Intraoperative Integrated Diagnostic System for Malignant Central Nervous System Tumors.

PURPOSE: The 2021 World Health Organization (WHO) classification of central nervous system (CNS) tumors uses an integrated approach involving histopathology and molecular profiling. Because majority of adult malignant brain tumors are gliomas and primary CNS lymphomas (PCNSL), rapid differentiation of these diseases is required for therapeutic decisions. In addition, diffuse gliomas require molecular information on single-nucleotide variants (SNV), such as IDH1/2. Here, we report an intraoperative integrated diagnostic (i-ID) system to classify CNS malignant tumors, which updates legacy frozen-section (FS) diagnosis through incorporation of a qPCR-based genotyping assay. EXPERIMENTAL DESIGN: FS evaluation, including GFAP and CD20 rapid IHC, was performed on adult malignant CNS tumors. PCNSL was diagnosed through positive CD20 and negative GFAP immunostaining. For suspected glioma, genotyping for IDH1/2, TERT SNV, and CDKN2A copy-number alteration was routinely performed, whereas H3F3A and BRAF SNV were assessed for selected cases. i-ID was determined on the basis of the 2021 WHO classification and compared with the permanent integrated diagnosis (p-ID) to assess its reliability. RESULTS: After retrospectively analyzing 153 cases, 101 cases were prospectively examined using the i-ID system. Assessment of IDH1/2, TERT, H3F3AK27M, BRAFV600E, and CDKN2A alterations with i-ID and permanent genomic analysis was concordant in 100%, 100%, 100%, 100%, and 96.4%, respectively. Combination with FS and intraoperative genotyping assay improved diagnostic accuracy in gliomas. Overall, i-ID matched with p-ID in 80/82 (97.6%) patients with glioma and 18/19 (94.7%) with PCNSL. CONCLUSIONS: The i-ID system provides reliable integrated diagnosis of adult malignant CNS tumors.

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.

Stereotactic intensity-modulated radiotherapy for skull base meningioma using the HybridArc with Novalis STx system.

Background: Skull base meningiomas are often difficult to remove completely with preserved nerve function and may require radiation therapy. However, the Gamma Knife is unsuitable for large tumor volume or the optic nerve, which is difficult to identify on imaging. We report the results of stereotactic radiotherapy with HybridArc using Novalis STx for skull base meningiomas. Methods: We retrospectively examined 28 patients with skull base meningioma who underwent stereotactic radiotherapy (54 Gy/30 fractions) with HybridArc. Results: The 28 patients, nine males and 19 females, were aged 31-83 years (mean 58.4 years), and the tumor volume was 2.6-97.1 mL (mean 29.7 mL). HybridArc irradiation was performed with D95 54 Gy/30 fractions for all patients with a median follow-up period of 36.0 months (range: 12-78 months). Tumor control rates at 1, 2, and 5 years after radiotherapy were 92.6%, 89.1%, and 82.8%, respectively. Only one non-atypical meningioma remained uncontrolled; thus, the tumor control rate for non-atypical meningioma at 1, 2, and 5 years was 94.1%. Tumor control rates for atypical meningioma at 1, 2, and 5 years were 85.7%, 71.4%, and 53.6%, respectively, significantly worse than for non-atypical meningiomas (P = 0.0395). Radiation injury was observed in two cases (7.1%). Visual field defects were observed in 16 patients, and diplopia in 6. Visual field and diplopia improvements were achieved in 5 and 2 patients, respectively (with overlap). Conclusion: Stereotactic radiotherapy (54 Gy/30 fractions) with HybridArc using Novalis STx is a safe and effective approach for relatively large skull base meningiomas.

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.

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.

Effects of two different radiotherapies for craniopharyngiomas using stereotactic radiosurgery/ stereotactic radiotherapy or fractionated stereotactic radiotherapy.

Background: Numerous studies have reported about good tumor control with both stereotactic radiosurgery (SRS) and fractionated stereotactic radiotherapy (FSRT) for residual and recurrent craniopharyngiomas, but no studies have reported on the appropriate use of different types of radiation modalities. This study aimed to report the outcomes of SRS/stereotactic radiotherapy (SRT) or FSRT and compare tumor control in a single center. Methods: From 2014 when TrueBeamTM STx with Novalis was introduced in our hospital to 2021, 21 patients underwent SRS/SRT or FSRT with gamma knife surgery (GKS) and Novalis. We have selected the radiation modalities considering mainly the distance of the optic nerve and chiasm. Imaging and clinical follow-up data were sent and reviewed. Results: The mean age was 52 years and there were 11 men. Of the 21 total patients, three experienced SRS (GKS, 50% isodose 12-15 Gy), five underwent SRT (GKS or Novalis, 19.5-24 Gy 3 fractions), and 13 patients underwent FSRT (Novalis, 54 Gy 30 fractions). The median follow-up was 32.6 (range 17-44) months after SRS/SRT and 34.0 (range 4-61) months after FSRT. In the SRS/SRT group, the mean tumor volume decreased from 1.103 to 0.131 cm3 (P < 0.01), and in the FSRT group, from 3.015 to 1.012 cm3 (P < 0.01). No radiation-induced optic neuropathy and other acute toxicity occurred. Conclusion: Craniopharyngioma can be expected to have very good tumor control by selecting SRS/SRT or FSRT depending on the distance between the optic nerve and the tumor.

Volume-Staged Radiosurgery for Large Arteriovenous Malformation: Retrospective Analysis of 19 Cases.

Introduction The effectiveness of Gamma Knife surgery (GKS) for small arteriovenous malformations (AVMs) is well known. However, for large AVMs, the prescribed dose should be decreased to reduce the risk of radiation damage, but it leads to a decrease in nidus obliteration rates. Therefore, it is very difficult to achieve complete obliteration of large AVMs in a single treatment, and methods using multiple irradiation such as volume-staged stereotactic radiosurgery (VS-SRS) have been suggested. We retrospectively reviewed our results of VS-SRS for large AVMs to assess the efficacy of VS-SRS. Methods Nineteen patients with AVMs of ≥10 ml and who consented to VS-SRS were treated by this surgical strategy and retrospectively analyzed. We excluded AVMs that were too large such as those >40 cc to avoid severe radiation damage. The components were divided mainly in the vertical direction, and each component was irradiated with a marginal dose of 18 Gy. Each irradiation was performed at intervals of 3-6 months, and the components with main feeders were irradiated first, and the components that included the main drainer were irradiated last. We tried to keep V18 to <10 ml if possible. The follow-up after GKS was performed by MRI every 6 months, and cerebral angiography was performed to confirm complete nidus obliteration, but if the patient refused, it was judged on the basis of MRI findings. Results Nineteen patients with a mean age of 40.2 years underwent VS-SRS. Each compartment was irradiated at 3--16 month (median, 3 months) intervals. The mean initial AVM volume was 19 ± 5.6 ml. Fourteen patients received two-stage radiosurgery and five received three-stage radiosurgery. The median target volume was 9.1 ml at stage 1, 9.0 ml at stage 2, and 10.1 ml at stage 3. The median margin dose was 18 Gy at each stage. The mean follow-up after the last stage of radiosurgery was 3.9 (1-11.4) years. Complete obliteration was confirmed by angiography in six patients, and by magnetic resonance angiography in one patient. The cumulative obliteration rates were 30.7% and 58.2% at 3 and 5 years following VS-SRS, respectively. The cumulative hemorrhage rates were 7.1% and 22.1% at 3 and 5 years, respectively. MRI showed T2-weighted prolongation in 15 patients (78.9%). Of these 15 patients, four were symptomatic (epilepsy in all) and two underwent surgical removal of symptomatic expanding hematomas. Conclusions In our experience, VS-SRS offers a viable treatment strategy in patients with large AVMs. Further optimization of the dose and volume at each stage is required.

Outcomes of Gamma Knife Radiosurgery for Brain Metastases From Anaplastic Lymphoma Kinase Rearrangement-Positive and EGFR Mutation-Positive Non-Small Cell Lung Cancer.

Introduction The outcomes after gamma knife radiosurgery (GKRS) were retrospectively analysed in patients with brain metastases from anaplastic lymphoma kinase (ALK) rearrangement-positive and epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC) to evaluate the efficacy, safety and difference for overall survival and local tumor control. Methods The medical records were retrospectively reviewed of 607 patients (25 ALK-positive, 171 EGFR-positive, and 411 wild type) with 2959 tumors who had undergone GKRS. Results The median overall survival time after initial GKRS was 14 months. Driver gene mutation-positive patients had significantly longer overall survival than wild type patients (p < 0.0001), and ALK-positive patients survived significantly longer than EGFR-positive patients (p = 0.04). Multivariate analysis showed the unfavorable factors significantly affecting overall survival outcomes were older age, lower Karnofsky Performance Status score, multiple intracranial metastases, uncontrolled primary cancer, uncontrolled extracranial metastases, no administration of immune checkpoint inhibitors, and driver gene mutation-negative cases. Seventy-three patients died of uncontrolled brain metastases at a median of 12 months. Driver gene mutations had no influence (p = 0.33), and ALK-positive and EGFR-positive patients showed no significant difference in neurological survival (p = 0.83). A total of 174 patients demonstrated distant brain control failure at a median of 15 months. ALK-positive type was significant compared with EGFR-positive type (p = 0.047), but driver gene mutation-positive and -negative types showed no significant difference in the development of new brain metastases (p = 0.2). The median tumor volume was 1.06 cm3 in the driver gene mutation-positive type and 1.85 cm3 in wild type. The median marginal dose was 20 Gy in both types. The 6-, 12-, and 24-month local tumor control rates were 97.3%, 96.1%, and 95.9%, respectively. Driver gene mutations had a significantly positive impact on local tumor control (p = 0.001), and ALK-positive and EGFR-positive types showed no significant difference (p = 0.95). A total of 193 tumors had radiation injury at a median of 12 months after GKRS. The 6-, 12-, and 24-month GKRS-related complication rates were 3.3%, 8.1%, and 8.7%, respectively. Driver gene mutations significantly induced radiation damage (p = 0.021), and the ALK-positive type was affected more than the EGFR-positive type (p = 0.02). Conclusions ALK rearrangement-positive NSCLC patients tended to have significantly longer survival, but had higher incidence of new intracranial metastases due to long-term survival after GKRS, compared with EGFR mutation-negative and driver gene mutation-negative NSCLC patients. GKRS induced significantly satisfactory local tumor control in driver gene mutation-positive tumors but GKRS-related complication frequency was higher, especially in ALK-positive NSCLC patients. Therefore, more careful imaging follow-up is necessary after GKRS for patients with driver gene mutation-positive NSCLC.

Acute Management of Gamma Knife Radiosurgery for Asymptomatic Obstructive Hydrocephalus Associated with Posterior Fossa Metastases.

OBJECTIVE: We retrospectively assessed the effectiveness and safety of Gamma Knife radiosurgery (GKRS) for asymptomatic obstructive hydrocephalus associated with posterior fossa metastases, which was known empirically but not well discussed. METHODS: We reviewed the medical records of 27 patients who underwent GKRS for asymptomatic obstructive hydrocephalus related to posterior fossa metastases. RESULTS: Cumulative control rates of hydrocephalus were 11.1%, 51.9%, 70.4%, and 74.6% at 1, 2, 3, and 6 months after GKRS. Primary gastrointestinal tract cancer (P = 0.001) was significantly correlated with unfavorable management. Evans ratio at GKRS (median 0.31) improved significantly compared with that at 1-3 months after GKRS (median 0.26) (P < 0.0001) and maintained at 6 to 12 months. Cumulative local tumor control rates were 91.7%, 70.8%, and 64.4% at 3, 6, and 12 months after GKRS. Primary gastrointestinal tract cancer (P = 0.018) and no conventional systemic agents (P = 0.027) were significantly correlated with unfavorable control. Cumulative incidence rates of adverse radiation effects were 0.0%, 16.7%, and 24.2% at 6, 9, and 12 months after GKRS. Primary gastrointestinal tract cancer (P < 0.0001) and single and 2- or 3-fraction GKRS (P < 0.0001) were significantly correlated with unfavorable outcomes. All but 1 patient avoided surgical procedure for hydrocephalus after GKRS. CONCLUSIONS: The present findings suggest that GKRS is an effective and safe treatment for asymptomatic obstructive hydrocephalus caused by posterior fossa metastases, and all but 1 could avoid invasive surgical procedures for hydrocephalus. Posterior fossa metastases from gastrointestinal tract cancer resulted in unsatisfactory outcomes for control of hydrocephalus, tumor progression, and adverse radiation effects.

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.

Gamma Knife Surgery for Residual or Recurrent Craniopharyngioma After Surgical Resection: A Multi-institutional Retrospective Study in Japan.

Objective The optimal treatment for a craniopharyngioma has been controversial. Complete resection is ideal, but it has been difficult to obtain total resection in many cases because of intimate proximity to critical structures such as the optic pathway, hypothalamus, and pituitary gland. A growing number of studies have demonstrated the utility of radiosurgery in controlling residual or recurrent craniopharyngioma. However, most of them are small series. The aim of this multi-institutional study was to clarify the efficacy and safety of Gamma Knife (Elekta, Stockholm, Sweden) surgery for patients with a craniopharyngioma. Methods This was a multi-institutional retrospective study by 16 medical centers of the Japan Leksell Gamma Knife Society. Data on patients with craniopharyngiomas treated with Gamma Knife Surgery (GKS) between 1991 and 2013 were obtained from individual institutional review board-approved databases at each center. A total of 242 patients with craniopharyngioma were included in this study. The mean age of the patients was 41 (range, 3 to 86) years. The median follow-up time was 61.4 months (range, 3 to 180 months). The mean radiosurgery target volume was 3.1 ml (range, 0.03-22.3 ml), and the mean marginal dose was 11.4 Gy (range, 8-20.4 Gy). Results Two-hundred twenty patients were alive at the time of the last follow-up visit. The three-, five-, and 10-year overall survival rates after GKS were 95.4%, 92.5%, and 82.0%, respectively. The three-, five-, and 10-year progression-free survival rates after GKS were 73.1%, 62.2%, and 42.6% respectively. The rate of radiation-induced complications was 6.2%. Conclusion GKS is effective for controlling the tumor growth of craniopharyngiomas with an acceptable complication rate.

PI3K/AKT/mTOR Pathway Alterations Promote Malignant Progression and Xenograft Formation in Oligodendroglial Tumors.

PURPOSE: Oligodendroglioma has a relatively favorable prognosis, however, often undergoes malignant progression. We hypothesized that preclinical models of oligodendroglioma could facilitate identification of therapeutic targets in progressive oligodendroglioma. We established multiple oligodendroglioma xenografts to determine if the PI3K/AKT/mTOR signaling pathway drives tumor progression. EXPERIMENTAL DESIGN: Two anatomically distinct tumor samples from a patient who developed progressive anaplastic oligodendroglioma (AOD) were collected for orthotopic transplantation in mice. We additionally implanted 13 tumors to investigate the relationship between PI3K/AKT/mTOR pathway alterations and oligodendroglioma xenograft formation. Pharmacologic vulnerabilities were tested in newly developed AOD models in vitro and in vivo. RESULTS: A specimen from the tumor site that subsequently manifested rapid clinical progression contained a PIK3CA mutation E542K, and yielded propagating xenografts that retained the OD/AOD-defining genomic alterations (IDH1 R132H and 1p/19q codeletion) and PIK3CA E542K, and displayed characteristic sensitivity to alkylating chemotherapeutic agents. In contrast, a xenograft did not engraft from the region that was clinically stable and had wild-type PIK3CA. In our panel of OD/AOD xenografts, the presence of activating mutations in the PI3K/AKT/mTOR pathway was consistently associated with xenograft establishment (6/6, 100%). OD/AOD that failed to generate xenografts did not have activating PI3K/AKT/mTOR alterations (0/9, P < 0.0001). Importantly, mutant PIK3CA oligodendroglioma xenografts were vulnerable to PI3K/AKT/mTOR pathway inhibitors in vitro and in vivo-evidence that mutant PIK3CA is a tumorigenic driver in oligodendroglioma. CONCLUSIONS: Activation of the PI3K/AKT/mTOR pathway is an oncogenic driver and is associated with xenograft formation in oligodendrogliomas. These findings have implications for therapeutic targeting of PI3K/AKT/mTOR pathway activation in progressive oligodendrogliomas.

Gamma Knife Radiosurgery for Metastatic Brain Tumors from Cancer of Unknown Primary.

OBJECTIVE: We retrospectively analyzed treatment efficacy and identified prognostic factors impacting tumor control and survival in patients with brain metastases from cancer of unknown primary (CUP) treated with gamma knife radiosurgery (GKRS). METHODS: We retrospectively reviewed the medical records of 87 patients with 520 tumors who underwent GKRS for brain metastases from CUP. RESULTS: The median overall survival time after initial GKRS was 6 months. The 6- and 12-month overall survival rates were 79.3% and 14.9%, respectively. Older age (P = 0.002), lower Karnofsky Performance Status Index score (P = 0.026), extracranial metastases (P = 0.013), and multiple brain metastases (P = 0.007) were significantly correlated with shorter survival periods. The 6- and 12-month neurologic death rates were 25.3% and 32.2%, respectively. The 6- and 12-month neurologic deterioration rates were 24.1% and 27.6%, respectively. The 6- and 12-month distant brain control failure rates were 21.8% and 24.1%, respectively. The median tumor volume was 1.7 cm3. The median marginal prescription dose was 18 Gy. The 6- and 12-month tumor recurrence rates were 5.1% and 15.7%, respectively. Larger tumor volume (P < 0.0001) and lower prescription dose (P = 0.001) were significantly correlated with local tumor control failure. Seven patients had symptomatic radiation injury. The 6- and 12-month GKRS-related complication rates were both 6.9%. CONCLUSIONS: Our findings suggest that GKRS is a relatively effective and safe treatment for control of tumor progression in patients with brain metastases from CUP. Overall and neurologic survivals were short, but we recommend GKRS treatment to prevent early neurologic dysfunction and death in patients with CUP.

Comparison of treatment results between 3- and 2-stage Gamma Knife radiosurgery for large brain metastases: a retrospective multi-institutional study.

OBJECTIVE: In order to obtain better local tumor control for large (i.e., > 3 cm in diameter or > 10 cm3 in volume) brain metastases (BMs), 3-stage and 2-stage Gamma Knife surgery (GKS) procedures, rather than a palliative dose of stereotactic radiosurgery, have been proposed. Here, authors conducted a retrospective multi-institutional study to compare treatment results between 3-stage and 2-stage GKS for large BMs. METHODS: This retrospective multi-institutional study involved 335 patients from 19 Gamma Knife facilities in Japan. Major inclusion criteria were 1) newly diagnosed BMs, 2) largest tumor volume of 10.0-33.5 cm3, 3) cumulative intracranial tumor volume ≤ 50 cm3, 4) no leptomeningeal dissemination, 5) no more than 10 tumors, and 6) Karnofsky Performance Status 70% or better. Prescription doses were restricted to between 9.0 and 11.0 Gy in 3-stage GKS and between 11.8 and 14.2 Gy in 2-stage GKS. The total treatment interval had to be within 6 weeks, with at least 12 days between procedures. There were 114 cases in the 3-stage group and 221 in the 2-stage group. Because of the disproportion in patient numbers and the pre-GKS clinical factors between these two GKS groups, a case-matched study was performed using the propensity score matching method. Ultimately, 212 patients (106 from each group) were selected for the case-matched study. Overall survival, tumor progression, neurological death, and radiation-related adverse events were analyzed. RESULTS: In the case-matched cohort, post-GKS median survival time tended to be longer in the 3-stage group (15.9 months) than in the 2-stage group (11.7 months), but the difference was not statistically significant (p = 0.65). The cumulative incidences of tumor progression (21.6% vs 16.7% at 1 year, p = 0.31), neurological death (5.1% vs 6.0% at 1 year, p = 0.58), or serious radiation-related adverse events (3.0% vs 4.0% at 1 year, p = 0.49) did not differ significantly. CONCLUSIONS: This retrospective multi-institutional study showed no differences between 3-stage and 2-stage GKS in terms of overall survival, tumor progression, neurological death, and radiation-related adverse events. Both 3-stage and 2-stage GKS performed according to the aforementioned protocols are good treatment options in selected patients with large BMs.

Gamma Knife Radiosurgery for Metastatic Brain Tumors from Malignant Melanomas: A Japanese Multi-Institutional Cooperative and Retrospective Cohort Study (JLGK1501).

BACKGROUND: The incidences of metastatic brain tumors from malignant melanomas have increased and survival has been prolonged by novel molecular targeted agents and immunotherapy. However, malignant melanomas are uncommon in Asian populations. OBJECTIVES: We retrospectively analyzed treatment efficacy and identified prognostic factors impacting tumor control and survival in Japanese melanoma patients with brain metastases treated with gamma knife radiosurgery (GKRS). METHODS: We retrospectively reviewed the medical records of 177 patients with 1,500 tumors who underwent GKRS for brain metastases from malignant melanomas. This study was conducted by the Japanese Leksell Gamma Knife Society (JLGK1501). RESULTS: Six and 12 months after GKRS, the cumulative incidences of local tumor recurrence were 9.2 and 13.8%. Intratumoral hemorrhage (p < 0.0001) and larger tumor volume (p = 0.001) in GKRS were associated with significantly poorer local control outcomes. The use of immune checkpoint inhibitors before GKRS was significantly associated with symptomatic adverse events (p = 0.037). The median overall survival time after the initial GKRS was 7.3 months. Lower Karnofsky performance status scores (p = 0.016), uncontrolled primary cancer (p < 0.0001), and multiple brain metastases (p = 0.014) significantly influenced unfavorable overall survival outcomes. The cumulative incidences of neurological death 6 and 12 months after GKRS were 9.7 and 17.4%, those of neurological deterioration were 14.2 and 19.6%, and those of new tumor appearance were 34.5 and 40.5%. CONCLUSIONS: The results of the present multicenter study suggest that GKRS is a relatively effective and safe modality for control of tumor progression in Japanese patients with brain metastases from malignant melanomas.

Two cases of cystic enlargement of vestibular schwannoma as a late complication following gamma knife surgery.

Cyst formation is the most common long-term complication after gamma knife surgery (GKS) for cerebral arteriovenous malformations; however, this rarely occurs after GKS for vestibular schwannoma (VS). We describe two patients that developed aggressive, symptomatic large cysts at more than 4 and 12years after GKS for VS, although the tumor control for these patients had been acceptable at 3 and 11years, respectively. During the surgery, a reddish lesion, which was distinct from the surrounding tumor, was observed. The microscopic examination of the reddish lesion revealed dilated capillary vessels and hemorrhage, which was compatible with late radiation changes; these were usually seen in arteriovenous malformations following radiosurgery. The present patients indicated that cyst formation and enlargement may occur as a late complication following GKS even in extra-axial benign tumors such as VS.

Gamma Knife Surgery for Metastatic Brain Tumors from Gynecologic Cancer.

OBJECTIVE: The incidences of metastatic brain tumors from gynecologic cancer have increased. The results of Gamma Knife surgery (GKS) for the treatment of patients with brain metastases from gynecologic cancer (ovarian, endometrial, and uterine cervical cancers) were retrospectively analyzed to identify the efficacy and prognostic factors for local tumor control and survival. METHODS: The medical records were retrospectively reviewed of 70 patients with 306 tumors who underwent GKS for brain metastases from gynecologic cancer between January 1995 and December 2013 in our institution. RESULTS: The primary cancers were ovarian in 33 patients with 147 tumors and uterine in 37 patients with 159 tumors. Median tumor volume was 0.3 cm(3). Median marginal prescription dose was 20 Gy. The local tumor control rates were 96.4% at 6 months and 89.9% at 1 year. There was no statistically significant difference between ovarian and uterine cancers. Higher prescription dose and smaller tumor volume were significantly correlated with local tumor control. Median overall survival time was 8 months. Primary ovarian cancer, controlled extracranial metastases, and solitary brain metastasis were significantly correlated with satisfactory overall survival. Median activities of daily living (ADL) preservation survival time was 8 months. Primary ovarian cancer, controlled extracranial metastases, and higher Karnofsky Performance Status score were significantly correlated with better ADL preservation. CONCLUSIONS: GKS is effective for control of tumor progression in patients with brain metastases from gynecologic cancer, and may provide neurologic benefits and preservation of the quality of life.

Differentiation of Brain Tumor Recurrence from Post-Radiotherapy Necrosis with 11C-Methionine PET: Visual Assessment versus Quantitative Assessment.

PURPOSE: The aim of this multi-center study was to assess the diagnostic capability of visual assessment in L-methyl-11C-methionine positron emission tomography (MET-PET) for differentiating a recurrent brain tumor from radiation-induced necrosis after radiotherapy, and to compare it to the accuracy of quantitative analysis. METHODS: A total of 73 brain lesions (glioma: 31, brain metastasis: 42) in 70 patients who underwent MET-PET were included in this study. Visual analysis was performed by comparison of MET uptake in the brain lesion with MET uptake in one of four regions (around the lesion, contralateral frontal lobe, contralateral area, and contralateral cerebellar cortex). The concordance rate and logistic regression analysis were used to evaluate the diagnostic ability of visual assessment. Receiver-operating characteristic curve analysis was used to compare visual assessment with quantitative assessment based on the lesion-to-normal (L/N) ratio of MET uptake. RESULTS: Interobserver and intraobserver κ-values were highest at 0.657 and 0.714, respectively, when assessing MET uptake in the lesion compared to that in the contralateral cerebellar cortex. Logistic regression analysis showed that assessing MET uptake in the contralateral cerebellar cortex with brain metastasis was significantly related to the final result. The highest area under the receiver-operating characteristic curve (AUC) with visual assessment for brain metastasis was 0.85, showing no statistically significant difference with L/Nmax of the contralateral brain (AUC = 0.89) or with L/Nmean of the contralateral cerebellar cortex (AUC = 0.89), which were the areas that were the highest in the quantitative assessment. For evaluation of gliomas, no specific candidate was confirmed among the four areas used in visual assessment, and no significant difference was seen between visual assessment and quantitative assessment. CONCLUSION: The visual assessment showed no significant difference from quantitative assessment of MET-PET with a relevant cut-off value for the differentiation of recurrent brain tumors from radiation-induced necrosis.

Pathological characteristics of cyst formation following gamma knife surgery for arteriovenous malformation.

BACKGROUND: The pathological characteristics of cyst development after gamma knife surgery (GKS) for arteriovenous malformation (AVM) were analysed. METHOD: Sixteen male and 12 female patients aged 17-67 years (mean 31.3 years) were retrospectively identified among 868 patients who underwent GKS for AVM at our hospital. The pathological characteristics of the reddish nodular lesion and chronic encapsulated expanding haematoma associated with cyst following GKS for AVM were examined. RESULTS: Cyst was associated with chronic encapsulated expanding haematoma in 13, and with nodular lesion in 12 patients. The nidus volume at GKS was 0.1-36 ml (median 6.0 ml), and the prescription dose at the nidus margin was 18-25 Gy (median 20 Gy). Cyst formation was detected from 1.1 to 16 years (mean 7.3 years) after GKS. Seven of the 12 patients with nodular lesion underwent surgery. Ten of the 13 patients with expanding haematoma underwent surgical removal of expanding haematoma. Histological examination was possible in 17 cases. Dilated capillary vessels with wall damage such as hyalinisation and fibrinoid necrosis, marked protein exudation and haemorrhage were the most common findings. Brain parenchyma was observed among the dilated vessels in some cases. Structureless necrotic tissue was not evident. CONCLUSIONS: The present study suggests that enhanced nodular lesion on magnetic resonance imaging and chronic encapsulated expanding haematoma associated with cyst may have common aetiopathology caused by late radiation effects, mainly consisting of dilated capillary vessels with wall damage. Massive protein exudation from such damaged capillary vessels is important in cyst development.

Long-term outcomes of gamma knife surgery for posterior fossa arteriovenous malformations.

The long-term outcomes of gamma knife surgery (GKS) in patients with posterior fossa arteriovenous malformations (AVMs) were retrospectively analyzed in 82 patients followed up for more than 5 years to evaluate the efficacy and safety. The median AVM volume at GKS was 0.95 cm(3). The prescribed dose to the AVM margin was median 18 Gy with 1-18 isocenters. The actual complete AVM obliteration rate was 58.5% at 3 years and 78.0% at 5 years. The significant factors for higher complete obliteration rate were younger patient age and smaller maximum/minimum nidus diameter ratio. Two patients experienced hemorrhage caused by residual AVM rupture at 4 and 49 months. Twenty patients developed peri-nidal edema as an adverse radiation-induced reaction at median 13 months. One patient developed radiationinduced necrosis at 6.8 years. Neurological complication was observed in 12 patients and 6 patients remained with neurological dysfunction permanently. Larger nidus volume and location adjacent to an eloquent area significantly increased the risk of neurological complication. Pittsburgh radiosurgery-based AVM grading scale was significantly correlated with the outcome of neurological symptoms after GKS. GKS achieved acceptable and complete obliteration rate for posterior fossa AVM with relatively low risk of morbidity on neuroimaging and neurological symptoms for the long-term period after treatment. We recommend conformable and selective treatment planning to achieve both obliteration of the AVM nidus and preservation of neurological function.