Radiation-induced Transformation Research Articles

RECQL4 Inhibits Radiation-Induced Tumor Immune Awakening via Suppressing the cGAS-STING Pathway in Hepatocellular Carcinoma.

Many patients with hepatocellular carcinoma (HCC) respond poorly to radiotherapy despite remarkable advances in treatment. A deeper insight into the mechanism of sensitivity of HCC to this therapy is urgently required. It is demonstrated that RECQL4 is upregulated in the malignant cells of patients with HCC. Elevated RECQL4 levels reduce the sensitivity of HCC to radiotherapy by repairing radiation-induced double-stranded DNA (dsDNA) fragments. Mechanistically, the inhibitory effect of RECQL4 on radiotherapy is due to the reduced recruitment of dendritic cells and CD8+ T cells in the tumor microenvironment (TME). RECQL4 disrupts the radiation-induced transformation of the TME into a tumoricidal niche by inhibiting the cGAS-STING pathway in dendritic cells. Knocking out STING in dendritic cells can block the impact of RECQL4 on HCC radiosensitivity. Notably, high RECQL4 expressions in HCC is significantly associated with poor prognosis in multiple independent cohorts. In conclusion, this study highlights how HCC-derived RECQL4 disrupts cGAS-STING pathway activation in dendritic cells through DNA repair, thus reducing the radiosensitivity of HCC. These findings provide new perspectives on the clinical treatment of HCC.

Induction of epithelial-mesenchymal transition in thyroid follicular cells is associated with cell adhesion alterations and low-dose hyper-radiosensitivity.

Epithelial-mesenchymal transition (EMT) is associated with altered cellular adhesion. We previously demonstrated that cellular adhesion influences Low-dose Hyper-Radiosensitivity (HRS) in a variety of tumor cells. However, the relationship of low-dose HRS with the phenotypic plasticity incurred by EMT during the neoplastic transformation remains to be elucidated. To investigate whether acquisition of EMT phenotype during progressive neoplastic transformation may affect low-dose radiation sensitivity. Primary thyroid cells obtained from a human cystic thyroid nodule were first subjected to nutritional stress. This yielded immortalized INM-Thy1 cell strain, which was further treated with either multiple γ-radiation fractions (1.5 Gy each) or repetitive cycles of 3-methylcholanthrene and phorbol-12-myristate-13-acetate, yielding two progressive transformants, viz., INM-Thy1R and INM-Thy1C. Morphological alterations, chromosomal double-minutes, cell adhesion proteins, anchorage dependency, tumorigenicity in nude mice and cellular radiosensitivity were studied in these strains. Both transformants (INM-Thy1R, INM-Thy1C) displayed progressive tumorigenic features, viz., soft agar colony growth and solid tumor growth in nude mice, coupled with features of epithelial-mesenchymal transition and activated Wnt pathway. Incidentally, the chemical-induced transformant (INM-Thy1C) displayed a prominent HRS (αs/αr=29.35) which remained unaffected at high cell density. However, the parental (INM-Thy1) cell line as well as radiation-induced transformant (INM-Thy1R) failed to show this hypersensitivity. The study shows that induction of EMT in thyroid follicular cells may accompany increased susceptibility to low-dose ionizing radiation, which was attenuated by adaptive resistance acquired during radiation-induced transformation.

Genomic Loss and Epigenetic Silencing of the FOSL1 Tumor Suppressor Gene in Radiation-induced Neoplastic Transformation of Human CGL1 Cells Alters the Tumorigenic Phenotype In Vitro and In Vivo.

The CGL1 human hybrid cell system has been utilized for many decades as an excellent cellular tool for investigating neoplastic transformation. Substantial work has been done previously implicating genetic factors related to chromosome 11 to the alteration of tumorigenic phenotype in CGL1 cells. This includes candidate tumor suppressor gene FOSL1, a member of the AP-1 transcription factor complex which encodes for protein FRA1. Here we present novel evidence supporting the role of FOSL1 in the suppression of tumorigenicity in segregants of the CGL1 system. Gamma-induced mutant (GIM) and control (CON) cells were isolated from 7 Gy gamma-irradiated CGL1s. Western, Southern and Northern blot analysis were utilized to assess FOSL1/FRA1 expression as well as methylation studies. GIMs were transfected to re-express FRA1 and in vivo tumorigenicity studies were conducted. Global transcriptomic microarray and RT-qPCR analysis were used to further characterize these unique cell segregants. GIMs were found to be tumorigenic in vivo when injected into nude mice whereas CON cells were not. GIMs show loss of Fosl/FRA1 expression as confirmed by Western blot. Southern and Northern blot analysis further reveals that FRA1 reduction in tumorigenic CGL1 segregants is likely due to transcriptional suppression. Results suggest that radiation-induced neoplastic transformation of CGL1 is in part due to silencing of the FOSL1 tumor suppressor gene promoter by methylation. The radiation-induced tumorigenic GIMs transfected to re-express FRA1 resulted in suppression of subcutaneous tumor growth in nude mice in vivo. Global microarray analysis and RT-qPCR validation elucidated several hundred differentially expressed genes. Downstream analysis reveals a significant number of altered pathways and enriched Gene Ontology terms genes related to cellular adhesion, proliferation, and migration. Together these findings provide strong evidence that FRA1 is a tumor suppressor gene deleted and epigenetically silenced after ionizing radiation-induced neoplastic transformation in the CGL1 human hybrid cell system.

Explosive desorption induced by radical–radical interaction in methane-doped Ar matrices

Delayed explosive desorption of particles from Ar matrices highly doped with CH4 stimulated by an electron irradiation was studied using emission spectroscopy methods. The recorded cathodoluminescence (CL) spectra of CH4-containig Ar matrices revealed following products of radiation-induced CH4 transformation: H, CH and C. Three series of experiments were performed with different irradiation and heating modes: (i) continuous irradiation at low temperature with accumulation of radiolysis products, (ii) heating of the pre-irradiated films with measurements of relaxation emissions, specifically thermally stimulated exoelectron emission (TSEE) and (iii) external heating of the pre-irradiated films under beam. These measurments of the, so called, nonstationary luminescenve (NsL) at the selected wavelenghs and nonstationary desorption (NsD) in combination with TSEE recorded provided an information on reactions of charged and neutral species of interest. Taking into account that the CH radical can be considered as a signature of the CH3 species [27] we obtained the information on a role of H atoms and CH3 radicals in stimulation of explosive delayed desorption of particles from Ar matrices doped with CH4. Two bursts of long-period self-oscillations together with short-period ones with a limited number of periods were observeed during stationary irradiation of all CH4-doped Ar matrices at low temperatures. Processes leading to the self-oscillations of particle yield are discussed.

Stability, reversibility, and recovery of radiation-induced phase transformations in nanowires under mechanical loads

Phase transformations in nanowires can be induced via an external stimulus including mechanical loads or radiation damage. Notably, FCC nanowires exposed to an irradiation environment can undergo a size-dependent FCC-to-HCP phase transformation caused by the formation and accumulation of radiation-induced stacking faults and twinning defects. In this study, using atomistic simulations, we examine whether or not such radiation-induced phase transformation is stable and/or reversible under mechanical loads. Our results show that this type of phase transformation is stable under tension, reversible via compressive strain, and possibly subsequently recovered under tensile strain. The prerequisite conditions for the stability, reversibility, and recovery of this phase transformation are intimately related to the yielding mechanism at play and the reminiscence of residual stacking faults and twinning upon compressive loading.

Radiation-induced transformation of the C2H2⋯NH3 complex in cryogenic media: Identification of C2H2⋯NH2∙ complex and evidence of cold synthetic routes

Acetylene and ammonia are important constituents of the interstellar medium, and their coupled chemistry induced by high-energy radiation may be responsible for the formation of a variety of prebiotically important organic-nitrogen compounds. In this work, we first comprehensively characterized the vibrational spectrum of the 1:1 C2H2⋯NH3 complex obtained by deposition of the C2H2/NH3/Ng (Ng = Ar, Kr, or Xe) gaseous mixtures at 5K using Fourier transform infrared spectroscopy and ab initio calculations at the CCSD(T)/L2a_3 level of theory and examined its radiation-induced transformations. The parent complex adopts a C3v symmetric top molecular structure with C2H2 acting as a proton donor. The x-ray-induced transformations of this complex result in the formation of the C2H2⋯NH2 ∙ complex and various CN-containing species (CH2CNH, CH3NC, CH2NCH, CH2NC∙, CCN∙, and CNC∙). The radical-molecule complex was identified based on comparison of experimental data with the results of the UCCSD(T)/L2a_3 computations. It is characterized by distinct features in the region of acetylene CHasym str mode, red-shifted from the corresponding absorptions of non-complexed acetylene by -72.9, -70.4, and -60.6cm-1 for Ar, Kr, and Xe, respectively. Additionally, in krypton and xenon matrices, the blue-shifted features in the CHasym bend region of acetylene were observed, which can be also tentatively attributed to the C2H2⋯NH2 ∙ complex. The extrapolated to the complete basis set limit unrestricted coupled cluster method with single and double, and perturbative triple excitations binding energy of the C2H2⋯NH2 ∙ complex (including zero-point vibration energy correction) is lower than that of the C2H2⋯NH3 complex (1.90 and 2.51kcal mol-1, respectively). We believe that the C2H2⋯NH2 ∙ complex may be an important intermediate in cold synthetic astrochemistry.

The effects of vascular endothelial cells on regulating post-irradiation microglia phenotype in irradiation-induced brain injury.

e14001 Background: The purpose was to elucidate the mechanism behind functional relevance between microglia and injured blood vessels after CRT and the role of fractalkine (FKN) for the dynamics in the microglia phenotype, hoping to provide a theoretical rationale for the therapeutic strategy of Radiation-induced brain injury (RIBI). Methods: The ultrastructural blood vessels in the hippocampus were examined by transmission electron microscopy. EMSA and dual-luciferase assays were used to confirm the activation of NF-κB induced by irradiation in. Migration and co-culture assays were used to investigate the the association between HUVEC and BV-2 cells after irradiation. We constructed CX3CR1-knockdown (receptor of FKN) lentiviral vector to produce CX3CR1-knockdown BV-2 cell lines. After cultured for 3h with/without FKN, BV-2 cells (Sh-NC/ Sh-CX3CR1) received 10-Gy irradiation. The CX3CR1wide-type/knockdownmice were used and subjected to lateral ventricular injection (ICV) of 5 μl FKN lentivirus or vector before CRT. The in vitro and in vivo phenotype transformation of microglia and its inflammatory factors release were detected by WB, real-time PCR, ELISA, and IF at different time-points after irradiation. Morris water maze test was used to test mice's cognitive function. Results: In the hippocampus of the CRT group, significant pathological changes were seen in ultrastructure of blood vessels.The NF-κB pathway was activated in vascular endothelial cells (ECs) after10-Gy irradiation. In vitro migration and Co-culture assays found that molecular signals, secreted by ECs via the NF-κB pathway, leading to the activation of microglia and their recruitment to blood vessels. ELISA and qRT-PCR revealed that 10-Gy irradiation promoted the secretion of FKN from the vascular ECs via activating the NF-κB pathway. Western blotting and Flow cytometry showed that pretreatment with exogenous FKN, before 10-Gy irradiation, promoted microglia M2 phenotype transformation, diminished radiation-induced pro-inflammatory factors, and enhanced phagocytosis capacity. In addition, in vivo experiments showed that up-regulation of FKN via FKN lentivirus promoted radiation-induced microglial M2 transformation in the hippocampus, and diminished the spatial memory injury of radiated mice. Lastly, while inhibiting the CX3CR1, which is exclusively expressed on microglia in the brain, the regulatory effect of FKN on microglia and cognitive ability of mice disappeared after radiation. Conclusions: FKN, mainly secreted by vascular ECs via the NF-κB pathway after radiation, may attenuate RIBI through microglia polarization toward M2 phenotype by binding to CX3CR1 on microglia. Our study has unveiled an important and novel role of FKN/CX3CR1 in RIBI, providing evidence to validate that promotion of the FKN/CX3CR1 axis could be a promising therapeutic strategy for the treatment of RIBI.

Gamma Irradiation on Genistein: Enhancement of Antioxidant property through Structural transformation

As an early stage of radiation transformation technology (RTT), this study briefly demonstrates radiation-induced structural transformation of genistein, one of flavonoids, and the enhanced anti-oxidative property of transformed genistein. The transformation of the structure of genistein by gamma irradiation was attempted. To prove radiation-induced transformation of genistein, HPLC, LC-MS and NMR analysis were performed. The enhanced anti-oxidative activity expected to appear as a result of changed structure was examined by measurement of DPPH radical scavenging activity. The purpose of this study is to show the possibility of using RTT to transform the structure of compound rather than using chemical method. Based on the advantages of convenience and fast results compared to chemical synthesis, radiation transformation can be a powerful method to produce various derivatives of polyphenols or compounds.

Modeling Radiation-Induced Neoplastic Cell Transformation In Vitro and Tumor Induction In Vivo with the Local Effect Model.

Ionizing radiation induces DNA damage to cycling cells which, if left unrepaired or misrepaired, can cause cell inactivation or heritable, viable mutations. The latter can lead to cell transformation, which is thought to be an initial step of cancer formation. Consequently, the study of radiation-induced cell transformation promises to offer insights into the general properties of radiation carcinogenesis. As for other end points, the effectiveness in inducing cell transformation is elevated for radiation qualities with high linear energy transfer (LET), and the same is true for cancer induction. In considering DNA damage as a common cause of both cell death and transformations, a worthwhile approach is to apply mathematical models for the relative biological effectiveness (RBE) of cell killing to also assess the carcinogenic potential of high-LET radiation. In this work we used an established RBE model for cell survival and clinical end points, the local effect model (LEM), to estimate the transformation probability and the carcinogenic potential of ion radiation. The provided method consists of accounting for the competing processes of cell inactivation and induction of transformations or carcinogenic events after radiation exposure by a dual use of the LEM. Correlations between both processes inferred by the number of particle impacts to individual cells were considered by summing over the distribution of hits that individual cells receive. RBE values for cell transformation in vitro were simulated for three independent data sets, which were also used to gauge the approach. The simulations reflect the general RBE systematics both in magnitude and in energy and LET dependence. To challenge the developed method, in vivo carcinogenesis was investigated using the same concepts, where the probability for cancer induction within an irradiated organ was derived from the probability of finding carcinogenic events in individual cells. The predictions were compared with experimental data of carcinogenesis in Harderian glands of mice. Again, the developed method shows the same characteristics as the experimental data. We conclude that the presented method is helpful to predictively assess RBE for both neoplastic cell transformation and tumor induction after ion exposure within a wide range of LET values. The theoretical concept requires a non-linear component in the photon dose response for carcinogenic end points as a precondition for the observed enhanced effects after ion exposure, thus contributing to a long debate in epidemiology. Future work will use the method for assessing cancer induction in radiation therapy and exposure scenarios frequently discussed in radiation protection.

Replication stress and FOXM1 drive radiation induced genomic instability and cell transformation.

In contrast to the vast majority of research that has focused on the immediate effects of ionizing radiation, this work concentrates on the molecular mechanism driving delayed effects that emerge in the progeny of the exposed cells. We employed functional protein arrays to identify molecular changes induced in a human bronchial epithelial cell line (HBEC3-KT) and osteosarcoma cell line (U2OS) and evaluated their impact on outcomes associated with radiation induced genomic instability (RIGI) at day 5 and 7 post-exposure to a 2Gy X-ray dose, which revealed replication stress in the context of increased FOXM1b expression. Irradiated cells had reduced DNA replication rate detected by the DNA fiber assay and increased DNA resection detected by RPA foci and phosphorylation. Irradiated cells increased utilization of homologous recombination-dependent repair detected by a gene conversion assay and DNA damage at mitosis reflected by RPA positive chromosomal bridges, micronuclei formation and 53BP1 positive bodies in G1, all known outcomes of replication stress. Interference with the function of FOXM1, a transcription factor widely expressed in cancer, employing an aptamer, decreased radiation-induced micronuclei formation and cell transformation while plasmid-driven overexpression of FOXM1b was sufficient to induce replication stress, micronuclei formation and cell transformation.

Neuroprotective Effect of Fractalkine on Radiation-induced Brain Injury Through Promoting the M2 Polarization of Microglia

Radiation-induced brain injury (RIBI) is a serious complication in cancer patients receiving brain radiotherapy, and accumulating evidence suggests that microglial activation plays an important role in its pathogenesis. Fractalkine (FKN) is a crucial mediator responsible for the biological activity of microglia. In this study, the effect of FKN on activated microglial after irradiation and RIBI was explored and the underlying mechanisms were investigated. Our study demonstrated treatment with exogenous FKN diminished radiation-induced production of pro-inflammatory factors, such as IL1-β and TNFα, promoted transformation of microglial M1 phenotype to M2 phenotype after irradiation, and partially recovered the spatial memory of irradiated mice. Furthermore, upregulation of FKN/CX3CR1 via FKN lentivirus promoted radiation-induced microglial M2 transformation in the hippocampus and diminished the spatial memory injury of irradiated mice. Furthermore, while inhibiting the expression of CX3CR1, which exclusively expressed on microglia in the brain, the regulatory effect of FKN on microglia and cognitive ability of mice disappeared after radiation. In conclusion, the FKN could attenuate RIBI through the microglia polarization toward M2 phenotype by binding to CX3CR1 on microglia. Our study unveiled an important role of FKN/CX3CR1 in RIBI, indicating that promotion of FKN/CX3CR1 axis could be a promising strategy for the treatment of RIBI.

Radiation-Induced Interfacial Hydroxyl Transformation on Boehmite and Gibbsite Basal Surfaces

Understanding the radiolytic reactivity of aluminum oxyhydroxide phases widely present in stored nuclear wastes is essential to develop reliable processing approaches. Recent experiments using vibr...

Tensile behavior of dual-phase titanium alloys under high-intensity proton beam exposure: Radiation-induced omega phase transformation in Ti-6Al-4V

A high-intensity proton beam exposure with 181 MeV energy has been conducted at Brookhaven Linac Isotope Producer facility on various material specimens for accelerator targetry applications, including titanium alloys as a beam window material. The radiation damage level of the analyzed capsule was 0.25 dpa at beam center region with an irradiation temperature around 120 °C. Tensile tests showed increased hardness and a large decrease in ductility for the dual α+β-phase Ti-6Al-4V Grade-5 and Grade-23 extra low interstitial alloys, with the near α-phase Ti-3Al-2.5V Grade-9 alloy still exhibiting uniform elongation of a few % after irradiation. Transmission Electron Microscope analyses on Ti-6Al-4V indicated clear evidence of a high-density of defect clusters with size less than 2 nm in each α-phase grain. The β-phase grains did not contain any visible defects such as loops or black dots, while the diffraction patterns clearly indicated ω-phase precipitation in an advanced formation stage. The radiation-induced ω-phase transformation in the β-phase could lead to greater loss of ductility in Ti-6Al-4V alloys in comparison with Ti-3Al-2.5V alloy with less β-phase.

Explosive desorption from solid methane and methane-containing argon matrices

The total yield of emitted particles from solid CH4 and Ar matrices doped with CH4 was studied under irradiation with electrons. The explosive desorption was detected for these systems. Strong bursts of particles were delayed with respect to the start of irradiation indicating the need for accumulation of radiolysis products. The study was performed using optical and current spectroscopy – cathodoluminescence (CL) together with thermally stimulated exoelectron emission (TSEE) and thermally stimulated post-desorption (TSpD). In the CL spectra, the products of radiation-induced transformation of CH4 molecules were recorded: H, CH, C. Dose dependencies of the optical emissions were measured in a correlated manner with the total yield of particles. It was found that the particles burst correlates with an increase in the concentration of H atoms. Scenario suggested for the delayed particle emission incorporates the recombination of CH3 radicals appearing simultaneously with H atoms in the reaction CH4 → CH3 + H.

Radiation-Induced Transformation of CHF3···CO to the CF3···CO Complex: Matrix Isolation and Ab Initio Study.

The X-ray-induced transformations of CHF3/CO/Ar and CHF3/CO/Kr systems were investigated by Fourier transform infrared (FTIR) matrix isolation spectroscopy at 6 K. It was found that addition of CO suppressed decomposition of fluoroform in an Ar matrix, probably because of trapping of matrix holes by CO and CHF3···CO complexes. Considerable increase of the CF3/CF2 ratio with increasing CO content in the matrix was attributed to stabilization of the CF3 radical with respect to further radiation-induced fragmentation because of its complexation with the CO molecule. The CF3···CO complex generated from the CHF3···CO precursor complex was characterized by FTIR spectroscopy and ab initio calculations at the CCSD(T) and MP2 levels of theory. To the best of our knowledge, it is the first experimentally observed complex of the CF3 radical. The computed interaction energy was found to be 0.35 kcal/mol at the CCSD(T)/L2a_3 level (0.36 kcal/mol at the MP2/L2a_3 level), taking into account zero-point energy and basis set superposition error corrections. Despite the very weak intermolecular bonding, the complex is characterized by distinct features in the regions of C-F symmetric and antisymmetric stretching (CF3) and CO stretching (the latter one was observed only in a krypton matrix). The geometrical structure of the radical-molecule complex is close to that of its molecular precursor.

Early versus delayed postoperative radiotherapy for treatment of low-grade gliomas.

This is an update of the review originally published in 2011 and first updated in 2015. In most people with low-grade gliomas (LGG), the primary treatment regimen remains a combination of surgery followed by postoperative radiotherapy. However, the optimal timing of radiotherapy is controversial. It is unclear whether to use radiotherapy in the early postoperative period, or whether radiotherapy should be delayed until tumour progression occurs. To assess the effects of early postoperative radiotherapy versus radiotherapy delayed until tumour progression for low-grade intracranial gliomas in people who had initial biopsy or surgical resection. Original searches were run up to September 2014. An updated literature search from September 2014 through November 2019 was performed on the following electronic databases: the Cochrane Central Register of Controlled Trials (CENTRAL; 2019, Issue 11), MEDLINE via Ovid (September 2014 to November week 2 2019), and Embase via Ovid (September 2014 to 2019 week 46) to identify trials for inclusion in this Cochrane review update. We included randomised controlled trials (RCTs) that compared early versus delayed radiotherapy following biopsy or surgical resection for the treatment of people with newly diagnosed intracranial LGG (astrocytoma, oligodendroglioma, mixed oligoastrocytoma, astroblastoma, xanthoastrocytoma, or ganglioglioma). Radiotherapy may include conformal external beam radiotherapy (EBRT) with linear accelerator or cobalt-60 sources, intensity-modulated radiotherapy (IMRT), or stereotactic radiosurgery (SRS). Three review authors independently assessed the trials for inclusion and risk of bias, and extracted study data. We resolved any differences between review authors by discussion. Adverse effects were also extracted from the study report. We performed meta-analyses using a random-effects model with inverse variance weighting. We included one large, multi-institutional, prospective RCT, involving 311 participants; the risk of bias in this study was unclear. This study found that early postoperative radiotherapy was associated with an increase in time to progression compared to observation (and delayed radiotherapy upon disease progression) for people with LGG but did not significantly improve overall survival (OS). The median progression-free survival (PFS) was 5.3 years in the early radiotherapy group and 3.4 years in the delayed radiotherapy group (hazard ratio (HR) 0.59, 95% confidence interval (CI) 0.45 to 0.77; P < 0.0001; 311 participants; 1 trial; low-quality evidence). The median OS in the early radiotherapy group was 7.4 years, while the delayed radiotherapy group experienced a median overall survival of 7.2 years (HR 0.97, 95% CI 0.71 to 1.33; P = 0.872; 311 participants; 1 trial; low-quality evidence). The total dose of radiotherapy given was 54 Gy; five fractions of 1.8 Gy per week were given for six weeks. Adverse effects following radiotherapy consisted of skin reactions, otitis media, mild headache, nausea, and vomiting. Rescue therapy was provided to 65% of the participants randomised to delayed radiotherapy. People in both cohorts who were free from tumour progression showed no differences in cognitive deficit, focal deficit, performance status, and headache after one year. However, participants randomised to the early radiotherapy group experienced significantly fewer seizures than participants in the delayed postoperative radiotherapy group at one year (25% versus 41%, P = 0.0329, respectively). Given the high risk of bias in the included study, the results of this analysis must be interpreted with caution. Early radiation therapy was associated with the following adverse effects: skin reactions, otitis media, mild headache, nausea, and vomiting. People with LGG who underwent early radiotherapy showed an increase in time to progression compared with people who were observed and had radiotherapy at the time of progression. There was no significant difference in overall survival between people who had early versus delayed radiotherapy; however, this finding may be due to the effectiveness of rescue therapy with radiation in the control arm. People who underwent early radiation had better seizure control at one year than people who underwent delayed radiation. There were no cases of radiation-induced malignant transformation of LGG. However, it remained unclear whether there were differences in memory, executive function, cognitive function, or quality of life between the two groups since these measures were not evaluated.

RTHP-04. PEDIATRIC STEREOTACTIC RADIOSURGERY FOR BENIGN NEUROLOGIC DISEASE: A 25-YEAR INSTITUTIONAL EXPERIENCE

Abstract Long-term outcomes and sequalae of pediatric stereotactic radiosurgery (SRS) for benign neurologic disease are poorly understood. We sought to explore the efficacy and late effects of SRS in pediatric patients treated our institution. After institutional review board approval, we performed a retrospective analysis of patients age 21 or younger treated between 1990 and 2016. Covariates were summarized with descriptive statistics. 56 consecutive patients were enrolled. Patients were primarily Caucasian (n=51, 93%) males (n=30, 54%). Diagnoses included arterio-venous malformation (n=41, 73%) and functional pituitary adenoma (n=9, 16%) as well as vestibular schwannoma, craniopharyngioma, meningioma, papilloma, and ganglioglioma. Average age was 14 years (95% CI 13–16 years). SRS was often the first intervention (n=22, 44%); treatments prior to SRS included embolization (n=18, 36%) and surgery (n=10, 20%). SRS was typically single fraction (n=45, 94%) with a median total dose of 16 Gy (IQR 15–18 Gy). Most patients had no acute side effects of SRS (n=40, 87%). Median follow-up time after SRS was 12 years (IQR 6–18 years, max 26 years). 91% of patients had no late sequelae of SRS. One patient was diagnosed with radionecrosis one year after repeat SRS for residual malformation. Two patients had malformation hemorrhage. One patient with brainstem malformation developed focal weakness after ischemia from treatment effect; another patient with malformation developed seizures related to SRS edema. Over 673 patient-years following SRS, no patient developed radiation-induced malignancy or malignant transformation. Median disease-free survival after SRS was 6 years (IQR 3–13) with 66% overall local control; 84% of local failures occurred within 5 years of SRS. At last follow-up, 95% of patients remained without evidence of disease with 100% overall survival. These data support the long-term safety and efficacy of pediatric SRS.

Curcumin Reverses Ionizing Radiation-induced Epithelial Mesenchymal Transformation of Non-small Cell Lung Cancer A549 Cells

Curcumin Reverses Ionizing Radiation-induced Epithelial Mesenchymal Transformation of Non-small Cell Lung Cancer A549 Cells

Radiation-Induced Malignancy following Stereotactic Radiosurgery for Benign Intracranial Pathology

Radiation-induced malignant transformation is a risk associated with stereotactic radiosurgery (SRS); however, prevalence is uncertain. We sought to characterize the cumulative incidence of radiation-induced malignancy at our institution. Based on other retrospective studies, we hypothesized that the five-year incidence of malignant transformation and radiation-associated secondary central nervous system (CNS) cancer after SRS is less than 1%. After IRB approval, we undertook a retrospective consecutive case series evaluating patients with at least 5 years of event-free clinical follow-up treated with non-invasive SRS or Linac-based SRS between 1990 and 2014 for benign CNS pathology including: arteriovenous malformation (AVM), pituitary adenoma, WHO grade I-II meningiomas, vestibular schwannoma, paraganglioma, angiofibroma, chordoma, craniopharyngioma, epilepsy, ganglioglioma, hemangioblastoma, hemangiopericytoma, oligodendroglioma, papilloma, parotid adenoma, tremor, and trigeminal neuralgia. Radiation-associated secondary intracranial cancer was defined as a new primary CNS malignancy within the plan’s 2 Gy isodose line. Biologically effective dose (BED) was calculated using an alpha/beta ratio of 2. Baseline characteristics and treatment details were recorded and summarized with descriptive statistics. After exclusion of 362 patients lacking follow-up, a total of 273 patients were enrolled. Median age at treatment was 44 years (range 2-82) including pediatric (n=33) and adult (n=240) patients. SRS indications included AVM (n=100, 37%), pituitary adenoma (n=67, 25%), WHO grade I-II meningioma (n=39, 14%), vestibular schwannoma (n=32, 12%), paraganglioma (n=13, 4.8%), and other (n=22, 8%). Median prescription dose was 18 Gy (range 6-140 Gy), median number of fractions was 1 (range 1-5), and median BED was 131 Gy2(range 24-9940 Gy2). Median follow-up after SRS was 10.5 years (range 4.7-27). Over 3,216 patient-years following SRS, two cases of radiation-induced malignant transformation occurred for a per-patient rate of 0.73% or case rate of 0.62 per 1,000 patient-years. The first patient was treated with Linac SRS for vestibular schwannoma with 21 Gy in 3 fractions, and 16 years later developed an ipsilateral malignant peripheral nerve sheath tumor in the cerebellopontine angle. The second patient was treated with non-invasive stereotactic radiosurgery for vestibular schwannoma and 3 years later developed a malignant peripheral nerve sheath tumor. The five-year incidence of radiation-associated malignant transformation and radiation-induced secondary malignancy following SRS for benign CNS pathology at our institution is reassuringly low at 0.62 cases per 1,000 patient-years. These data support the safety of SRS for benign intracranial pathology.

Resolving the 3D Orientation of Terphenylthiol Molecules on Noble Metals with Kelvin Probe Force Microscopy

The local work function is an invaluable feature for the specific analysis of the influences of atomic and molecular nanostructures on each other as well as the underlying surface. Adsorbate molecules can modify this parameter by introducing an electrical dipole moment, which affects the local contact potential. This can be accessed by Kelvin probe force microscopy (KPFM). In this paper, we demonstrate, by combining highly resolved topographic atomic force microscopy (AFM) data with the simultaneously acquired local work function signal, how each of these channels yield one angular coordinate, resulting in the three-dimensional determination of surface molecular dipole orientations. We studied the adsorption of terphenylthiol (TPT) self-assembled monolayers on Au(111) and Ag(111), as it is relevant in the light of electron radiation-induced transformation to carbon nanomembranes. We present noncontact AFM data combined with frequency-modulated KPFM in ultrahigh vacuum at room temperature without any kind of deliberate tip functionalization. Our results show a surface coverage-dependent Langmuir-like evolution of phases with domains of flat lying as well as with upright molecular arrangements. Whereas we found an almost complete vertical orientation on silver, the orientation on gold was found to be tilted, corresponding to sp- and sp3-hybridized bond angles, respectively.