Combining a noble gas with radiotherapy: glutamate receptor antagonist xenon may act as a radiosensitizer in glioblastoma.

BACKGROUND: Ionotropic glutamate receptors α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) and N-methyl-D-aspartate receptor (NMDAR) modulate proliferation, invasion and radioresistance in glioblastoma (GB). Pharmacological targeting is difficult as many in vitro-effective agents are not suitable for in patient applications. We aimed to develop a method to test the well tolerated AMPAR- and NMDAR-antagonist xenon gas as a radiosensitizer in GB. METHODS: We designed a diffusion-based system to perform the colony formation assay (CFA), the radiobiological gold standard, under xenon exposure. Stable and reproducible gas atmosphere was validated with oxygen and carbon dioxide as tracer gases. After checking for AMPAR and NMDAR expression via immunofluorescence staining we performed the CFA with the glioblastoma cell lines U87 and U251 as well as the non-glioblastoma derived cell line HeLa. Xenon was applied after irradiation and additionally tested in combination with NMDAR antagonist memantine. RESULTS: The gas exposure system proved compatible with the CFA and resulted in a stable atmosphere of 50% xenon. Indications for the presence of glutamate receptor subunits were present in glioblastoma-derived and HeLa cells. Significantly reduced clonogenic survival by xenon was shown in U87 and U251 at irradiation doses of 4-8 Gy and 2, 6 and 8 Gy, respectively (p < 0.05). Clonogenic survival was further reduced by the addition of memantine, showing a significant effect at 2-8 Gy for both glioblastoma cell lines (p < 0.05). Xenon did not significantly reduce the surviving fraction of HeLa cells until a radiation dose of 8 Gy. CONCLUSION: The developed system allows for testing of gaseous agents with CFA. As a proof of concept, we have, for the first time, unveiled indications of radiosensitizing properties of xenon gas in glioblastoma.

Feasibility of interstitial stepping-source electronic brachytherapy to locally inoperable tumors.

PURPOSE: Radiotherapy is the mainstay in the treatment of locally inoperable tumors. Interstitial electronic needle-based kilovoltage brachytherapy (EBT) could be an economic alternative to high-dose-rate (HDR) brachytherapy or permanent seed implantation (PSI). In this work, we evaluated if locally inoperable tumors treated with PSI at our institution may be suitable for EBT. MATERIAL AND METHODS: A total of 10 post-interventional computed tomography (CT) scans of patients, who received PSI and simulated stepping-source EBT applied with Intrabeam system and needle applicator were used. EBT treatment planning software with 3-dimensional image and projection of applicator were applied for designing trajectories and establishing dwell positions. Dwell position doses were summarized, and doses covering 90% of the target volume (D90) achieved with stepping-source EBT were compared to those of PSI. Additionally, conformality of dose distributions and total irradiation time were assessed using conformation number (CN) or conformal index (COIN). RESULTS: In all patients, D90 of EBT exceeded the prescribed dose or D90 of PSI on average by 4.7% or 21.3% relative to the prescribed dose, respectively. Mean number of trajectories was 5.0 for EBT and 6.9 for PSI. Average CN/COIN for EBT was 0.69, with a mean irradiation time of 27.8 minutes for standardized dose of 13 Gy. CONCLUSIONS: Stepping-source EBT allowed for a conformal treatment of inoperable interstitial tumors with similar D90. Fewer trajectories were required for EBT in majority of cases.

Long-term outcome after combined kyphoplasty and intraoperative radiotherapy (Kypho-IORT) for vertebral tumors.

INTRODUCTION: The spine represents the site which is most frequently affected by bone metastases in patients with systemic cancer. Of all local treatment options, combined kyphoplasty and intraoperative radiotherapy (Kypho-IORT) provides both, instantaneous stabilization and immediate pain relief. We here report on the long-term outcomes of the largest cohort treated with Kypho-IORT to date. METHODS: Between 2009 and 2019 a total of 104 patients underwent Kypho-IORT to vertebral tumors in the thoracic, lumbar, or sacral spine with transpedicular kyphoplasty and intraoperative irradiation with a needle-shaped electronic brachytherapy source at our center. Patients were treated either on trial, within the prospective Kypho-IORT studies (NCT01280032 and NCT02773966), or, after completion of the study, off trial but compliant with the study protocol. Follow-up and imaging with computed tomography (CT) or magnetic resonance imaging was scheduled after 3 and 6 months and then bi-annually. RESULTS: A total of 143 vertebrae (89 thoracic spine, 53 lumbar spine, and 1 sacral spine) were treated in 104 patients. The median follow-up was 14.5 months (range 0.4-109). Local progression occurred in 10 patients (10 vertebrae) after a median time of 22.3 months (range 1.5-73) resulting in local control rates of 97.1, 95.9, and 94.2% at 6, 12, and 24 months, respectively. Overall survival was 74.6, 61.7, and 50.3% at 6, 12, and 24 months, respectively. A single serious adverse event was reported. CONCLUSION: In addition to immediate pain reduction and stabilization, Kypho-IORT shows excellent long-term local control with minimal side effects.

Prospective assessment of mask versus frame fixation during Gamma Knife treatment for brain metastases.

PURPOSE: The newest generation of the Leksell Gamma Knife (GK) allows frame based as well as frameless treatment. We here report outcomes of a prospective non-randomized study on mask fixation (MF) versus frame fixation (FF) for GK treatment of brain metastases. METHODS: The decision for FF or MF was made on a case-by-case basis. Factors considered were patients' preference, proximity of critical structures, V12 and treatment time. Either stereotactic radiosurgery or fractionated stereotactic radiotherapy in up to 3 fractions was performed. For MF, a PTV margin of 1 mm was added. Follow-up included quarterly MRI scans. The primary outcome was local control. Secondary endpoints were progression-free survival (PFS), overall survival (OS) and the incidence of radionecrosis. RESULTS: A total of 197 lesions (169 FF and 28 MF) were treated in 76 patients (59 FF and 17 MF). 187 lesions were treated with SRS and 10 with FSRT. Median dose was 22 Gy in both groups and median follow-up was 9.3 months. There was a higher local failure rate (HR: 3.69; 95%CI: 1.13-12.0; p = 0.03) with 11 local failures in the FF and none in the MF cohort. No differences were observed between the groups for OS (median: n.r. vs. 16.9 months; HR:1.00; 95%CI: 0.41-2.46; p = 0.999) and PFS (median: 6.9 vs. 8.4 months; HR: 0.92; 95%CI: 0.47-1.79; p = 0.800). Three cases of radionecrosis occurred with FF but none with MF (p = 0.67). CONCLUSIONS: Gamma Knife treatment with MF does not result in worse outcome or increased rates of radionecrosis in this non-randomized study.

Fetal glucocorticoid receptor (Nr3c1) deficiency alters the landscape of DNA methylation of murine placenta in a sex-dependent manner and is associated to anxiety-like behavior in adulthood.

Prenatal stress defines long-term phenotypes through epigenetic programming of the offspring. These effects are potentially mediated by glucocorticoid release and by sex. We hypothesized that the glucocorticoid receptor (Gr, Nr3c1) fashions the DNA methylation profile of offspring. Consistent with this hypothesis, fetal Nr3c1 heterozygosity leads to altered DNA methylation landscape in fetal placenta in a sex-specific manner. There was a significant overlap of differentially methylated genes in fetal placenta and adult frontal cortex in Nr3c1 heterozygotes. Phenotypically, Nr3c1 heterozygotes show significantly more anxiety-like behavior than wildtype. DNA methylation status of fetal placental tissue is significantly correlated with anxiety-like behavior of the same animals in adulthood. Thus, placental DNA methylation might predict behavioral phenotypes in adulthood. Our data supports the hypothesis that Nr3c1 influences DNA methylation at birth and that DNA methylation in placenta correlates with adult frontal cortex DNA methylation and anxiety-like phenotypes.

A technique for administering xenon gas anesthesia during surgical procedures in mice.

Carrying out invasive procedures in animals requires the administration of anesthesia. Xenon gas offers advantages as an anesthetic agent compared with other agents, such as its protection of the brain and heart from hypoxia-induced damage. The high cost of xenon gas has limited its use as an anesthetic in animal experiments, however. The authors designed and constructed simple boxes for the induction and maintenance of xenon gas and isoflurane anesthesia in small rodents in order to minimize the amount of xenon gas that is wasted. While using their anesthesia delivery system to anesthetize pregnant mice undergoing caesarean sections, they measured the respiratory rates of the anesthetized mice, the survival of the pups and the percentages of oxygen and carbon dioxide within the system to confirm the system's safety.