hemorrhage at a specific age equals the risk for hemorrhage times the number of patients at risk at that age. For a subset of the patients, the information regarding occurrence of AVM hemorrhage after treatment of the first hemorrhage was used for further analysis of the influence on risk from AVM location and pregnancy.RESULTSThe age distribution for the first AVM hemorrhage was used to determine the average annual risk for hemorrhage in unruptured AVMs at adult ages (25-60 years). It was concluded to be 3.1% ± 0.2% and unrelated to AVM volume but influenced by its location, with the highest risk for centrally located AVMs. The hemorrhage risk was found to be significantly higher for females in their fertile years.CONCLUSIONSThe present methodology allowed the authors to determine the average annual risk for the first AVM hemorrhage at 3.1% ± 0.2% without the need for individual patient follow-up. This methodology has potential also for other similar types of investigations. The conclusion that centrally located AVMs carry a higher risk was confirmed by follow-up information. Follow-up information was also used to conclude that pregnancy causes a substantially greater AVM hemorrhage risk. The age distribution for AVM hemorrhage is incompatible with AVMs present at birth having the same hemorrhage risk as AVMs in adults. Plausibly, they instead develop in the early years of life, possibly with a lower hemorrhage risk during that time period.

Effects of Surgery With Salvage Stereotactic Radiosurgery Versus Surgery With Whole-Brain Radiation Therapy in Patients With One to Four Brain Metastases (JCOG0504): A Phase III, Noninferiority, Randomized Controlled Trial.

Purpose Whereas whole-brain radiotherapy (WBRT) has been the standard treatment of brain metastases (BMs), stereotactic radiosurgery (SRS) is increasingly preferred to avoid cognitive dysfunction; however, it has not been clearly determined whether treatment with SRS is as effective as that with WBRT or WBRT plus SRS. We thus assessed the noninferiority of salvage SRS to WBRT in patients with BMs. Patients and Methods Patients age 20 to 79 years old with performance status scores of 0 to 2-and 3 if caused only by neurologic deficits-and with four or fewer surgically resected BMs with only one lesion > 3 cm in diameter were eligible. Patients were randomly assigned to WBRT or salvage SRS arms within 21 days of surgery. The primary end point was overall survival. A one-sided α of .05 was used. Results Between January 2006 and May 2014, 137 and 134 patients were enrolled in the WBRT and salvage SRS arms, respectively. Median overall survival was 15.6 months in both arms (hazard ratio, 1.05; 90% CI, 0.83 to 1.33; one-sided P for noninferiority = .027). Median intracranial progression-free survival of patients in the WBRT arm (10.4 months) was longer than that of patients in the salvage SRS arm (4.0 months). The proportions of patients whose Mini-Mental Status Examination and performance status scores that did not worsen at 12 months were similar in both arms; however, 16.4% of patients in the WBRT arm experienced grade 2 to 4 cognitive dysfunction after 91 days postenrollment, whereas only 7.7% of those in the SRS arm did ( P = .048). Conclusion Salvage SRS is noninferior to WBRT and can be established as a standard therapy for patients with four or fewer BMs.

Multi-institutional study of the variability in target delineation for six targets commonly treated with radiosurgery.

BACKGROUND: Although accurate delineation of the target is a key factor of success in radiosurgery there are no consensus guidelines for target contouring. AIM: The aim of the present study was therefore to quantify the variability in target delineation and discuss the potential clinical implications, for six targets regarded as common in stereotactic radiosurgery. MATERIAL AND METHODS: Twelve Gamma Knife centers participated in the study by contouring the targets and organs at risks and performing the treatment plans. Analysis of target delineation variability was based on metrics defined based on agreement volumes derived from overlapping structures following a previously developed method. The 50% agreement volume (AV50), the common and the encompassing volumes as well as the Agreement Volume Index (AVI) were determined. RESULTS: Results showed that the lowest AVI (0.16) was found for one of the analyzed metastases (range of delineated volumes 1.27-3.33 cm3). AVI for the other two metastases was 0.62 and 0.37, respectively. Corresponding AVIs for the cavernous sinus meningioma, pituitary adenoma and vestibular schwannoma were 0.22, 0.37 and 0.50. CONCLUSIONS: This study showed that the variability in the contouring was much higher than expected and therefore further work in standardizing the contouring practice in radiosurgery is warranted.

Mid-term prognosis of non-functioning pituitary adenomas with high proliferative potential: really an aggressive variant?

Pituitary adenomas with high proliferation rate and rapid growth are well known, but the clinical characteristics, prognosis, and treatment algorithm remain unclear. The clinical characteristics and mid-term prognosis of patients with non-functioning pituitary adenomas with high proliferative potential were retrospectively investigated. This study identified 53 patients with Ki-67 labeling index of > 3% among 845 patients with non-functioning pituitary adenoma (6.3%) initially treated by surgery. Prophylactic treatment was not applied for patients with residual tumor, but salvage treatment was performed if tumor progression was identified within the follow-up period. Twenty-two patients remained progression-free, whereas 31 patients suffered tumor progression. Comparison of gross total removal (n = 22) and non-total removal (n = 31) groups showed significantly longer progression-free period in the former group (P < 0.001). As salvage treatment gamma knife radiosurgery was applied for 11 patients resulting in 10 patients remaining progression-free and regrowth in 1 patient. Fractionated irradiation was applied for 10 patients, resulting in 2 patients remaining progression-free, deaths in 5 patients including 3 of transformation to pituitary carcinoma, dementia in 1 patient caused by frontal lobe dysfunction, and progression in 2 patients requiring additional surgery and gamma knife radiosurgery. Temozolomide was administered in 2 patients, resulting in deaths in both patients including 1 transformation to pituitary carcinoma. Total removal and gamma knife radiosurgery can result in good outcome. However, the prognosis is extremely poor for patients inadequate for gamma knife radiosurgery. Development of new salvage treatments is essential.

Clinical Features of Precocious, Synchronous, and Metachronous Brain Metastases and the Role of Tumor Resection.

OBJECTIVE: The purpose of this study was to clarify clinical features, outcomes, and the role of tumor resection in precocious, synchronous, and metachronous brain metastases. METHODS: Brain metastases were found before primary cancer detection in the precocious group, within 2 months after primary cancer detection in the synchronous group, and 2 months or later after primary cancer detection in the metachronous group. RESULTS: Of 471 patients with brain metastases, 93 (20%) were included in the precocious group, 76 (16%) in the synchronous group, and 302 (64%) in the metachronous group. The precocious group tended to be symptomatic, show a low Karnofsky Performance Status, and have a large single tumor, infrequent extracranial metastases, and frequent tumor resection compared with the other 2 groups. There were no differences in overall survival from the detection of brain metastases among the 3 groups in univariate and multivariate analyses. Of 471 cases, 97 (21%) underwent surgeries. Among this surgical cohort, overall survival from surgery was significantly shorter in the precocious group than in the metachronous group (P = 0.039). After adjustment for age, sex, tumor size, primary cancer, and the Graded Prognostic Assessment score, the hazard ratio for metachronous metastases was 0.52 (confidence interval, 0.29-0.95; P = 0.035). CONCLUSIONS: The timing of brain metastasis diagnosis is not a modifiable factor but affects patient demographics and treatment strategies. In particular, the precocious group is a unique subset of brain metastases that require special consideration during clinical decision making.