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Background: Glioblastoma (GBM) is a rapidly growing and most life-threatening malignant brain tumor. The significance of early treatment to the clinical outcomes of patients with GBM is unclear., Objective: To determine whether early diagnosis and surgery improve the preoperative and postoperative Karnofsky performance status (KPS) and prognosis of patients with GBM., Methods: Data of isocitrate dehydrogenase-wildtype patients with GBM treated at our institution between January 2010 and December 2019 were reviewed. Patients were classified into early or late diagnosis groups with a threshold of 14 days from initial symptoms. In addition, patients were divided into early, intermediate, and late surgery groups with thresholds of 21 and 35 days. Representative symptoms and patient prognoses were examined., Results: Of 153 patients, 72 and 81 were classified into the early and late diagnosis groups. The median tumor volume was significantly smaller in the former group. The proportion of patients with preoperative KPS scores 90 was 48.6% and 29.6% in the early and late diagnosis groups ( P = .016). The early, intermediate, and late surgery groups included 43, 24, and 86 patients. The median overall survival was significantly longer in the early surgery group than in the late surgery group (28.4 vs 18.7 months, P = .006). Multivariate analysis demonstrated that significant predictors of shorter survival included extent of tumor resection (partial or biopsy), preoperative and postoperative KPS 60, and O6-methylguanine-DNA-methyltransferase promoter status (unmethylated)., Conclusion: Early diagnosis within 2 weeks and surgical interventions within 3 weeks from the symptom onset are associated with prolonged patient survival. Early GBM treatment will benefit patients with GBM., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc on behalf of Congress of Neurological Surgeons.)

Invasive extramammary Paget's disease may cause lymph node and distant metastases. Complete lymph node dissection is generally performed for extramammary Paget's disease presenting with lymph node metastases. Patients with extramammary Paget's disease and multiple lymph node metastases typically have poor prognoses, and there is no effective postoperative treatment to prevent recurrence or further metastases in such patients to date. This study aimed to evaluate the efficacy of postoperative radiotherapy in patients with extramammary Paget's disease and multiple lymph node metastases. We enrolled 26 patients with extramammary Paget's disease with ≥3 lymph node metastases who were treated at the National Cancer Center Hospital in Japan between January 2000 and June 2021. The patients were divided into those who underwent complete lymph node dissection only or with postoperative radiotherapy. We evaluated recurrence-free survival, distant metastasis-free survival, and overall survival outcomes with Kaplan-Meier curves. Among the 26 enrolled patients, 16 underwent complete lymph node dissection only and 10 underwent complete lymph node dissection with postoperative radiotherapy. The median follow-up period was 16 months. The 5-year recurrence-free, distant metastasis-free, and overall survival values were 47.3%, 63.0%, and 90% in those with complete lymph node dissection and postoperative radiotherapy, while these outcomes were all 0% (p = 0.001, 0.004, and 0.009, respectively) in those with only complete lymph node dissection. Thus, survival was significantly prolonged with postoperative radiotherapy. Additional postoperative radiotherapy may substantially improve the prognoses of patients with extramammary Paget's disease and ≥3 lymph node metastases, and undergoing curative surgery., (© 2022 Japanese Dermatological Association.)

Background and Purpose: To minimize cognitive decline without increasing brain tumor recurrence (BTR) by reduced-dose whole-brain radiotherapy (RD-WBRT) (25 Gy, 10 fractions) + stereotactic radiosurgery (SRS) in patients with ≤ 4 brain metastases., Materials and Methods: Eligible patients with ≤ 4 brain metastases on contrast-enhanced MRI and Karnofsky Performance Status ≥ 70. The primary endpoint was the non-inferiority of BTR at distant sites in the brain (BTR-distant)-free survival at 6 months compared to that of the standard dose (SD)-WBRT (30 Gy, 10 fractions) + SRS arm in a randomized clinical trial (JROSG99-1) of SRS with/without SD-WBRT. Secondary endpoints included BTR at any brain sites (BTR-all) and neurocognitive function assessed by a six-test standardized battery., Results: Forty patients from seven institutions were enrolled (median age 69 years). The primary tumor site was a lung in 28 patients; 20 patients had a solitary brain metastasis. The median survival time was 19.0 months (95 %CI: 13.8 %-27.5 %). The BTR-distant-free survival at 6 months was 76.9 % (59.5 %-87.7 %), which is comparable to that of historical control although predetermined non-inferiority (>71 %) could not be confirmed (p = 0.16). The cumulative incidence of BTR-all at 6 months accounting for the competing risk of death was 23.0 % (11.4-37.1), which was not worse than that of historical control (p = 0.774). The frequency of the cumulative incidence of persistent cognitive decline at 6 months was 48.6 % under the [>2.0 SD in ≥ 1 test] definition., Conclusions: RD-WBRT may yield comparable intracranial tumor control when combined with SRS, and may reduce the risk of neurocognitive decline compared to that after SD-WBRT., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Author(s).)

The aim of the present study was to determine which individual or combined CpG sites among O 6 -methylguanine DNA methyltransferase CpG 74-89 in glioblastoma mainly affects the response to temozolomide resulting from CpG methylation using statistical analyses focused on the tumor volume ratio (TVR). We retrospectively examined 44 patients who had postoperative volumetrically measurable residual tumor tissue and received adjuvant temozolomide therapy for at least 6 months after initial chemoradiotherapy. TVR was defined as the tumor volume 6 months after the initial chemoradiotherapy divided by that before the start of chemoradiotherapy. Predictive values for TVR as a response to adjuvant therapy were compared among the averaged methylation percentages of individual or combined CpGs using the receiver operating characteristic curve. Our data revealed that combined CpG 78 and 79 showed a high area under the curve (AUC) and a positive likelihood ratio and that combined CpG 76-79 showed the highest AUC among all combinations. AUCs of consecutive CpG combinations tended to be higher for CpG 74-82 in exon 1 than for CpG 83-89 in intron 1. In conclusion, the methylation status at CpG sites in exon 1 was strongly associated with TVR reduction in glioblastoma., Competing Interests: The authors declare no conflict of interest.

The first magnetic resonance (MR)-guided radiotherapy system in Japan was installed in May 2017. Implementation of online MR-guided adaptive radiotherapy (MRgART) began in February 2018. Online MRgART offers greater treatment accuracy owing to the high soft-tissue contrast in MR-images (MRI), compared to that in X-ray imaging. The Japanese Society for Magnetic Resonance in Medicine (JSMRM), Japan Society of Medical Physics (JSMP), Japan Radiological Society (JRS), Japanese Society of Radiological Technology (JSRT), and Japanese Society for Radiation Oncology (JASTRO) jointly established the comprehensive practical guidelines for online MRgART. These guidelines propose the essential requirements for clinical implementation of online MRgART with respect to equipment, personnel, institutional environment, practice guidance, and quality assurance/quality control (QA/QC). The minimum requirements for related equipment and QA/QC tools, recommendations for safe operation of MRI system, and the implementation system are described. The accuracy of monitor chamber and detector in dose measurements should be confirmed because of the presence of magnetic field. The ionization chamber should be MR-compatible. Non-MR-compatible devices should be used in an area that is not affected by the static magnetic field (outside the five Gauss line), and their operation should be checked to ensure that they do not affect the MR image quality. Dose verification should be performed using an independent dose verification system that has been confirmed to be reliable through commissioning. This guideline proposes the checklists to ensure the safety of online MRgART. Successful clinical implementation of online MRgART requires close collaboration between physician, radiological technologist, nurse, and medical physicist., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: Pelvic sidewall recurrence after hysterectomy for uterine malignances has a poor prognosis, and the salvage therapy for this type of recurrence is still challenging. The purpose of this study was to investigate the efficacy of freehand high-dose-rate interstitial brachytherapy (HDR-ISBT) through the perineum using transrectal ultrasonography for this disease., Methods and Materials: We retrospectively evaluated 42 patients with pelvic sidewall recurrence after hysterectomy for uterine cervical and endometrial cancers. We investigated patients' characteristics, the 2-year local control and survival rates, and late adverse events of the rectum and bladder., Results: The 2-year overall survival, local control, and progression-free survival rates were 73.7% (95% confidence interval [CI], 60.8-89.3%), 69.4% (95% CI, 55.4-80.1%), and 37.3% (95% CI, 24.6-56.5%), respectively. In Cox multivariate analysis, tumor size at recurrence (<45 mm vs. ≥45 mm) (p = 0.04) and disease-free periods after hysterectomy (<10 months vs. ≥10 months) (p < 0.01) were significant prognostic factors for overall survival. Lymph node metastasis at recurrence (p < 0.01) was also a significant prognostic factor for progression-free survival. Three patients experienced Grade 3-4 late proctitis (7%)., Conclusions: Transperineal freehand salvage HDR-ISBT using transrectal ultrasonography was demonstrated to be a curative treatment option for patients with pelvic sidewall recurrence following hysterectomy. Based on the findings of this study, we emphasize the importance of HDR-ISBT for pelvic sidewall recurrence., (Copyright © 2022 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

Objective: This is the preliminary results of a multi-center prospective clinical trial evaluating the feasibility of the hybrid of intracavitary and interstitial brachytherapy for locally advanced cervical cancer., Methods: Patients with FIGO stage IB2, IIA2, IIB, IIIA, IIIB and IVA uterine cervical cancer pretreatment width of which was ≥5 cm measured by MRI were eligible. Protocol therapy consisted of 30-30.6 Gy in 15-17 fractions of whole pelvic radiotherapy concurrent with weekly CDDP, followed by 24 Gy in 4 fractions of hybrid of intracavitary and interstitial and pelvic radiotherapy with central shield up to 50-50.4 Gy in 25-28 fractions. The primary endpoint of phase I part was that the rate of grade ≥ 3 acute non-hematologic adverse events related to hybrid of intracavitary and interstitial would be <10%., Results: Between October 2015 and October 2019, 74 patients underwent primary registration, with 52 patients eventually proceeding to the secondary registration. The median pretreatment tumor width was 5.7 cm, and FIGO Stages were IB2 10, IIA2 2, IIB 20 and IIIB 20, respectively. The median high-risk clinical target volume D90 was 72.0 Gy (54.8-86.6 Gy, EQD2), rectum D2cc was 53.7 Gy (29.3-80.3 Gy) and bladder D2cc was 69.8 Gy (38.9-84.8 Gy). The rate of grade ≥ 3 non-hematologic adverse events related to hybrid of intracavitary and interstitial was 1.9% (1/52), and 17.3% (9/52) of patients experienced non-hematologic adverse events related to hybrid of intracavitary and interstitial of any grade. In multivariate analysis, high-risk clinical target volume ≥ 35 ml was associated with an increased risk of any grade of acute non-hematologic adverse events related to hybrid of intracavitary and interstitial (P = 0.036)., Conclusion: The feasibility and reproducibility of hybrid of intracavitary and interstitial were demonstrated from a multi-center prospective clinical trial., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: There are limited reports on outcomes of three-dimensional image-guided brachytherapy (3D-IGBT) for cervical adenocarcinoma in Asia. In a multi-institutional retrospective study, we assessed the clinical outcomes of three-dimensional image-guided brachytherapy for cervical adenocarcinoma or adenosquamous carcinoma (CA/CAC) in Asian countries., Material and Methods: Patients who had undergone definitive radiation therapy/concurrent chemoradiotherapy for untreated cervical cancer between 2000 and 2016 were registered. Those who had undergone 3D-IGBT for histologically proven CA/CAC were included. Data on patients' characteristics and treatment were collected, including tumor reduction rate (defined as a percentage of reduction in tumor size before brachytherapy compared with that at diagnosis) and high-risk clinical target volume D 90 . Overall survival (OS), local control (LC), and progression-free survival (PFS) rates were calculated using Kaplan-Meier method. Late toxicities were assessed using common terminology criteria for adverse events version 4.0., Results: Anonymized data of 498 patients were collected. Of the 498 patients, 36 patients met inclusion criteria. The median follow-up period was 39 months. The 3-year OS, LC, and PFS rates were 68.4%, 68.5%, and 44.4%, respectively. After treatment, five patients had tumor re-growth without complete disappearance of the tumor. Two patients developed grade 3 vaginal toxicity or grade 4 rectal toxicity; none developed other severe late toxicities. A tumor reduction rate of > 26.3% was the only significant factor in multivariate analyses, and was associated with significantly better OS ( p = 0.018), LC ( p = 0.022), and PFS ( p = 0.013). There were no significant trends in local control or dose to high-risk clinical target volume D 90 ., Conclusions: LC rate of CA/CAC was insufficient despite 3D-IGBT. Meanwhile, tumor reduction rate was associated with LC, OS, and PFS rates. Therefore, CA/CAC may require a different treatment strategy than that applied in cervical squamous cell carcinoma., Competing Interests: Dr Okonogi reports grants and other (investigational drug supply) from AstraZeneca clinical trial, outside the submitted work. Dr Igaki reports grants and personal fees from HekaBio, grants from CICS, grants from Elekta KK, personal fees from AstraZeneca, personal fees from Itochu, personal fees from HIMEDIC, and personal fees from Varian, outside the submitted work. Dr Itami reports grants from Elekta KK, grants and personal fees from Itochu, personal fees from ViewRay, personal fees from Palette Science, personal fees from Alpha-TAU, and personal fees from HekaBio, outside the submitted work. This study received no financial support from any company; thus, there are no conflicts of interests to declare., (Copyright © 2022 Termedia.)

Although the international study on MRI-guided brachytherapy in cervical cancer (EMBRACE-I) demonstrated excellent local control regardless of the T stage, up to 14.6% of grade 3-5 late radiation-related toxicities were observed, which is unacceptable. While the efficacy of hydrogel spacers has been established in prostate radiotherapy, its implementation speed in cervical cancer brachytherapy is relatively slow, despite the fact that several articles have reported its efficacy in cervical cancer brachytherapy. The authors believe that using a spacer in cervical cancer brachytherapy and brachytherapy for other gynecologic malignancies will reduce late radiation-related toxicity and improve patients' quality of life; therefore, its rapid implementation is required., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Purpose: To assess the accuracy of the movement of a brachytherapy source using a high-speed camera for evaluating source position, dwell time, and transit dose., Methods: A high-speed camera was used to record the source position of an Ir-192 source relative to a ruler within a custom positioning jig in a remote afterloading system. The analyzed frames can be used to assess dwell positions and times. Treatment plans had multiple dwell times equal to 0.1, 0.5, 1.0, and 2.0 s in 2.5- and 5-mm step sizes. Images were acquired at a rate of 146 frames/s. Acquired images were processed to automatically track the actual source using the correlation between a template image and each frame. The brachytherapy dose calculation formalism (AAPM TG43-U1) was applied to each frame to evaluate the transit dose contribution to the total dose., Results: The differences in measured source positions from the nominal for dwell times equal to 0.1, 0.5, 1.0, and 2.0 s in treatment plans were approximately ≤1 mm. The corresponding differences in measured dwell times from the nominal values at 5 mm steps were -15, -9, -5, and 5 ms, respectively. The source velocities at 5 mm steps were approximately 393 mm/s. The dose differences at 5 mm from the source movement with and without the transit dose for these dwell times were 38%, 7%, 3%, and 2%, respectively., Conclusions: Recording a brachytherapy source using a high-speed camera allowed the evaluation of positional and dwell time accuracies as well as dosimetry assessments, such as the transit dose, based on the application of AAPM TG-43U1., (© 2022 American Association of Physicists in Medicine.)

Purpose: The clinical characteristics and prognosis of HPV-related nasopharyngeal cancer (NPC) remain controversial. The relationship between p16 status and outcome was retrospectively investigated in the NPC patients., Materials and Methods: Between May 2009 and May 2019, 81 NPC patients who received definitive radiation therapy, in a hospital in Japan, were identified and the prognosis was investigated. p16, p53, and Epstein-Barr virus (EBV) status were assessed. Also, circumferential tumor extent in the nasopharyngeal cavity was assessed on a 5-point scale., Results: Nine and 72 patients were p16-positive and p16-negative, respectively. Fewer patients were EBV-encoded RNA in situ hybridization (EBER-ISH)-positive in the p16-positive group than in the p16-negative group ( p  < .01). Seventy-five patients were nonkeratinizing NPCs, and six patients were keratinizing NPCs. There were two p16-positive patients among the keratinizing NPCs.The mean circumferential tumor extent scores of 16-positive and p16-negative NPCs were 4.2 and 3.2, respectively with a statistically significant difference ( p  = .02). Two-year progression-free survival (PFS) of p16-positive and p16-negative patients undergoing chemoradiation therapy were 100% and 69%, respectively ( p  = .13)., Conclusion: In this study conducted in Japan, p16-positive NPC patients are minor but not very low, and the proportion of keratinizing NPCs was small. p16-positive NPCs were seen both in keratinizing and nonkeratinizing NPCs. P16-positive NPC had a tendency of better PFS than p16-negative NPC. This better prognosis might be due to the higher radiosensitivity of the p16-positive cell. Additionally, p16-positive NPCs seemed to spread more extensively in circumference along the nasopharyngeal mucosa than p16-negative NPCs., Competing Interests: Dr. Itami reports personal fees from HekaBio, AlphaTAU, and Palette Science, research grants from Elekta, and ITOCHU outside the submitted work. Dr. Igaki reports grants and personal fees from Heka‐Bio, grants from CICS, grants from Elekta KK, personal fees from AstraZeneca, personal fees from Itochu, personal fees from HIMEDIC, personal fees from Varian, outside the submitted work. Dr. Inaba reports personal fees from Boston Scientific Japan, outside the submitted work. Dr. Kashihara reports personal fees from Astra Zeneca, outside the submitted work. The other authors have no conflicts of interest., (© 2022 The Authors. Laryngoscope Investigative Otolaryngology published by Wiley Periodicals LLC on behalf of The Triological Society.)

Background and Purpose: Online magnetic resonance-guided adaptive radiotherapy (MRgART) is a new technology of radiotherapy and requires a new quality control program in many aspects. This study aimed to gain a deeper understanding of risks in online MRgART through the application of failure mode and effect analysis (FMEA) for more enhanced and effective quality assurance (QA) programs., Materials and Methods: We present an FMEA conducted by a multidisciplinary team with more than two years of experience. A process map describing the whole process of online MRgART was developed and potential failure modes were identified. High-risk failure modes and their potential causes and corrective measures were also identified. Failure modes were classified into three categories, MRgRT, online ART, and conventional RT, to investigate their features. A comparison with previous studies was also conducted to gain a general perspective., Results: In total, 153 failure modes and 49 high risks were identified. Among all failure modes, 51, 63, and 66 were related to MRgRT, online ART, and conventional RT, respectively. The hazardous processes were structure segmentation, treatment planning, and treatment beam delivery. Lists of failure modes identified in this study and previous studies were presented. Based on the results, characteristics and general aspects of the risks were discussed., Conclusion: Exploring the results of the FMEA enhanced our understanding of risk characteristics to improve QA program of online MRgART., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

This study is an international multi-institutional retrospective study comparing the clinical outcomes between intracavitary brachytherapy (ICBT) and the hybrid of intracavitary and interstitial brachytherapy (HBT) for locally advanced cervical cancer patients treated with definitive radiation therapy. Locally advanced cervical cancer, the initial size of which is larger than 4 cm and treated by concurrent chemoradiotherapy and image-guided adaptive brachytherapy, were eligible for this retrospective study. Patients who received HBT at least once were included in the HBT group, and patients who received only ICBT were included in the ICBT group. Anonymized data from 469 patients from 13 institutions in Japan, one from Korea and one from Thailand, were analyzed. Two hundred eighty and 189 patients were included in the ICBT group and the HBT group, respectively. Patients in the HBT group had more advanced stage, non-Scc histopathology, a higher rate of uterine body involvement, larger tumor at diagnosis, larger tumor before brachytherapy and a lower tumor reduction ratio. With a median follow-up of 51.3 months (2.1-139.9 months), 4-y local control (LC), progression-free survival (PFS) and overall survival (OS) for the entire patient population were 88.2%, 64.2% and 83%, respectively. The HBT group received a higher HR-CTV D90 than that of the ICBT group (68.8 Gy vs 65.6 Gy, P = 0.001). In multivariate analysis, the non-Scc histological subtype, HR-CTV D95 ≤ 60 Gy, reduction ratio ≤ 29% and total treatment time (TTT) ≥ 9 weeks were identified as the independent adverse prognostic factors for LC. Regarding LC, no difference was found between ICBT and HBT (4-y LC 89.3% vs 86.8%, P = 0.314). After adjustment for confounding factors by propensity score matching, no advantage of applying HBT was demonstrated regarding LC, PFS, or OS. Despite the fact that HBT patients had more adverse clinical factors than ICBT patients, HBT delivered a higher dose to HR-CTV and resulted in comparable LC., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Next-generation sequencing-based comprehensive genomic profiling test (CGPT) enables clinicians and patients to access promising molecularly targeted therapeutic agents. Approximately 10% of patients who undergo CGPT receive an appropriate agent. However, its coverage of glioma patients is seldom reported. The aim of this study was to reveal the comprehensive results of CGPT in glioma patients in our institution, especially the clinical actionability. We analyzed the genomic aberrations, tumor mutation burden scores, and microsatellite instability status. The Molecular Tumor Board (MTB) individually recommended a therapeutic agent and suggested further confirmation of germline mutations after considering the results. The results of 65/104 patients with glioma who underwent CGPTs were reviewed by MTB. Among them, 12 (18.5%) could access at least one therapeutic agent, and 5 (7.7%) were suspected of germline mutations. A total of 49 patients with IDH -wildtype glioblastoma showed frequent genomic aberrations in the following genes: TERT promoter (67%), CDKN2A (57%), CDKN2B (51%), MTAP (41%), TP53 (35%), EGFR (31%), PTEN (31%), NF1 (18%), BRAF (12%), PDGFRA (12%), CDK4 (10%), and PIK3CA (10%). Since glioma patients currently have very limited standard treatment options and a high recurrence rate, CGPT might be a facilitative tool for glioma patients in terms of clinical actionability and diagnostic value.

Background: Validity of the risk classification by Ang for human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) remains to be studied in the patients treated by modalities other than chemoradiotherapy and in Japanese patients., Materials and Methods: Between 2010 and 2018, 122 patients with HPV-related OPSCC in stages III and IV by the TNM classification 7th edition (TNM-7) were treated curatively at a single institution in Japan. The median age was 62.7 years. Over 50% of the patients underwent surgery with or without adjuvant therapy. The influence of multiple factors on survival was analyzed., Results: The amount of smoking dichotomized at 10 pack-year, which was used in Ang's risk classification, was not predictive of prognosis, and Ang's risk classification was not significantly influential on prognosis in multivariate analysis. In the patients treated with definitive radiation therapy, Ang's risk classification was not predictive of the prognosis in univariate analysis. The impact of smoking was significant only in the patients undergoing the definitive operation., Conclusions: Ang's risk classification was not robust in predicting the prognosis of general Japanese HPV-related OPSCC patients. The amount of smoking might have different prognostic influences depending on the therapeutic method.

Background: We sought to clarify the optimal follow-up, therapeutic strategy, especially the role of reirradiation, and the diagnostic impact of isocitrate dehydrogenase (IDH) 1 and 2 mutation status in patients with radiation-induced glioma (RIG)., Methods: We retrospectively reviewed the clinical characteristics and treatment outcomes of 11 patients with high-grade glioma who satisfied Cahan's criteria for RIG in our database during 2001-2021. IDH 1/2 mutations were analyzed by Sanger sequencing and/or pyrosequencing., Results: The RIGs included glioblastoma with IDH 1/2 wild-type (n = 7), glioblastoma not otherwise specified (n = 2), anaplastic astrocytoma with IDH1/2 wild-type (n = 1), and anaplastic astrocytoma not otherwise specified (n = 1). The median period from primary disease and RIG diagnosis was 17 years (range: 9-30 years). All patients underwent tumor removal or biopsy, 5 patients postoperatively received reirradiation combined with chemotherapy, and 6 patients were treated with chemotherapy alone. The median progression-free and survival times were 11.3 and 28.3 months. The median progression-free survival time of patients treated with reirradiation and chemotherapy (n = 5) tended to be longer than that of patients that received chemotherapy alone (n = 6) (17.0 vs 8.1 months). However, the median survival time was similar (29.6 vs 27.4 months). Local recurrence was observed in 5 patients treated with chemotherapy alone, whereas in 2 patients among 4 patients treated with reirradiation and chemotherapy. None of the patients developed radiation necrosis. In one case, the primary tumor was diffuse astrocytoma with IDH2 mutant, and the secondary tumor was glioblastoma with IDH 1/2 wild-type. Based on the difference of IDH2 mutation status, the secondary tumor with IDH 1/2 wild-type was diagnosed as a de novo tumor that was related to the previous radiation therapy., Conclusions: RIG can occur beyond 20 years after successfully treating the primary disease using radiotherapy; thus, cancer survivors should be informed of the long-term risk of developing RIG and the need for timely neuroimaging evaluation. Reirradiation combined with chemotherapy appears to be feasible and has favorable outcomes. Determining the IDH1/2 mutational status is useful to establish RIG diagnosis when the primary tumor is glioma., (© 2022. The Author(s).)

Purpose: Although the usefulness of O 6 -methylguanine DNA methyltransferase (MGMT) promoter methylation analysis for predicting response to chemoradiotherapy and the prognosis of patients with glioblastoma has been widely reported, there is still no consensus regarding how to define MGMT promoter methylation percentage (MGMTpm%) cutoffs by pyrosequencing method. The aim of this study was to determine the optimal cutoff value of MGMT promoter methylation status using volumetric analysis focused on the tumor volume ratio (TVR) measured by MRI., Methods: This retrospective study included newly diagnosed IDH wild-type glioblastoma patients with residual tumor after surgery, followed by local radiotherapy with temozolomide. TVR was defined as the tumor volume at 6 months after the initial chemoradiotherapy administration divided by the tumor volume before the start of therapy. The mean MGMTpm% of 16 CpG islands (74-89) was analyzed using pyrosequencing. We statistically analyzed the correlation between MGMTpm%, TVR, and change in Karnofsky performance status., Results: The study included 44 patients with residual tumors. Thirteen (92.9%) of 14 patients with MGMTpm% ≥ 23.9% showed 50% or more volumetric response, leading to prolonged survival, and 17 (70.8%) of 24 patients with MGMTpm% < 8.2% had progressive disease after initial chemoradiotherapy administration. Three (50.0%) of six patients with MGMTpm% 8.2% to < 23.9% had stable disease or partial response., Conclusion: Evaluation of MGMTpm% by pyrosequencing is important in predicting the volumetric response and prognosis of glioblastoma patients with residual tumors., (© 2022. The Author(s).)

We report on a patient with metastatic extraskeletal myxoid chondrosarcoma (EMC), who was treated with palliative high-dose-rate (HDR) interstitial brachytherapy (ISBT). The patient was an 87-year-old woman who underwent an amputation for a bulky tumor in her right ankle joint. EMC was histopathologically confirmed. She presented with a large right inguinal lymph node metastasis of EMC 16 months after surgery. Palliative HDR-ISBT (30 Gy/2 fractions in 1 day) for the right inguinal lymph node metastasis was administered to shorten treatment period. Additional HDR-ISBT (30 Gy/2 fractions in 1 day) was administered for the management of subsequent subcutaneous metastasis to the right breast and right popliteal fossa. HDR-ISBT provided significant long-term control of the recurrent tumor in all three sites, without severe acute and late toxicity. Thus, HDR-ISBT regimen of 30 Gy/2 fractions in 1 day can be a suitable option for both palliation and long-term local control for patients with metastatic EMC., Competing Interests: The authors report no conflict of interest., (Copyright © 2022 Termedia.)

We suggested de-escalation would be possible for cervical cancer like human papillomavirus (HPV)-related oropharyngeal cancer. However, the classification was based on tumor shrinkage that can be obtained after half of the treatment was finished. Our other article found adverse factors which can be obtained prior to treatment, and they might classify patients earlier., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Cutaneous angiosarcomas is a rare cancer with poor prognoses. The common radiotherapy techniques that have been reported so far are two pairs of lateral X-ray and electron fields. However, it is quite difficult to irradiate scalp angiosarcomas (SAs) homogeneously with this technique. In this study, safety, effectiveness, and risk factors were assessed for localized SAs ≥ 5 cm treated with intensity-modulated radiotherapy (IMRT) or volumetric modulated arc therapy (VMAT) with boluses. Sixty-eight angiosarcoma patients who had received radiotherapy in our institution between January 2007 and November 2020 were retrieved from our radiotherapy database. Of these patients, 27 localized SA patients were included in the retrospective analysis. The 2-year overall survival, local progression-free rate, and distant metastases-free survival were 41.8%, 48.4%, and 33.1%. All the patients experienced acute radiation dermatitis ≥ grade 2, with18 (66.7%) ≥ grade 3. No nodule lesion was a significant unfavorable predictive factor of acute radiation dermatitis ≥ grade 3. Tumor bleeding at the initiation of radiotherapy and tumor invasion to the face were significant predictive factors of overall survival, and tumor bleeding at the initiation of radiotherapy was also a significant predictive factor of local progression-free rate., (© 2022. The Author(s).)

Boron neutron capture therapy (BNCT) is a non-invasive therapeutic technique for treating malignant tumors, however, methods to evaluate its therapeutic efficacy and adverse reactions are lacking. High mobility group box 1 (HMGB1) is an inflammatory molecule released during cell death. Therefore, we aimed to investigate HMGB1 as a biomarker for BNCT response, by examining the early responses of tumor cells to 10 B-boronophenylalanine (BPA)-based BNCT in the Kyoto University Nuclear Reactor. Extracellular HMGB1 release was significantly increased in human squamous carcinoma SAS and melanoma A375 cells 24 h after neutron irradiation but not after γ-irradiation. At 3 days post-BPA-based BNCT irradiation in a SAS xenograft mouse model, plasma HMGB1 levels were higher than those in the non-irradiation control, and HMGB1 was detected in both nuclei and cytoplasm in tumor cells. Additionally, increased plasma HMGB1 levels post-BNCT irradiation were detected even when tumors decreased in size. Collectively, these results indicate that the extracellular HMGB1 release occurs at an early stage and is persistent when tumors are reduced in size; therefore, it is a potential biomarker for evaluating the therapeutic response during BNCT.

Purpose The purpose of this study is to propose algorithms and methods for achieving high accuracy in tracking and interception irradiation technology for tumors that move by respiration using MR-linac (MRIdian®, ViewRay Inc.) and to use deep learning to predict the movement of moving tumors in real time during radiation therapy and reconstruct cine magnetic resonance imaging (cine-MRI) into four-dimensional (4D) movies. Methods In this study, we propose a reconstruction algorithm using 4DCT for treatment planning taken before irradiation as training data in consideration of the actual treatment flow. In the algorithm, two neural networks made before treatment are used to reconstruct 4D movies that predict tumor movement in real time during treatment. Cycle GAN (generative adversarial network) was used to convert MR images to CT images, and long short-term memory was used to convert cine-MRI to 4D movies and predict tumor movement. Results We succeeded in predicting the time including the imaging time of the MR images, the lag until irradiation, and the calculation time in the algorithm. In addition, the conversion and prediction results at each phase of reconstruction were generally good so that they could be clinically applied. Conclusions The reconstruction algorithm proposed in this study enables high-precision radiotherapy while predicting the volume information of the tumor and the actual tumor position, which could not be obtained during radiotherapy., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Tamura et al.)

This paper presents the first version of clinical practice guidelines for intrahepatic cholangiocarcinoma (ICC) established by the Liver Cancer Study Group of Japan. These guidelines consist of 1 treatment algorithm, 5 background statements, 16 clinical questions, and 1 clinical topic, including etiology, staging, pathology, diagnosis, and treatments. Globally, a high incidence of ICC has been reported in East and Southeast Asian countries, and the incidence has been gradually increasing in Japan and also in Western countries. Reported risk factors for ICC include cirrhosis, hepatitis B/C, alcohol consumption, diabetes, obesity, smoking, nonalcoholic steatohepatitis, and liver fluke infestation, as well as biliary diseases, such as primary sclerosing cholangitis, hepatolithiasis, congenital cholangiectasis, and Caroli disease. Chemical risk factors include thorium-232, 1,2-dichloropropane, and dichloromethane. CA19-9 and CEA are recommended as tumor markers for early detection and diagnostic of ICC. Abdominal ultrasonography, CT, and MRI are effective imaging modalities for diagnosing ICC. If bile duct invasion is suspected, imaging modalities for examining the bile ducts may be useful. In unresectable cases, tumor biopsy should be considered when deemed necessary for the differential diagnosis and drug therapy selection. The mainstay of treatment for patients with Child-Pugh class A or B liver function is surgical resection and drug therapy. If the patient has no regional lymph node metastasis (LNM) and has a single tumor, resection is the treatment of choice. If both regional LNM and multiple tumors are present, drug therapy is the first treatment of choice. If the patient has either regional LNM or multiple tumors, resection or drug therapy is selected, depending on the extent of metastasis or the number of tumors. If distant metastasis is present, drug therapy is the treatment of choice. Percutaneous ablation therapy may be considered for patients who are ineligible for surgical resection or drug therapy due to decreased hepatic functional reserve or comorbidities. For unresectable ICC without extrahepatic metastasis, stereotactic radiotherapy (tumor size ≤5 cm) or particle radiotherapy (no size restriction) may be considered. ICC is generally not indicated for liver transplantation, and palliative care is recommended for patients with Child-Pugh class C liver function., (Copyright © 2022 by The Author(s). Published by S. Karger AG, Basel.)

Purpose: This study reports the first-in-human use of a linear accelerator-based boron neutron capture therapy (BNCT) system and the first treatment of patients with scalp-angiosarcoma with accelerator-based BNCT., Patients and Methods: A single-center open-label phase I clinical trial has been conducted using the system since November 2019. Patients with a localized node-negative scalp-angiosarcoma along with the largest diameter of the tumor ≤ 15 cm who refused primary surgery and chemotherapy were enrolled. After administration of boronophenylalanine (BPA), a single treatment of BNCT with the maximum dose delivered to the skin being 12 Gy-Eq was performed. The safety and effectiveness of accelerator-based BNCT therapy for localized scalp angiosarcoma were evaluated., Results: Scalp-angiosarcoma of the two patients did not develop the dose-limiting toxicity in the clinical trial. They reached CR within half a year and did not exhibit in-field failure 20 months after BNCT without any severe treatment-related adverse events. Although a grade 3 adverse event of an asymptomatic but increased serum amylase level was noted in both patients, it relieved without any treatment. Additionally, no severe acute dermatitis was observed for both patients, which is typically seen with conventional primary radiotherapy., Conclusions: It was suggested that BNCT would be a promising treatment modality for scalp-angiosarcoma, which is difficult to treat., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Purpose: Hyaluronate gel has been injected as a spacer into the rectovaginal fossa and vesicouterine fossa during brachytherapy for patients with cervical cancer at our institution. The effect of hyaluronate gel injection (HGI) on dose-volume parameters was investigated in this study., Methods and Materials: Between July 2008 to January 2020, a total of 104 patients (non-HGI group: 52 patients; HGI group: 52 patients) who underwent curative radiation therapy for cervical cancer were selected. The total doses of external beam radiation therapy and brachytherapy for high-risk clinical target volume (CTV HR ) D 90 , bladder D 2cc , and rectal D 2cc were converted to the equivalent dose in 2 Gy fractions (EQD2) and were analyzed for association with HGI., Results: Median CTV HR D 90 (EQD2) in the non-HGI group was 76.0 Gy (63.7-99.5 Gy), and in the HGI group it was 79.4 Gy (52.6-97.5 Gy) ( P  = .017). The median bladder D 2cc and rectal D 2cc (EQD2) were 62.9 Gy and 56.0 Gy in the non-HGI group and 63.7 Gy and 54.8 Gy in the HGI group, which had no significant difference., Conclusions: In cases with HGI, a significant CTV HR D 90 dose increase was obtained with sufficient bladder and rectal doses suppression., (© 2022 The Author(s).)

Introduction: Patients with recurrent gynecologic malignancies having had pelvic irradiation, generally have limited salvage options. This study investigated patients with gynecologic malignancies, who had a history of pelvic irradiation and received salvage re-irradiation using image-guided high-dose-rate brachytherapy (IG-HDR-BT)., Material and Methods: Patients with gynecologic malignancies, who had a history of previous irradiation and received re-irradiation using IG-HDR-BT for disease recurrences from June 2014 to March 2020 were included in this study., Results: A total of 37 patients were included in this retrospective analysis. Primary tumor was uterine cervical cancer in 31 patients, endometrial cancer in 5 patients, and vaginal cancer in 1 patient. Median follow-up period of patients who were alive at the time of analysis was 15.4 months (range, 4.1-61.4 months). Two-year overall survival, progression-free survival, and local control were 68.9%, 49.3%, and 67.5%, respectively. Severe late toxicities ≥ grade 3, which were related to re-irradiation, were observed in 9 patients (24.3%). Usage of bevacizumab in the entire course of treatment was associated with development of late ≥ grade 3 fistula formation, bowel perforation, or vaginal ulcer (50% vs. 6.9%, p = 0.013). Tumor size ≥ 2.5 cm was associated with development of late ≥ grade 3 of rectum, bladder, or vaginal toxicities (0% vs. 28%, p = 0.047)., Conclusions: If the recurrent disease was found in small size and there was no history of bevacizumab usage, re-irradiation with IG-HDR-BT could be considered, even in patients with a previous history of pelvic irradiation., Competing Interests: The authors report no conflict of interest., (Copyright © 2022 Termedia.)

Background and Purpose: High-dose-rate interstitial brachytherapy (HDR-ISBT) is recommended to obtain a better local tumor control for uterine cancer patients in specific situations such as bulky lesions, an extension to the lateral parametrium, or tumors with irregular shapes. Our group uses real-time transrectal ultrasonography (TRUS) to guide freehand interstitial needle insertion. Occasionally, target tumors locate deeper beyond the rectum and cannot be visualized by TRUS. CT can guide needles to deeply located tumors, but in such cases, repeated image obtainment is required to achieve ideal needle localization. In this report, we present nine cases of patients who underwent HDR-ISBT for deeply situated tumors guided by a combination of transrectal and transabdominal ultrasonography (TR/TA-US)., Material and Methods: Nine uterine cancer patients whose tumors were located deeper than the reach of TRUS and underwent HDR-ISBT guided by TR/TA-US were presented. All nine cases had no distal organ metastasis and underwent external beam radiation therapy (EBRT) to the pelvic region for 45-50.4 Gy in 25-28 fractions followed by boost HDR-ISBT for deeply situated tumors guided by TR/TA-US., Results: There were seven cervical cancer and two endometrial cancer patients: six with extensive uterine corpus invasion, one cervical cancer with massive pelvic lymph node metastasis, one cervical cancer with postoperative pelvic recurrence, and one with left ovarian direct tumor invasion. The median follow-up period was 15 months (range 3-28 months). The average clinical target volume at the time of first HDR-ISBT was 131 ml (range 44-335 ml). The linear distance from the vaginal entrance to the deepest part of the tumor at first time brachytherapy of nine cases was 14.0 (9.0-17.0) cm. HDR-ISBT dose fractionation was 24-30 Gy in four or five fractions. Seven out of nine cases had no local recurrence in the follow-up period. One had local in-field recurrence 25 months after HDR-ISBT. Another case with carcinosarcoma could not obtain local control and underwent salvage hysterectomy for a residual uterine tumor 11 months after HDR-ISBT. Four cases had extra-field recurrence in lymph nodes or distant organs., Conclusions: In brachytherapy for gynecologic malignancies, deeply situated tumors located out of reach of TRUS may obtain favorable local control by HDR-ISBT guided with TR/TA-US., Competing Interests: JI reports grants from Elekta, during the conduct of the study; personal fees from Heka-Bio; personal fees from Alpha-TAU; grants and others from ITOCHU; and personal fees from Palette Life Science, outside the submitted work. HI reports grants and personal fees from Heka-Bio, grants from CICS, grants from Elekta KK, personal fees from AstraZeneca, personal fees from Itochu, personal fees from HIMEDIC, and personal fees from Varian, outside the submitted work. KI reports personal fees from Boston Scientific Japan, outside the submitted work. TaK reports personal fees from Astra Zeneca, outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Shimizu, Murakami, Chiba, Kaneda, Okamoto, Nakamura, Takahashi, Kashihara, Takahashi, Inaba, Okuma, Nakayama, Itami and Igaki.)

Background: The 106-Ruthenium contact plaque applicator is utilized for the treatment of intraocular tumor within a thickness of less than 6 mm. If anything obstructs the placement of the plaque applicator, the treatment is generally difficult because the applicator has to be temporarily located just on the opposite side of the retinal tumor. Furthermore, the plaque applicator edge of approximately 1 mm does not contain 106 Ru, estimating the delivered radiation dose for eccentric tumor is challenging because the lateral dose profile is inadequately provided by the manufacture's certification. This study aims to simulate tumor coverage of the tilted applicator placement for treating an infant with juxtapapillary retinoblastoma and to achieve the effective treatment., Case Presentation: We present an infant with retinoblastoma whose tumor involved macular and was invading just temporal side of the optic disc. Additionally, posterior staphyloma was induced by a series of previous treatments, making it more difficult to treat the standard plaque placement. Thus, the applicator type of CCA was intentionally tilted to the eyeball and the distance between the posterior edge of the applicator and the eyeball had to be then equal to or more than 2 mm based on the dose distribution of the applicator calculated using Monte Carlo simulation to minimize damage to surrounding tissues while covering the tumor. It was then comparable to the certification and previous reports. Based on the acquired dose distribution, the optimal placement of the applicator was derived from varying the distance between the applicator's edge and the eyeball, and the distance was then determined to be 2 mm. In this case, the minimum dose rate in the tumor was 25.5 mGy/min, and the time required to deliver the prescribed dose was 26.2 h. Therefore, the tilted 106 Ru plaque applicator placement could deliver the required dose for the treatment. The physical examination revealed no active tumor as a result of the treatment., Conclusions: Optimizing the placement of the 106 Ru plaque applicator, it was possible to guarantee that the prescribed dose will be delivered to the tumor even if the standard placement is not possible for the juxtapapillary tumor., (© 2022. The Author(s).)

Mycosis fungoides (MF) is a common, low-grade non-Hodgkin's lymphoma of skin-homing T lymphocytes that can be treated via skin-directed radiotherapy. Our institution has implemented total skin electron therapy (TSET) with a 4.3 m source-to-surface distance (SSD) and 6 MeV electron beams with a beam spoiler. A 35-year-old male undergoing TSET desired to avoid radiotherapy-induced hair loss and temporary infertility; therefore, leakage dose to scalp and testicles was reduced with a special radiation shield composed of stacked lead sheets. The shields for the scalp and scrotal were of 3 mm and 6 mm, respectively. To assess leakage doses, a radiophotoluminescence glass dosimeter (RPLD) was placed at every fraction. The difference dose between the measured and prescribed dose at the calibration point was 2%. The top of the head and scrotal surface exhibited 18 cGy and 10 cGy, respectively. Thus, the dose to the scrotal surface was not beyond the testicular tolerance dose of 20 cGy. Results of semen analysis two months postradiotherapy were normal. There was no hair loss during or after radiation therapy. Therefore, the RPLD is a useful in vivo dosimeter that provides technical information on radiation shielding to allow for completion of TSET without hair loss or temporary infertility., (© The Author(s) 2021. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

High-dose-rate brachytherapy by remote afterloading is now performed under three-dimensional image guidance by CT or MRI. Three-dimensional image-guided brachytherapy in cervical cancer disclosed that the traditional intracavitary brachytherapy by Manchester method cannot deliver an adequate dose to the large tumor with resulting local recurrence. To improve the local control rate, combined interstitial and intracavitary (hybrid) brachytherapy can increase the dose to the large parametrial involvement without increasing the dose to the rectum and bladder. Whether hybrid brachytherapy can be performed safely on a multi-institutional basis remains to be studied. From 2015, phase I/II study of hybrid brachytherapy was launched in Japan, and it was revealed that hybrid brachytherapy can be performed safely and with a high quality of radiation dose distribution in a multi-institutional study. In Japan, the number of patients undergoing hybrid brachytherapy in cervical cancer is rapidly rising. Education and clinical trial are very important to establish hybrid brachytherapy in the management of cervical cancer., Competing Interests: The authors report research grant from Elekta and ITOCHU and consultation honoraria from HekaBio, Alpha-TAU, and Palette Science., (Copyright © 2022 Itami, Murakami, Watanabe, Sekii, Kasamatsu, Kato, Hirowatari, Ikushima, Ando, Ohno, Okamoto, Okuma and Igaki.)

Purpose: In this study, we report on our proposed phantom based on the new end-to-end (E2E) methodology and its results. In addition, we verify whether the proposed phantom can replace conventional phantoms., Methods: The hexagonal-shaped newly designed phantom has pockets on each side for a film dosimeter of size 80 × 90 mm 2 , which is easily removable, considering the 60 Co penumbra. The new phantom comprises water, shell, and auxiliary shell phantoms. The shell and auxiliary shell materials are Solid Water HE. A mock tumor (aluminum oxide) was attached by a single prop in the water phantom and placed at the center of the new phantom. The results of a conventional E2E test were compared with those of the novel E2E test using the newly designed phantom. The irradiated film dosimeter in the novel E2E test was scanned in a flatbed scanner and analyzed using an in-house software developed with MATLAB. The irradiated field center, laser center, and mock tumor center were calculated. In the novel image-matching E2E (IM-E2E) test, image matching is performed by aligning the laser center with ruled lines. In the novel irradiation-field E2E (IF-E2E) test, the displacement of the irradiation-field center was defined as its distance from the laser center. In the composite E2E test, the overall displacement, which included the accuracy of the irradiated field and image matching, was defined as the distance between the irradiated field center and mock tumor center. In addition, using the newly designed phantom, the overall irradiation accuracy of the machine was evaluated by calculating the three-dimensional (3D) center of the irradiated field, phantom, and laser. The composite E2E test could be performed using the newly designed phantom only., Results: In the IM-E2E test, the results of the conventional and novel IM-E2E tests were significantly different in each direction (left-right direction: p-value < < 0.05, anterior-posterior direction: p-value = 0.002, and superior-inferior direction: p-value = 0.002). The displacement directions were the same in both the conventional and novel IM-E2E tests. In the analysis of the IF-E2E test, no significant difference was evident between the results in each direction. Moreover, the displacement directions were the same in the conventional and novel IF-E2E tests, except for the left-right lateral direction of head three. In addition, the 3D analysis results of the novel IF-E2E test were less than 1 mm in all directions. In the analysis of the composite E2E test, the maximum displacement was 1.4 mm in all directions. In addition, almost all results of 3D analysis for the composite E2E test were less than 1 mm in all directions., Conclusion: The newly designed E2E phantom simplifies the E2E test for MRIdian, and is a possible alternative to the conventional E2E test. Furthermore, we can perform the previously unfeasible composite E2E tests that include the entire treatment process., (© 2021 American Association of Physicists in Medicine.)

Purpose: To increase the superficial dose and reduce the brain dose for radiotherapy of scalp angiosarcoma, we propose a novel irradiation technique of tangential irradiation volumetric modulated arc therapy (TI-VMAT)., Methods: TI-VMAT and the conventional VMAT treatment plans for thirteen scalp angiosarcoma patients were created with a prescribed dose of 70 Gy. Each treatment was normalized to cover 95% of the planning target volume (PTV) with its prescribed dose. To realize TI-VMAT, an avoidance structure (AS) function was applied. AS was defined as a contour subtracted PTV by a certain space from the brain contour. TI-VMAT treatment plans for six different spaces between PTV and AS were developed and compared with the conventional VMAT treatment plan with respect to the following dosimetric parameters: homogeneity index (HI) and conformity index (CI) of the PTV, mean brain dose, and brain volume irradiated with 20% (V 20% [cc]), 40% (V 40% [cc]), 60% (V 60% [cc]), 80% (V 80% [cc]), and 100% (V 100% [cc]) of the prescribed dose., Results: HI and CI were comparable between TI-VMAT and the conventional VMAT, the mean brain dose for TI-VMAT with AS defined by a space of 2.0 cm and jaw tracking was 14.27 Gy, which was significantly lower than that for the conventional VMAT (21.20 Gy). In addition, dosimetric parameters such as V 20% [cc] were significantly suppressed compared to those for high doses., Conclusion: Our proposed irradiation technique TI-VMAT shows the potential to reduce radiation doses in the brain with maintaining higher dose coverage on the PTV., (Copyright © 2021 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.)

Objective: The majority of uterine cervical cancer is known to be related to human papillomavirus (HPV), and HPV-related tumors are known to be radio-sensitive. In the management of HPV-related oropharyngeal cancer, de-intensification of treatment has been attempted; however, no such attempt is performed in the management of cervical cancer. The aim of this study was to identify a group of patients who can safely be treated by de-escalated treatment intensity., Methods: From the Asian international multi-institutional retrospective study involving 13 Japanese, one Thailand, and one Korean institutions based on 469 patients, squamous cell carcinoma (Scc), tumor reduction ratio ≥29%, tumor size before brachytherapy ≤4 cm, and total treatment time (TTT) <9 weeks were identified as factors having an influence on local control. Based on these findings, low-risk patients having these four factors were extracted, and treatment outcomes categorized in 10 Gy increment of CTV HR D 90 were compared., Results: Among 469 patients, 162 patients (34.5%) met the criteria of low-risk group, and 63, 41, 43, and 15 patients were categorized in CTV HR D 90 50-60 Gy, 60-70 Gy, 70-80 Gy, and >80 Gy, respectively. While 4-y progression-free survival ranged from 66 to 80%, 4-y local control was consistently over 90% in every dose group. Rectum and bladder D 2cc and incidence of late adverse events decreased as CTV HR D 90 decreased., Conclusions: The low-risk patients achieved favorable local control with CTV HR D 90 <80 Gy. A personalized treatment strategy based on tumor response could also be adopted for cervical cancer., (Copyright © 2021 Elsevier Inc. All rights reserved.)

In this technical report, patient with total pharyngolaryngectomy and jejunum interposition experienced lymph node metastasis in the reconstructed mesenteric lymph nodes. Because this patient received 45 Gy of whole neck radiation therapy 24 years ago and small bowel's tolerance dose of the reconstructed jejunum was considered to be low, spacer gel injection was applied during image-guided interstitial brachytherapy to decrease doses to the reconstructed jejunum and previously irradiated carotid artery., (Copyright © 2021 Termedia.)

Background: Contour delineation, a crucial process in radiation oncology, is time-consuming and inaccurate due to inter-observer variation has been a critical issue in this process. An atlas-based automatic segmentation was developed to improve the delineation efficiency and reduce inter-observer variation. Additionally, automated segmentation using artificial intelligence (AI) has recently become available. In this study, auto-segmentations by atlas- and AI-based models for Organs at Risk (OAR) in patients with prostate and head and neck cancer were performed and delineation accuracies were evaluated., Methods: Twenty-one patients with prostate cancer and 30 patients with head and neck cancer were evaluated. MIM Maestro was used to apply the atlas-based segmentation. MIM Contour ProtégéAI was used to apply the AI-based segmentation. Three similarity indices, the Dice similarity coefficient (DSC), Hausdorff distance (HD), and mean distance to agreement (MDA), were evaluated and compared with manual delineations. In addition, radiation oncologists visually evaluated the delineation accuracies., Results: Among patients with prostate cancer, the AI-based model demonstrated higher accuracy than the atlas-based on DSC, HD, and MDA for the bladder and rectum. Upon visual evaluation, some errors were observed in the atlas-based delineations when the boundary between the small bowel or the seminal vesicle and the bladder was unclear. For patients with head and neck cancer, no significant differences were observed between the two models for almost all OARs, except small delineations such as the optic chiasm and optic nerve. The DSC tended to be lower when the HD and the MDA were smaller in small volume delineations., Conclusions: In terms of efficiency, the processing time for head and neck cancers was much shorter than manual delineation. While quantitative evaluation with AI-based segmentation was significantly more accurate than atlas-based for prostate cancer, there was no significant difference for head and neck cancer. According to the results of visual evaluation, less necessity of manual correction in AI-based segmentation indicates that the segmentation efficiency of AI-based model is higher than that of atlas-based model. The effectiveness of the AI-based model can be expected to improve the segmentation efficiency and to significantly shorten the delineation time., (© 2021. The Author(s).)

Granulocyte-macrophage colony-stimulating factor (GM-CSF) promotes dendritic cell differentiation from precursors, and consequently, enhances the antigen presentation process and adaptive immune responses. With such functions, GM-CSF has been used as immunotherapy in combination with radiotherapy for cancer treatment to augment the survival and activity of immune cells. However, an immune-suppressive tumor microenvironment may cause anergy of T cells. It has also been reported that GM-CSF contributes to the development of myeloid-derived suppressor cells from the precursors. In this study, to analyze the combined effect of GM-CSF and released factors from cancer cells after gamma-ray irradiation on bone marrow cell differentiation and dynamics, we established an in vitro culture system using mouse bone marrow cells, GM-CSF, and conditioned medium from gamma ray irradiated mouse melanoma B16 cells at 24 Gy. We analyzed the gene expression changes of the bone marrow-derived cells on day 6. The results showed that GM-CSF dose-dependently enhanced the differentiation of macrophages from bone marrow cells, their antigen-presenting function and polarization to type I. The results implied the induced macrophages from the bone marrow may potentially contribute to tumor immune responses in a systemic manner when GM-CSF is boosted during photon-beam radiation therapy.

Background: There is no standard treatment for patients with recurrent high-grade gliomas who progress after bevacizumab treatment. We evaluated the outcomes of re-irradiation combined with bevacizumab for patients refractory to bevacizumab., Methods: Between January 2015 and September 2019, patients with progression after bevacizumab treatment were treated with re-irradiation combined with bevacizumab (25 Gy in five fractions)., Results: Fourteen patients [glioblastoma, isocitrate dehydrogenase (IDH) wild type (N = 6), glioblastoma, IDH mutant (N = 4), anaplastic astrocytoma, IDH wild type (N = 1), anaplastic astrocytoma, IDH mutant (N = 1), glioblastoma, not otherwise specified (N = 1) and radiologically diagnosed brainstem glioma (N = 1)] were included in this study. The median survival and progression-free survival times after re-irradiation combined with bevacizumab were 6.1 and 3.8 months, respectively. The 6-month survival and progression-free survival rates were 54.5 and 15.7%, respectively. Patients with a Karnofsky performance status of ≥70 tended to have longer median survival time (9.3 vs. 5.4 months, respectively; P = 0.058) and had a significantly longer median progression-free survival time (4.2 vs. 3.7 months, respectively; P = 0.046) than those with a Karnofsky performance status of <70. Four patients (28.6%) achieved a complete or partial radiological response, and three patients (21.4%) had an improved Karnofsky performance status after re-irradiation combined with bevacizumab. Grade 3/4 toxicities included leukopenia in four patients (28.6%), hypertension in three (21.4%), proteinuria in one (7.1%) and gastrointestinal hemorrhage in one (7.1%)., Conclusions: Re-irradiation combined with bevacizumab for patients with recurrent high-grade gliomas who progress after bevacizumab treatment was feasible. Re-irradiation combined with bevacizumab is a potential treatment option, especially for patients with a Karnofsky performance status of ≥70., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Purpose: We investigated the synchronization of respiration-induced motions at the primary tumor and organs at risk at radiation planning for pancreatic cancer., Methods and Materials: Four-dimensional computed tomography images were acquired under the condition of shallow free breathing in patients with pancreatic cancer. The gross tumor volume (GTV), duodenum (DU), and stomach (ST) were contoured. The center of mass was computed for each 4-dimensional volume of interest. The respiration dependence of coordinates for the center of each volume of interest was computed relative to its location at the 50% (maximum exhalation) phase. Based on the shift of the GTV, we investigated the synchronization of respiration-induced motions between each contouring target. We examined the differences in the volume averaged dose to the ST and DU in each respiratory phase., Results: Nine patients with pancreatic cancer were analyzed in this study. The mean maximum 3-dimensional excursions at the GTV, DU, and ST were 9.6, 9.8, and 11.4 mm, respectively. At phase 0% and 90% (inhale phases), mean distance changes in the positional relationship with the GTV were 0.3 and 0.7 mm respectively for the DU and -2.5 and -2.4 mm respectively for the ST. There was no significant respiration associated change (RAC) between each respiratory phase in the DU ( P  = .568), and there was a significant RAC in the ST ( P < .001). There was a significant RAC of the volume averaged dose to the ST ( P  = .023)., Conclusions: Our results indicate that the DU but not the ST might move synchronously with GTV due to respiration., (© 2021 The Author(s).)

Although systemic therapy is the standard treatment for metastatic prostate cancer, a randomized controlled trial showed radiotherapy to the prostate improved overall survival of metastatic prostate cancer patients with the low metastatic burden. Additionally, a randomized phase II trial showed that metastasis-directed therapy for oligo-recurrent prostate cancer improved androgen-deprivation therapy (ADT)-free survival. Therefore, administering radiotherapy to both prostate and metastatic regions might result in better outcomes. Thus, we report the treatment results of radiotherapy to both prostate and metastatic regions. Our institutional database was searched for patients who received radiotherapy to the prostate and metastatic regions. We summarized patient characteristics and treatment efficacy and performed statistical analysis to find possible prognostic factors. A total of 35 patients were included in this study. The median age was 66 years, and the median initial prostate-specific antigen (PSA) level was 32 ng/ml. The Gleason score was 7 in 10 patients, 8 in 13 patients, and 9 in 12 patients. The median radiotherapy dose was 72 Gy to the prostate and 50 Gy to the metastatic bone region. The 8-year overall survival, cause-specific survival, progression-free survival, and freedom from biochemical failure rate were 81, 85, 53, and 57%. Among the 35 patients, 12 were disease-free even after ADT was discontinued. In selected patients with metastatic prostate cancer, ADT and radiotherapy to the prostate and metastatic sites were effective. Patients with good response to ADT may benefit from radiotherapy to both prostate and metastatic regions., (© The Author(s) 2021. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Gliomas are infiltrative tumors that are difficult to cure by surgery alone. Postoperative radiotherapy or chemoradiotherapy is the treatment option for patients with high-grade gliomas. However, most pathological types of glioma other than glioblastoma do not have enough evidence, especially concerning the dose-fractionation scheme and clinical target volume definition for radiotherapy. This study presents standard methods of radiotherapy for each pathological type of glioma and recent radiotherapy technologies including their significance and treatment results.

Background and Purpose: Most locoregional recurrences after definitive radiotherapy for head and neck squamous cell carcinoma (HNSCC) develop "in-field." Dose escalation while sparing organs at risk can be a good solution for improving local control without increasing adverse effects. This study investigated the safety and effectiveness of volumetric modulated arc therapy (VMAT) using intentionally internal high-dose policy (IIHDP) to treat neck lymph node metastases (NLNM) ≥ 2 cm in HNSCC patients., Materials and Methods: We analyzed 71 NLNM from 51 HNSCC patients who had received definitive radiotherapy to treat NLNM ≥ 2 cm using the VMAT technique in our institution between February 2017 and August 2019. Thirty-seven NLNM from 25 patients were treated using IIHDP VMAT (group A), and 34 NLNM from 27 patients were treated with homogeneous-dose distribution policy (HDDP) VMAT (group B). One patient with three NLNM had one lymph node assigned to group A and the other two to group B. Adverse events and local recurrence-free survival (LRFS) was compared between the two groups., Results: In the median follow-up period of 527 days, there were no significant differences between the groups in terms of dermatitis or mucositis ≥ grade 2/3, but LRFS was significantly longer in group A (p = 0.007). In the Cox regression analysis after adjustment for the propensity score, group A also showed an apparently superior LFRS., Conclusion: Our initial experience of IIHDP VMAT suggested that IIHDP VMAT to treat HNSCC neck lymph node metastases measuring ≥ 2 cm was feasible and possibly led to better local control than HDDP VMAT., Competing Interests: YN reports personal fees from AstraZeneca, outside the submitted work. YK reports grants from Canon Medical Systems, outside the submitted work. KI reports grants from Elekta K.K., outside the submitted work. HI reports personal fees from Itochu, personal fees from ViewRay Inc., grants from HekaBio, outside the submitted work. JI reports grants and non-financial support from KeyJ, personal fees from Alpha Tau, personal fees from ItoChu, outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Kashihara, Nakamura, Murakami, Ito, Matsumoto, Kobayashi, Omura, Mori, Honma, Kubo, Okamoto, Takahashi, Inaba, Okuma, Igaki, Nakayama, Kato, Matsumoto, Yoshimoto and Itami.)

An accelerator-based boron neutron capture therapy (BNCT) system employing a solid-state Li target can achieve sufficient neutron flux for treatment although the neutron flux is reduced over the lifetime of its target. In this study, the reduction was examined in the five targets, and a model was then established to represent the neutron flux. In each target, a reduction in neutron flux was observed based on the integrated proton charge on the target, and its reduction reached 28% after the integrated proton charge of 2.52 × 10 6 mC was delivered to the target in the system. The calculated neutron flux acquired by the model was compared to the measured neutron flux based on an integrated proton charge, and the mean discrepancies were less than 0.1% in all the targets investigated. These discrepancies were comparable among the five targets examined. Thus, the reduction of the neutron flux can be represented by the model. Additionally, by adequately revising the model, it may be applicable to other BNCT systems employing a Li target, thus furthering research in this direction. Therefore, the established model will play an important role in the accelerator-based BNCT system with a solid-state Li target in controlling neutron delivery and understanding the neutron output characteristics.

Purpose: This study compared the applicator position relative to the tracheal wall and dosimetric parameters between conventional and novel applicators among patients receiving endobronchial brachytherapy (EBBT) for intratracheal tumors., Methods and Materials: Data from 7 patients who received EBBT for intratracheal tumors were retrospectively analyzed; 4 and 3 patients were treated with conventional (2-wing) or novel (5-wing) applicators, respectively. Applicator centrality was evaluated using the distance between the center of the trachea and main bronchus (TMB) lumen and path of source (L). Dosimetric parameters, including plans normalized to D 2cc of the TMB = 45 Gy (normalized plan), were compared between the applicators., Results: The mean and maximum values of L in cases of the 2-wing applicator group were approximately 5.0 mm and 10.0 mm, respectively. In the novel applicator group, the corresponding values were approximately 3.0 and 6.0 mm, respectively. In the normalized plan of the 2-wing applicator group, the ranges of median V 90% of clinical target volume (CTV) and D 0.1cc of the TMB in all cases were 23.0-91.9% and 66.3-153.1 Gy, respectively. In the 5-wing applicator group, the corresponding values were 69.2-83.8% and 60.4-84.5 Gy, respectively., Conclusions: In the 5-wing applicator group, the range was narrow in all dose-volume parameters except for D 2cc of the TMB. Compared to the conventional applicator, the 5-wing applicator can give a stable dose to the CTV and can reduce the maximum dose of the TMB. This suggests that stable EBBT can be given to any patient using the 5-wing applicator., (Copyright © 2020 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

Synovial sarcoma is a rare tumor requiring new treatment methods. A 46-year-old woman with primary monophasic synovial sarcoma in the left thigh involving the sciatic nerve, declining surgery because of potential dysfunction of the affected limbs, received two courses of BNCT. The tumor thus reduced was completely resected with no subsequent recurrence. The patient is now able to walk unassisted, and no local recurrence has been observed, demonstrating the applicability of BNCT as adjuvant therapy for synovial sarcoma. Further study and analysis with more experience accumulation are needed to confirm the real impact of BNCT efficacy for its application to synovial sarcoma., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objective: This study aimed to assess the dosimetric effect of intestinal gas of stereotactic magnetic resonance (MR)-guided adaptive radiation therapy (SMART) on target and critical organs for pancreatic cancer without online electron density correction (EDC)., Methods: Thirty pancreatic cancer patients who underwent online SMART were selected for this study. The treatment time of each stage and the total treatment time were recorded and analyzed. The concerned dose-volume parameters of target and organs-at-risk (OAR) were compared with and without an intestinal gas EDC using the Wilcoxon-signed rank test. Analysis items with p value < 0.05 were considered statistically significant. The relationships between dosimetric differences and intestinal gas volume variations were investigated using the Spearman test., Results: The average treatment time was 82 min, and the average EDC time was 8 min, which accounted for 10% of the overall treatment time. There were no significant differences in CTV (GTV), PTV, bowel, stomach, duodenum, and skin ( p > 0.05) with respect to dose volume parameters. For the D max of gastrointestinal organs ( p = 0.03), the mean dose of the liver ( p = 0.002) and kidneys ( p = 0.03 and p = 0.04 for the left and right kidneys, respectively), there may be a risk of slight overestimation compared with EDC, and for the D max of the spinal cord ( p = 0.02), there may be a risk of slight underestimation compared with EDC. A weak correlation for D 95 in the PTV and D 0.5 cc in the duodenum was observed., Conclusion: For patients with similar inter-fractional intestinal gas distribution, EDC had little dosimetric effects on the D 0.5 cc of all GI organs and dose volume parameters of target in most plans., Advances in Knowledge: By omitting the EDC of intestinal gas, the online SMART treatment time can be shortened.

Cervical esophageal squamous cell carcinoma (CESCC) is rare, accounting for 5% of all esophageal carcinomas. Several diagnostic and predictive markers have been studied. However, to the best of our knowledge, no biomarker is known to determine patient management except the clinical stage. The present study aimed to evaluate whether human papilloma virus (HPV) infection, epidermal growth factor receptor (EGFR) and its pathway-related gene mutations, known to be sensitive biomarkers of oropharyngeal carcinomas, could be used as biomarkers for the prediction of the prognosis of patients with CESCC. The present retrospective study included patients with CESCC who received chemoradiotherapy or surgery. HPV infection and the genomic status of EGFR , KRAS , BRAF , NRAS and PIK3CA of each tumor sample from patients with CESCC were analyzed by in situ hybridizations (ISH) and PCR methods, respectively. The present study included 33 patients with CESCC (male/female, 29/4; median age, 62 years; age range, 41-86 years; clinical stage I/II/III/IV, 2/6/10/15). The present study detected HPV in one patient (3.0%) by ISH and PCR. Concerning the investigation of EGFR and its pathway-related gene mutations, the present study detected 15.1% of EGFR , 6.0% of NRAS , 3.5% of BRAF , 3.0% of KRAS and 3.0% for PIK3CA mutations, with no significant relationship between any gene mutations and the clinical prognostic factors. The HPV-infected patient did not exhibit any gene mutations. The present study indicated that HPV infection, EGFR and its pathway-related gene mutations rarely exist in patients with CESCC. The relationship between these biomarkers and the prognosis in patients with CESCC is still unclear., (Copyright: © Fukahori et al.)

Purpose: In this single-institution retrospective study, configuration analysis was performed to determine the optimal location and volume of hyaluronic acid gel spacer injection into the rectovaginal or vesicovaginal septum for effective dose reduction (DR) to the organs at risk (OARs), the rectum and bladder., Methods and Materials: 70 and 50 intracavitary brachytherapy treatment plans used only vaginal cylinders with gel spacers for the rectal and bladder sides, respectively, whereas 28 did not use spacers. Correlation analysis was performed between the geometrical parameters and injection position of the gel spacers and the 2-cm 3 covering doses of the OARs for each treatment., Results: A higher DR was predicted for hyaluronic acid gel spacer injection within ±5 mm and ±2.5 mm in the lateral-medial direction from the midpoint on the rectal and bladder sides, and ±10 mm in the cranial-caudal direction from the midpoint on the rectal side. There were correlations between 2-cm 3 covering doses and the gel spacer parameters: the volume on the rectal (p = 0.02) and bladder (p = 0.04) sides; the craniocaudal length on the rectal side (p << 0.05); and ventrodorsad thickness on each OAR (p << 0.05) sides. There was no significant difference in the DR between a volume of ∼10 cm 3 and that of a higher volume (p >> 0.05)., Conclusions: A gel spacer volume of ∼10 cm 3 provides sufficient OAR DR if its gravity point is on the midpoint between the cylinder applicator and OAR, and its craniocaudal length covers the active length of the cylinder applicator., (Copyright © 2021 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

Background/aim: We established a data-driven method for extracting spatial patterns of dose distribution associated with radiation injuries, based on patients with prostate cancer who underwent iodine-125 (I-125) seed implantation., Patients and Methods: Seventy-five patients underwent I-125 seed implantation for prostate cancer. We modeled the severity of lower urinary tract symptoms (LUTS) to be estimated using a linear model, which is formulated as an inner product between the dose distribution D and voxel-wise radiosensitivity B inside the prostate. For the estimation, tensor regression based on a low-rank decomposition with generalized fused lasso penalty was applied., Results: The spatial distribution of B was visually assessed. Positive parameters appeared dominantly in the region close to the urethra and the prostate base., Conclusion: Our tensor regression-based model can predict intra-organ radiosensitivity in a data-driven manner, providing a compelling parameter distribution associated with the development of LUTS after I-125 seed implantation for prostate cancer., (Copyright© 2021, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)