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Objective We aimed to evaluate recent trends in characteristics and treatments among patients with brain metastases in clinical practice. Methods All newly diagnosed patients with brain metastases during 2016–2021 at a single cancer center were enrolled. We collected the detailed features of each patient and estimated the number of candidates considered to meet the following criteria used in common clinical trials: Karnofsky performance status ≥ 70 and mutated non-small cell lung cancer, breast cancer or melanoma. The brain metastases treatments were classified as follows: (i) stereotactic radiosurgery, (ii) stereotactic radiosurgery and systemic therapy, (iii) whole-brain radiotherapy, (iv) whole-brain radiotherapy and systemic therapy, (v) surgery, (vi) immune checkpoint inhibitor or targeted therapy, (vii) cytotoxic agents and (ix) palliative care. Overall survival and intracranial progression-free survival were estimated from brain metastases diagnosis to death or intracranial progression. Results A total of 800 brain metastases patients were analyzed; 597 (74.6%) underwent radiotherapy, and 422 (52.7%) underwent systemic therapy. In addition, 250 (31.3%) patients were considered candidates for common clinical trials. Compared to 2016, the later years tended to shift from whole-brain radiotherapy to stereotactic radiosurgery (whole-brain radiotherapy: 35.7–29.1% and stereotactic radiosurgery: 33.4–42.8%) and from cytotoxic agents to immune checkpoint inhibitor/targeted therapy (cytotoxic agents: 10.1–5.0 and immune checkpoint inhibitor/targeted therapy: 7.8–10.9%). There was also an increase in the proportion of systemic therapy combined with radiation therapy (from 26.4 to 36.5%). The median overall survival and progression-free survival were 12.7 and 5.3 months, respectively. Conclusions This study revealed the diversity of brain metastases patient characteristics, recent changes in treatment selection and the percentage of candidates in clinical trials.

The present study aimed to reduce the parotid gland dose in the hippocampus avoidance with whole-brain radiotherapy (HA-WBRT) using the helical tomotherapy (HT). Ten patients who had previously undergone WBRT were randomly selected and enrolled in this study. During the treatment planning, two different techniques to the jaw were applied for each patient, namely, 1.0 cm fixed jaw and 2.5 cm dynamic jaw. To efficiently reduce the dose in the bilateral parotid glands, directional block (DB) mode was set. The DB is a function of a treatment planning system for the dose reduction in organs at risk. The standard HA-WBRT plan which did not reduce the parotid gland dose was also designed to compare the plan quality. Compared with the standard HA-WBRT plan, the parotid gland dose could be reduced by approximately 70% without extending the delivery time by adding the parotid gland on the DB mode to the dose constraint. In addition, the differences in dosimetric parameters observed between the plans employing the 1.0 cm fixed jaw and 2.5 cm dynamic jaw were almost negligible. Moreover, delivery time in the 2.5 cm dynamic jaw could be greatly reduced by 60% compared with that in the 1.0 cm fixed jaw.

Highlights • Auto-contouring accuracy and contouring time were evaluated using two procedures. • Dice coefficient was better for the multiple atlases procedure than for one atlas. • Contouring time of the multiple atlases procedure is clinically acceptable., Atlas-based auto-segmentation (ABS) procedure used in radiotherapy can be classified into two groups, one using one atlas per patient (sSM) and the other using multiple atlases (sMM). This study evaluated auto-contouring accuracy and contouring time in patients with prostate cancer using the two procedures. The Dice similarity coefficient of sMM was significantly better than that of sSM (prostate [median, 0.81 (range, 0.66–0.91) vs. 0.64 (0.27–0.71), p

This study aimed to evaluate the clinical benefits of systemic therapy (ST) combined with stereotactic radiosurgery (SRS) for brain metastases (BM).The patient data were extracted from the institutional disease database from 2016 to 2021. Surgical and whole-brain radiotherapy cases and poor Karnofsky performance status (KPS 70) were excluded. The eligible patients were divided into monotherapy (SRS alone or ST alone) and combined therapy (SRS and ST, combined within a month). Univariate and multivariate Cox proportional hazards analyses were used to examine factors associated with increased risk of death and intracranial progression. The propensity score for selecting treatment was calculated based on existing prognostic covariates. Two groups were matched 1:1 and compared for intracranial progression-free survival (PFS) and overall survival (OS).We identified 1605 patients and analyzed 928 (monotherapy: n = 494, combined therapy: n = 434). In a multivariable model, the combined therapy was independently associated with improved PFS and OS relative to the monotherapy. At the median follow-up of 383 days in the matched dataset, the combined therapy group showed significantly longer PFS (median, 7.4 vs. 5.0 months, P 0.001) and OS (median, 23.1 vs. 17.2 months, P = 0.036) than the monotherapy group. The overall intracranial progression and mortality risk was reduced in the combined therapy group, with an estimated HR of 0.70 and 0.78.Combined therapy exhibited longer PFS and OS than monotherapy in BM patients. The results support the recent trend toward combining systemic and local therapies, encouraging future clinical trials.

Katsunori Yogo,1 Masaki Misawa,2 Morihito Shimizu,2 Hidetoshi Shimizu,3 Tomoki Kitagawa,3 Ryoichi Hirayama,4 Hiromichi Ishiyama,5 Takako Furukawa,1 Hiroshi Yasuda6 1Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan; 2Health and Medical Research Institute, National Institute of Advanced Industrial Science & Technology (AIST), Tsukuba, Ibaraki, Japan; 3Department of Radiation Oncology, Aichi Cancer Center Hospital, Nagoya, Aichi, Japan; 4National Institute of Radiological Sciences (NIRS), National Institutes for Quantum and Radiological Science and Technology (QST), Chiba-shi, Chiba, Japan; 5Graduate School of Medical Science, Kitasato University, Sagamihara, Kanagawa, Japan; 6Department of Radiation Biophysics, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, JapanCorrespondence: Katsunori YogoNagoya University Graduate School of Medicine, 1-1-20 Daiko-Minami, Higashi-Ku, Nagoya, Aichi 461-8673, JapanTel +81 52 719 1103Fax +81 52 719 3172Email yogo@met.nagoya-u.ac.jpPurpose: Gold nanoparticles (AuNPs) are candidate radiosensitizers for medium-energy photon treatment, such as γ-ray radiation in high-dose-rate (HDR) brachytherapy. However, high AuNP concentrations are required for sufficient dose enhancement for clinical applications. Here, we investigated the effect of positively (+) charged AuNP radiosensitization of plasmid DNA damage induced by 192Ir γ-rays, and compared it with that of negatively (−) charged AuNPs.Methods: We observed DNA breaks and reactive oxygen species (ROS) generation in the presence of AuNPs at low concentrations. pBR322 plasmid DNA exposed to 64 ng/mL AuNPs was irradiated with 192Ir γ-rays via HDR brachytherapy. DNA breaks were detected by observing the changes in the form of the plasmid and quantified by agarose gel electrophoresis. The ROS generated by the AuNPs were measured with the fluorescent probe sensitive to ROS. The effects of positively (+) and negatively (−) charged AuNPs were compared to study the effect of surface charge on dose enhancement.Results: +AuNPs at lower concentrations promoted a comparable level of radiosensitization by producing both single-stranded breaks (SSBs) and double-stranded breaks (DSBs) than those used in cell assays and Monte Carlo simulation experiments. The dose enhancement factor (DEF) for +AuNPs was 1.3 ± 0.2 for SSBs and 1.5 ± 0.4 for DSBs. The ability of +AuNPs to augment plasmid DNA damage is due to enhanced ROS generation. While −AuNPs generated similar ROS levels, they did not cause significant DNA damage. Thus, dose enhancement using low concentrations of +AuNPs presumably occurred via DNA binding or increasing local +AuNP concentration around the DNA.Conclusion: +AuNPs at low concentrations displayed stronger radiosensitization compared to −AuNPs. Combining +AuNPs with 192Ir γ-rays in HDR brachytherapy is a candidate method for improving clinical outcomes. Future development of cancer cell-specific +AuNPs would allow their wider application for HDR brachytherapy.Keywords: gold nanoparticles, high-dose-rate brachytherapy, DNA damage, radiosensitization, 192Ir γ-rays, positively charged nanoparticles

Purpose We developed a thermoset shape memory bolus (shape memory bolus) made from poly-e-caprolactone (PCL) polymer. This study aimed to investigate whether the shape memory bolus can be applied to radiotherapy as a bolus that conformally adheres to the body surface, can be created in a short time, and can be reused. Methods The shape memory bolus was developed by cross-linking tetrabranch PCL with reactive acrylate end groups. Dice similarity coefficient (DSC) was used to evaluate shape memory characterization before deformation and after restoration. In addition, the degree of adhesion to the body surface and crystallization time were calculated. Moreover, dosimetric characterization was evaluated using the water equivalent phantom and an Alderson RANDO phantom. Results The DSC value between before deformation and after restoration was close to 1. The degree of adhesion of the shape memory bolus (1.9%) was improved compared with the conventional bolus (45.6%) and was equivalent to three-dimensional (3D) printer boluses (1.3%-3.5%). The crystallization time was approximately 1.5 min, which was clinically acceptable. The dose calculation accuracy, dose distribution, and dose index were the equivalent compared with 3D boluses. Conclusion The shape memory bolus has excellent adhesion to the body surface, can be created in a short time, and can be reused. In addition, the shape memory bolus needs can be made from low-cost materials and no quality control systems are required for individual clinical departments, and it is useful as a bolus for radiotherapy.

Introduction: The epidural disease progression is the most common pattern of failure after spine stereotactic body radiotherapy. The aim of this study was to clarify the effect of the dose calculation grid size (CGS) during volumetric modulated arc therapy planning on the dose to the epidural space target. Materials and Methods: In the planning, the volume obtained by subtracting the planning organ at risk volume (PRV) of the spinal cord and/or cauda equina from the planning target volume (PTV) was defined as the PTVeval. First, we compared the epidural space dose that overlapped with the PTVeval at dose CGSs of 1 mm and 2 mm. Next, we compared the dose that can be given, according to the isotropic distance from the PRV of the spinal cord and/ or cauda equina at dose CGSs of 1 mm and 2 mm. Results: The dose to the epidural space overlapping with the PTVeval was significantly larger at the dose CGS of 1 mm (60 to 80 cGy, 3% of the prescription dose) than at the dose CGS of 2 mm (p

Objective: To clarify the peripheral dose changes, especially in the eye lens and thyroid gland regions, using an acrylic-lead shield in cone-beam computed tomography (CBCT). Methods: The acrylic-lead shield consists of system walls and a system mat. The radiophotoluminescence glass dosemeter was set on the eye lens and thyroid gland regions on the RANDO phantom. The system mat was laid under the RANDO phantom ranging from the top of the head to the shoulders, and then, the system walls shielded the phantom’s head. Additionally, the phantom was covered anteriorly with a band that had the same shielding ability as the system mat to cover the thyroid gland region. Protocols for CBCT imaging of the thoracic or pelvic region in clinical practice were used. The measurement was performed with and without the acrylic-lead shield. Results: The dose to the eye lens region was reduced by 45% using the system wall. Conversely, the dose to the thyroid gland was unchanged. The use of the system mat reduced the dose to the thyroid gland region by 47%, and the dose to the eye lens was reduced by 22%. The dose to the eye lens region decreased to the background level using the system walls and mat. Conclusion: The newly proposed device using an acrylic-lead shield reduced the peripheral dose in CBCT imaging. Advances in knowledge: Attention is focused on managing peripheral dose in image-guided radiation therapy. The peripheral dose reduction using the acrylic-lead shield is a new proposal in radiotherapy that has never been studied.

This study aimed to develop a poly-ε-caprolactone (PCL) material that has a low melting point while maintaining the deformation ability. The new PCL (abbreviated as 4b45/2b20) was fabricated by mixing two types of PCL with different molecular weights, numbers of branches, and physical properties. To investigate the melting point, crystallization temperature, elastic modulus, and elongation at break for 4b45/2b20 and three commercially available masks, differential scanning calorimetry and tensile tests were performed. The melting point of 4b45/2b20 was 46.0 °C, and that of the commercially available masks was approximately 56.0 °C (55.7 °C–56.5 °C). The elastic modulus at 60 °C of 4b45/2b20 was significantly lower than the commercially available masks (1.1 ± 0.3 MPa and 46.3 ± 5.4 MPa, p = 0.0357). In addition, the elongation at break of 4b45/2b20 were significantly larger than the commercially available masks (275.2 ± 25.0% and 216.0 ± 15.2%, p = 0.0347). The crystallization temperature of 4b45/2b20 (22.1 °C) was clinically acceptable and no significant difference was found in the elastic modulus at 23 °C (253.7 ± 24.3 MPa and 282.0 ± 44.3 MPa, p = 0.4). As a shape memory-based thermoset material, 4b45/2b20 has a low melting point and large deformation ability. In addition, the crystallization temperature and strength are within the clinically acceptable standards. Because masks made using the new PCL material are formed with less pressure on the face than commercially available masks, it is a promising material for making a radiotherapy mask that can reduce the burden on patients.

As the couch used in external radiation therapy attenuate radiation by interaction, it is necessary to correct attenuation of radiation by inserting a couch model in the treatment planning systems. For a couch whose thickness is different in the superior-inferior direction, it is possible to perform dose calculations with an error within ±1% by using separate different couch models provided by vendors. However, it is difficult to correct attenuation correction accurately with a single couch model. In this study, we created an in-house couch model which can set couch shape and physical density in detail by acquiring CT images of actual couch. When we performed dose calculation by optimizing the physical densities of in-house and vendor couch, it was found that the difference between the measured and the calculated values can be significantly reduced by using in-house couch model. Additionally, by using in-house couch model, it is found that the dose attenuation can be corrected within ±1% for a couch whose thickness is different in the superior-inferior direction.

Deep-inspiration breath-hold radiotherapy (DIBH-RT) to reduce the cardiac dose irradiation is widely used but some patients experience little or no reduction. We constructed and compared two prediction models to evaluate the usefulness of our new synthetic DIBH-CT (sCT) model. Ninety-four left-sided breast cancer patients (training cohort: n = 64, test cohort: n = 30) underwent both free-breathing and DIBH planning. The U-Net-based sCT generation model was developed to create the sCT treatment plan. A linear prediction model was constructed for comparison by selecting anatomical predictors of past literature. The primary prediction outcome is the mean heart dose (MHD) reduction, and the coefficient of determination (R2), root mean square error (RMSE) and mean absolute error (MAE) were calculated. Moreover, we evaluated the heart and lungs contours’ similarity and Hounsfield unit (HU) difference between both images. The median MHD reduction was 1.14 Gy in DIBH plans and 1.09 Gy in sCT plans (P = 0.96). The sCT model achieved better performance than the linear model (R2: 0.972 vs 0.450, RMSE: 0.120 vs 0.551, MAE: 0.087 vs 0.412). The organ contours were similar between DIBH-CT and sCT: the median Dice (DSC) and Jaccard similarity coefficients (JSC) were 0.912 and 0.838 for the heart and 0.910 and 0.834 for the lungs. The HU difference in the soft-tissue region was smaller than in the air or bone. In conclusion, our new model can generate the affected CT by breath-holding, resulting in high performance and well-visualized prediction, which may have many potential uses in radiation oncology.

The in-room laser which is used for patient positioning in radiotherapy is generally projected on the radiation isocenter determined by the Winston-Lutz test and so on. In this study, a couch-mounted verification device was developed that could evaluate all in-room lasers' alignment including the horizontality and verticality at one time. The device has the function to perform the light/radiation field coincidence test and the Winston-Lutz test at the same time. The aim of this report was to introduce the verification procedure for two tests, using the newly developed software and device, and to present the tuning flow of the in-room laser. Moreover, the analysis accuracy of the developed software was evaluated in comparison with commercial software.First, the light/radiation field was evaluated by using tungsten markers on the central surface of the device. Next, after aligning the long-carved lines on the front and sides of the device with the in-room lasers, the Winston-Lutz test was carried out by using the tungsten sphere in the center of the device. The acquired images were collectively analyzed using the developed software equipped with the reporting function. Additionally, the result of this Winston-Lutz test was compared with the result from commercial software.A series of the light/radiation field coincidence test and the Winston-Lutz test were analyzed using the developed device and software. The results could be easily confirmed using the reporting function of the software. Regarding the result of the Winston-Lutz test, most of the analysis differences between the developed software and commercially available software were within the pixel size (0.22 mm).Since the accuracy of the radiation field affects the result of the Winston-Lutz test, the presented procedure of performing the light/radiation coincidence field test in advance facilitates the interpretation of the error of the Winston-Lutz test. Based on the results of the Winston-Lutz test, we were able to demonstrate the tuning flow of all in-room lasers including the horizontality and verticality by using the developed device.We have developed a couch-mounted verification device and software that can evaluate the light/radiation coincidence field test and the alignment including the horizontality and verticality of the in-room laser used for patient positioning in radiotherapy, and reported its usefulness. The analysis accuracy of the developed software was comparable to that of commercially available software. The use of this device and the developed software would contribute to not only the efficiency of adjusting all in-room lasers' alignment including the horizontality and verticality but also reflect accurately the result of the Winston-Lutz test.

Polyamines are involved in various biological functions, including cell proliferation, differentiation, gene regulation, etc. Recently, it was found that polyamines exhibit biphasic effects on gene expression: promotion and inhibition at low and high concentrations, respectively. Here, we compared the effects of three naturally occurring tetravalent polyamines, spermine (SPM), thermospermine (TSPM), and N4-aminopropylspermidine (BSPD). Based on the single DNA observation with fluorescence microscopy together with measurements by atomic force microscopy revealed that these polyamines induce shrinkage and then compaction of DNA molecules, at low and high concentrations, respectively. We also performed the observation to evaluate the effects of these polyamine isomers on the activity of gene expression by adapting a cell-free luciferase assay. Interestingly, the potency of their effects on the DNA conformation and also on the inhibition of gene expression activity indicates the highest for TSPM among spermine isomers. A numerical evaluation of the strength of the interaction of these polyamines with negatively charged double-strand DNA revealed that this ordering of the potency corresponds to the order of the strength of the attractive interaction between phosphate groups of DNA and positively charged amino groups of the polyamines.

In radiotherapy, the dose to organs-at-risk must be kept as low as possible to preserve their function. We aimed to determine the acceptable f-value upper bound of the Feasibility DVH in the PlanIQ software to achieve dose reduction to the normal lung in patients with stage III non-small cell lung cancer.By using the Feasibility DVH, the f-values corresponding to the pulmonary dosimetric parameters of each treatment plan for 11 patients were calculated. The acceptable f-value upper bound was defined as the value that added one standard deviation of the f-value to the mean. Additionally, the treatment plan for additional fourteen patients was designed to evaluate the effectiveness of the acceptable f-value upper bound for the normal lung dose reduction. The value beyond the acceptable f-value upper bound was judged as inadequate dose reduction.The acceptable f-value upper bound was different for dosimetric parameters (range, 0.22-0.26). These values were 0.5, which is typically used as the acceptable f-value upper bound. Evaluation by the treatment plan of fourteen patients detected that the f-value of the normal lung of five patients exceeded the acceptable f-value upper bound, and the replanning was able to reduce the dose of the normal lung.We could efficiently reduce the normal-lung dose using the acceptable f-value upper bound calculated in this study and provide an effective acceptable f-value upper bound of the normal lung dose in the lung cancer radiotherapy.

Background: Deep inspiration breath-hold (DIBH) radiotherapy is effective but requires specific devices for tracking the respiratory cycle or surface motion. There are some reports of DIBH without such devices. However, to the best of our knowledge, no study has evaluated all three components which are: setup accuracy, dose assessment, and treatment time. We evaluated the accuracy, effect of dose reduction on organs at risk (OARs), and the treatment time of our DIBH technique, which avoids the use of such devices.Methods: We analyzed 64 left-sided early breast cancer patients. Three-dimensional conformal radiotherapy treatment plans of 42.56 Gy in 16 fractions were created in free-breathing (FB) and DIBH settings. Thirty patients were evaluated for inter- and intra-fractional displacement. The treatment room entry-to-exit times were measured and retrospectively compared with those of 44 right breast cancer patients who received FB radiotherapy (Right-FB) in the same period. The volumes and dose metrics of the clinical target volume (CTV) and contoured OARs (HEART, left anterior descending artery [LAD], and LUNG) were compared between FB and DIBH.Results: The average inter-fractional, intra-fractional, and overall setup displacement were 2.32 ± 1.30, 0.55 ± 0.43, and 2.46 ± 1.24 mm, respectively. Compared to Right-FB, the medians of entry-to-exit times slightly increased in DIBH (9 vs 7 minutes, P = 3.95e-23). The LUNG volume in DIBH was 1.58 times larger than that in FB, but other volumes were not statistically different. Compared to FB, the median HEART, LAD, and mean LUNG doses decreased significantly in DIBH: 1.67 vs 0.71 (P = 9.72e-15), 13.0 vs 2.3 (P = 6.65e-15), and 2.42 vs 2.03 (P = 6.80e-8) Gy, respectively. CTV doses were not statistically different.Conclusions: With only minor setup errors, this simple and cost-effective DIBH technique is a feasible method. It can be easily tested for new facilities and is expected to accelerate the further clinical implementation.Trial registration

The parotid gland is recognized as a major‐risk organ in whole‐brain irradiation; however, the beam delivery from the left and right sides cannot reduce the parotid gland dose. The four‐field box technique using a head‐tilting device has been reported to reduce the parotid gland dose by excluding it from the radiation field. This study aimed to determine the appropriate head tilt angle to reduce the parotid gland dose in the four‐field box technique. The bilateral, anterior, and posterior beams were set for each of ten patients. The orbitomeatal plane angle (OMPA) was introduced as an indicator that expresses the head tilt angle. Next, principal component analysis (PCA) was performed to understand the interrelationship between variables (dosimetric parameters of the lens and parotid gland and OMPA). In PCA, the angle between the OMPA vector and maximum lens dose or mean parotid gland dose vector was approximately opposite or close, indicating a negative or positive correlation [r = −0.627 (p

Reactive blending has been usually utilized to stabilize morphology and to improve the properties of multi-component polymer blends by generating copolymers in situ at the interface. However, the present study on blends composed of poly(butylene terephthalate) (PBT) and functionalized styrene–acrylonitrile random copolymer (SAN) demonstrates another possibility for this method, i.e. tailoring morphology and thereby controlling the properties of polymer blends. By varying reaction conditions it was demonstrated that blends could be formed having the same ratio of [PBT]/[SAN] but which possessed completely different microstructural forms: a sea–island morphology with and without micelles, a corded dispersed phase morphology, and a highly oriented, layer-like morphology.

Pancreatic β-cells are interconnected by gap junctions, which allow small molecules to pass from cell to cell. In spite of the importance of the gap junctions in cellular communication, modeling studies have been limited by the complexity of the system. Here, we propose a mathematical gap junction model that properly takes into account biological functions, and apply this model to the study of the β-cell cluster. We consider both electrical and metabolic features of the system. Then, we find that when a fraction of the ATP-sensitive K+ channels are damaged, robust insulin secretion can only be achieved by gap junctions. Our finding is consistent with recent experiments conducted by Rocheleau et al. Our study also suggests that the free passage of potassium ions through gap junctions plays an important role in achieving metabolic synchronization between β-cells.