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Desheng Xu, Qiang Jia, Yanhe Li, Chunsheng Kang and Peiyu Pu

Object

The authors sought to study the combined potential of wild-type p53 gene transfer and Gamma Knife surgery (GKS) for the treatment of glioblastomas multiforme. Modification of the radiation response in C6 glioma cells in vitro and in vivo by the wild-type p53 gene was investigated.

Methods

Stable expression of wild-type p53 in C6 cells was achieved by transduction of the cells with adenoviral p53. Two days later, some cells were treated with GKS. Forty-eight hours after irradiation, the comparative survival rate was assessed by monotetrazolium (MTT) assays. Treated and control C6 glioma cells (4 × 103 per well) were plated into a 96-well plate in octuplicate and tested every 24 hours. Meanwhile, immunohistopathological examination of proliferating cell nuclear antigen (PCNA) and terminal deoxynucleotidyl transferase—mediated deoxyuridine triphosphate (TUNEL) assays were performed. The MTT assays indicated the p53, GKS, and combined treated cells proliferated at a significantly lower rate than those of the control group (p < 0.01, Days 2–6) and the positive fraction of PCNA in p53-treated group and GKS-treated group was 70.18 ± 3.61 and 50.71 ± 2.61, respectively, whereas the percentage in the combined group was 30.68 ± 1.49 (p < 0.01).

Fifty-six male Sprague–Dawley rats were anesthetized and inoculated with 106 cultured C6 glioma cells into the cerebrum. Forty-eight hours after transduction with adenoviral p53, some rats underwent GKS. A margin dose of 15 Gy was delivered to the 50% isodose line. Two days later, six rats in each group were killed. Their brains were removed and paraffin-embedded section were prepared for immunohistopathological examination and TUNEL assays. The remaining rats were observed for the duration of the survival period. The survival curve indicated that a modest but significant enhancement of survival duration was seen in the p53-treated or GKS alone groups, whereas a more marked and highly significant enhancement of survival duration was achieved when these two treatment modalities were combined. When PCNA expression was downregulated, apoptotic cells become obvious after TUNEL staining.

Conclusions

The findings of this study suggest that p53-based gene therapy in combination with GKS may be superior to single-modality treatment of C6 glioma.

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Dong Liu, Yanhe Li, Yipei Zhang, Zhiyuan Zhang, Guoxiang Song and Desheng Xu

OBJECTIVE

This article is a preliminary evaluation of the efficacy of volume-staged Gamma Knife radiosurgery (GKRS) in the treatment of patients with orbital venous malformations (OVMs).

METHODS

Twenty patients with moderate to large OVMs were treated with volume-staged GKRS between March 2005 and October 2015. The series included 8 male and 12 female patients with an average age of 22.5 years (range 9–45 years). The diagnoses were confirmed intraoperatively and at pathological examination in 14 cases and presumed in accordance with clinical and imaging findings in 6 cases. The median OVM volume was 12.2 cm3 (range 7.1–34.6 cm3). The median interval between stages was 10 months (range 6–12 months). The tumor margin dose for each stage ranged from 11.0 to 13.5 Gy. The median duration of follow-up was 45.5 months (range 18–98 months).

RESULTS

Periodically scheduled MRI studies demonstrated evidence of a significant reduction of the original OVM volume in all cases. Visual acuity (VA) was preserved in 18 cases (90%). Five patients (25%) experienced vision improvement of varying degrees, and 13 (65%) experienced long-term preservation of VA at their pre-GKRS level. Deterioration in VA was observed in only 2 cases (10%). MRI demonstrated OVM regression after treatment in all cases, and all patients were found to have reduction of exophthalmos after volume-staged GKRS. Follow-up MRI revealed recurrence in only 1 case (5%). Three patients (15%) developed transient conjunctival edema.

CONCLUSIONS

This retrospective investigation indicates that volume-staged GKRS provides an effective management option in selected patients with OVMs, providing excellent visual outcomes. The study adds substantial support for volume-staged GKRS as a major treatment for OVMs.

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Youlin Ge, Dong Liu, Zhiyuan Zhang, Yanhe Li, Yiguang Lin, Guokai Wang, Yongqing Zong and Enhu Liu

OBJECTIVE

The authors retrospectively analyzed the follow-up data in 130 patients with intracranial benign meningiomas after Gamma Knife radiosurgery (GKRS), evaluated the tumor progression-free survival (PFS) rate and neurological function preservation rate, and determined the predictors by univariate and multivariate survival analysis.

METHODS

This cohort of 130 patients with intracranial benign meningiomas underwent GKRS between May 2012 and May 2015 at the Second Hospital of Tianjin Medical University. The median age was 54.5 years (range 25–81 years), and women outnumbered men at a ratio of 4.65:1. All clinical and radiological data were obtained for analysis. No patient had undergone prior traditional radiotherapy or chemotherapy. The median tumor volume was 3.68 cm3 (range 0.23–45.78 cm3). A median margin dose of 12.0 Gy (range 10.0–16.0 Gy) was delivered to the tumor with a median isodose line of 50% (range 50%–60%).

RESULTS

During a median follow-up of 36.5 months (range 12–80 months), tumor volume regressed in 37 patients (28.5%), was unchanged in 86 patients (66.2%), and increased in 7 patients (5.4%). The actuarial tumor progression-free survival (PFS) rate was 98%, 94%, and 87% at 1, 3, and 5 years, respectively, after GKRS. Tumor recurred in 7 patients at a median follow-up of 32 months (range 12–56 months). Tumor volume ≥ 10 cm3 (p = 0.012, hazard ratio [HR] 8.25, 95% CI 1.60–42.65) and pre-GKRS Karnofsky Performance Scale score < 90 (p = 0.006, HR 9.31, 95% CI 1.88–46.22) were independent unfavorable predictors of PFS rate after GKRS. Of the 130 patients, 101 (77.7%) presented with one or more neurological symptoms or signs before GKRS. Neurological symptoms or signs improved in 40 (30.8%) patients, remained stable in 83 (63.8%), and deteriorated in 7 (5.4%) after GKRS. Two (1.5%) patients developed new cranial nerve (CN) deficit. Tumor volume ≥ 10 cm3 (p = 0.042, HR = 4.73, 95% CI 1.06–21.17) and pre-GKRS CN deficit (p = 0.045, HR = 4.35, 95% CI 0.84–22.48) were independent unfavorable predictors for improvement in neurological symptoms or signs. Six (4.6%) patients developed new or worsening peritumoral edema with a median follow-up of 4.5 months (range 2–7 months).

CONCLUSIONS

GKRS provided good local tumor control and high neurological function preservation in patients with intracranial benign meningiomas. Patients with tumor volume < 10 cm3, pre-GKRS Karnofsky Performance Scale score ≥ 90, and no pre-GKRS CN deficit (I–VIII) can benefit from stereotactic radiosurgery. It can be considered as the primary or adjuvant management of intracranial benign meningiomas.

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Xiaomin Liu, Qi Yu, Zhiyuan Zhang, Yipei Zhang, Yanhe Li, Dong Liu, Qiang Jia, Ligao Zheng and Desheng Xu

Object

The goal of this study was to evaluate the efficacy and safety of same-day stereotactic aspiration and Gamma knife surgery (GKS) for cystic intracranial tumors.

Methods

Between 1996 and 2007, 77 patients harboring cystic intracranial tumors underwent a same-day procedure of MRI-guided cyst aspiration followed by GKS. The diagnoses were metastatic tumor in 43 patients, glial tumor in 12 patients, vestibular schwannoma in 10 patients, craniopharyngioma in 9 patients, and hemangioblastoma in 3 patients.

Results

An improvement in symptoms was achieved in 68 patients (88.3%) immediately after cyst aspiration. The mean tumor volume in this group of patients was 25.1 cm3 before aspiration and 11.1 cm3 afterward. Hemorrhage during the course of aspiration was encountered in 1 patient. Transient nausea after cyst aspiration developed in 3 patients. There was no treatment-related hematoma, seizure, neurological deficit, or infection. The median follow-up period was 16 months (range 6–108 months). Tumor control was achieved in 50 (80.6%) of 62 patients who participated in follow-up for at least 6 months.

Conclusions

The same-day stereotactic aspiration and GKS procedure was safe in patients with cystic brain tumors. Prompt symptom relief was obtained after cyst aspiration. The decrease in tumor volume following aspiration made GKS more effective because a higher prescription dose could be administered with a lower possibility of radiation-induced side effects.

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Yanhe Li, Desheng Xu, Zhiyuan Zhang, Yipei Zhang, Dong Liu, Xiaomin Liu, Guokai Wang and Yiguang Lin

Object

The goal of this study was to assess neuroimaging and clinical outcomes in patients harboring brainstem metastases that were treated with the Leksell Gamma Knife.

Methods

Twenty-eight patients with brainstem metastases (32 lesions: 8 midbrain, 21 pontine, and 3 medullary) were consecutively treated with GKS. The primary cancer diagnoses in this group included 22 cases of lung cancer, 5 cases of breast cancer, and 1 case of rectal cancer. The median age of the patients was 61 years (range 45–83 years). The median treated lesion volume was 0.78 cm3 (range 0.03–5.6 cm3), and the median GKS margin dose was 16 Gy (range 12–20 Gy). Overall survival in these patients was calculated using the Kaplan-Meier method.

Results

The median survival time was 9 months after GKS (range 2–32 months). Survival was 39.3% at 1 year and 10.7% at 2 years. The tumor control rate in the series was 90.6% (29 of 32 lesions). Development of peritumoral edema occurred in 1 patient after GKS; 4 months after GKS, the edema disappeared.

Conclusions

Gamma Knife surgery using a median margin dose of 16 Gy is a safe and effective local therapy for patients with brainstem metastases.

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Qiang Jia, Yanhe Li, Desheng Xu, Zhenjiang Li, Zhiyuan Zhang, Yipei Zhang, Dong Liu, Xiaomin Liu, Peiyu Pu and Chunsheng Kang

Object

The authors sought to evaluate modification of the radiation response of C6 glioma cells in vitro and in vivo by inhibiting the expression of Ku70. To do so they investigated the effect of gene transfer involving a recombinant replication-defective adenovirus containing Ku70 short hairpin RNA (Ad-Ku70shRNA) combined with Gamma Knife treatment (GKT).

Methods

First, Ad-Ku70shRNA was transfected into C6 glioma cells and the expression of Ku70 was measured using Western blot analysis. In vitro, phenotypical changes in C6 cells, including proliferation, cell cycle modification, invasion ability, and apoptosis were evaluated using the MTT (3′(4,5-dimethylthiazol-2-yl)2,5-diphenyltetrazolium bromide) assay, Western blot analysis, and cell flow cytometry. In vivo, parental C6 cells transfected with Ad-Ku70shRNA were implanted stereotactically into the right caudate nucleus in Sprague-Dawley rats. After GKS, apoptosis was analyzed using the TUNEL (terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick-end labeling) method. The inhibitory effects on growth and invasion that were induced by expression of proliferating cell nuclear antigen and matrix metalloproteinase–9 were determined using immunohistochemical analyses.

Results

The expression of Ku70 was clearly inhibited in C6 cells after transfection with Ad-Ku70shRNA. In vitro following transfection, the C6 cells showed improved responses to GKT, including suppression of proliferation and invasion as well as an increased apoptosis index. In vivo following transfection of Ad-Ku70shRNA, the therapeutic efficacy of GKT in rats with C6 gliomas was greatly enhanced and survival times in these animals were prolonged.

Conclusions

Our data support the potential for downregulation of Ku70 expression in enhancing the radiosensitivity of gliomas. The findings of our study indicate that targeted gene therapy–mediated inactivation of Ku70 may represent a promising strategy in improving the radioresponsiveness of gliomas to GKT.

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Dong Liu, Desheng Xu, Zhiyuan Zhang, Yipei Zhang, Yanhe Li, Xiaomin Liu, Qiang Jia, Ligao Zheng and Guoxiang Song

Object

The goal of this study was to assess the long-term results of Gamma Knife surgery (GKS) in patients harboring an optic nerve sheath meningioma (ONSM).

Methods

Thirty patients harboring an ONSM were treated with GKS between 1998 and 2003. Gamma Knife surgery was performed as the sole treatment option in 21 of these patients and resection had been performed previously in 9 patients. The mean volume of the tumor at the time of GKS was 3.6 cm3 (range 1.4–9.7 cm3), and the mean prescription peripheral dose was 13.3 Gy (range 10–17 Gy). The mean number of isocenters used to treat these lesions was 8 (range 5–14 isocenters).

Results

At a median follow-up of 56 months, visual acuity improved in 11 patients, remained stable in 13 patients (including 4 patients who were completely blind before GKS), and deteriorated in 6 patients. Follow-up images were available in all patients and showed tumor regression in 20 patients and stable tumor in 8 patients. Persistent imaging evidence of progression was only present in 2 patients. With the exception of reversible conjunctival edema in 4 cases, no other serious acute side effect was observed.

Conclusions

Gamma Knife surgery provides long-term tumor control for ONSM. The results of this study add substantial evidence that GKS may definitely become a standard treatment approach in selected cases of ONSM.

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Desheng Xu, Dong Liu, Zhiyuan Zhang, Yipei Zhang, Yanhe Li, Xiaomin Liu, Qiang Jia, Ligao Zheng and Guoxiang Song

Object

The authors evaluated the results they obtained using Gamma Knife surgery (GKS) in patients with orbital tumors.

Methods

This is a retrospective clinical evaluation of 202 patients with orbital tumors who were treated with GKS between September 1995 and October 2008. The series included 84 men and 118 women with a mean age of 39.5 ± 14.6 years (range 5–85 years). The diagnoses were determined based on pathological analyses in 113 patients and presumed based on characteristic clinical and imaging findings in 89 patients. There were 84 meningiomas, 38 epithelial tumors of the lacrimal gland, 23 schwannomas, 18 malignant choroidal melanomas, 12 optic nerve gliomas, 11 orbital metastases, 10 pseudotumors of the orbit, 3 retinoblastomas, and 3 cases of fibromatosis. The median target volume was 5.4 cm3 (range 0.04–35.6 cm3). The tumor margin dose ranged from 10 to 40 Gy.

Results

At a median follow-up period of 34.5 ± 14.7 months (range 12–114 months), tumor shrinkage was observed in 118 patients (58.4%) and stable tumor size in 71 patients (35.1%). Regularly scheduled neuroimaging studies demonstrated evidence of tumor progression in only 13 patients (6.4%): 9 of these patients underwent repeated GKS and 4 received surgical treatment. Visual acuity was preserved in 129 patients. Seventy-two patients experienced some degree of improvement in vision. Severe deterioration of visual acuity was found in 18 of 147 patients who had useful vision before treatment. Nineteen patients (9.4%) experienced transient conjunctival edema; no other serious acute side effect was observed.

Conclusions

Gamma Knife surgery provides an effective management strategy in patients with orbital tumors; it achieves excellent preservation of neurological function and is associated with few treatment-related complications.