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.

Identification of metabolic genes for the prediction of prognosis and tumor microenvironment infiltration in early-stage non-small cell lung cancer.

Early-stage non-small cell lung cancer (NSCLC) patients are at substantial risk of poor prognosis. We attempted to develop a reliable metabolic gene-set-based signature that can predict prognosis accurately for early-stage patients. Least absolute shrinkage and selection operator method Cox regression models were performed to filter the most useful prognostic genes, and a metabolic gene-set-based signature was constructed. Forty-two metabolism-related genes were finally identified, and with specific risk score formula, patients were classified into high-risk and low-risk groups. Overall survival was significantly different between the two groups in discovery (HR: 5.050, 95% CI: 3.368-7.574, P < 0.001), internal validation series (HR: 6.044, 95% CI: 3.918-9.322, P < 0.001), GSE30219 (HR: 2.059, 95% CI: 1.510-2.808, P < 0.001), and GSE68456 (HR: 2.448, 95% CI: 1.723-3.477, P < 0.001). Survival receiver operating characteristic curve at the 5 years suggested that the metabolic signature (area under the curve [AUC] = 0.805) had better prognostic accuracy than any other clinicopathological factors. Further analysis revealed the distinct differences in immune cell infiltration and tumor purity reflected by an immune and stromal score between high- and low-risk patients. In conclusion, the novel metabolic signature developed in our study shows robust prognostic accuracy in predicting prognosis for early-stage NSCLC patients and may function as a reliable marker for guiding more effective immunotherapy strategies.

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 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.

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.

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.

Prognostic value of site-specific metastases in lung cancer: A population based study.

Background: Studies on prognosis of different metastasis sites in patients with lung cancer are limited. The aim of present study was to investigate the prognostic value of metastases sites among patients with metastatic lung cancer. Methods: Between 2010 and 2014, patients diagnosed with metastatic lung cancer were selected using the Surveillance, Epidemiology, and End Results (SEER) database. Kaplan-Meier methods were adopted and multivariable Cox regression models were built to compare the prognosis of different metastasis sites. Results: A total of 54,697 eligible patients were identified, including 10,945 (20.0%) patients had isolated bone metastases, 8,294(15.2%) with isolated brain metastases, 5,677(10.4%) with isolated liver metastases, 9,430(17.2%) with isolate lung metastases, and 20,351(37.2%) with multiple organ metastases. The percentage of bone, brain, liver, lung and multisite metastases were 22.3%, 15.4%, 6.1%, 20.1% and 36.1% for non-small cell lung cancer (NSCLC), 12.5%, 14.3%, 24.3%, 7.9%, and 40.9% for small cell lung cancer (SCLC), the difference was statistical(P<0.001). In univariate and multivariable analysis, patients with liver metastases demonstrated a statistically significant disadvantage in cause-specific survival, while those with lung metastases have reduced risk of died of metastases when compared with brain metastases(P<0.001).The difference was consistent when make subgroup analysis in both NSCLC and SCLC(P<0.001). Conclusions: In patients with distant metastases, those with liver metastases have the poorest survival, whereas those with lung metastases have the best survival. Therefore, we should take into consideration of such discrepancy when making treatment strategies.

Hypofractionated stereotactic radiosurgery: a new treatment strategy for giant cavernous sinus hemangiomas.

OBJECTIVE Cavernous sinus hemangiomas (CSHs) are rare benign vascular tumors that arise from the dural venous sinuses lateral to the sella. Stereotactic radiosurgery (SRS) has emerged as a principal alternative to microresection for small- and medium-sized CSHs. Resection is a reasonable option for large (3-4 cm in diameter) and giant (> 4 cm in diameter) CSHs. However, management of giant CSHs remains a challenge for neurosurgeons because of the high rates of morbidity and even death that stem from uncontrollable and massive hemorrhage during surgery. The authors report here the results of their study on the use of hypofractionated SRS (H-SRS) to treat giant CSH. METHODS Between January 2008 and April 2014, 31 patients with a giant CSH (tumor volume > 40 cm3, > 4 cm in diameter) treated using CyberKnife radiosurgery were enrolled in a cohort study. Clinical status and targeted reduction of tumor volume were evaluated by means of serial MRI. The diagnosis for 27 patients was determined on the basis of typical imaging features. In 4 patients, the diagnosis of CSH was confirmed histopathologically. The median CSH volume was 64.4 cm3 (range 40.9-145.3 cm3). Three or 4 sessions of CyberKnife radiosurgery were used with a prescription dose based on the intent to cover the entire tumor with a higher dose while ensuring dose limitation to the visual pathways and brainstem. The median marginal dose to the tumor was 21 Gy (range 19.5-21 Gy) in 3 fractions for 11 patients and 22 Gy (range 18-22 Gy) in 4 fractions for 20 patients. RESULTS The median duration of follow-up was 30 months (range 6-78 months) for all patients. Follow-up MRI scans revealed a median tumor volume reduction of 88.1% (62.3%-99.4%) at last examination compared with the pretreatment volume. Ten patients developed new or aggravated temporary headache and 5 experienced vomiting during the treatment; these acute symptoms were relieved completely after steroid administration. Among the 30 patients with symptoms observed before treatment, 19 achieved complete symptomatic remission, and 11 had partial remission. One patient reported seizures, which were controlled after antiepileptic drug administration. No radiation-induced neurological deficits or delayed complications were reported during the follow-up period. CONCLUSIONS Hypofractionated SRS was an effective and safe modality for treating giant CSH. Considering the risks involved with microsurgery, it is possible that H-SRS might be able to serve as a definitive primary treatment option for giant CSH.

MicroRNA-494 improves functional recovery and inhibits apoptosis by modulating PTEN/AKT/mTOR pathway in rats after spinal cord injury.

Multiple cellular, molecular, and biochemical changes contribute to the etiology and treatment outcome of contusion spinal cord injury (SCI). MicroRNAs (miRNAs) aberrant expression have been found after SCI in recent studies. However, little is known about the functional significance of the unique role of miRNAs in SCI. Here, we established a rat SCI model and performed the miRNA microarray to analyze miRNAs expression at different times post-SCI. Microarray data revealed that 14 miRNAs were upregulated and 46 miRNAs were downregulated by 2 times compared with sham rat spinal cords, and miR-494 was one of the miRNAs being most significantly downregulated. Subsequently, we investigated miR-494 function and found that upregulation of miR-494 by agomir-494 improves functional recovery, reduces lesion size and inhibits apoptotic cell in rats following SCI. Moreover, our data showed that miR-494 suppresses phosphatase and tensin homolog (PTEN), a negative regulator of AKT/mTOR pathway, through directly targeting its 3'-UTR in BV-2 cells. Most importantly, we demonstrated that overexpression of miR-494 activates AKT/mTOR signaling pathway via inhibiting PTEN expression in rat SCI model. These findings suggested that miR-494 harbored the protective effect after SCI by modulating PTEN/AKT/mTOR pathway in rats and it is a potential candidate for SCI therapeutics.

[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.