Use of trans sodium crocetinate for sensitizing glioblastoma multiforme to radiation

Object Adjuvant treatment with radiation (radiation therapy or radiosurgery) is a mainstay of treatment for patients harboring glioblastomas multiforme (GBM). Hypoxic regions within the tumor make cells less sensitive to radiation therapy. Trans sodium crocetinate (TSC) has been shown to increase oxygen diffusion in the brain and elevate the partial brain oxygen level. The goal of this study was to evaluate the radiosensitizing effects of TSC on GBM tumors. Methods A rat C6 glioma model was used, in which C6 glioma cells were stereotactically injected into the rat brain to create a tumor. Following creation of a right frontal tumor, animals were randomized into 1 of 4 groups: 1) TSC alone (animal treated with moderate-dose TSC only); 2) radiation (animals receiving 8 Gy of cranial radiation); 3) radiation and low-dose TSC (animals receiving 8 Gy of radiation and 50 μg/kg of TSC); or 4) radiation and moderate-dose TSC (animals receiving 8 Gy of radiation and 100 μg/kg of TSC). Animals were observed clinically for 60 days or until death. Magnetic resonance (MR) imaging was performed at 2-week intervals on each animal and quantitatively evaluated for tumor response. Immunohistochemical analysis was performed on all brain tumors. Survival differences were also evaluated using the Kaplan–Meier method. Results On MR imaging, a statistically significant reduction in tumor size was seen in the group receiving moderate-dose TSC and radiation treatment compared with the group receiving radiation treatment alone. The rate of tumor growth was significantly less for the combination of TSC and radiation treatment compared with either modality alone. Median survival times for the TSC-only and the radiation therapy–only groups were 15 and 30 days, respectively. The 60-day median survival times for the groups receiving a combination of either low- or moderate-dose TSC with radiation therapy were statistically improved compared with those for the other treatment groups. Conclusions Use of TSC improves the extent of GBM tumor regression following radiation therapy and enhances survival. Radiosensitization of hypoxic tumors through increased oxygen diffusion may have clinical utility in patients with GBM tumors but must be explored in a clinical trial.

Download Full-text

Trans-sodium crocetinate enhancing survival and glioma response on magnetic resonance imaging to radiation and temozolomide

Journal of Neurosurgery ◽

10.3171/2009.11.jns091314 ◽

2010 ◽

Vol 113 (2) ◽

pp. 234-239 ◽

Cited By ~ 15

Author(s):

Jason Sheehan ◽

Christopher P. Cifarelli ◽

Kasandra Dassoulas ◽

Claire Olson ◽

Jessica Rainey ◽

...

Keyword(s):

Radiation Therapy ◽

Brain Tumors ◽

Mr Imaging ◽

Tumor Size ◽

Glioma Cells ◽

C6 Glioma ◽

C6 Glioma Cells ◽

Radiotherapy Group ◽

Hypoxic Brain ◽

Gb Model

Object Glioblastoma (GB) tumors typically exhibit regions of hypoxia. Hypoxic areas within the tumor can make tumor cells less sensitive to chemotherapy and radiation therapy. Trans-sodium crocetinate (TSC) has been shown to transiently increase oxygen to hypoxic brain tumors. The authors examined whether this improvement in intratumor oxygenation translates to a therapeutic advantage when delivering standard adjuvant treatment to GBs. Methods The authors used C6 glioma cells to create a hypoxic GB model. The C6 glioma cells were stereotactically injected into the rat brain to create a tumor. Fifteen days later, MR imaging was used to confirm the presence of a glioma. The animals were randomly assigned to 1 of 3 groups: 1) temozolomide alone (350 mg/m2/day for 5 days); 2) temozolomide and radiation therapy (8 Gy); or 3) TSC (100 μg/kg for 5 days), temozolomide, and radiation therapy. Animals were followed through survival studies, and tumor response was assessed on serial MR images obtained at 15-day intervals during a 2-month period. Results Mean survival (± SEM) of the temozolomide-alone and the temozolomide/radiotherapy groups was 23.2 ± 0.9 and 29.4 ± 4.4 days, respectively. Mean survival in the TSC/temozolomide/radiotherapy group was 39.8 ± 6 days, a statistically significant improvement compared with either of the other groups (p < 0.05). Although tumor size was statistically equivalent in all groups at the time of treatment initiation, the addition of TSC to temozolomide and radiotherapy resulted in a statistically significant reduction in the MR imaging–documented mean tumor size at 30 days after tumor implantation. The mean tumor size in the TSC/temozolomide/radiotherapy group was 18.9 ± 6.6 mm2 compared with 42.1 ± 2.7 mm2 in the temozolomide-alone group (p = 0.047) and 35.8 ± 5.1 mm2 in the temozolomide/radiation group (p = 0.004). Conclusions In a hypoxic GB model, TSC improves the radiological and clinical effectiveness of temozolomide and radiation therapy. Further investigation of this oxygen diffusion enhancer as a radiosensitizer for hypoxic brain tumors seems warranted.

Download Full-text

Effect of trans sodium crocetinate on brain tumor oxgenation

Journal of Neurosurgery ◽

10.3171/2009.3.jns081339 ◽

2009 ◽

Vol 111 (2) ◽

pp. 226-229 ◽

Cited By ~ 12

Author(s):

Jason Sheehan ◽

Jonathan Sherman ◽

Christopher Cifarelli ◽

Jay Jagannathan ◽

Kasandra Dassoulas ◽

...

Keyword(s):

Brain Tumor ◽

Mr Imaging ◽

Brain Tissue ◽

Cerebral Hemisphere ◽

Tissue Oxygenation ◽

C6 Glioma ◽

Tumor Oxygenation ◽

C6 Glioma Cells ◽

Saline Control ◽

The Brain

Object Glioblastoma multiforme tumors typically exhibit regions of hypoxia. Hypoxic regions within the tumor make cells less sensitive to radiosurgery and radiation therapy. Trans sodium crocetinate (TSC) has been shown to be a radiosensitizer. The goal of this research was to elucidate the underlying mechanism of TSC's radiosensitizing effect. Methods A rat C6 glioma model was used. The C6 glioma cells were stereotactically injected into the rat brain to create a tumor. Two weeks later, MR imaging was used to confirm the presence of a glioma. Following demonstration on MR imaging of a brain tumor, animals were randomized into 1 of 2 groups: 1) TSC alone (100 μg/kg), or 2) saline control. Licox probes were inserted into the brain tumor and contralateral cerebral hemisphere. Tissue oxygenation measurements were recorded before and after intravenous infusion of either TSC or saline. Results Not surprisingly, tissue oxygenation measurements revealed that the brain tumor was hypoxic relative to the contralateral cerebral hemisphere brain tissue. Two to 8 minutes after TSC was infused, tissue oxygenation measurements in the brain tumor increased above baseline by as much as 60%. After this temporary elevation following TSC infusion, tumor oxygenation measurements returned to baseline. No significant elevations in tissue oxygenation were seen on the contralateral side. Similarly, the saline vehicle was not observed to increase tissue oxygenation in either the brain tumor or the contralateral brain tissue. Conclusions Administration of TSC transiently improves tissue oxygenation in hypoxic gliomas. Such an effect is one potential mechanism for the radiosensitization previously observed after addition of TSC.

Download Full-text

Phase III Trial of Carmustine and Cisplatin Compared With Carmustine Alone and Standard Radiation Therapy or Accelerated Radiation Therapy in Patients With Glioblastoma Multiforme: North Central Cancer Treatment Group 93-72-52 and Southwest Oncology Group 9503 Trials

Journal of Clinical Oncology ◽

10.1200/jco.2005.04.6979 ◽

2006 ◽

Vol 24 (24) ◽

pp. 3871-3879 ◽

Cited By ~ 54

Author(s):

Jan C. Buckner ◽

Karla V. Ballman ◽

John C. Michalak ◽

Gary V. Burton ◽

Terrence L. Cascino ◽

...

Keyword(s):

Radiation Therapy ◽

Glioblastoma Multiforme ◽

Median Survival ◽

Survival Rates ◽

Sensory Neuropathy ◽

Phase Iii ◽

Survival Times ◽

North Central ◽

Newly Diagnosed Glioblastoma ◽

Improvement In Survival

Purpose In patients with newly diagnosed glioblastoma multiforme, to determine whether cisplatin plus carmustine (BCNU) administered before and concurrently with radiation therapy (RT) improves survival compared with BCNU and RT and whether survival using accelerated RT (ART) is equivalent to survival using standard RT (SRT). Patients and Methods After surgery, patients were stratified by age, performance score, extent of surgical resection, and histology (glioblastoma v gliosarcoma) and then randomly assigned to arm A (BCNU plus SRT), arm B (BCNU plus ART), arm C (cisplatin plus BCNU plus SRT), or arm D (cisplatin plus BCNU plus ART). Results Four hundred fifty-one patients were randomly assigned, and 401 were eligible. Frequent toxicities included myelosuppression, vomiting, sensory neuropathy, and ototoxicity and were worse with cisplatin. There was no difference in toxicity between SRT and ART. Median survival times and 2-year survival rates for patients who received BCNU plus RT (arms A and B) compared with cisplatin, BCNU, and RT (arms C and D) were 10.1 v 11.5 months, respectively, and 11.5% v 13.7%, respectively (P = .19). Median survival times and 2-year survival rates for patients who received SRT (arms A and C) compared with ART (arms B and D) were 11.2 v 10.5 months, respectively, and 13.8% v 11.4%, respectively (P = .33). Conclusion Cisplatin administered concurrently with BCNU and RT resulted in more toxicity but provided no significant improvement in survival. SRT and ART produced similar toxicity and survival.

Download Full-text

PEGPH20, a PEGylated Human Hyaluronidase, Induces Radiosensitization by Reoxygenation In Pancreatic Cancer Xenografts. A Molecular Imaging Study

10.1101/2022.01.11.475894 ◽

2022 ◽

Author(s):

Tomohiro Seki ◽

Yu Saida ◽

Shun Kishimoto ◽

Jisook Lee ◽

Yasunori Otowa ◽

...

Keyword(s):

Pancreatic Cancer ◽

Radiation Therapy ◽

Blood Volume ◽

Radiation Treatment ◽

Photoacoustic Imaging ◽

Imaging Study ◽

Tumor Oxygenation ◽

Glycolytic Flux ◽

Wild Type ◽

Survival Times

PEGylated human hyaluronidase (PEGPH20) enzymatically depletes hyaluronan, an important component of the extracellular matrix, in tumors. The resultant improvement in vascular patency and perfusion has been shown to increase the delivery of therapeutic molecules. We show that PEGPH20 also improves the efficacy of radiation therapy in a human pancreatic adenocarcinoma BxPC3 mouse model overexpressing hyaluronan synthase 3 (BxPC3-HAS3) while exerting little effect on the corresponding wild type tumors. Mice overexpressing HAS3 developed fast growing, radiation resistant tumors that became rapidly more hypoxic as time progressed. Treatment with PEGPH20 increased survival times when used in combination with radiation therapy, significantly more than either radiation therapy or PEGPH20 alone. Radiosensitization in BxPC3-HAS3 tumors was attributed to an increase in local pO2 as studied by by EPR imaging. No effect on survival, radiation treatment, or pO2 was seen in wild type tumors after PEGPH20 treatment. Dynamic contrast enhanced (DCE) MRI and MRI based blood volume imaging showed improved perfusion/permeability and local blood volume, respectively, in BxPC3-HAS3 tumors after PEGPH20 treatment, accounting for the increase in tumor oxygenation. Photoacoustic imaging indicated immediate changes in tumor oxygenation after treatment. Metabolic MRI using hyperpolarized [1-13C] pyruvate suggested a metabolic shift towards decreased glycolytic flux after PEGPH20 treatment. In summary, the results showed that PEGPH20 may be useful for radiosensitization of pancreatic cancer but only in the subset of tumors with substantial hyaluronan accumulation and the response of the treatment may potentially be monitored non-invasive imaging of the hemodynamic and metabolic changes in the tumor microenvironment.

Download Full-text

Correlates of survival and the Daumas-Duport grading system for astrocytomas

Journal of Neurosurgery ◽

10.3171/jns.1991.74.1.0027 ◽

1991 ◽

Vol 74 (1) ◽

pp. 27-37 ◽

Cited By ~ 104

Author(s):

Tai Seung Kim ◽

Andrea L. Halliday ◽

E. Tessa Hedley-Whyte ◽

Karen Convery

Keyword(s):

Radiation Therapy ◽

Survival Time ◽

Median Survival ◽

Median Survival Time ◽

Massachusetts General Hospital ◽

Cox Proportional Hazards Model ◽

Grading System ◽

Survival Times ◽

Histological Features ◽

Grade 3

✓ In order to examine the correlation between prognosis and the histological features of nuclear atypia, mitosis, endothelial proliferation, and necrosis in supratentorial adult astrocytomas, the authors reviewed 251 such cases treated at the Massachusetts General Hospital between 1972 and 1980. One point was given for the presence of each feature. The total number of features was translated into a grade as follows: none of the four features = Grade 1 (one patient), one feature = Grade 2 (36 patients), two features = Grade 3 (33 patients), and three or four features = Grade 4 (181 patients). The period of survival was significantly associated with grade, the presence or absence of each of the four histological features, patient's age, type of operation, radiation therapy, and extent of tumor (log rank, p < 0.05). The variables associated with grade were age (p < 0.001) and radiation therapy (p < 0.02). After adjustment for these variables using a Cox proportional-hazards model, the difference in overall survival time between patients in Grades 2 and 3 was not statistically significant. When comparable groups of patients were examined in terms of age or receipt of radiation therapy, the median survival times differed markedly. Patients 50 years of age or less had a median survival time of 68 months (Grade 2 tumors), 29 months (Grade 3 tumors), and 13 months (Grade 4 tumors). Patients over 50 years of age had a median survival time of 6 months (Grade 2 and 4 tumors) and 9 months (Grade 3 tumors). Those patients who had received radiation therapy had a median survival time of 68 months (Grade 2 tumors), 21 months (Grade 3 tumors), and 11 months (Grade 4 tumors). Those patients who did not receive radiation therapy had a median survival time of 1 month (Grade 2 tumors) and 2 months (Grade 3 and 4 tumors); over half of these patients died within 2 months of surgery. This grading system, originally proposed by Daumas-Duport, et al., is simple, objective, and reproducible, and correlates well with survival times. The authors recommend that astrocytomas be graded on a scale of 1 to 4, with Grade 1 reserved for the rare adult supratentorial astrocytoma with none of the four histological features.

Download Full-text

Magnetic Resonance Imaging-Guided Adaptive Radiotherapy for Colorectal Liver Metastases

Cancers ◽

10.3390/cancers13071636 ◽

2021 ◽

Vol 13 (7) ◽

pp. 1636

Author(s):

Paul B. Romesser ◽

Neelam Tyagi ◽

Christopher H. Crane

Keyword(s):

Radiation Therapy ◽

Magnetic Resonance ◽

Mr Imaging ◽

Liver Metastases ◽

Colorectal Liver Metastases ◽

Radiation Treatment ◽

Treatment Delivery ◽

Radiation Technology ◽

Safe Delivery ◽

Intrafraction Motion

Technological advances have enabled well tolerated and effective radiation treatment for small liver metastases. Stereotactic ablative radiation therapy (SABR) refers to ablative dose delivery (>100 Gy BED) in five fractions or fewer. For larger tumors, the safe delivery of SABR can be challenging due to a more limited volume of healthy normal liver parenchyma and the proximity of the tumor to radiosensitive organs such as the stomach, duodenum, and large intestine. In addition to stereotactic treatment delivery, controlling respiratory motion, the use of image guidance, adaptive planning and increasing the number of radiation fractions are sometimes necessary for the safe delivery of SABR in these situations. Magnetic Resonance (MR) image-guided adaptive radiation therapy (MRgART) is a new and rapidly evolving treatment paradigm. MR imaging before, during and after treatment delivery facilitates direct visualization of both the tumor target and the adjacent normal healthy organs as well as potential intrafraction motion. Real time MR imaging facilitates non-invasive tumor tracking and treatment gating. While daily adaptive re-planning permits treatment plans to be adjusted based on the anatomy of the day. MRgART therapy is a promising radiation technology advance that can overcome many of the challenges of liver SABR and may facilitate the safe tumor dose escalation of colorectal liver metastases.

Download Full-text

Radiation Plus Anti-PD-1 Therapy for NSCLC Brain Metastases: A Retrospective Study

Frontiers in Oncology ◽

10.3389/fonc.2021.742971 ◽

2021 ◽

Vol 11 ◽

Author(s):

Guixiang Liao ◽

Yuting Qian ◽

Sumbal Arooj ◽

Zhihong Zhao ◽

Maosheng Yan ◽

...

Keyword(s):

Radiation Therapy ◽

Adverse Events ◽

Brain Metastases ◽

Median Survival ◽

Cox Regression ◽

Small Cell Lung Carcinoma ◽

Fisher Exact Test ◽

Survival Times ◽

Cell Lung Carcinoma ◽

Nsclc Patients

BackgroundRadiation therapy (RT) is the mainstay of brain metastases (BMs), and anti-PD-1 blockade has led to intracranial responses in non-small cell lung carcinoma (NSCLC) patients with BMs.ObjectiveThis study aimed to evaluate the efficacy and safety of adding anti-PD-1 blockade to RT in the management of NSCLC patients with BM in terms of survival outcome.Materials and MethodsWe retrospectively reviewed 70 NSCLC patients with BMs who were treated with whole brain radiation therapy (WBRT) between January 2016 and January 2021. Of the 70 patients, 29 additionally received anti-PD-1 therapy within 30 days of WBRT initiation. Baseline characteristics of the patients and efficacy outcomes such as progression-free survival (PFS) and overall survival (OS) were statistically compared using SPSS v26. Results were obtained using the Chi-square test/Fisher exact test, t-test, Kaplan-Meier, and Cox regression survival analyses.ResultsThe median survival for the entire cohort was 24 months (95% CI, 19.5–28.5). The median survival times for WBRT alone and WBRT plus anti-PD-1 therapy cohorts were 20 months (95% CI, 11.6–28.3) and 27 months (95% CI, 19.5–28.5), respectively (p=0.035). There was no statistical difference in PFS for the treatment cohorts (median PFS for WBRT alone: 7 months vs. 12 months for WBRT plus anti-PD-1, p=0.247). In EGFR wild-type subgroup (n=31), both PFS (p=0.037) and OS (p=0.012) were significantly improved. Only the treatment group (WBRT plus anti-PD-1) was a significant predictor of OS on univariate and multivariate analyses (p=0.040). There were no significant differences in adverse events among the treatment groups.ConclusionsNSCLC patients with BM receiving additional anti-PD-1 therapy may derive better OS than WBRT alone without any increase in adverse events. Prospective well-designed studies are warranted to validate and elucidate the additive effects of the two modalities in this group of patients.

Download Full-text

Radiosensitivity of glioma to Gamma Knife treatment enhanced in vitro and in vivo by RNA interfering Ku70 that is mediated by a recombinant adenovirus

Journal of Neurosurgery ◽

10.3171/2010.7.gks10972 ◽

2010 ◽

Vol 113 (Special_Supplement) ◽

pp. 228-235 ◽

Cited By ~ 4

Author(s):

Qiang Jia ◽

Yanhe Li ◽

Desheng Xu ◽

Zhenjiang Li ◽

Zhiyuan Zhang ◽

...

Keyword(s):

Western Blot ◽

Gamma Knife ◽

Blot Analysis ◽

Western Blot Analysis ◽

Glioma Cells ◽

C6 Glioma ◽

C6 Glioma Cells ◽

C6 Cells

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.

Download Full-text