Physiologically based pharmacokinetic modelling to predict potential drug-drug interactions of dersimelagon (MT-7117).

AIMS: Dersimelagon is a novel, investigational, orally administered, selective agonist of the melanocortin-1 receptor that has demonstrated efficacy at increasing symptom-free light exposure and an acceptable safety profile in patients with protoporphyria. A phase 1 drug-drug interaction (DDI) study demonstrated that dersimelagon 300 mg has the potential for clinically relevant DDIs with drugs that are substrates for breast cancer resistance protein, such as atorvastatin and rosuvastatin. This study uses physiologically based pharmacokinetic (PBPK) modelling to further investigate the DDI effects at lower doses of dersimelagon with substrate drugs. METHODS: The data from in silico, in vitro and in vivo studies were used to construct a PBPK model for dersimelagon to assess the DDI potential between dersimelagon and substrate drugs for cytochrome P450 3A, P-glycoprotein, organic anion transporting polypeptide 1B1/1B3, organic anion transporter 3 and breast cancer resistance protein, including atorvastatin and rosuvastatin. RESULTS: The systemic exposure of atorvastatin based on the maximum plasma concentration and area under the plasma concentration-time curve was predicted to increase 1.21-fold and 1.25-fold, respectively, if coadministered with dersimelagon 100 mg, and 1.42-fold and 1.45-fold with dersimelagon 200 mg. The systemic exposure of rosuvastatin followed trends similar to atorvastatin (1.67-fold and 1.34-fold increase in maximum plasma concentration and area under the plasma concentration-time curve, respectively, with dersimelagon 100 mg, and 2.40-fold and 1.69-fold with dersimelagon 200 mg). CONCLUSION: Overall, PBPK modelling results indicate that the simulated changes in plasma exposure of atorvastatin and rosuvastatin following coadministration with dersimelagon 100 or 200 mg are not clinically significant, but caution and appropriate clinical monitoring should be recommended.

Risk Stratification by Combination of Heart and Lung Dose in Locally Advanced Non-Small-Cell Lung Cancer after Radiotherapy.

Background/Objectives: Despite advancements in treatment for patients with unresectable locally advanced non-small cell lung cancer (LA-NSCLC), overall survival (OS) remains poor. The specific effects of varying heart and lung doses on OS in LA-NSCLC patients have not been thoroughly investigated, especially their combined impact on survival. This study aimed to examine the impact on OS of both individual and combined heart and lung doses in patients with LA-NSCLC treated with radiotherapy over a three-year follow-up period. Methods: A total of 120 patients who received definitive radiotherapy for LA-NSCLC (stage III, 92.5%) from January 2015 to January 2020 were retrospectively reviewed. The endpoint in this study was OS. Each patient was followed for a fixed period of three years. Results: Univariate Cox regression analysis showed that OS was significantly related to mean heart dose (MHD, hazard ratio [HR], 3.4 [1.8-6.3]; p < 0.001), pericardium V40 (HR, 3.2 [1.7-6.0]; p < 0.001), and total lung V20 (HR, 2.6 [1.4-5.0]; p = 0.003), and these were independent predictors for worse OS in multivariate analysis. Kaplan-Meier curve analysis with log-rank tests revealed that survival was significantly worse in patients with higher MHD (p < 0.001), pericardium V40 (p < 0.001), and total lung V20 (p = 0.002). Combining MHD and total lung V20, and pericardium V40 and total lung V20 provided enhanced risk stratification for OS (p < 0.001 for both combinations). Conclusions: The combination of heart and lung doses provided enhanced and more detailed risk stratification in prediction of OS for a fixed period of three years in LA-NSCLC patients treated with radiotherapy.

Development of an external system for monitoring the couch speed in radiotherapy using continuous bed movement.

PURPOSE: Total body irradiation before bone marrow transplantation for hematological malignancies using Radixact, a high-precision radiotherapy machine, can potentially reduce side effects and the risk of secondary malignancies. However, stable control of couch speed is critical, and direct assessment methods outlined in quality assurance guidelines are lacking. This study aims to develop a real-time couch speed verification system for the Radixact. METHODS: The developed system used a linear encoder to measure couch speed directly. Accuracy was verified via a linear stage, comparing measurements with a laser distance sensor. After placing a phantom simulating the human body on the Radixact couch, the couch speed was verified using predefined speed plans. RESULTS: Operating the linear stage at 0.1, 0.5, and 1.0 mm/s revealed that the maximum position error of the developed verification system compared to the laser distance sensor was nearly equivalent to the distance resolution of the system (0.05 mm/pulse), with negligible average speed error. When the Radixact couch operated at 0.1, 0.5, and 1.0 mm/s, the values obtained by the verification system agreed with the theoretical values within the sampling period (0.01 s) and distance resolution (0.05 mm). CONCLUSION: The verification system developed provides real-time monitoring of the speed of the Radixact table, ensuring treatment effectiveness and patient safety. It would guarantee the couch speed's soundness and contribute to the "visualization" of safety.

A cross-national investigation of CT, MRI, PET, mammography, and radiation therapy resources and utilization.

PURPOSE: This study aimed to analyze the domestic and international landscape of imaging diagnostics and treatments, focusing on Japan, to provide current insights for policymaking, clinical practice enhancement, and international collaboration. METHODS: Data from 1996 to 2021 were collected from Japan's Ministry of Health, Labor and Welfare database for medical device counts of CT, MRI, PET, mammography, and radiotherapy. The National Database of Health Insurance Claims and Specific Health Checkups of Japan was utilized for examination numbers. An international comparison was made with data from 41 countries using the Organization for Economic Cooperation and Development (OECD) database. RESULTS: The data included a total of 108,596 CT devices, 47,233 MRI devices, 2998 PET devices, 20,641 MMG devices, and 8023 RT devices during the survey period. Upon international comparison, Japan ranked first in CT and MRI devices per million people and second in examination numbers per 1000 people. The number of PET devices per million people exceeded OECD averages; however, the number of examinations per 1000 people was below the OECD average in 2020 (Japan: 4.0, OECD: 4.9). Although Japan exceeded OECD averages in mammography device counts (Japan: 33.8, OECD: 24.5 in 2020), radiotherapy device counts were similar to OECD averages (Japan: 8.3, OECD: 7.9 in 2020). CONCLUSION: We have analyzed the utilization of equipment in the context of diagnostic imaging and radiotherapy in Japan. Since the initial survey year, all devices have shown an upward trend. However, it is essential not only to increase the number of devices and examinations but also to address the chronic shortage of radiologists and allied health professionals. Based on the insights gained from this study, understanding the actual status of diagnostic imaging and radiation therapy equipment is critical for grasping the domestic situation and may contribute to improving the quality of healthcare in Japan.

First-in-human study evaluating safety, pharmacokinetics, and pharmacodynamics of lorundrostat, a novel and highly selective aldosterone synthase inhibitor.

Dysregulation of the mineralocorticoid hormone aldosterone is an increasingly prevalent cause of hypertension. Aldosterone synthase (CYP11B2) shares 93% homology to 11ß-hydroxylase (CYP11B1), which produces cortisol. Lorundrostat, a highly selective inhibitor of CYP11B2, is a potential safe and effective treatment for aldosterone-dependent, uncontrolled hypertension, including treatment-resistant hypertension. Lorundrostat showed highly selective inhibition of CYP11B2 in vitro, with 374-fold selectivity for CYP11B2 vs. CYP11B1. A first-in-human study of single ascending doses ranging from 5 to 800 mg and multiple ascending doses ranging from 40 to 360 mg once daily was conducted in healthy participants. After single- and multiple-dose administration, lorundrostat plasma levels peaked 1-3 h after administration with a t1/2 of 10-12 h. Plasma aldosterone decreased up to 40% with single 100-mg to 200-mg doses and up to 70% with single 400 to 800-mg doses. Plasma aldosterone returned to baseline within 16 h after single 100-mg doses and multiple once-daily 120-mg doses. Lorundrostat demonstrated a favorable safety profile in healthy participants. Dose- and exposure-dependent inhibition of renal tubular sodium reabsorption was observed across a clinically relevant dose range with no suppression of basal or cosyntropin-stimulated cortisol production and only a modest increase in mean serum potassium.

Incidence and risk factors associated with the development of hypothyroidism after postoperative chemoradiotherapy for head and neck cancer patients with high-risk features: Supplementary analysis of JCOG1008.

BACKGROUND AND PURPOSE: Hypothyroidism is a recognized late adverse event following radiotherapy for head and neck cancer (HNC). In the JCOG1008 trial, we treated patients with high-risk HNC with postoperative chemoradiotherapy. We aimed to elucidate factors associated with hypothyroidism by analyzing the JCOG1008 data. MATERIALS AND METHODS: In 2012-2018, 261 patients from 28 institutions were enrolled in JCOG1008. Thyroid function tests were conducted to assess hypothyroidism, including free thyroxine (FT4) and thyroid-stimulating hormone assays. Hypothyroidism was defined as Grade 2 or higher in CTCAE v4.0. Various clinical and dosimetric parameters were analyzed. In radiotherapy, there were no dose constraints for the thyroid. Multivariable analysis was conducted on these variables to identify predictive factors for hypothyroidism. RESULTS: The analysis included 162 patients (57 with 3D-CRT and 105 with IMRT), with a median follow-up of 4.7 years (0.3-9.3 years). Among these, 27 (16.7 %) developed hypothyroidism within 2 years after radiotherapy. In a multivariable analysis, the weekly cisplatin [OR=7.700 (CI: 1.632-36.343, p = 0.010)] and baseline FT4 [OR=0.009 (CI: <0.001-0.313, p = 0.010)] were significantly associated with hypothyroidism in the IMRT group. Regarding dosimetric characteristics, V60Gy [OR=1.069 (CI: 0.999-1.143, p = 0.054)] was potentially associated with the development of hypothyroidism. CONCLUSION: The study revealed that the incidence of hypothyroidism within 2 years after postoperative chemoradiotherapy for high-risk HNC was 16.7 % based on analytical results from prospective clinical trials.

Frequency of and risk factors associated with local recurrence after spinal stereotactic body radiation therapy without surgery.

PURPOSE: This study aimed to identify factors associated with local recurrence after spinal stereotactic body radiation therapy (SBRT), focusing on patient movement during treatment and tumor characteristics. METHODS: A total of 48 patients who underwent spinal SBRT alone without surgery from August 2017 to October 2022 were evaluated. Logistic regression analysis was conducted to identify factors associated with local recurrence, including patient movement and tumor characteristics such as soft tissue involvement and tumor volume. Patient movement during treatment was measured using cone beam computed tomography before and after irradiation. RESULTS: Among the included cases, 68.7% and 42.6% had soft tissue involvement and movement exceeding 1 mm, respectively. The median follow-up duration for local recurrence was 11.6 (range: 0.7-44.9) months, whereas the median duration to local recurrence was 6.3 months. Within 12 months, 29.3% of the patients experienced local recurrence, among whom 43.9% moved ≥ 1 mm during treatment, whereas 15.8% did not move. Univariable analysis found that both soft tissue involvement (OR = 10.3, 1.21-87.9; p = 0.033) and patient movement ≥ 1 mm (OR = 5.75, 1.45-22.8; p = 0.013) were associated with local recurrence. Multivariable analysis identified patient movement as an independent prognostic factor for local recurrence (OR = 5.15, 1.06-25.0; p = 0.042). CONCLUSION: Our results suggest that patient movement during spinal SBRT was associated with local recurrence, emphasizing the need for better immobilization techniques and shorter delivery times to improve tumor control.

Deep Learning-based Lung dose Prediction Using Chest X-ray Images in Non-small Cell Lung Cancer Radiotherapy.

Purpose: This study aimed to develop a deep learning model for the prediction of V20 (the volume of the lung parenchyma that received ≥20 Gy) during intensity-modulated radiation therapy using chest X-ray images. Methods: The study utilized 91 chest X-ray images of patients with lung cancer acquired routinely during the admission workup. The prescription dose for the planning target volume was 60 Gy in 30 fractions. A convolutional neural network-based regression model was developed to predict V20. To evaluate model performance, the coefficient of determination (R2), root mean square error (RMSE), and mean absolute error (MAE) were calculated with conducting a four-fold cross-validation method. The patient characteristics of the eligible data were treatment period (2018-2022) and V20 (19.3%; 4.9%-30.7%). Results: The predictive results of the developed model for V20 were 0.16, 5.4%, and 4.5% for the R2, RMSE, and MAE, respectively. The median error was -1.8% (range, -13.0% to 9.2%). The Pearson correlation coefficient between the calculated and predicted V20 values was 0.40. As a binary classifier with V20 <20%, the model showed a sensitivity of 75.0%, specificity of 82.6%, diagnostic accuracy of 80.6%, and area under the receiver operator characteristic curve of 0.79. Conclusions: The proposed deep learning chest X-ray model can predict V20 and play an important role in the early determination of patient treatment strategies.

Trends and distribution of external radiation therapy facilities in Japan based on Survey of Medical Institutions from the Ministry of Health, Labour and Welfare.

This study aimed to explore the distribution of external radiation therapy (RT) facilities, the status of related device installations and the adoption of high-precision RT using Survey of Medical Institutions from the Ministry of Health, Labour and Welfare in Japan. Analysis, categorized by the hospital size and prefecture, provides specific insights into the trends in treatment facility healthcare capabilities. Data on the number of RT facilities, high-precision RT facilities, RT devices and treatment planning systems (TPS) categorized by the number of beds and prefecture from 1996 to 2020 were analyzed. In addition, the study examined the correlation between the high-precision implementation rate and the number of TPSs or radiation oncologists and other medical staff. High-precision RT exceeded 95% in large facilities (800+ beds) but remained <50% in medium-sized facilities (300-499 beds). In a prefecture-by-prefecture analysis, calculation of the maximum-minimum ratio of RT facilities per million population and per 30 km2 revealed a disparity of 3.7 and 73.1 times in the population ratio and the density ratio, respectively. Although a correlation was found between the number of TPSs per RT device or the number of medical physicists per million population and the rate of high-precision RT implementation, no correlation was found among other professions. Detailed analysis based on the hospital size and prefecture provided more specific information on the medical functions of RT facilities in Japan. These findings can potentially contribute to the future development of RT, including the standardization of treatment techniques and optimal resource allocation.

Impact of concurrent antibody-drug conjugates and radiotherapy on symptomatic radiation necrosis in breast cancer patients with brain metastases: a multicenter retrospective study.

AIM: We aimed to investigate the impact of concurrent antibody-drug conjugates (ADC) and radiotherapy on symptomatic radiation necrosis (SRN) in breast cancer patients with brain metastases (BM). METHODS: This multicenter retrospective study uses four institutional data. Eligibility criteria were histologically proven breast cancer, diagnosed BM with gadolinium-enhanced MRI, a Karnofsky performance status of 60 or higher, and radiotherapy for all BM lesions between 2017 and 2022. Patients with leptomeningeal dissemination were excluded. Concurrent ADC was defined as using ADC within four weeks before or after radiotherapy. The cumulative incidence of SRN until December 2023 with death as a competing event was compared between the groups with and without concurrent ADC. Multivariable analysis was performed using the Fine-Gray model. RESULTS: Among the 168 patients enrolled, 48 (29%) received ADC, and 19 (11%) had concurrent ADC. Of all, 36% were HER2-positive, 62% had symptomatic BM, and 33% had previous BM radiation histories. In a median follow-up of 31 months, 18 SRNs (11%) were registered (11 in grade 2 and 7 in grade 3). The groups with and without concurrent ADC had 5 SRNs in 19 patients and 13 SRNs in 149, and the two-year cumulative incidence of SRN was 27% vs. 7% (P = 0.014). Concurrent ADC was associated with a higher risk of SRN on multivariable analysis (subdistribution hazard ratio, 3.0 [95% confidence interval: 1.1-8.3], P = 0.030). CONCLUSIONS: This study suggests that concurrent ADC and radiotherapy are associated with a higher risk of SRN in HER2-positive breast cancer patients.

Classification of Patients With Painful Tumors to Predict Response to Palliative Radiation Therapy.

PURPOSE: This study aimed to identify factors affecting pain response to develop a patient classification system for palliative radiation therapy (RT). METHODS AND MATERIALS: Our prospective observational study (UMIN000044984) provided data on patients who received palliative RT for painful tumors. The eligibility criteria were having a numerical rating scale (NRS) score of 2 or more before treatment and receiving palliative RT between August 2021 and September 2022. Post-RT follow-up was scheduled prospectively at 2, 4, 12, 24, 36, and 52 weeks. Pain response was assessed using the International Consensus Pain Response Endpoints criteria, with the primary outcome being the response rate within 12 weeks. Multivariable logistic regression was performed to identify factors affecting pain response and develop the classification system. Each class evaluated the differences in response rate, time to response, and progression. RESULTS: Of the 488 registered lesions, 366 from 261 patients met the criteria. Most patients had bone metastases (75%), of whom 72% were using opioids and 22% underwent reirradiation. Conventional RT (eg, 8-Gy single fraction, 20 Gy in 5 fractions) was administered to 93% of patients. Over a median of 6.8 months of follow-up, the average NRS decreased from 6.1 to 3.4 at 12 weeks for 273 evaluable lesions, with a 60% response rate. Opioid use and reirradiation negatively affected the response rate in multivariate analysis (P < .01). Lesions were categorized into class 1 (no opioid use and no reirradiation; 89 lesions), class 2 (neither class 1 nor 3; 211 lesions), and class 3 (opioid use and reirradiation; 66 lesions), with respective response rates of 75%, 61%, and 36% (P < .001). Time to response was similar across the classes (P = .91), but the progression rates at 24 weeks differed (11%, 27%, and 63%, respectively; P < .001). CONCLUSIONS: Opioid use and reirradiation are factors leading to significant variations in pain response rates and time to progression.

Palliative radiotherapy for painful non-bone lesions in patients with advanced cancer: a single center retrospective study.

PURPOSE: This retrospective study aimed to assess the efficacy and safety of palliative radiotherapy for painful non-bone lesions in patients with advanced cancer. MATERIALS AND METHODS: We enrolled patients with painful non-bone lesions who underwent conventional palliative radiotherapy between September 2018 and September 2022. The treatment targets included primary tumor lesions, lymph node metastases, non-bone hematogenous metastases, and other lesions. The primary endpoint was the overall pain response rate in evaluable patients, determined based on the International Consensus Pain Response Endpoint criteria. The secondary endpoints included overall survival, pain recurrence, and adverse events. RESULTS: Of the 420 screened patients, 142 received palliative radiotherapy for painful non-bone lesions, and 112 were evaluable. A pain response was achieved in 67 patients (60%) of the 112 evaluable patients within a median of 1.2 months. Among these patients, 25 exhibited complete response, 42 partial response, 18 indeterminate response, and 27 pain progression. The median survival time was 5.5 months, recorded at a median follow-up of 6.0 months, during which 67 patients died. Multivariate analysis identified poor performance status scores of 2-4, opioid use, and re-irradiation as independent factors associated with a reduced likelihood of achieving a pain response. Pain recurrence occurred in 18 patients over a median of 4.1 months. Seventeen patients had grade 1-2 adverse events, while none experienced grade 3 or higher toxicity. CONCLUSION: Palliative radiotherapy can potentially be a safe and well-tolerated modality for managing painful non-bone lesions, with a low rate of adverse events.

Re-irradiation spine stereotactic body radiotherapy following high-dose conventional radiotherapy for metastatic epidural spinal cord compression: a retrospective study.

PURPOSE:  We aimed to evaluate the efficacy and safety of re-irradiation stereotactic body radiation therapy (SBRT) in patients with metastatic epidural spinal cord compression (MESCC) following high-dose conventional radiotherapy. MATERIALS AND METHODS:  Twenty-one patients met the following eligibility criteria: with an irradiation history of 50 Gy2 equivalent dose in 2-Gy fractions (EQD2) or more, diagnosed MESCC in the cervical or thoracic spines, and treated with re-irradiation SBRT of 24 Gy in 2 fractions between April 2018 and March 2023. Prior treatment was radiotherapy alone, not including surgery. The primary endpoint was a 1-year local failure rate. Overall survival (OS) and treatment-related adverse events were assessed as the secondary endpoints. Since our cohort includes one treatment-related death (TRD) of esophageal perforation, the cumulative esophageal dose was evaluated to find the dose constraints related to severe toxicities. RESULTS:  The median age was 68, and 14 males were included. The primary tumor sites (esophagus/lung/head and neck/others) were 6/6/7/2, and the median initial radiotherapy dose was 60 Gy2 EQD2 (range: 50-105 Gy2, 60-70/ > 70 Gy2 were 11/4). Ten patients underwent surgery followed by SBRT and 11 SBRT alone. At the median follow-up time of 10.4 months, 17 patients died of systemic disease progression including one TRD. No radiation-induced myelopathy or nerve root injuries occurred. Local failure occurred in six patients, with a 1-year local failure rate of 29.3% and a 1-year OS of 55.0%. Other toxicities included five cases of vertebral compression fractures (23.8%) and one radiation pneumonitis. The cumulative esophageal dose was recommended as follows: Dmax < 203, D0.035 cc < 187, and D1cc < 167 (Gy3 in biological effective dose). CONCLUSION:  Re-irradiation spine SBRT may be effective for selected patients with cervical or thoracic MESCC, even with high-dose irradiation histories. The cumulative dose assessment across the original and re-irradiated esophagus was recommended to decrease the risk of severe esophageal toxicities.

Changing trends in gamma knife surgery to linear accelerator brain stereotactic radiotherapy in Japan: a survey based on the nationwide claims database.

PURPOSE: This study evaluated the trends in the platform for stereotactic radiotherapy to the brain (SRT), utilizing the open data of the National Database published by the Ministry of Health, Labour, and Welfare. MATERIALS AND METHODS: This study analyzed data from FY2014 to FY2021. The practices included in the study were gamma knife surgery (GKS) and SRT with a linear accelerator (LINAC). The total number of outpatient and inpatient cases in each SRT system was evaluated annually. RESULTS: From April 2014 to March 2022, the study included 212,016 cases (102,691 GKS and 109,325 LINAC) of the registered 1,996,540 radiotherapy cases. In the first year, 13,117 (54.1%) cases were GKS, and 11,128 (45.9%) were LINAC; after that, GKS decreased, and LINAC increased, reaching the same rate in FY2017. Compared to the first year, the final year showed 11,702 GKS (- 1415 or - 10.8%) and 17,169 LINAC (+ 6041 or + 54.3%), with an increase of 4626 total SRT cases to 28,871 (+ 19.1%). The percentage of outpatient treatment also increased from 4.6 to 11.8% for GKS and from 44.7 to 57.9% for LINAC. CONCLUSION: The study found a gradual decrease in the selection of GKS, an increasing trend in the selection of LINAC, and an increase in the overall number of stereotactic irradiations. In particular, the proportion of outpatient treatment increased, indicating that more than half of LINAC was selected for outpatient treatment.

CT number calibration audit in photon radiation therapy.

BACKGROUND: Inadequate computed tomography (CT) number calibration curves affect dose calculation accuracy. Although CT number calibration curves registered in treatment planning systems (TPSs) should be consistent with human tissues, it is unclear whether adequate CT number calibration is performed because CT number calibration curves have not been assessed for various types of CT number calibration phantoms and TPSs. PURPOSE: The purpose of this study was to investigate CT number calibration curves for mass density (ρ) and relative electron density (ρe ). METHODS: A CT number calibration audit phantom was sent to 24 Japanese photon therapy institutes from the evaluating institute and scanned using their individual clinical CT scan protocols. The CT images of the audit phantom and institute-specific CT number calibration curves were submitted to the evaluating institute for analyzing the calibration curves registered in the TPSs at the participating institutes. The institute-specific CT number calibration curves were created using commercial phantom (Gammex, Gammex Inc., Middleton, WI, USA) or CIRS phantom (Computerized Imaging Reference Systems, Inc., Norfolk, VA, USA)). At the evaluating institute, theoretical CT number calibration curves were created using a stoichiometric CT number calibration method based on the CT image, and the institute-specific CT number calibration curves were compared with the theoretical calibration curve. Differences in ρ and ρe over the multiple points on the curve (Δρm and Δρe,m , respectively) were calculated for each CT number, categorized for each phantom vendor and TPS, and evaluated for three tissue types: lung, soft tissues, and bones. In particular, the CT-ρ calibration curves for Tomotherapy TPSs (ACCURAY, Sunnyvale, CA, USA) were categorized separately from the Gammex CT-ρ calibration curves because the available tissue-equivalent materials (TEMs) were limited by the manufacturer recommendations. In addition, the differences in ρ and ρe for the specific TEMs (ΔρTEM and Δρe,TEM , respectively) were calculated by subtracting the ρ or ρe of the TEMs from the theoretical CT-ρ or CT-ρe calibration curve. RESULTS: The mean ± standard deviation (SD) of Δρm and Δρe,m for the Gammex phantom were -1.1 ± 1.2 g/cm3 and -0.2 ± 1.1, -0.3 ± 0.9 g/cm3 and 0.8 ± 1.3, and -0.9 ± 1.3 g/cm3 and 1.0 ± 1.5 for lung, soft tissues, and bones, respectively. The mean ± SD of Δρm and Δρe,m for the CIRS phantom were 0.3 ± 0.8 g/cm3 and 0.9 ± 0.9, 0.6 ± 0.6 g/cm3 and 1.4 ± 0.8, and 0.2 ± 0.5 g/cm3 and 1.6 ± 0.5 for lung, soft tissues, and bones, respectively. The mean ± SD of Δρm for Tomotherapy TPSs was 2.1 ± 1.4 g/cm3 for soft tissues, which is larger than those for other TPSs. The mean ± SD of Δρe,TEM for the Gammex brain phantom (BRN-SR2) was -1.8 ± 0.4, implying that the tissue equivalency of the BRN-SR2 plug was slightly inferior to that of other plugs. CONCLUSIONS: Latent deviations between human tissues and TEMs were found by comparing the CT number calibration curves of the various institutes.

Radiological imaging protection: a study on imaging dose used while planning computed tomography for external radiotherapy in Japan.

Previous studies have primarily focused on quality of imaging in radiotherapy planning computed tomography (RTCT), with few investigations on imaging doses. To our knowledge, this is the first study aimed to investigate the imaging dose in RTCT to determine baseline data for establishing national diagnostic reference levels (DRLs) in Japanese institutions. A survey questionnaire was sent to domestic RT institutions between 10 October and 16 December 2021. The questionnaire items were volume computed tomography dose index (CTDIvol), dose-length product (DLP), and acquisition parameters, including use of auto exposure image control (AEC) or image-improving reconstruction option (IIRO) for brain stereotactic irradiation (brain STI), head and neck (HN) intensity-modulated radiotherapy (IMRT), lung stereotactic body radiotherapy (lung SBRT), breast-conserving radiotherapy (breast RT), and prostate IMRT protocols. Details on the use of motion-management techniques for lung SBRT were collected. Consequently, we collected 328 responses. The 75th percentiles of CTDIvol were 92, 33, 86, 23, and 32 mGy and those of DLP were 2805, 1301, 2416, 930, and 1158 mGy·cm for brain STI, HN IMRT, lung SBRT, breast RT, and prostate IMRT, respectively. CTDIvol and DLP values in institutions that used AEC or IIRO were lower than those without use for almost all sites. The 75th percentiles of DLP in each treatment technique for lung SBRT were 2541, 2034, 2336, and 2730 mGy·cm for free breathing, breath holding, gating technique, and real-time tumor tracking technique, respectively. Our data will help in establishing DRLs for RTCT protocols, thus reducing imaging doses in Japan.

Evaluation of Age-Related Changes in Teneligliptin Pharmacokinetics in Japanese and European Descent Subjects Using a Physiologically Based Pharmacokinetic Model.

INTRODUCTION: Drugs often show differing pharmacokinetic (PK) profiles, such as higher plasma concentrations, in older people than in younger people owing to age-related decreases in physiological functions. However, it is difficult to evaluate the PK in older populations. Therefore, we simulated the plasma age-related changes in the PK of teneligliptin, a dipeptidyl peptidase-4 inhibitor, using physiologically based PK (PBPK) models. METHODS: The previously developed PBPK model was revalidated by comparison between simulated data and clinical study data that included older subjects (up to 75 years old). We then simulated the plasma concentration-time profiles for teneligliptin at a dose of 20 mg (single and multiple doses) in virtual Japanese (20-70 years old) and European descent (20-98 years old) subjects. PK parameters were calculated by race and age group. RESULTS: We confirmed the validity of the previous PBPK model by comparison between simulated data and clinical study data. In the evaluation of age-related changes in PK after single and multiple doses using the PBPK model, the area under the plasma concentration-time curve (AUC) of teneligliptin tended to increase slightly with age in both populations up to 70 years old. However, no clear age-related change in the maximum plasma concentration (Cmax) of teneligliptin was observed. In the European descent subjects aged ≥ 70 years, the AUC tended to increase but the ratio of the change in Cmax was smaller than that in AUC. In both populations, there were positive correlations between AUC and age, but not between Cmax and age. CONCLUSION: The simulation using a PBPK model showed a tendency for the AUC of teneligliptin to increase with age, whereas Cmax was less affected by age than AUC.