Generality Assessment of a Model Considering Heterogeneous Cancer Cells for Predicting Tumor Control Probability for Stereotactic Body Radiation Therapy Against Non-Small Cell Lung Cancer.

The generality of a model for predicting tumor control probability from in vitro clonogenic survival considering of cancer stem-like cells, the so-called integrated microdosimetric-kinetic model, is presented by comparing the model to public data on stereotactic body radiation therapy for non-small cell lung cancer cells.

Monte Carlo simulations of organ and effective doses and dose-length product for dental cone-beam CT.

OBJECTIVES: The use of dental cone-beam CT (CBCT) has increased in recent years. We aimed to calculate the organ and effective doses in dental CBCT using Monte Carlo simulation (MCS) and to correlate the effective dose with the dose-length product (DLP), which is a radiation dose index. METHODS: Organ and effective doses were calculated by MCS using the adult male and female reference phantoms of the International Commission on Radiological Protection publication 110 in a half-rotation scan of the CBCT scanner Veraviewepocs 3Df. The simulations were performed by setting nine protocols in combination with the field-of-view (FOV) and imaging region. In addition, DLPs were calculated by MCS using the virtual CT Dose Index (CTDI) and CBCT phantoms, with the same protocol. RESULTS: The effective doses were 55 and 195 µSv at the minimum FOV of Φ40 × H40 mm and maximum FOV of Φ 80 × H80 mm, respectively. The organs with the major contribution to the effective dose were the red bone marrow (11.0‒12.8%), thyroid gland (4.0‒12.7%), salivary gland (21.8‒33.2%), and remaining tissues (35.1‒45.7%). Positive correlations were obtained between the effective dose and calculated DLP using the CTDI and CBCT phantoms. CONCLUSIONS: Organ and effective doses for each protocol of dental CBCT could be estimated using MCS. There was a positive correlation between the effective dose and DLP, suggesting that DLP can be used to estimate the effective dose of CBCT.

Are Online Simulations for Radiation Emergency Medical Preparedness Less Effective in Teaching Than Face-to-Face Simulations?

OBJECTIVE: The study clarified differences in understanding and satisfaction between face-to-face and online training on radiation emergency medical preparedness (REMP) training. METHODS: The training was held at Hirosaki University between 2018 and 2022, with 46 face-to-face participants and 25 online participants. RESULTS: Face-to-face training was significantly more understandable than online for the use of the Geiger counter (P < 0.05), but the educational effect of virtual reality (VR) was not significantly different from the actual practice. For the team exercise of taking care of the victims, online resulted in a significantly higher understanding (P < 0.05). CONCLUSIONS: Interactive exercises can be done online with equipment sent to learners, and VR is also as effective. The use of videos was more effective for first-timers to learn the practical process from a bird's-eye view, especially for team-based medical procedures.

Translational study for stereotactic body radiotherapy against non-small cell lung cancer, including oligometastases, considering cancer stem-like cells enable predicting clinical outcome from in vitro data.

BACKGROUND: Curative effects of stereotactic body radiotherapy (SBRT) for non-small cell lung cancer (NSCLC) have been evaluated using various biophysical models. Because such model parameters are empirically determined based on clinical experience, there is a large gap between in vitro and clinical studies. In this study, considering the heterogeneous cell population, we performed a translational study to realize the possible linkage based on a modeling approach. METHODS: We modeled cell-killing and tumor control probability (TCP) considering two populations: progeny and cancer stem-like cells. The model parameters were determined from in vitro survival data of A549 and EBC-1 cells. Based on the cellular parameters, we predicted TCP and compared it with the corresponding clinical data from 553 patients collected at Hirosaki University Hospital. RESULTS: Using an all-in-one developed model, the so-called integrated microdosimetric-kinetic (IMK) model, we successfully reproduced both in vitro survival after acute irradiation and the 3-year TCP with various fractionation schemes (6-10 Gy per fraction). From the conventional prediction without considering cancer stem cells (CSCs), this study revealed that radioresistant CSCs play a key role in the linkage between in vitro and clinical outcomes. CONCLUSIONS: This modeling study provides a possible generalized biophysical model that enables precise estimation of SBRT worldwide.

DNA­PKcs phosphorylation specific inhibitor, NU7441, enhances the radiosensitivity of clinically relevant radioresistant oral squamous cell carcinoma cells.

Radioresistant cancer cells lead to poor prognosis after radiotherapy. However, the mechanisms underlying cancer cell radioresistance have not been fully elucidated. Thus, the DNA damage response of clinically relevant radioresistant oral squamous cell carcinoma HSC2-R cells, established by long-term exposure of parental HSC2 cells to fractionated radiation, was investigated. The DNA double-strand break (DSB) repair protein-specific inhibitor, NU7441, which targets DNA-dependent protein kinase catalytic subunit (DNA-PKcs) phosphorylation, and IBR2, which targets Rad51, were administered to HSC2 and HSC2-R cells. NU7441 administration eliminated colony formation in both cell lines under 6 Gy X-ray irradiation, whereas IBR2 did not affect colony formation. NU7441 and IBR2 significantly enhanced 6 Gy X-ray irradiation-induced apoptosis in HSC2-R cells. In HSC2-R cells, cell cycle arrest released earlier than in HSC2 cells, and phosphorylated-H2A histone family member X (γH2AX) expression rapidly decreased. Following NU7441 administration, γH2AX expression and the cell percentages of the G2/M phase were not decreased at 48 h after treatment in HSC2-R cells. DNA-PKcs has been demonstrated to regulate non-homologous end-joining (NHEJ) and homologous recombination (HR) repair, and the later phase of DSB repair is dominated by HR. Therefore, the results of the present study indicated that the DSB repair mechanism in HSC2-R cells strongly depends on NHEJ and loss of HR repair function. The present study revealed a potential mechanism underlying the acquired radioresistance and therapeutic targets in radioresistant cancer cells.

4-Methylumebelliferone Enhances Radiosensitizing Effects of Radioresistant Oral Squamous Cell Carcinoma Cells via Hyaluronan Synthase 3 Suppression.

Radioresistant (RR) cells are poor prognostic factors for tumor recurrence and metastasis after radiotherapy. The hyaluronan (HA) synthesis inhibitor, 4-methylumbelliferone (4-MU), shows anti-tumor and anti-metastatic effects through suppressing HA synthase (HAS) expression in various cancer cells. We previously reported that the administration of 4-MU with X-ray irradiation enhanced radiosensitization. However, an effective sensitizer for radioresistant (RR) cells is yet to be established, and it is unknown whether 4-MU exerts radiosensitizing effects on RR cells. We investigated the radiosensitizing effects of 4-MU in RR cell models. This study revealed that 4-MU enhanced intracellular oxidative stress and suppressed the expression of cluster-of-differentiation (CD)-44 and cancer stem cell (CSC)-like phenotypes. Interestingly, eliminating extracellular HA using HA-degrading enzymes did not cause radiosensitization, whereas HAS3 knockdown using siRNA showed similar effects as 4-MU treatment. These results suggest that 4-MU treatment enhances radiosensitization of RR cells through enhancing oxidative stress and suppressing the CSC-like phenotype. Furthermore, the radiosensitizing mechanisms of 4-MU may involve HAS3 or intracellular HA synthesized by HAS3.

Service-Learning Experiences Related to Health Support Activities for Residents Who Have Returned Home after Evacuation Due to a Radiation Disaster.

Hirosaki University has regularly offered health support activities to residents of X town in Fukushima, and thus, some interactive benefits are expected as a service-learning experience for nursing students. This study aimed to clarify the experiences of students who participated in service-learning and consider which methods and content were effective. In total, 52 nursing students were recruited into the program, which was held from 2018 to 2021. The roles of students included assisting in health consultations related to a radiation disaster. Questionnaires designed by researchers with experience in risk communication programs were conducted on the students after the program, and included the reasons why they joined, their most memorable experiences, and their opinions regarding required support for residents. The data were analyzed by content analysis. The nursing students thought about the health of residents through health support activities in the affected areas. Furthermore, by communicating with residents via on-site service-learning, they could experience the humanity of the residents and the current status of the affected areas, learn the importance of person-to-person relationships, and think about reconstruction. Thus, service-learning was found to be effective and to offer substantial benefits for both residents and students in affected areas.

Training of Medical Responders to Nuclear Disaster: Hybrid Program in the COVID-19 Pandemic.

OBJECTIVE: The spread of COVID-19 has made it difficult to provide training in medical treatment in a radiation disaster. In this study, we will examine the effects and challenges of using a hybrid approach that combines online and face-to-face components. METHODS: A total of 5 face-to face and 25 online medical staff participated in the training program. This program was conducted by using multiple cameras for live coverage, while protective clothing and decontamination kits had been sent in advance to the participants so that they could experience face-to-face and online learning at the same time. RESULTS: Participants reported a high level of satisfaction and achievement with the style of delivery. They also experienced problems such as fatigue due to long hours, and dissatisfaction with the debriefing. CONCLUSIONS: In designing new online training, it is necessary to consider the quantity and content of the program, and to take participant fatigue into consideration.

Identification of novel prognostic factors focusing on clinical outcomes in patients with non-small cell lung cancer after stereotactic body radiotherapy.

Stereotactic body radiotherapy (SBRT) has attracted extensive attention as an effective treatment for patients with early-stage non-small cell lung cancer. However, the factors affecting prognosis after SBRT have not been fully elucidated. The aim of the present study was to investigate the prognostic factors associated with overall survival (OS) and local control (LC) after SBRT. Between March 2003 and March 2020, 497 patients with primary or oligo-metastatic lung cancer who underwent SBRT treatment were retrospectively reviewed. Univariate analysis was performed against various factors related to patient and tumor characteristics using Kaplan-Meier method. Furthermore, the factors with statistically significant differences identified via univariate analysis underwent a stratified Cox proportional hazard regression analysis. The median follow-up period for all patients was 26.17 months (range, 0.36-194.37), and the 5-year OS and LC rates were 66.3 and 86.0%, respectively. Multivariate analysis showed that surfactant protein-D (SP-D), tumor CT values (TCTV) and iodine density values (IDV) were independent prognostic factors for OS, and histology, TCTV and IDV were for LC. Although histology was not selected as a prognostic factor related to OS, it was indicated that patients with squamous cell carcinoma were associated with the SP-D high group compared with the SP-D normal group. In addition, TCTV was correlated to water density values, which tended to decrease with increasing IDV. From these findings, SP-D and TCTV were identified as potential new candidate prognostic factors after SBRT, and it is possible that combining SP-D and histology, and TCTV and IDV may improve the accuracy of prognostic prediction.

Tumor radioresistance caused by radiation-induced changes of stem-like cell content and sub-lethal damage repair capability.

Cancer stem-like cells (CSCs) within solid tumors exhibit radioresistance, leading to recurrence and distant metastasis after radiotherapy. To experimentally study the characteristics of CSCs, radioresistant cell lines were successfully established using fractionated X-ray irradiation. The fundamental characteristics of CSCs in vitro have been previously reported; however, the relationship between CSC and acquired radioresistance remains uncertain. To efficiently study this relationship, we performed both in vitro experiments and theoretical analysis using a cell-killing model. Four types of human oral squamous carcinoma cell lines, non-radioresistant cell lines (SAS and HSC2), and radioresistant cell lines (SAS-R and HSC2-R), were used to measure the surviving fraction after single-dose irradiation, split-dose irradiation, and multi-fractionated irradiation. The SAS-R and HSC2-R cell lines were more positive for one of the CSC marker aldehyde dehydrogenase activity than the corresponding non-radioresistant cell lines. The theoretical model analysis showed that changes in both the experimental-based ALDH (+) fractions and DNA repair efficiency of ALDH (-) fractions (i.e., sub-lethal damage repair) are required to reproduce the measured cell survival data of non-radioresistant and radioresistant cell lines. These results suggest that the enhanced cell recovery in SAS-R and HSC2-R is important when predicting tumor control probability in radiotherapy to require a long dose-delivery time; in other words, intensity-modulated radiation therapy is ideal. This work provides a precise understanding of the mechanism of radioresistance, which is induced after irradiation of cancer cells.

The Effect of High-Dose-Rate Pulsed Radiation on the Survival of Clinically Relevant Radioresistant Cells.

We demonstrated that low dose pulsed radiation (0.25 Gy) at a high-dose-rate, even for very short intervals (10 s), decreases cell survival to a greater extent than single exposure to a similar total dose and dose rate. The objective of this study was to clarify whether high-dose-rate pulsed radiation is effective against SAS-R, a clinically relevant radioresistant cell line. Cell survival following high-dose-rate pulsed radiation was evaluated via a colony assay. Flow cytometry was utilized to evaluate γH2AX, a molecular marker of DNA double-strand breaks and delayed reactive oxygen species (ROS) associated with radiation-induced apoptosis. Increased cytotoxicity was observed in SAS-R and parent SAS cells in response to high dose rate pulsed radiation compared to single dose, as determined by colony assays. Residual γH2AX in both cells subjected to high-dose-rate pulsed radiation showed a tendency to increase, with a significant increase observed in SAS cells at 72 h. In addition, high-dose-rate pulsed radiation increased delayed ROS more than the single exposure did. These results indicate that high-dose-rate pulsed radiation was associated with residual γH2AX and delayed ROS, and high-dose-rate pulsed radiation may be used as an effective radiotherapy procedure against radioresistant cells.

4-Methylumbelliferone administration enhances radiosensitivity of human fibrosarcoma by intercellular communication.

Hyaluronan synthesis inhibitor 4-methylumbelliferone (4-MU) is a candidate of radiosensitizers which enables both anti-tumour and anti-metastasis effects in X-ray therapy. The curative effects under such 4-MU administration have been investigated in vitro; however, the radiosensitizing mechanisms remain unclear. Here, we investigated the radiosensitizing effects under 4-MU treatment from cell experiments and model estimations. We generated experimental surviving fractions of human fibrosarcoma cells (HT1080) after 4-MU treatment combined with X-ray irradiation. Meanwhilst, we also modelled the pharmacological effects of 4-MU treatment and theoretically analyzed the synergetic effects between 4-MU treatment and X-ray irradiation. The results show that the enhancement of cell killing by 4-MU treatment is the greatest in the intermediate dose range of around 4 Gy, which can be reproduced by considering intercellular communication (so called non-targeted effects) through the model analysis. As supposed to be the involvement of intercellular communication in radiosensitization, the oxidative stress level associated with reactive oxygen species (ROS), which leads to DNA damage induction, is significantly higher by the combination of 4-MU treatment and irradiation than only by X-ray irradiation, and the radiosensitization by 4-MU can be suppressed by the ROS inhibitors. These findings suggest that the synergetic effects between 4-MU treatment and irradiation are predominantly attributed to intercellular communication and provide more efficient tumour control than conventional X-ray therapy.

Estimation of Effect of Radiation Dose Reduction for Internal Exposure by Food Regulations under the Current Criteria for Radionuclides in Foodstuff in Japan Using Monitoring Results.

This study examined the effect of food regulations under the current criteria (e.g., 100 Bq/kg for general foods) established approximately a year after the Fukushima Dai-ichi Nuclear Power Plant (FDNPP) accident. Foods are monitored to ensure that foods exceeding the standard limit are not distributed; ~300,000 examinations per year have been performed especially since FY2014. This study comprehensively estimated the internal exposure dose resulting from the ingestion of foods containing radioactive cesium using the accumulated monitoring results. Committed effective dose was conservatively calculated as the product of the radioactive concentration randomly sampled from test results, food intake, and dose coefficient. The median, 95th, and 99th percentile of the dose were 0.0479, 0.207, and 10.6 mSv/y, respectively, in the estimation with all test results (without regulation), and 0.0430, 0.0790, and 0.233 mSv/y, respectively, in the estimation with results within the standard limits (with regulation) in FY2012. In FY2016, the dose with and without regulation were similar, except for high percentile, and those doses were significantly smaller than 1 mSv/y, which was adopted as the basis for the current criteria. The food regulation measures implemented in Japan after the FDNPP accident have been beneficial, and food safety against radionuclides has been ensured.

Matrix Metalloproteinase-2 Activated by Ultraviolet-B Degrades Human Ciliary Zonules In Vitro.

The ciliary zonules, also known as the zonules of Zinn, help to control the thickness of the lens during focusing. The ciliary zonules are composed of oxytalan fibers, which are synthesized by human nonpigmented ciliary epithelial cells (HNPCEC). The ciliary zonules are exposed to ultraviolet (UV), especially UV-A and UV-B, throughout life. We previously demonstrated that UV-B, but not UV-A, degrades fibrillin-1- and fibrillin-2-positive oxytalan fibers. However, the mechanism by which UV-B degrades oxytalan fibers remains unknown. In this study, we investigate the involvement of matrix metalloproteinase-2 (MMP-2) in the UV-B-induced degradation of fibrillin-1- and fibrillin-2-positive oxytalan fibers in cultured HNPCECs. Enzyme-linked immunosorbent assay revealed that UV-B irradiation at levels of 100 and 150 mJ/cm2 significantly increased the level of active MMP-2. Notably, MMP-2 inhibitors completely suppressed the degradation of fibrillin-1- and fibrillin-2-positive oxytalan fibers. In addition, we show that UV-B activates MMP-2 via stress-responsive kinase p38. Taken together, the results suggest that UV-B activates a production of active type of MMP-2 via the p38 pathway, and subsequently, an active-type MMP-2 degrades the fibrillin-1- and fibrillin-2-positive oxytalan fibers in cultured HNPCECs.

Apparent diffusion coefficient measurement using thin-slice diffusion-weighted magnetic resonance imaging: assessment of measurement errors and repeatability.

We investigated the measurement error and repeatability of the apparent diffusion coefficient (ADC) obtained using thin-slice imaging. Diffusion-weighted images of an ice-water phantom were acquired using 1.5-T and 3.0-T scanners with 1-, 3-, and 5-mm thickness. ADC maps were generated at b = 0 and 1000 mm2/s using five consecutive scans. Measurement errors were assessed with accuracy and precision. Repeatability was assessed using the within-subject coefficient of variation. The ADC accuracy of both scanners agreed with the ADC of water at 0 °C. At 1-mm, precisions were 2.9% and 8.4% for the 3.0-T and 1.5-T scanners, respectively. The repeatabilities of 1-mm thickness were 1.3% and 3.4% in the 3.0-T and 1.5-T scanners, respectively. The 3.0-T scanner showed acceptable measurement errors and moderate repeatability compared with Quantitative Imaging Biomarkers Alliance recommendation. A 3.0-T scanner can be used for reliable ADC measurement, even with a 1-mm thickness at a reasonable scan time.

Prognostic value of quantitative FDG-PET in the prediction of survival and local recurrence for patients with advanced oral cancer treated with superselective intra-arterial chemoradiotherapy.

The current study aimed to evaluate the relationship between 18F-fluorodeoxyglucose positron emission tomography with computed tomography (FDG-PET-CT) standardized uptake value (SUV) [pre-treatment SUV (pre-SUV) and post-treatment SUV (post-SUV)] and treatment results in patients with advanced oral cancer treated with superselective intra-arterial chemoradiotherapy (SSIACRT). A total of 37 patients with advanced oral cancer were treated with SSIACRT. The treatment consisted of superselective intra-arterial chemotherapy (docetaxel (DOC) 40 mg/mm2 and nedaplatin (CDGP) 80 mg/mm2) and concurrent radiotherapy (60-70 Gy) for a period of seven weeks. Pre-SUV and post-SUV of the primary tumor were measured. Overall survival (OS) and local control (LC) rates were selected as endpoints to evaluate prognosis. The median follow-up was 40 months (range 6-112 months). The 5-year OS and LC rates were 64.5 and 85.5%, respectively, and SSIACRT achieved high LC rate even in advanced oral cancers. In the log-rank test, post-SUV was a significant prognostic factor for OS and LC rates. The results of the current study demonstrated that SSIACRT is a reliable treatment with respect to survival in advanced oral cancer and post-SUV was a significant prognostic factor for OS and LC rates.

4-methylumbelliferone inhibits clonogenic potency by suppressing high molecular weight-hyaluronan in fibrosarcoma cells.

The inflammatory response is closely associated with cancer cell survival. It has been reported that inflammatory signaling cascades promote tumor survival and exert detrimental effects in normal tissue. Hyaluronans have different cellular functions depending on their molecular weights and high molecular weight-hyaluronan (HMW-HA) exhibits anti-inflammatory effects. A previous study determined that the co-administration of 4-methylumbelliferone (4-MU) and X-ray irradiation enhanced anti-tumor and anti-inflammatory effects in HT1080 human fibrosarcoma cells. However, many mechanisms underlie the effect of hyaluronan molecular weight on cells and the induction of anti-inflammatory effects via 4-MU. The present study aimed to determine the relationship between hyaluronan synthesis inhibition by 4-MU and its anti-inflammatory and radio-sensitizing effect in the context of hyaluronan molecular weight. The hyaluronan concentration following 2 Gy X-ray irradiation and/or 4-MU administration was analyzed via ELISA. Additionally, the mRNA expressions of hyaluronan synthase (HAS) by 4-MU and various inflammatory cytokines and interleukins (IL) following exogenous HMW-HA administration were evaluated via Reverse transcription-quantitative PCR. Invasive potential was assessed by matrigel transwell assays and cell survival following exposure to 4-MU with HMW-HA was determined using a clonogenic potency assay. The results of the present study demonstrated that 4-MU suppressed HMW-HA production by inhibiting HAS2 and HAS3 expression. In addition, the surviving fraction of fibrosarcoma cells were rescued from the cell-killing effect of 4-MU via the exogenous administration of HMW-HA. The mRNA levels of certain inflammatory cytokines, including IL-1α, IL-36γ and IL-37 were elevated following HMW-HA administration. The surviving fraction of cells irradiated with 2 Gy alone did not increase following exogenous HMW-HA administration. The results of the present study indicated that the radio-sensitizing effect of 4-MU and the inhibitory effect on hyaluronan synthesis were not closely associated. It was also revealed that IL-1α, IL-36γ and IL-37 were associated with the cell-killing effect of 4-MU in HT1080 cells.

THE IMPACT ON THE EYE LENS OF RADIATION EMITTED BY NATURAL RADIONUCLIDES (LEAD-210) PRESENT IN RADIATION PROTECTION GLASSES.

Most radiation protection items made from modern lead contain 210Pb. This study estimated the impact on eye lens of radiation derived from the 210Pb in three types of radiation protection glasses. The counts from the glasses were measured using a Geiger-Müeller survey meter. The net count rate was 92 ± 1 cpm at a distance of 0.5 cm for one type of glasses. Additionally, we conducted a qualitative γ-ray spectrum analysis using a high-purity germanium semiconductor detector. The absorbed dose in the eye lens was related to 210Pb and its daughter radionuclide, 210Bi; this dose was calculated by applying dose conversion coefficients provided by the International Commission on Radiological Protection. The absorbed dose rate in eye lens was conservatively calculated to be on the order of 10 nGy/h for the type of glasses containing the most 210Pb. The dose from ß-rays accounted for >99%. In addition, we investigated the dose-reduction effect using a thin acrylic plate. The count rate approximately decreased to background level by inserting a plate with a thickness of 1 mm. We conclude that the impact of 210Pb contained in radiation protection glasses is negligibly small, particularly considering the usefulness of the significant external exposure reduction.