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.

Gamma Knife Radiosurgery for Metastatic Brain Tumors from Uterine Cervical and Endometrial Carcinomas: Histopathological Analysis of Survival and Local Control. A Japanese Multi-Institutional Cooperative and Retrospective Cohort Study.

OBJECTIVE: A retrospective comparative analysis of the outcomes of gamma knife radiosurgery (GKRS) for brain metastases from uterine cervical carcinoma (CC) and endometrial carcinoma (EC), investigated the efficacy and prognostic factors for survival and local tumor control. Histopathological analysis was also performed. METHODS: The authors retrospectively reviewed 61 patients with 260 tumors of CC and 73 patients with 302 tumors of EC who had undergone GKRS. RESULTS: The survival times after GKRS had no difference between CC and EC. Uncontrolled primary cancer was significant unfavorable factor. CC resulted in significantly higher neurological death and post-GKRS neurological deterioration. New lesions appeared intracranially after GKRS, with no significant difference between CC and EC. Local tumor control rates at 6, 12, and 24 months after GKRS were 90.0%, 86.6%, and 78.0% for CC and 92.2%, 87.9%, and 86.4% for EC. Primary cancer of CC, more than 7 cm3 volume, and prescription dose less than 20 Gy were significantly correlated in control failure. Local tumor control rates were significantly lower for squamous cell carcinoma in CC. No significant differences were found between histopathological subtypes of EC. CONCLUSIONS: This study established a relationship between the efficacy of GKRS for CC and EC brain metastases and the histopathological. Though, survival time after GKRS has no difference between CC and EC, CC was significantly higher neurogenic death and neurological deterioration after GKRS. Squamous cell carcinoma had a significantly lower rate of local tumor control among all CC, thereby resulting in CC having lower local tumor control than EC.

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.

Gamma Knife radiosurgery for metastatic brain tumors from ovarian cancer: histopathological analysis of survival and local control. A Japanese multi-institutional cooperative and retrospective cohort study.

OBJECTIVE: Brain metastasis is rare in ovarian cancer patients. The results of Gamma Knife radiosurgery (GKRS) for the treatment of patients with brain metastases from ovarian cancer were retrospectively analyzed to derive the efficacy and prognostic factors for survival and local tumor control. Further histopathological analysis was also performed. METHODS: The authors retrospectively reviewed the medical records of 118 patients with 566 tumors who had undergone GKRS at the 10 GKRS institutions in Japan. RESULTS: After the initial GKRS, the median overall survival time was 18.1 months. Multivariate analysis showed that uncontrolled primary cancer (p = 0.003) and multiple intracranial metastases (p = 0.034) were significant unfavorable factors. Ten patients died of uncontrolled brain metastases at a median of 17.1 months. The 6-, 12-, and 24-month neurological death rates were 3.2%, 4.6%, and 11.9%, respectively. The 6-, 12-, and 24-month neurological deterioration rates were 7.2%, 13.5%, and 31.4%, respectively. The 6-, 12-, and 24-month distant brain control failure rates were 20.6%, 40.2%, and 42.3%, respectively. Median tumor volume was 1.6 cm3 and marginal dose was 20 Gy. The 6-, 12-, and 24-month local tumor control rates were 97.6%, 95.2%, and 88.0%, respectively. Peritumoral edema (p = 0.043), more than 7-cm3 volume (p = 0.021), and prescription dose less than 18 Gy (p = 0.014) were factors that were significantly correlated in local tumor control failure. Eight patients had symptomatic radiation injury. The 6-, 12-, and 24-month GKRS-related complication rates were 3.3%, 7.8%, and 12.2%, respectively. Primary ovarian cancer was histopathologically diagnosed for 313 tumors in 69 patients. Serous adenocarcinoma was found in 37 patients and other types in 32 patients. Median survival times were 32.3 months for the serous type and 17.4 months for other types after initial GKRS. Patients with serous-type tumors survived significantly longer than patients with other types (p = 0.039). The 6-, 12-, and 24-month local tumor control rates were 100%, 98.8%, and 98.8%, respectively. Serous-type tumors were a significantly good prognosis factor for local tumor control after GKRS (p = 0.005). CONCLUSIONS: This study established a relationship between the efficacy of GKRS treatment for brain metastases and the histological type of primary ovarian cancer. GKRS for ovarian cancer brain metastasis can provide satisfactory survival and local control, especially in cases of serous adenocarcinoma.

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.

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.

Salvage gamma knife radiosurgery for active brain metastases from small-cell lung cancer after whole-brain radiation therapy: a retrospective multi-institutional study (JLGK1701).

PURPOSE: To evaluate the efficacy of gamma knife radiosurgery (GKS) for brain metastases (BMs) from small-cell lung cancer after whole-brain radiotherapy (WBRT). METHODS: We retrospectively analyzed the usefulness and safety of GKS in 163 patients from 15 institutions with 1-10 active BMs after WBRT. The usefulness and safety of GKS were evaluated using statistical methods. RESULTS: The median age was 66 years, and 79.1% of patients were men. The median number and largest diameter of BM were 2.0 and 1.4 cm, respectively. WBRT was administered prophylactically in 46.6% of patients. The median overall survival (OS) was 9.3 months, and the neurologic mortality was 20.0%. Crude incidences of local control failure and new lesion appearance were 36.6% and 64.9%, respectively. A BM diameter ≥ 1.0 cm was a significant risk factor for local progression (hazard ratio [HR] 2.556, P = 0.039) and neurologic death (HR 4.940, P = 0.031). Leukoencephalopathy at the final follow-up was more prevalent in the therapeutic WBRT group than in the prophylactic group (P = 0.019). The symptom improvement rate was 61.3%, and neurological function was preserved for a median of 7.6 months. Therapeutic WBRT was not a significant risk factor for OS, neurological death, local control, or functional deterioration (P = 0.273, 0.490, 0.779, and 0.560, respectively). Symptomatic radiation-related adverse effects occurred in 7.4% of patients. CONCLUSIONS: GKS can safely preserve neurological function and prevent neurologic death in patients with 1-10 small, active BMs after prophylactic and therapeutic WBRT.

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.

A Multi-institutional Prospective Observational Study of Stereotactic Radiosurgery for Patients With Multiple Brain Metastases (JLGK0901 Study Update): Irradiation-related Complications and Long-term Maintenance of Mini-Mental State Examination Scores.

PURPOSE: The JLGK0901 study showed the noninferiority of stereotactic radiosurgery (SRS) alone as initial treatment of 5 to 10 brain metastases (BMs) compared with 2 to 4 BMs in terms of overall survival and most secondary endpoints (Lancet Oncol 2014;15:387-95). However, observation periods were not long enough to allow confirmation of the long-term safety of SRS alone in patients with 5 to 10 BMs. METHODS AND MATERIALS: This was a prospective observational study of Gamma Knife SRS-treated patients with 1 to 10 newly diagnosed BMs enrolled at 23 facilities between March 1, 2009, and February 15, 2012. RESULTS: The 1194 eligible patients were categorized into the following groups: group A, 1 tumor (n=455); group B, 2 to 4 tumors (n=531); and group C, 5 to 10 tumors (n=208). Cumulative rates of Mini-Mental State Examination (MMSE) score maintenance (MMSE score decrease <3 from baseline) determined with a competing risk analysis of groups A, B, and C were 93%, 91%, and 92%, respectively, at the 12th month after SRS; 91%, 89%, and 91%, respectively, at the 24th month; 89%, 88%, and 89%, respectively, at the 36th month; and 87%, 86%, and 89%, respectively, at the 48th month (hazard ratio [HR] of group A vs group B, 0.719; 95% confidence interval [CI], 0.437-1.172; P=.18; HR of group B vs group C, 1.280; 95% CI, 0.696-2.508; P=.43). During observations ranging from 0.3 to 67.5 months (median, 12.0 months; interquartile range, 5.8-26.5 months), as of December 2014, 145 patients (12.1%) had SRS-induced complications. Cumulative complication incidences by competing risk analysis for groups A, B, and C were 7%, 8%, and 6%, respectively, at the 12th month after SRS; 10%, 11%, and 11%, respectively, at the 24th month; 11%, 11%, and 12%, respectively, at the 36th month; and 12%, 12%, and 13%, respectively, at the 48th month (HR of group A vs group B, 0.850; 95% CI, 0.592-1.220; P=.38; HR of group B vs group C, 1.052; 95% CI, 0.666-1.662, P=.83). Leukoencephalopathy occurred in 12 of the 1074 patients (1.1%) with follow-up magnetic resonance imaging and was detected after salvage whole-brain radiation therapy in 11 of these 12 patients. In these 11 patients, leukoencephalopathy was detected by magnetic resonance imaging 5.2 to 21.2 months (median, 11.0 months; interquartile range, 7.0-14.4 months) after whole-brain radiation therapy. CONCLUSIONS: Neither MMSE score maintenance nor post-SRS complication incidence differed among groups A, B, and C. This longer-term follow-up study further supports the already-reported noninferiority hypothesis of SRS alone for patients with 5 to 10 BMs versus 2 to 4 BMs.

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.

Pituitary metastases: current practice in Japan.

OBJECT: With advancement of cancer treatment and development of neuroimaging techniques, contemporary clinical pictures of pituitary metastases (PMs) must have changed from past reports. The goal of this paper was to elucidate the clinical features of PMs and current clinical practice related to those lesions. In this retrospective study, questionnaires were sent to 87 physicians who had treated PMs in Japan. RESULTS: Between 1995 and 2010, 201 patients with PMs were treated by the participating physicians. The diagnosis of PM was histologically verified in 69 patients (34.3%). In the other 132 patients (65.7%), the PM was diagnosed by their physicians based on neuroimaging findings and clinical courses. The most frequent primary tumor was lung (36.8%), followed by breast (22.9%) and kidney (7.0%) cancer. The average interval between diagnosis of primary cancer and detection of PM was 2.8 ± 3.9 (SD) years. Major symptoms at diagnosis were visual disturbance in 30.3%, diabetes insipidus in 27.4%, fatigue in 25.4%, headache in 20.4%, and double vision in 17.4%. Major neuroimaging features were mass lesion in the pituitary stalk (63.3%), constriction of tumor at the diaphragmatic hiatus (44.7%), hypothalamic mass lesion (17.4%), and hyperintensity in the optic tract (11.4%). Surgical treatment was performed in 26.9% of patients, and 74.6% had radiation therapy; 80.0% of patients who underwent radiotherapy had stereotactic radiotherapy. The median survival time was 12.9 months in total. Contributing factors for good prognosis calculated by Cox proportional hazard analysis were younger age, late metastasis to the pituitary gland, smaller PM size, and radiation therapy. The Kaplan-Meier survival was significantly better in patients with breast cancer and renal cell cancer than in those with lung cancer. CONCLUSIONS: At the time of this writing, approximately 60% (120/201) of PMs had been treated by stereotactic radiation therapy in Japan. The median survival time was much longer than that reported in past series. To confirm the changes of clinical features and medical practice, a prospective and population-based survey is mandatory.