A phase II open label, single arm study of hypofractionated stereotactic radiotherapy with chemoradiotherapy using intensity-modulated radiotherapy for newly diagnosed glioblastoma after surgery: the HSCK-010 trial protocol.

BACKGROUND: The most frequently diagnosed primary brain tumor is glioblastoma (GBM). Nearly all patients experience tumor recurrence and up to 90% of which is local recurrence. Thus, increasing the therapeutic ratio of radiotherapy using hypofractionated stereotactic radiotherapy (HSRT) can reduce treatment time and may increase tumor control and improve survival. To evaluate the efficacy and toxicity of the combination of HSRT and intensity-modulated radiotherapy (IMRT) with temozolomide after surgery in GBM patients and provide evidence for further randomized controlled trials. METHODS/DESIGN: HSCK-010 is an open-label, single-arm phase II trial (NCT04547621) which includes newly diagnosed GBM patients who underwent gross total resection. Patients will receive the combination of 30 Gy/5fx HSRT, and 20 Gy/10fx IMRT adjuvant therapy with concurrent temozolomide and adjuvant chemotherapy. The primary endpoint is overall survival (OS). Secondary outcomes include progression-free survival (PFS) rate, objective-response rate (ORR), quality of life (Qol) before and after the treatment, cognitive function before and after the treatment, and rate of treatment-related adverse events (AE). The combination of HSRT and IMRT with temozolomide can benefit the patients after surgery with good survival, acceptable toxicity, and reduced treatment time. TRIAL REGISTRATION: NCT04547621 . Registered on 14 September 2020.

Safety and efficacy of Hypofractionated stereotactic radiosurgery for high-grade Gliomas at first recurrence: a single-center experience.

BACKGROUND: The optimal treatment for recurrent high-grade gliomas (rHGGs) remains uncertain. This study aimed to investigate the efficacy and safety of hypofractionated stereotactic radiosurgery (HSRS) as a first-line salvage treatment for in-field recurrence of high-grade gliomas. METHODS: Between January 2016 and October 2019, 70 patients with rHGG who underwent HSRS were retrospectively analysed. The primary endpoint was overall survival (OS), and secondary endpoints included both progression-free survival (PFS) and adverse events, which were assessed according to Common Toxicity Criteria Adverse Events (CTCAE) version 5. The prognostic value of key clinical features (age, performance status, planning target volume, dose, use of bevacizumab) was evaluated. RESULTS: A total of 70 patients were included in the study. Forty patients were male and 30 were female. Forty-nine had an initial diagnosis of glioblastoma (GBM), and the rest (21) were confirmed to be WHO grade 3 gliomas. The median planning target volume (PTV) was 16.68 cm3 (0.81-121.96 cm3). The median prescribed dose was 24 Gy (12-30 Gy) in 4 fractions (2-6 fractions). The median baseline of Karnofsky Performance Status (KPS) was 70 (40-90). With a median follow-up of 12.1 months, the median overall survival after salvage treatment was 17.6 months (19.5 and 14.6 months for grade 3 and 4 gliomas, respectively; p = .039). No grade 3 or higher toxicities was recorded. Multivariate analysis showed that concurrent bevacizumab with radiosurgery and KPS > 70 were favourable prognostic factors for grade 4 patients with HGG. CONCLUSIONS: Salvage HSRS showed a favourable outcome and acceptable toxicity for rHGG. A prospective phase II study (NCT04197492) is ongoing to further investigate the value of hypofractionated stereotactic radiosurgery (HSRS) in rHGG.

Cyberknife radiosurgery on the brainstem metastases of non-small cell lung cancer.

OBJECTIVE: Management of brainstem metastatic tumor is challenging. This study aimed to evaluate overall survival and quality-of-life in patients with non-small cell lung cancer (NSCLC) brainstem metastases who were treated with the Cyberknife stereotactic radiosurgery. METHODS: From August 2007 through August 2016, a total of 32 patients with 34 brainstem metastases of NSCLC were consecutively enrolled and treated with the Cyberknife radiosurgery (CKRS) at The Huashan Hospital. The study was limited to patients with NSCLC, which was confirmed by postoperative pathological examination. Patients were treated by CKRS as an initial treatment or a second treatment after whole-brain radiation therapy (WBRT). Quality of life was assessed by the SF-12 score and neurological examination. RESULTS: Four out of the 32 (12.5%) patients received WBRT before or concurrent with CKRS treatment. The mean survival time after CKRS was 10.0 (95%CI: 6.0-14.0) months. Karnofsky performance score was not the independent predictor of survival after radiosurgery as analyzed by log-rank test (p = 0.392). Age, however, was a significant predictor of improved survival as analyzed by multivariate analysis (p = 0.024). SF-12 physical component scores demonstrated no significant change after treatment. CONCLUSIONS: The CKSR is a non-invasive, safe, and effective modality in the treatment of patients with brainstem metastases of NSCLC. Better therapeutic outcomes of CKSR for brainstem metastasis might be achieved in the patients older than 65 years old.

[Multisession cyberknife radiosurgery for cavernous sinus hemangiomas: medium- and long-term outcomes].

OBJECTIVE: To investigate the medium- and long-term outcomes of multisession cyberknife radiosurgery intreating cavernous sinus hemangiomas (CSH). METHODS: Between January 2008 and February 2012, 45 patients with CSH, including 35 female and 10 male patients with a mean age of 53 years (range: 26-80 years), underwent multisession cyberknife radiosurgery. The mean diameter of the CSH was 47.0 mm (range: 23.0-75.0 mm). The tumor volume ranged from 2.9 to 140.1 cm³, with a mean of 40.1 cm³. Eleven giant CSH with tumor volume ≥ 40.0 cm³ were irradiated by cyberknife in 4 fractions, 28 large tumors with tumor volume 10.0-40.0 cm³ in 3 fractions, 4 tumors with tumor volume 5.0-10.0 cm³ in 2 fractions, 2 small tumors with tumor volume ≤ 5.0 cm³ in 1 fraction. After the treatment, all patients had regular clinical and radiological follow-up at 6-month intervals. A combination of the neurologic examination and MRI information was used to evaluate the overall response. RESULTS: All patients were followed up for 22-70 months with a mean of 37.7 months. One patient died of stroke 3 years post cyberknife, but the follow-up MRI showed that the CSH shrank in volume. Eight patients with giant CSH had slight headache after finishing cyberknife radiosurgery, and relieved with mannitol and dexamethasone treatment. Neurological deficits in patients had improved or disappeared at 6 to 12 months post cyberknife. None of these patients showed any deterioration in symptoms or new cranial nerve deficits during the follow-up. Latest follow-up imaging demonstrated that tumors decrease > 80% in 15 patients, > 60% to 80% in 18 patients (including the death patient), 40%-60% in 12 patients post cyberknife. Two patients reported occurrence of seizures and maintaining seizure control after antiepileptic drugs administration. CONCLUSIONS: Multisession cyberknife radiosurgery is confirmed to provide medium and long-term local tumor control and symptom improvement. It is a safe and effective treatment modality for CSH, and may serve as a promising treatment option in the future.

A new strategy of CyberKnife treatment system based radiosurgery followed by early use of adjuvant bevacizumab treatment for brain metastasis with extensive cerebral edema.

Bevacizumab blocks the effects of vascular endothelial growth factor in leakage-prone capillaries and has been suggested as a new treatment for cerebral radiation edema and necrosis. CyberKnife is a new, frameless stereotactic radiosurgery system. This work investigated the safety and efficacy of CyberKnife followed by early bevacizumab treatment for brain metastasis with extensive cerebral edema. The eligibility criteria of the patients selected for radiosurgery followed by early use of adjuvant bevacizumab treatment were: (1) brain tumors from metastasis with one solitary brain lesion and symptomatic extensive cerebral edema; (2) >18 years of age; (3) the patient refused surgery due to the physical conditions and the risk of surgery; (4) no contraindications for bevacizumab. (5) bevacizumab was applied for a minimum of 2 injections and a maximum of 6 injections with a 2-week interval between treatments, beginning within 2 weeks of the CyberKnife therapy; (6) Karnofsky performance status (KPS) ≥30. Tumor size and edema were monitored by magnetic resonance imaging (MRI). Dexamethasone dosage, KPS, adverse event occurrence and associated clinical outcomes were also recorded. Eight patients were accrued for this new treatment. Radiation dose ranged from 20 to 33 Gy in one to five sessions, prescribed to the 61-71 % isodose line. Bevacizumab therapy was administered 3-10 days after completion of CyberKnife treatment for a minimum of two cycles (5 mg/kg, at 2-week intervals). MRI revealed average reductions of 55.8 % (post-gadolinium) and 63.4 % (T2/FLAIR). Seven patients showed significant clinical neurological improvements. Dexamethasone was reduced in all patients, with five successfully discontinuing dexamethasone treatment 4 weeks after bevacizumab initiation. Hypertension, a bevacizumab-related adverse event, occurred in one patient. After 3-8 months, all patients studied were alive and primary brain metastases were under control, 2 developed new brain metastases and underwent salvage CyberKnife treatment. Recurrent edema and emerging radiation necrosis were not observed. CyberKnife radiosurgery followed by early use of bevacizumab is promising and appears safe for treatment of brain metastases with extensive cerebral edema.

[Cyberknife radiosurgery for cerebral arteriovenous malformations: outlining of the radiosurgical target and obliteration].

OBJECTIVE: To explore the therapeutic outcomes of cyberknife for patients with arteriovenous malformations (AVM) and outline the content of AVM targets. METHODS: Between January 2008 and October 2011, 51 patients underwent cyberknife radiosurgery for cerebral AVMs. The mean age was 27 (8-47) years. The procedures included prior embolization (n = 24), gamma knife before cyberknife (n = 2) and cyberknife initially (n = 25). The delineation of AVM targets was as follows: AVM with prior embolization, radiosurgical targets included AVM nidus, embolization areas and some small draining veins. However, low radiation dose was delivered to embolization parts and draining veins. For 25 patients without embolization, the radiosurgical target was AVM nidus. The mean target volume was 7.8 (1.2-22.0) cm³ and 15 of them were larger than 10.0 cm³. In patients harboring AVM with target volumes < 4 cm³, cyberknife radiation was delivered in a single session. And the remainder had 2 (n = 25) or 3 (n = 19) sessions. The mean marginal dose was 23(18-28) Gy. RESULTS: AVM obliteration was confirmed by magnetic resonance imaging (MRI) or angiography in 40 (78%) patients during a mean follow-up of 46 (36-70) months. Marked size reduction of AVM was obtained in 11 incompletely obliterated patients. Among them, there were second cyberknife treatment (n = 3), third embolization for complex AVM (n = 1), gamma knife (n = 1) and further follow-ups (n = 6). The higher obliteration rate of AVM was correlated with small volume of AVM in noncritical areas, prior embolization and radiation target of embolization areas. Three patients had hemorrhage during the follow-up period and recovered. Brain edema was found in patients with basal ganglion or parietal AVMs. A permanent neurological deficit (paralysis) due to adverse radiation effects developed in 1 patient. CONCLUSION: Cyberknife radiosurgery is particularly effective for patients with smaller AVMs in noncritical areas of brain. In patients with prior embolization, delineation of AVM targets including embolization areas is essential for a higher rate of obliteration.

Dosimetric quality of HyperArc in boost radiotherapy for single glioblastoma: comparison with CyberKnife and manual VMAT.

BACKGROUND: Stereotactic radiotherapy (SRT) and hypo-fractionated radiotherapy are feasible treatment options for single glioblastoma multiforme when combined with conventional radiotherapy or delivered alone. HyperArc (HA), a novel linac-based method with 4 noncoplanar arcs, has been introduced into stereotactic radiosurgery (SRS) for single and multiple metastases. In this study, we compared the dosimetric quality of HyperArc with the well-established CyberKnife (CK) and conventional VMAT methods of SRT for a single, large target. METHODS: Sixteen patients treated in our center with their clinical CK plans were enrolled, and the linac-based plans were designed in silico. From the aspect of normal tissue protection and treatment efficacy, we compared the conformity index (CI), gradient index (GI), homogeneity index (HI), dose distribution in planning target volume, dose in the normal brain tissue, and mean dose of several organs at risk (OARs). All of the data were evaluated with nonparametric Kruskal‒Wallis tests. We further investigated the relationship of the dose distribution with the tumor volume and its location. RESULTS: The results showed that with a higher CI (0.94 ± 0.03) and lower GI (2.57 ± 0.53), the HA plans generated a lower dose to the OARs and the normal tissue. Meanwhile, the CK plans achieved a higher HI (0.35 ± 0.10) and generated a higher dose inside the tumor. Although manual VMAT showed slight improvement in dose quality and less monitoring units (2083 ± 225), HA can save half of the delivery time of CK (37 minutes) on average. CONCLUSION: HA plans have higher conformity and spare OARs with lower normal tissue irradiation, while CK plans achieve a higher mean dose in tumors. HA with 4 arcs is sufficient in dosimetric quality for a single tumor with great convenience in planning and treatment processes compared with conventional VMAT. The tumor size and location are factors to be considered when selecting treatment equipment.

Long-term clinical outcomes of hypofractionated stereotactic radiotherapy using the CyberKnife robotic radiosurgery system for jugular foramen schwannomas.

OBJECTIVE: Jugular foramen schwannomas (JFSs) are rarely seen, benign tumors with slow growth. Today, management options for JFSs include observation, surgery, and radiation. However, the optimal treatment strategy remains controversial. Stereotactic radiosurgery serves as a minimally invasive alternative or adjuvant therapeutic regimen of microsurgery. Gamma Knife radiosurgery is suitable for patients with JFS who have small- and medium-sized tumors and normal cranial nerve (CN) function. Hypofractionated stereotactic radiotherapy (HSRT) offers a potential radiobiological advantage and may result in better preservation of normal structures compared to single-fraction stereotactic radiosurgery. The aim of the article was to review the clinical and radiographic outcomes of patients with JFS who were treated using HSRT. METHODS: The authors retrospectively analyzed 74 patients with JFS who received HSRT between January 2009 and January 2020 in the authors' center. Among them, 53 patients were newly diagnosed with JFS, 19 patients had a previous history of microsurgical resection, and the other 2 patients underwent CyberKnife because of tumor recurrence after Gamma Knife radiosurgery. A total of 73 patients had preexisting CN symptoms and signs. The median tumor volume was 14.8 cm3 (range 0.5-41.2 cm3), and most of them (70.3%) were ≥ 10 cm3. The radiation dose regimen was prescribed depending on the tumor size, and more fractions were used in larger tumors. The median margin doses prescribed were 18.2 Gy/2 fractions, 21.0 Gy/3 fractions, and 21.6 Gy/4 fractions. RESULTS: The median follow-up was 103 months (range 18-158 months). After treatment, 42 (56.8%) patients had tumor regression, 27 (36.5%) patients had stable tumors, and 5 (6.8%) experienced tumor progression. Among them, MRI revealed that 1 patient had a complete response. Three patients received surgery at a median of 25 months because of tumor progression. One patient underwent ventriculoperitoneal shunt insertion for hydrocephalus that developed after HSRT independent of tumor progression. The 5-year progression-free survival rate was 93.2%. Preexisting cranial neuropathies improved in 46 patients, remained stable in 14, and worsened in 14. CONCLUSIONS: HSRT proved to be a safe and effective primary or adjuvant treatment strategy for JFSs, although 14 patients (18.9%) experienced some degree of delayed symptomatic deterioration posttreatment. This therapeutic option was demonstrated to provide both excellent tumor control and improvement in CN function.

The role of stereotactic radiosurgery in cavernous sinus hemangiomas: a systematic review and meta-analysis.

Cavernous sinus hemangioma is a rare and complex vascular tumor. A direct microsurgical approach usually results in massive hemorrhage. Stereotactic radiosurgery has emerged as a treatment alternative to microsurgery. To conduct a meta-analysis assessing the effect and complications of stereotactic radiosurgery in cavernous sinus hemangioma, a systematic review and meta-analysis of all cases of cavernous hemangioma in the cavernous sinus treated with stereotactic radiosurgery was performed. The search revealed ten papers with a total enrollment of 59 patients. Tumor size ranged from 1.5-51.4 cm(3) (mean 9.6 cm(3)). The mean follow-up period was 49.2 months (range 6-156 months). The most recent MR images demonstrated remarkable tumor shrinkage in 40 patients (67.8%), partial shrinkage in 15 patients (25.4%), and no change in four patients (6.8%). There was no significant correlation between lesion volume and tumor shrinkage. Patients with remarkable tumor shrinkage received higher doses than those with partial or no change tumor shrinkage (P = 0.031). Thirteen patients (22.0%) had no cranial nerve impairments before stereotactic radiosurgery. Among those 46 patients with cranial nerve impairments before stereotactic radiosurgery, complete resolution was achieved in seven patients and improvement in 28, and these impairments remained essentially unchanged in 11 patients. Only one patient had additional trigeminal nerve disturbance. There is no statistical significance in tumor control between patients treated with or without surgery (P = 0.091). The meta-analysis suggests stereotactic radiosurgery avoids the complications associated with attempted microsurgical resection. Stereotactic radiosurgery is an alternative for cavernous sinus hemangiomas confirmed by typical imaging.

[Expert Consensus on the Treatment of Antiangiogenic Agents for Radiation Brain Necrosis].

Vascular damage is followed by vascular endothelial growth factor (VEGF) expression at high levels, which is an important mechanism for cerebral radiation necrosis (CRN) development. Antiangiogenic agents (Bevacizumab) alleviates brain edema symptoms caused by CRN through inhibiting VEGF and acting on vascular tissue around the brain necrosis area. Many studies have confirmed that Bevacizumab effectively relieves symptoms caused by brain necrosis, improves patients' performance status and brain necrosis imaging. Considering that the efficacy of antiangiogenic therapy is mainly related to the duration of drug action, low-dose antiangiogenic agents can achieve favorable efficacy. Prevention is the best treatment. The occurrence of CRN is associated with tumor-related factors and treatment-related factors. By controlling these factors, CRN can be effectively prevented.
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Safety and Efficacy of Hypofractionated Stereotactic Radiotherapy with Anlotinib Targeted Therapy for Glioblastoma at the First Recurrence: A Preliminary Report.

(1) Background: Hypofractionated stereotactic radiotherapy (HSRT) and anti-vascular endothelial growth factor (VEGF) antibodies have been reported to have a promising survival benefit in recent studies. Anlotinib is a new oral VEGF receptor inhibitor. This report describes our experience using HSRT and anlotinib for recurrent glioblastoma (rGBM). (2) Methods: Between December 2019 and June 2020, rGBM patients were retrospectively analysed. Anlotinib was prescribed at 12 mg daily during HSRT. Adjuvant anlotinib was administered d1-14 every 3 weeks. The primary endpoint was the objective response rate (ORR). Secondary endpoints included overall survival (OS), progression-free survival (PFS) after salvage treatment, and toxicity. (3) Results: Five patients were enrolled. The prescribed dose was 25.0 Gy in 5 fractions. The median number of cycles of anlotinib was 21 (14-33). The ORR was 100%. Three (60%) patients had the best outcome of a partial response (PR), and 2 (40%) achieved a complete response (CR). One patient died of tumour progression at the last follow-up. Two patients had grade 2 hand-foot syndrome. (4) Conclusions: Salvage HSRT combined with anlotinib showed a favourable outcome and acceptable toxicity for rGBM. A prospective phase II study (NCT04197492) is ongoing to further investigate the regimen.

Dose-staged Gamma Knife radiosurgery for meningiomas: A retrospective study in a single center.

Objective: This study aimed to study the efficiency and safety of a dose-staged Gamma Knife radiosurgery strategy for large meningiomas or meningiomas close to important nerve structures. Methods: This study evaluates the outcome of a prospectively accrued series of 71 consecutive patients with meningiomas treated with staged dose-fractionated Gamma Knife radiosurgery. The average peripheral doses for the first and second fractions were 9.0 ± 0.9 Gy (8-12 Gy) and 8.6 ± 0.7 Gy (range, 7-10 Gy), respectively. The interval between fractions was 6.1 ± 1.9 months (range, 3-12 months). The median follow-up time was 36 months (12-96 months). Results: During the follow-up period after the second fraction, 97.2% achieved tumor control in our series. A total of 2 patients exhibited local recurrence at 30 and 60 months after the second fraction, respectively. No treatment-related complications or new long-term neurological dysfunctions were reported. MRIs observed slightly or moderately increased peritumoral edema in six patients, but no specific neurological complaints are attributed to this finding. Conclusion: This study investigates the efficiency and safety of dose-staged Gamma Knife radiosurgery as an alternative option for meningiomas that were large in volume, adjacent to crucial structures, or in patients with contraindications to craniotomy.

Suppressing Grating Lobes for Transcranial Focused Ultrasound System by Frequency-Modulated Excitation.

Transcranial focused ultrasound is a novel noninvasive therapeutic modality for glioblastoma and other disorders of the brain. However, because the phase aberrations caused by the skull need to be corrected with computed tomography (CT) images, the transcranial transducer is tightly fixed on the patient's head to avoid any variation in the relative position, and the focus shifting relies mainly on the capacity for electronic beam steering. Due to the presence of grating lobes and the rapid degradation of the focus quality with increasing focus-shifting distance, transcranial focus-shifting sonication may damage healthy brain tissue unintentionally. To reduce the risks associated with transcranial focused ultrasound therapy, linear frequency-modulated (FM) excitation is proposed. The k-space corrected pseudospectral time domain (PSTD) and acoustic holography approach based on the Rayleigh integral are combined to calculate the distribution of the deposited acoustic power. The corresponding simulation was performed with axial/lateral focus shifting at different distances. The distributions of the deposited acoustic power show that linear FM excitation can effectively suppress undesired prefocal grating lobes without compromising focus quality.

Design of a Versatile Angle-Rotatable Skull-Shaped Conformal Transcranial Focused Ultrasound Transducer for Noninvasive Brain Therapy.

Phase-controlled focused ultrasound transducers have opened up a new way to noninvasively treat brain diseases. However, due to the geometry and the heterogeneous medium of the human skull, the currently used hemispherical transducers cannot guarantee that the ultrasound emitted by the transducer penetrates the skull normally; consequently, the impact of the shear wave on the treatment area has to be considered. The usual approach is to turn off elements in the transducer with excessively large incident angles, but this approach reduces the efficiency of the transducer. This article presents the design of a novel transducer that can be rotated according to the different geometric shapes of the skull. The incident angles of the elements in the transducer are modified so that the effect of the shear wave on the treatment area can be ignored and the efficiency of the transducer is improved. The results of computed tomography (CT) model simulation of nine skulls verify the versatility and feasibility of the new transducer. We believe that this kind of rotatable transducer has clinical and engineering significance.

[Radiosurgery for cavernous sinus hemangiomas: medium- and long-term results].

OBJECTIVE: To describe the personal experiences of treating cavernous sinus hemangiomas (CSH) with gamma knife or cyberknife and evaluate the medium and long-term outcomes. METHODS: From June 1999 to December 2008, 20 CSH patients were treated by radiosurgery (gamma knife or cyberknife). Among them, 11 had residual tumor after surgery and 9 were diagnosed by neuroradiology. All cases on magnetic resonance imaging (MRI) showed well-defined and homogeneous hyperintensity on T2-weighted images. The mean maximum diameter of tumors was 38.7 ± 9.3 mm (range: 23.0 - 60.6). The volume of tumors ranged between 4.1 - 52.6 cm(3) with a mean of (18.7 ± 12.5) cm(3). The tumor margin dose irradiated by gamma knife ranged from 9 to 16 Gy (mean 12.3 ± 2.3 Gy). The tumor margin dose irradiated by cyberknife was 20 - 21 Gy in 3 fractions. The mean follow-up period was (60 ± 32) months (range: 12 - 120). RESULTS: Follow-up imaging showed tumor volume decreased over 90% (n = 5), tumor regressed over 50% in volume (n = 9) and no change in tumor volume (n = 1). One patient with large tumor (irradiated 10 Gy) was operated by open surgery at 5 months after gamma knife. Four giant tumors decreased over 50% in volume after cyberknife. Neurologically, none of these patients showed any deterioration. And 16 patients demonstrated an obvious improvement after radiosurgery. At the last follow-up, there were no complications related to radiosurgery. CONCLUSION: Radiosurgery (Gamma knife or cyberknife) is a safe and effective modality for small- and medium-sized CSH. Fractionated Cyberknife proves to be an effective treatment for large or giant CSH. Thus radiosurgery will be an alternative option to surgery.

Stereotactic radiosurgery combined with anlotinib for limited brain metastases with perilesional edema in non-small cell lung cancer: Rvision-001 study protocol.

INTRODUCTION: About 50% of patients with non-small cell lung cancers (NSCLC) are diagnosed with brain metastases during treatment, and stereotactic radiosurgery (SRS) is an important treatment for brain oligometastasis. Some patients with brain metastases have cerebral edema before treatment, and radiation therapy may also cause, or aggravate brain edema. Vascular endothelial growth factor (VEGF) promotes angiogenesis and increase vascular permeability, and previous studies have shown that anti-VEGF treatment can reduce brain edema. We hypothesized that anlotinib hydrochloride can reduce perilesional edema around brain metastases, create conditions for subsequent SRS, increase local control rate and improve patient prognosis. METHODS: From one week before stereotactic radiosurgery, patients begin to receive anlotinib once a day (12 mg) from day 1-14 of a 21 day cycle, with two cycles in total. Brain magnetic resonance imaging (MRI) scan is taken before treatment, one week and one month after medication. A total of 50 patients will be included in this study. The primary endpoint is the Edema Index, and the secondary endpoints are intracranial objective response rate (iORR), intracranial progression-free survival (iPFS), objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), safety, and the rate of SRS after anlotinib treatment. DISCUSSION: This study is a multicenter, prospective, single-arm, phase II clinical study, and explores the efficacy and tolerability of SRS with anlotinib in NSCLC patients with limited brain metastases. The aim of the study is to provide new treatment options for NSCLC patients with brain metastases.

An efficient and accurate parallel hybrid acoustic signal correction method for transcranial ultrasound.

Phased-control focused ultrasound transducers provide a new and noninvasive treatment method for brain disease. However, improving the accuracy of phase correction and reducing the calculation time during treatment have always been contradictory constraints. In this paper, a hybrid acoustic signal correction (HASC) method combined with k-Wave stage and holography stage was introduced for phase correction and simulation of transcranial focused ultrasound. The k-Wave stage is mainly used to calculate the sound field in a heterogeneous medium (skull), which divides the sound field calculation process into paths that can be calculated in parallel, and the transcranial correction phase can also be obtained during the calculation. The holography stage is sufficient to simulate the acoustic field in the homogenous intracranial medium after ultrasound transmitting through the skull. The agreement of the k-space corrected pseudospectral time domain method and HASC method was assessed by statistical methods: linear regression between the two methods provided a slope of 0.9735, intercept of 0.0078, and R 2 of 0.9982. The Bland-Altman method provided a bias of 0.0015 and 95% limits of agreement 0.065 apart. We demonstrated that the difference in sound intensity at the focal point corrected by HASC and time reversal phase correction method was 0.2% and 0.5% in the results of simulation and experiment, respectively. Not only that, the phase calculation time by the HASC phase correction method can be reduced to 11 min on a multi GPU array, which has clinical potential for ultrasound treatment of brain therapy.

Tyrosine Kinase Inhibitor Resistance Increased the Risk of Cerebral Radiation Necrosis After Stereotactic Radiosurgery in Brain Metastases of Non-small-Cell Lung Cancer: A Multi-Institutional Retrospective Case-Control Study.

Objective: This study aimed to investigate the relationship between the timing of stereotactic radiosurgery (SRS) intervention and the complications of cerebral radiation necrosis (CRN) in patients with brain metastases of lung adenocarcinoma who received tyrosine kinase inhibitor (TKI) treatment. Methods: A total of 361 targets from 257 patients with brain oligometastases of lung adenocarcinoma who received CyberKnife treatment between 2010 and 2017 were retrospectively collected from three CyberKnife centers. The difference in brain necrosis between patients with or without TKI application was statistically counted. Logistic regression analysis was used to analyze the effect of applying TKI on the occurrence of CRN in patients and the effect of SRS before and after TKI resistance on CRN. Results: The rate of CRN in the TKI group was significantly higher than that in the non-TKI group. The incidence of brain necrosis in patients undergoing SRS after drug resistance was significantly higher than that in patients undergoing SRS before drug resistance. Regression analysis showed that combination of TKI with SRS, and SRS after TKI resistance were important influencing factors for CRN. Conclusion: Performing the SRS for brain metastases after TKI resistance worsened the occurrence of CRN of patients treated with TKI. Clinical Trial Registration: Chinese clinical trial registry, http://www.chictr.org.cn/edit.aspx?pid=38395&htm=4, Registration number: ChiCTR1900022750.

Hypofractionated Radiosurgery Plus Bevacizumab for Locally Recurrent Brain Metastasis with Previously High-Dose Irradiation.

BACKGROUND: Selection of appropriate treatment for patients with recurrent brain metastasis (BM) remains uncertain. Recent studies have demonstrated a significant response rate and acceptable toxicity using fractionated stereotactic radiosurgery (FSRS) in patients with locally recurrent large BM. The aim of this study was to evaluate efficacy and toxicity of FSRS with bevacizumab as a new salvage treatment for locally recurrent BM with previous high-dose irradiation. METHODS: Patients with recurrent BM previously irradiated were enrolled. Salvage FSRS dose was 9.5-29 Gy (2-5 fractions) with 62%-75% isodose line by CyberKnife according to the brain tumor volume, site, and previous dose. Bevacizumab was prescribed for 4 cycles (5 mg/kg, every 3 weeks). The primary objective was to identify the overall survival after salvage treatment. Secondary objectives included clinical response (Karnofsky performance scale), imaging response (magnetic resonance imaging) and treatment-related adverse events. RESULTS: From December 2009 to October 2016, 24 patients were enrolled. The 1-year overall survival after salvage stereotactic radiosurgery was 87.5%. Twenty-three (96%) patients had a positive imaging response with a T2 volume reduction range of 6-22 cm3 (median 14 cm3, P = 0.032, paired t test). Significant clinical improvement was achieved (best Karnofsky performance scale score, P < 0.05, paired t test). Grade 1/2 fatigue was observed in 8 (33%) patients. Grade 3 fatigue and headache occurred in 1 patient. CONCLUSIONS: FSRS with adjuvant bevacizumab treatment showed favorable clinical and radiologic control as a salvage treatment regimen. The diagnoses of radiation necrosis and local recurrence after salvage FSRS warrant further study.

[Gamma knife for elderly patients with large vestibular schwannomas: 11-year follow-up].

OBJECTIVE: To evaluate the effect of Leksell Gamma Knife (LGK) on elderly patients with large vestibular schwannomas (VS) and to summarize the indications for LGK in patients with large VS. METHODS: From July 1994 to July 2000, 50 elderly patients (age range: 60.0 - 81.0 years) with large VS were treated by LGK as primary treatment modality. The maximal tumor diameter ranged from 31.0 to 61.0 mm [mean, (36.0 +/- 6.1) mm] and mean tumor volume was (14.8 +/- 8.0) cm(3) (range, 7.5 - 54.0 cm(3)). The maximal dose irradiated to tumor ranged from 22.0 to 28.0 Gy [mean: (25.0 +/- 1.6) Gy] and the mean tumor marginal dose was (12.3 +/- 0.9) Gy (range, 9.5 - 14.0 Gy). The mean follow-up duration was (86 +/- 12) months (range: 68 - 138 months). RESULTS: Of the 50 patients with follow-up data, 4 were deceased and 46 survived. Two patients with giant VS died at 6 and 9 months post-LGK respectively because of tumor swelling. Another two patients died of stroke or heart attack at 3 years and 4 years after LGK respectively, but their tumors decreased in volume. Clinical response: hearing: 14 (28%) patients preserved useful hearing as pre-LGK; 32 patients had unchanged or deteriorated hearing. Facial palsy: two patients developed mild facial palsy at 4 and 8 months respectively, one of them recovered and another improved later. Seven patients developed hydrocephalus around 6 months post-LGK and had V-P shunt. Eighteen patients had deteriorated facial numbness because of tumor swelling, 15 of them improved 3 years later. Tumor response: in 46 surviving patients, 43 tumors decreased markedly in size, 2 tumors remained stable in volume, 1 tumor progressed at five years and had second LGK. In this series tumor control rate was 94% (47/50). CONCLUSION: LGK provides an effective treatment for some selected large VS (maximal diameter