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Over the past few decades, tetrafluoroethane (TFE, R134a Freon)-based gases have been widely used in the operation of phenolic resistive plate chambers (RPCs) in many high-energy experiments. However, TFE has a high global warming potential (GWP); therefore, a search for new eco-friendly gases to replace traditional TFE-based ones is now unavoidable. In this research, we present cosmic-ray test results of a prototype RPC for the SHiP (search for hidden particles) experiment using 1.6- and 1.4-mm-thick RPC electrodes containing mixtures of various gases, including 1,3,3,3-tetrafluoropropene (HFO1234ze), CO2, iC4H10 and SF6. We compare the performance data gathered with these new gas mixtures with those gathered with a traditional TFE-based gas used for RPCs in compact muon solenoid (CMS) and a toroidal LHC apparatus (ATLAS) experiments. The addition of CO2 to the HFO1234ze-based gas was found to be fairly effective in reducing the working-point high voltage (HVWP) for RPC operation. The results of our experiments lead us to the conclusion that adding 40% CO2 or less, when combined with HFO1234ze-based gas, is conducive to reliable detector performance for SHiP single-gap phenolic RPCs.

This study describes a simple method of inter-fractional photon beam monitoring to measure the entrance dose of radiation treatment using Gafchromic EBT3 film.The film was placed at the center of a 1-cm thick phantom shaped like a block tray and fixed on the accessory tray of the gantry. The entrance dose was measured following the placement of the film in the accessory tray. The dose distribution calculated with the treatment planning system was compared with the dose distribution on the irradiated EBT3 films. The effectiveness of this methodology, as determined by gamma passing rates, was evaluated for the 22 fields of eight three-dimensional conformal radiotherapy (3D-CRT) plans and the 41 fields of nine intensity-modulated radiotherapy (RT) plans. The plans for three-dimensional conformal RT included treatments of the rectum, liver, breast, and head and neck, whereas the plans for intensity-modulated RT included treatments of the liver, brain, and lung.The gamma passing rates for 3D-CRT ranged from 96.4% to 99.5%, with the mean gamma passing rate for 22 fields being 98.0%. The gamma passing rate for intensity-modulated RT ranged from 96.1% to 98.9%, with the mean gamma passing rate for 41 fields being 97.7%. All gamma indices were over the 95% tolerance level.The methodology described in this study, based on Gafchromic EBT3 film, can be utilized for inter-fractional entrance dose monitoring as quality assurance during RT. Clinical application of this method to patients can verify the accuracy of beam delivery in the treatment room.

Tumor-treating fields (TTFields) therapy is increasingly utilized clinically because of its demonstrated efficacy in cancer treatment. However, the risk of skin burns must still be reduced to improve patient safety and posttreatment quality of life.The purpose of this study was to evaluate the methods of constructing electrode arrays that reduce current density exceeding threshold values, which can cause skin burns during TTFields therapy.Electrode and body models were generated using COMSOL software. The body model had the dielectric properties of the scalp. The average current density beneath the central region of the electrode was maintained at ∼31 mA/cmWhile using a single circular electrode, adjustment of the ceramic thickness ratio, adjustment of the metal plate radius, and insertion of an insulator near the edge reduced the deviations of current density by 14.6%, 67.7%, and 75.3%, respectively. Similarly, while using circular electrode arrays, inserting an insulator at the edge of each electrode reduced the deviations of current density significantly, from 8.62 to 2.40 mA/cmInsertion of an insulator at the edge of each electrode was found to be the most effective method of attaining uniform current density distribution beneath the electrode, thereby lowering the risk of adverse effects of TTFields therapy.

This study describes a method that uses a genetic algorithm to select optimal beam angles in proton therapy and evaluates the effectiveness of the proposed algorithm in actual patients. In the use of the genetic algorithm to select the optimal angle, a gene represents the angle of each field and a chromosome represents the combination of beam angles. The fitness of the genetic algorithm, which represents the suitability of the chromosome to the solution, was quantified by using the dose distribution. The weighting factors of the organs used for fitness were obtained from clinical data through logistic regression, reflecting the dose characteristics of actual patients. Genetic operations, such as selection, crossover, mutation, and replacement, were used to modify the population and were repeated until an evaluation based on fitness reached the termination criterion. The proposed genetic algorithm was tested by assessing its ability to select optimal beam angles in three patients with liver cancer. The optimal results for fitness, planning target volume (PTV), normal liver, and skin in the population were compared with the clinical treatment plans, a process that took an average of 36.8 minutes. The dose-volume histograms (DVHs) and the fitness of the genetic algorithm plans did not differ significantly from the actual treatment plans. These findings indicate that the proposed genetic algorithm can automatically generate proton treatment plans with the same quality as actual clinical treatment plans.

The main goals of the Search for Hidden Particles (SHiP) experiment are to observe hidden particles and to run a high-statistics study of tau neutrino events. Two different types of resistive plate chambers (RPCs) will be used in the future SHiP experiment: one for triggers to select the decayed muons emitted via tau neutrino interactions and one for precision time measurements of charged particles, which are expected from the decays of hidden particles. In the present research, we constructed and tested a prototype RPC module to study the fundamental detector performance of the muon trigger RPCs in the tau neutrino detector of the SHiP experiment. The required detector characteristics, such as the intrinsic noise rate, the time response, and the spatial resolution, were proven through the test of the present prototype detector with cosmic muons.

Glioblastoma multiforme (GBM), the most common type of brain tumor, is a very aggressive and treatment-refractory cancer, with a 5-year survival rate of approximately 5%. Hyperthermia (HT) and tumor treating fields (TTF) therapy have been used to treat cancer, either alone or in combination with other treatment methods. Both treatments have been reported to increase the efficacy of other treatment techniques and to improve patient prognosis. The present study evaluated the therapeutic effects of combining HT and TTF on GBM cell lines. Cells were subjected to HT, TTF, HT+TTF, or neither treatment, followed by comparisons of cell proliferation, apoptosis, migration and invasiveness. Clonogenic assays showed that the two treatments had a synergistic effect. The levels of cleaved PARP and cleaved caspase-3 were higher and apoptosis was increased in cells treated with HT+TTF than in cells treated with HT or TTF alone. In addition, HT+TTF showed greater inhibition of GBM cell migration and invasiveness and greater downregulation of STAT3 than either HT or TTF alone. The stronger anticancer effect of HT+TTF suggested that this combination treatment can increase the survival rate of patients with difficult-to-treat cancers such as GBM.

A newly diagnosed or recurrent Glioblastoma multiforme (GBM) can be treated with Tumor-treating fields (TTFields), an emerging type of alternative electric field-based therapy using low-intensity electric fields. TTFields have a penchant to arrest mitosis, eventually leading to apoptosis. Therefore, it is regarded as a potential anticancer therapy. However, in this study, we confirmed the combined efficacy of sorafenib and TTFields to improve the treatment efficiency of malignant GBM. Experimentation revealed the ability of sorafenib to decrease the signal transducer and activator of transcription 3 (STAT3) and this inhibition increased the sensitivity of TTFields in preventing tumor expansion. It was found that both combinatorial as well as monotherapy aimed to inhibit or reduce the level of STAT3, but the extent was different and based upon the reaction conditions. This drug is also capable of arresting multiple kinase pathways along with STAT3-related proteins (Mcl-1 and Survivin). STAT3 silencing can also be accomplished by RNA interference and can increase the TTFields-sensitizing effect of sorafenib. If the effects are reversed and gene regulating STAT3 is expressed more, it annihilates the effects of treatment. Moreover, sorafenib plus TTFields significantly inhibited xenograft tumor growth and combinatorial treatment reduced STAT3 expression more effectively in vivo. These in vitro and in vivo results indicate that sorafenib tends to sensitize GBM cells to TTFields-induced apoptosis by inhibiting STAT3.

Tumor-treating fields therapy involves placing pads onto the patient’s skin to create a low-intensity (1 - 3 V/cm), intermediate frequency (100 - 300 kHz), alternating electric field to treat cancerous tumors. This new treatment modality has been approved by the Food and Drug Administration in the USA to treat patients with both newly diagnosed and recurrent glioblastoma. To deliver the prescribed electric field intensity to the tumor while minimizing exposure of organs at risk, we developed an optimization method for the electric field distribution in the body and compared the electric field distribution in the body before and after application of this optimization algorithm. To determine the electric field distribution in the body before optimization, we applied the same electric potential to all pairs of electric pads located on opposite sides of models. We subsequently adjusted the intensity of the electric field to each pair of pads to optimize the electric field distribution in the body, resulting in the prescribed electric field intensity to the tumor while minimizing electric fields at organs at risk. A comparison of the electric field distribution within the body before and after optimization showed that application of the optimization algorithm delivered a therapeutically effective electric field to the tumor while minimizing the average and the maximum field strength applied to organs at risk. Use of this optimization algorithm when planning tumor-treating fields therapy should maintain or increase the intensity of the electric field applied to the tumor while minimizing the intensity of the electric field applied to organs at risk. This would enhance the effectiveness of tumor-treating fields therapy while reducing dangerous side effects.

Current lung cancer treatments are far from satisfactory; thus, finding novel treatment targets is crucial. We recently identified procollagen-lysine, 2-oxoglutarate 5-dioxygenase 3 (PLOD3), which is involved in fibrosis and tissue remodeling as a radioresistance-related protein in lung cancer cells; however, its mechanism is unclear. In this study, we designed human PLOD3-specific short interfering (si)RNAs and tested their effects on tumor growth inhibition in vitro and in vivo. PLOD3 knockdown overcame chemoresistance and decreased radioresistance by inducing caspase-3-dependent apoptosis in lung cancer cells. Furthermore, PLOD3 interacted with PKCδ to activate caspase-2,4-dependent apoptosis through ER-stress-induced IRE1α activation and the downstream unfolded-protein response pathway. In a mouse xenograft model, PLOD3 knockdown promoted radiation-induced tumor growth inhibition, without side effects. Moreover, lung cancer patients with high PLOD3 expression showed poorer prognosis than those with low PLOD3 expression upon radiotherapy, suggesting that PLOD3 promotes tumor growth. Therefore, PLOD3 siRNA suppresses radioresistance and chemoresistance by inducing apoptosis and renders PLOD3 as a candidate lung cancer biomarker. PLOD3 gene therapy might enhance the efficacy of radiotherapy or chemotherapy in lung cancer patients.

Tumor treating fields (TTFs) are a newly developed cancer therapy technology using an alternating electric field that may be a possible candidate for overcoming the limitations of conventional treatment methods currently used in cancer treatment. Although clinical results using TTFs appear promising, concerns regarding side effects must be clarified to demonstrate the effectiveness of this treatment method. To investigate the side effects of TTF treatment, the damage to normal cell lines and normal tissue of a mouse model was compared with the damage to tumor cells and tumors in a mouse model after TTF treatment. No serious damage was found in the normal cells and normal tissues of the mouse model, suggesting that the side effects of TTF treatment may not be serious. Our evidence based on in vitro and in vivo experiments suggests that TTF may cause selective damage to cancer cells, further demonstrating the potential of TTF as an attractive alternative to conventional cancer treatment modalities.

Tumor-treating fields (TTFs) - a type of electromagnetic field-based therapy using low-intensity electrical fields - has recently been characterized as a potential anticancer therapy for glioblastoma multiforme (GBM). However, the molecular mechanisms involved remain poorly understood. Our results show that the activation of autophagy contributes to the TTF-induced anti-GBM activity in vitro or in vivo and GBM patient stem cells or primary in vivo culture systems. TTF-treatment upregulated several autophagy-related genes (~2-fold) and induced cytomorphological changes. TTF-induced autophagy in GBM was associated with decreased Akt2 expression, not Akt1 or Akt3, via the mTOR/p70S6K pathway. An Affymetrix GeneChip miRNA 4.0 Array analysis revealed that TTFs altered the expression of many microRNAs (miRNAs). TTF-induced autophagy upregulated miR-29b, which subsequently suppressed the Akt signaling pathway. A luciferase reporter assay confirmed that TTFs induced miR-29b to target Akt2, negatively affecting Akt2 expression thereby triggering autophagy. TTF-induced autophagy suppressed tumor growth in GBM mouse models subjected to TTFs as determined by positron emission tomography and computed tomography (PET-CT). GBM patient stem cells and a primary in vivo culture system with high Akt2 levels also showed TTF-induced inhibition. Taken together, our results identified autophagy as a critical cell death pathway triggered by TTFs in GBM and indicate that TTF is a potential treatment option for GBM.

Quality assurance (QA) for medical linear accelerators is indispensable for appropriate cancer treatment. Some international organizations and western advanced countries provide QA guidelines for linear accelerators. Currently, QA regulations for linear accelerators in Korean hospitals specify a system in which each hospital stipulates its independent hospital-based protocols for QA procedures (HP_QAPs) and conducts QA based on these HP_QAPs while regulatory authorities verify whether items under these HP_QAPs have been performed. However, because this regulatory method cannot guarantee the quality of universal treatment, and QA items with tolerance criteria are different in many hospitals, the presentation of standardized QA items and tolerance criteria is essential. In this study, QA items in HP_QAPs from various hospitals and those presented by international organizations. Concordance rates between QA items for linear accelerators that were presented by the aforementioned organizations and those currently being implemented in Korean hospitals were shown to exhibit a daily QA of 50%, a weekly QA of 22%, a monthly QA of 43%, and an annual QA of 65%, and the overall concordance rates of all QA items were approximately 48%. In comparison between QA items being implemented in Korean hospitals and those being implemented in western advanced countries, concordance rates were shown to exhibit a daily QA of 50%, a weekly QA of 33%, a monthly QA of 60%, and an annual QA of 67%, and the overall concordance rate of all QA items were approximately 57%. The results of this study indicate that the HP_QAPs currently implemented by Korean hospitals as QA standards for linear accelerators used in radiation therapy do not meet international standards. To solve this problem, it is necessary to develop national standardized QA items and procedures for linear accelerators., Comment: 22 pages, 12 tables

Glioblastoma, the most common primary brain tumor in adults, is an incurable malignancy with poor short-term survival and is typically treated with radiotherapy along with temozolomide. While the development of tumor-treating fields (TTFields), electric fields with alternating low and intermediate intensity has facilitated glioblastoma treatment, clinical outcomes of TTFields are reportedly inconsistent. However, combinatorial administration of chemotherapy with TTFields has proven effective for glioblastoma patients. Sorafenib, an anti-proliferative and apoptogenic agent, is used as first-line treatment for glioblastoma. This study aimed to investigate the effect of sorafenib on TTFields-induced anti-tumor and anti-angiogenesis responses in glioblastoma cells in vitro and in vivo. Sorafenib sensitized glioblastoma cells to TTFields, as evident from significantly decreased post-TTFields cell viability (p &lt, 0.05), and combinatorial treatment with sorafenib and TTFields accelerated apoptosis via reactive oxygen species (ROS) generation, as evident from Poly (ADP-ribose) polymerase (PARP) cleavage. Furthermore, use of sorafenib plus TTFields increased autophagy, as evident from LC3 upregulation and autophagic vacuole formation. Cell cycle markers accumulated, and cells underwent a G2/M arrest, with an increased G0/G1 cell ratio. In addition, the combinatorial treatment significantly inhibited tumor cell motility and invasiveness, and angiogenesis. Our results suggest that combination therapy with sorafenib and TTFields is slightly better than each individual therapy and could potentially be used to treat glioblastoma in clinic, which requires further studies.

Alternating electric fields at an intermediate frequency (100~300 kHz), called tumor treating fields (TTFs), are reported to interrupt the process of mitosis via apoptosis and to act as an inhibitor of cell proliferation. Although the presence of an antimitotic effect of TTFs has been widely reported, the efficacy of TTFs is still controversial issue among medical experts. To resolve this controversial issue, the comparison study between the effects of TTFs and the effect of other conventional cancer treatment techniques need to be carried out. In this study, experimental evidence of the synergistic antimitotic effect of TTFs in combination with ionizing radiation (IR) is reported. For these experiments, aggressive brain cancer cells, glioblastoma multiforme (GBM) cells (U373 and U87), were treated either with TTFs alone, with IR alone or with TTFs followed by ionizing radiation (IR). The percentages of cell apoptosis, DNA damage, and mitotic abnormalities were increased by the application of TTFs alone and its quantity was markedly increased when TTFs were combined with IR. Our results also suggested that radiotherapy together with TTFs may be clinically beneficial since the combination treatment seemed to synergistically suppress both cell migration and invasion, based on the inhibition of MMP-9 and vimentin. Citation Format: Eun Ho Kim, Yunhui Jo, Jiwon Sung, Hyo Sook Song, Myonggeun Yoon. Effect of tumor treating fields on cell proliferation and synergistic antitumor efficacy in combination with ionizing radiation [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 838. doi:10.1158/1538-7445.AM2017-838

Tumor treating fields (TTFs) treatment has been reported to have great potential to treat various cancers. Inspired by a similarity between TTFs and radiotherapy in electromagnetic property, TTFs using a fractionated treatment scheme originally designed for radiotherapy were applied to cancer (Human glioblastoma, U373) and normal cells (intestinal epithelial, IEC-6) for three days with durations of 3, 6, 9, or 24 hours/day. As the treatment time of TTFs increases from 3 to 24 hours/day, the relative cancer cell growth rates in both cell lines were reduced. While the difference in cancer cell growth rate compared to control was ~25% (decreased from 100% to ~75%) for the treatment time of 6 hours/day, the growth rates of cells treated for additional 6 hours (i.e., 12 hours/day) and additional 18 hours (i.e., 24 hours/day) differed only ~5% and ~8% from that of cells treated for 6 hours/day, respectively. Our results suggested that the dependence on treatment time in cancer cell inhibition is weakened distinctly at treatment times over 6 hours/day. For normal cells, the relative growth rates corresponding to the treatment time of TTFs was not decreased much for the treatment time of 3, 6, 12 hours/day revealing 93.3%, 90.0%, 89.3% of cell growth rates compared to control, respectively, but it suddenly reduced to ~73% for 24 hours/day of treatment. The experimental results indicated that the effects of TTFs on growth rates of cancer cells are higher than the effects of TTFs on growth rates of normal cells for treatment times of 3-12 hours/day, but the difference became minimal for treatment times of 24 hours/day. Our results suggest that the fractionated scheme in the treatment of tumor treating fields may reduce treatment time while maintaining efficacy, suggesting that this method can increase patients’ quality of life. Citation Format: Yunhui Jo, Jiwon Sung, Hyo Sook Song, Eun Ho Kim, Myonggeun Yoon. Feasibility study of a fractionation method in the treatment of tumor treating fields [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 2312. doi:10.1158/1538-7445.AM2017-2312