Jennifer Glen

Randomized study of brachytherapy in the initial management of patients with malignant astrocytoma.

PURPOSE A randomized study was undertaken to assess the role of brachytherapy as a boost to external beam radiation therapy in the initial management of patients with malignant astrocytomas. METHODS AND MATERIALS Inclusion criteria included the following: biopsy-proven supratentorial malignant astrocytoma of brain < or =6 cm in size, not crossing midline or involving corpus callosum, age 18-70, Karnofsky Performance Status (KPS) > or =70. Patients were randomized to external radiation therapy only delivering 50 Gray (Gy) in 25 fractions over 5 weeks or external radiation therapy plus a temporary stereotactic iodine-125 implants delivering a minimum peripheral tumor dose of 60 Gy. Patients were stratified to age < or =50 or >50, and KPS > or =90 or < or =80. RESULTS There were 140 patients randomized between 1986 and 1996, 71 to the implant arm and 69 to external irradiation only. Pathologically 125 patients had necrosis noted in their tumor specimen. Factors associated with improved survival in univariate analysis were age < or =50, KPS > or =90, chemotherapy at recurrence, and reoperation at the original tumor site. The Cox proportional hazards model revealed the following significant factors: treatment at recurrence (chemotherapy or reoperation) with a relative risk (RR) of 0.6 (p = 0.004) and KPS > or =90 with a RR 0.6 (p = 0.007). Randomization to the implant arm was associated with a RR of 0.7 (p = 0.07). Median survival for patients randomized to brachytherapy or not were 13.8 vs. 13.2 months, respectively, p = 0.49. CONCLUSIONS We conclude that stereotactic radiation implants have not demonstrated a statistically significant improvement in survival in the initial management of patients with malignant astrocytoma.

Brachytherapy for recurrent malignant astrocytoma

PURPOSE To assess the efficacy of interstitial brachytherapy in the treatment of patients with recurrent malignant astrocytoma. METHODS AND MATERIALS Forty-six patients with recurrent malignant astrocytoma were treated with stereotactic high-activity temporary iodine-125 implants between September, 1986 and October, 1992. All patients had been initially treated for malignant astrocytoma (44) or low-grade astrocytoma (2) with surgery and external fractionated radiation. The median time between initial diagnosis and recurrence treated with brachytherapy was 12.5 months. Twenty-five patients received chemotherapy prior to brachytherapy. RESULTS All but four patients have died; median survival time following brachytherapy is 46 weeks. Twelve patients underwent reoperation for radiation necrosis at a median interval of 6.5 months after treatment (26%). Five patients incurred complications directly due to brachytherapy (11%). Forty-four patients are evaluable regarding pattern of failure following brachytherapy. Six of these 44 patients (13.6%) recurred at a distance from the treatment volume (4 in brain and 2 in spinal subarachnoid space). CONCLUSION Brachytherapy confers modest but meaningful prolongation of survival in selected patients with recurrent malignant astrocytoma, but complications are significant, reoperation frequently required, and recurrence outside the treatment volume common.

Protection of Iodine-125 Brachytherapy Brain Injury in the Rat with the 21-Aminosteroid U-74389F

Radiation protection was studied in a rat brachytherapy brain injury model. Radiation lesions were produced by stereotactic placement of high-activity iodine-125 seeds on the frontal lobe of F-344 rats. A minimum dose of 80 Gy was delivered to a 5.5-mm-radius volume. Radiation damage was evaluated 24 h after removal of the seeds by T1-weighted gadolinium-enhanced magnetic resonance imaging on a 1.5-T unit. Computerized three-dimensional reconstruction of the lesions seen on magnetic resonance imaging was performed to calculate the volume of radiation injury. Two experiments were performed with rats of different weights (mean, 300 g; mean, 180 g). All animals underwent surgical placement of an indwelling internal jugular catheter before brachytherapy. Treated animals received the 21-aminosteroid U-74389F 5 mg/kg intravenously every 6 hours during the implant and for 24 hours after the removal of the iodine-125 seed. Control animals were administered vehicle only. In both experiments, a statistically significant reduction in volume of radiation damage was observed in the U-74389F-treated group compared with the control group.

Adenoviral Vector-mediated Gene Transfer: Timing of Wild-type P53 Gene Expression in vivo and Effect of Tumor Transduction on Survival in a Rat Glioma Brachytherapy Model

AbstractObjective. This study sought to investigate modification of the radiation response in a rat 9L brain tumor model in vivo by the wild-type p53 gene (wtp53). Determination of the timing and dose of radiation therapy required the assessment of the duration of the effect of wtp53 expression on 9L tumors after in vivo transfection. Methods. Anesthetized male F-344 rats each were stereotactically inoculated with 4 × 104 9L gliosarcoma cells through a skull screw into the cerebrum in the right frontal region. Twelve-day-old tumors were inoculated through the screw with recombinant adenoviral vectors under isoflurane anaesthesia: control rats with Ad5/RSV/GL2 (carrying the luciferase gene), and study rats with Ad5CMV-p53 (carrying the wtp53 gene). Brain tumors removed at specific times after transfection were measured, homogenized, and lysed and wtp53 expression determined by Western blot analysis. Four groups of nine rats were, subsequently, implanted with iodine-125 seeds 15 days post-tumor inoculation to give a minimum tumor dose of 40 or 60 Gy. Results. We demonstrated transfer of wtp53 into rat 9L tumors in vivo using the Ad5CMV-p53 vector. The expression of wtp53 was demonstrated to be maximum between days 1 and 3 post-vector inoculation. Tumors expressing wtp53 were smaller than controls transfected with Ad5/RSV/GL2 but this difference was not statistically significant. Radiation made a significant difference to the survival of tumor-bearing rats. Moreover, wtp53 expression conferred a significant additional survival advantage. Conclusion. The expression of wtp53 significantly improves the survival of irradiated tumor-bearing rats in our model.

Effect of implant dose/volume and surgical resection on survival in a rat glioma brachytherapy model: implications for brain tumor therapy.

OBJECTIVE This study sought to investigate the effects of implant dose/volume and surgical resection on survival in a rat glioma brachytherapy model. Two doses were investigated to determine a suitable therapeutic range. METHODS We performed two experiments. Three treatment groups and one control group of male F-344 rats bearing 9L brain tumors 12 days after tumor inoculation were used in the first experiment. Day 12 tumors were an average of 4 to 6 mm in diameter. Animals treated with brachytherapy received a tumor dose of 80 Gy delivered to a 5.5-mm-radius volume. Total macroscopic tumor removal was achieved by microsurgical techniques. A subsequent experiment compared the survival of tumor-burdened rats treated with an implant dose of 60 Gy delivered to a 5.5-mm-radius volume with a control group. RESULTS Surgery alone produced an increased life span of 28.6% over control animals treated with sham surgery and dummy seed implants, a statistically significant increase in survival (P = 0.0023, log-rank test). Brachytherapy alone produced the most significant increase in survival over control animals (P = 0.0001, log-rank test; median survival not attained with an implant dose of 80 Gy delivered to a 5.5-mm-radius volume; and P = 0.0001, increased life span 121% with an implant dose of 60 Gy delivered to a 5.5-mm-radius volume). This was not improved by the addition of surgical tumor removal. CONCLUSION We have demonstrated a relationship between implant dose/volume and survival of tumor-burdened rats in this model that is not improved by the addition of tumor removal. Implications for brain tumor brachytherapy are discussed.

Tirilazad does not protect rat brain from brachytherapy-induced injury

BACKGROUND Acute and chronic brain injury are common sequelae of high-dose focused radiation, as in radiosurgery and brachytherapy. Development of protectors of radiation injury, which would work in brain but not in tumor, would help enhance the therapeutic ratio of focused-radiation therapy. METHODS Radiation protection by a clinically available 21-aminosteroid, Tirilazad, was studied in a rat brain brachytherapy model, both in tumor and non-tumor bearing animals. For the tumor model, 9L Glioma/SF line cells were implanted stereotactically into the right frontal lobe of F-344 rats and grew to a sphere of 5.0-mm diameter after 12 days. Animals received a standard brachytherapy dose of 80 Gy to a 5.5-mm radius volume administered by a high-activity removable iodine-125 seed. Radiation damage was evaluated 24 hours after removal of the seeds in all animals and again at 3 months in non-tumor-bearing animals, by T1-weighted gadolinium-enhanced and T2-weighted magnetic resonance imaging (MRI) on a 1.5-T unit. Treated animals received Tirilazad 5 mg/kg intravenously 15 minutes prior to implant, 1 hour after implant, every 6 hours for the duration of the implant, and for 24 hours after removal of the seed. Control animals were administered vehicle only. RESULTS In both non-tumor-bearing and tumor-bearing rats, no difference in the volume of lesions on enhanced T1 or T2 MRI was seen between the Tirilazad-treated and control groups. In the non-tumor-bearing rats, volume of both T1 enhanced and T2 MRI lesions was significantly reduced at 3 months compared to the values at 24 hours. CONCLUSIONS In the present model, Tirilazad failed to reduce the volume of radiation brain injury from brachytherapy as seen on MRI, studied acutely in tumor-bearing and non-tumor-bearing animals and also at 3 months in non-tumor-bearing rats.

Stereotactic High-Activity Brachytherapy for Malignant Intra-Axial Brain Tumors

Over the last several decades in Europe and 15 years in North America, numerous centers have used stereotactic high-activity brachytherapy for patients with malignant brain tumors. A number of nonrandomized series have contributed information regarding the efficacy compared to historical controls for patients with de novo and recurrent malignant gliomas and metastases. Two randomized studies for patients with de novo malignant astrocytoma and glioblastoma are nearing completion. Based on the authors personal experience with 115 patients and the reported literature, we conclude that brachytherapy is appropriate for a minority of patients with malignant brain tumors, that reoperation is frequently required, and complications of therapy can be significant. However, a proportion of highly selected patients benefit significantly from this therapy.

Abstract 4336: Human mesodermal-derived CNS metastasis-associated stromal cells induce a fibrotic response to limit tumor growth

Metastasis to the central nervous system (CNS) remains a major cause of mortality and morbidity in patients with systemic cancer. However, the mechanistic interactions of the neural niche with disseminated tumors cells in CNS metastases (CM) are still poorly understood. To better understand the cross-talk between the neural niche and metastatic tumors, we generated five different patient-derived cell lines (PDCs) originating from surgically resected CM. To assess the genetic and epigenetic characteristics of each PDC, DNA and RNA sequencing, and DNA methylation analysis was performed. Non-tumoral PDCs revealed normal copy number profiles, and retention of germline mutations as seen in patient-matched germline DNA. In contrast, one PDC (CM04) resembled its patient tumor, showing numerous copy number and somatic alterations. RNA-seq and DNA methylation analysis demonstrated that non-tumoral PDCs highly resembled each other, suggestive of a common cell of origin. Additionally, PDCs revealed gene expression signatures associated with cancer associated fibroblasts, epithelial to mesenchymal transition, and mesenchymal stem cells. Further in vivo studies demonstrated that CM04 cells were tumorigenic, whereas non-tumoral PDC (CM08) cells were unable to form tumors in mice. However, CM04:CM08 mixed tumors were significantly smaller than CM04 only tumors and revealed induction of a fibrotic response by immunohistochemistry. These data offer the first evidence that CNS metastasis-associated stromal cells (cMASCs) produce a collagen and fibronectin-rich extracellular matrix constituting a protective host response, which impedes growth of tumor cells. The therapeutic potential of these cells merits further exploration. Citation Format: Christophe Legendre, Gerald C. Gooden, Kyle N. Johnson, Rae Anne Martinez, Mark Bernstein, Jennifer Glen, Jeffrey Kiefer, Aleksander Hinek, Steven A. Toms, Bodour Salhia. Human mesodermal-derived CNS metastasis-associated stromal cells induce a fibrotic response to limit tumor growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4336. doi:10.1158/1538-7445.AM2017-4336