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Background and purpose We aimed to determine the risk factors for radiation-induced brain injury (RIBI 1 ) after carbon ion radiotherapy (CIRT) to predict their probabilities in long-term survivors. Materials and methods We evaluated 104 patients with head, neck, and skull base tumors who underwent CIRT in a regimen of 32 fractions and were followed up for at least 24 months. RIBI was assessed using the Common Terminology Criteria for Adverse Events. Results The median follow-up period was 45.5 months; 19 (18.3 %) patients developed grade ≥2 RIBI. The maximal absolute dose covering 5 mL of the brain (D5ml) was the only significant risk factor for grade ≥2 RIBI in the multivariate logistic regression analysis (p = 0.001). The tolerance doses of D5ml for the 5% and 50% probabilities of developing grade ≥2 RIBI were estimated to be 55.4 Gy (relative biological effectiveness [RBE]) and 68.4 Gy (RBE) by a logistic model, respectively. Conclusion D5ml was most significantly associated with grade ≥2 RIBI and may enable the prediction of its probability.

Background Particle radiotherapy has increasingly gained acceptance for locally advanced pancreatic cancers owing to superior tumor conformity and dosimetry compared to conventional photon radiotherapy. However, the close proximity of the pancreas to the stomach and duodenum leads to radiation-induced gastrointestinal toxicities, which hinder the delivery of curative doses to the tumor. To overcome this problem, a surgical spacer was placed between the tumor and gastrointestinal tract, and subsequent proton radiotherapy was performed in this study. Methods Data from 9 patients who underwent surgical spacer placement and subsequent proton radiotherapy were analyzed. The safety and feasibility of the spacer placement surgery were evaluated; the impact of the spacer on dosimetry was also assessed using dose volume histogram (DVH) analyses, before and after surgical spacer placement. Results Surgical spacer placement and subsequent proton radiotherapy were successfully completed in all cases. Surgical spacer placement significantly improved the dose intensity covering 95%, mean, and minimum doses for the gross tumor volume, and the clinical and planning target volume based on the DVH, while respecting the dose constraints of the gastrointestinal tract. Based on the Common Terminology Criteria for Adverse Events, two patients (22.2%) developed gastrointestinal ulcer (Grade 2) at 1 and 35 months, and one patient (11.1%) developed gastric perforation (Grade 4) at 4 months after proton radiotherapy. Conclusions Surgical spacer placement in the locally advanced pancreatic body and tail cancers is relatively safe and technically feasible. Comparing radiation plans, surgical spacer placement seems to improve the dose distribution in the locally advanced pancreatic body and tail cancers, which are close to the gastrointestinal tract.

Background Sacral chordomas are rare malignant bone tumors and are often very large for complete resection. Particle therapy for these tumors, which are adjacent to the gastrointestinal tract, is restricted because the tolerance dose of the intestine is low. This study aimed to demonstrate the technical aspects and treatment results of space-making particle therapy with surgical spacer placement for sacral chordoma. We aimed to investigate the dosimetric change in the particle therapy before and after spacer placement and the safety, efficacy, and long-term outcomes of space-making particle therapy. Study Design Twenty-one patients with sacral chordomas who were excluded from typical particle therapy were enrolled between 2007 and 2015. Gore-Tex sheets (WL Gore & Assoc) were folded and placed between the sacral and rectum. Particle therapy with 70.4 Gy (relative biologic effectiveness) was then performed. Results The mean volume that allows 95% of the treatment plan dose of the gross tumor volume and clinical tumor volume after spacer placement was improved to 97.7% and 96.4% from preoperative values of 91.0% and 89.5%, respectively. The recurrence rate within the gross tumor volume was only 4.8%. The 4-year local progression-free survival rate was 68.4%. The 5-year overall survival rate was 100% and the adverse events were acceptable. Conclusions Considering improvements in the dose-volume histogram after spacer placement, low recurrence rates within the gross tumor volume, good survival rates, and low incidences of side effects, treatment of sacral chordoma with space-making particle therapy shows promise.

Background: The outcomes of chemotherapy for patients with perihilar cholangiocarcinoma (PHC) are unsatisfactory, and photon therapy for unresectable PHC reportedly results in improved outcomes. Proton beam therapy (PBT) can be a treatment option for these patients; however, the role of PBT in these patients is poorly defined as PHC is rare. Herein, we evaluated the efficacy and safety of PBT for unresectable PHC.Methods: This observational retrospective cohort study conducted at a single institution included patients with unresectable PHC who received definitive PBT. Patients who had nodal metastasis at presentation or those who underwent surgery or other radiation therapies before PBT were excluded. To compare different dose fractionations, biologically equivalent doses with α/β=10 [BED10] were calculated.Results: Overall, 26 patients were eligible. The commonly prescribed doses were 67.5 Gy (relative biological effectiveness [RBE]) in 25 fractions or 70.2 Gy (RBE) in 26 fractions. The median follow-up period was 19.4 months (range, 4.2-137.4 months). The Kaplan–Meier estimates of the 1-, 2-, and 5-year overall survival (OS) rates were 72.9%, 47.7%, and 17.4%, respectively, and the median survival time was 23.7 months. The multivariate analysis demonstrated that Child–Pugh classification B was a significant prognostic factor for unfavorable OS (hazard ratio [HR] 4.92; p=0.009) and that a mean gross tumor volume dose of ≥79.2 Gy (RBE) [BED10] was a significant prognostic factor for favorable OS (HR 0.19; p=0.025). Grade ≥3 late adverse events were observed in seven patients (26.9%).Conclusions: We demonstrated that definitive PBT for patients with unresectable PHC might improve the prognosis. Further large-scale prospective studies are warranted to validate our findings.

Background Factors associated with long-term survival in gemcitabine-concurrent proton radiotherapy (GPT) for non-metastatic, locally advanced pancreatic cancer (LAPC) remain unclear. This study aimed to determine the factors associated with long-term survival in GPT for non-metastatic LAPC. Methods The medical records of 123 patients with LAPC treated with GPT between February 2009 and December 2019 at Hyogo Ion Beam Medical Center were retrospectively reviewed to assess the factors associated with long-term survival outcomes. Results The median overall survival of the total cohort treated with GPT was 18.7 months. The 1- and 2-year overall, local progression-free, and progression-free survival rates were 70.4% and 35.7%, 78.2% and 59.0%, and 38.6% and 20.8%, respectively. Multivariate analysis revealed that LAPCs at the pancreatic body-tail and those without anterior peripancreatic invasion were independently associated with longer overall survival (P = 0.040 and P = 0.015, respectively). The median overall survival of patients with LAPC at the pancreatic body-tail and those with LAPC without anterior peripancreatic invasion were 24.1 and 28.1 months, respectively. LAPCs at the pancreatic body-tail had a higher volume ratio irradiated over 60 Gy equivalents at gross tumor volume than those at the pancreatic head (P P = 0.039). Conclusions GPT is a promising treatment option for patients with LAPC at the pancreatic body-tail and those with LAPC without anterior peripancreatic invasion.

Introduction: Although the primary treatment option for hilar cholangiocarcinoma (HC) has been surgical resection, most patients present with unresectable advanced tumors at the time of diagnosis. Particle therapy (PT) holds great potential for HC, even though the anatomical proximity to the gastrointestinal tract prevents delivering a radical dose to the tumor. Space-making PT (SMPT), consisting of spacer placement surgery and subsequent PT, has been developed to minimize complications and maximize the therapeutic benefit of dose escalation for HC. This study aimed to conduct a dosimetric evaluation and examine the effectiveness of SMPT for the treatment of HC. Methods: Between 2007 and 2018, 12 patients with unresectable HC treated with SMPT were enrolled. The treatment outcomes and effectiveness of spacer placement surgery were evaluated through analyses of pre- and post-surgical parameters of dose-volume histograms. Results: All patients completed the planned SMPT protocol. The median survival time was 29.6 months, and the 1- and 3-year overall survival rates were 82.5% and 45.8%, respectively. The mean V95% value (volume irradiated with 95% of the planned treatment dose) of the gross tumor volume and clinical target volume after spacer placement surgery improved to 98.5% and 96.6% from preoperative values of 85.6% and 78.1%, respectively (p = 0.0196 and p = 0.0053, respectively). Grade 3 or higher adverse events after SMPT were seen in 6 patients. Discussion/Conclusion: SMPT led to improvements in dosimetric parameters and showed good feasibility and excellent outcomes. SMPT can be a promising novel alternative for unresectable HC.

Purpose The QA team of the Japan carbon‐ion radiation oncology study group (J‐CROS) was organized in 2015 to enhance confidence in the accuracy of clinical dosimetry and ensure that the facility QA procedures are adequate. The team conducted onsite dosimetry audits in all the carbon‐ion radiation therapy centers in Japan. Materials and Methods A special phantom was fabricated for the onsite dosimetry audit. Target volumes such as the GTV, CTV, and PTV were contoured to the obtained CT images, and two plans with different isocenter depths were created. The dose at the isocenter was measured by an ionization chamber, in the onsite audit and compared with the calculated dose. Results For all the centers, the average of the percentage ratio between the measured and calculated doses (measured/calculated) was 0.5% (−2.7% to +2.6%) and the standard deviation, 1.7%. In all the centers, the beams were within the set tolerance level of 3%. Conclusions The audit demonstrated that the dose at a single point in the water phantom was within tolerance, but it is a big step to say that all doses are correct. In addition, this external dosimetry audit encouraged centers to improve the quality of their dosimetry systems.

Background The usefulness of particle therapy for skull base chordoma has not been established. The aim of this retrospective study was to analyse the treatment outcomes of proton therapy (PT) and carbon ion therapy (CIT) in patients with skull base chordoma at a single institution. Methods All patients who underwent PT or CIT with curative intent between 2003 and 2014 at Hyogo Ion Beam Medical Center were included in this study. Twenty-four patients were enrolled. Eleven (46%) received PT and 13 (54%) received CIT. Overall survival (OS), progression-free survival (PFS) and local control (LC) were calculated using the Kaplan–Meier method. Late toxicities were evaluated according to the Common Terminology Criteria for Adverse Events version 4.0. Results The median follow-up was 71.5 months (range, 14–175 months). The five-year LC, PFS and OS rates were 85, 81, and 86%, respectively. The LC (P = 0.048), PFS (P = 0.028) and OS (P = 0.012) were significantly improved in patients who had undergone surgery before particle therapy. No significant differences were observed in the LC rate and the incidence of grade 2 or higher late toxicities between patients who received PT and CIT. Conclusions Both PT and CIT appear to be effective and safe treatments and show potential to become the standard treatments for skull base chordoma. To increase the local control, surgery before particle therapy is preferable.

Purpose To evaluate the efficacy and safety of definitive proton beam therapy (PBT) for primary sacral chordoma. Methods and Materials We conducted a retrospective analysis of the clinical outcomes of eligible patients with primary sacral chordoma who had undergone definitive PBT with 70.4 Gy (relative biological effectiveness) in 32 fractions at our institution from September 2009 to October 2015. Local progression-free survival, distant metastasis-free survival, disease-free survival, cause-specific survival, and overall survival were evaluated. To explore the factors that influenced local progression, the following parameters were analyzed: sex, the presence of a spacer (Gore-Tex sheets), gross tumor volume, and extent of cranial tumor extension. Adverse events were evaluated using the Common Terminology Criteria for Adverse Events, version 4.0. To assess the impact of PBT on pain relief, the change in pain grades was investigated between the initiation of PBT and the last follow-up visit. Results Thirty-three eligible patients were analyzed. The median follow-up period was 37 months. The 3-year estimated local progression-free survival, distant metastasis-free survival, disease-free survival, cause-specific survival, and overall survival rates were 89.6%, 88.2%, 81.9%, 95.7%, and 92.7%, respectively. No significant association was between the patients’ clinicopathologic characteristics and local progression-free survival. Four patients developed grade 3 adverse events, including acute dermatitis (n = 1), ileus (n = 1), and pain due to sacral insufficiency fractures (n = 2). The pain grades had improved, were unchanged, or had deteriorated in 15, 7, and 11 patients, respectively. Conclusions Definitive PBT with 70.4 Gy (relative biological effectiveness) in 32 fractions is an effective treatment with acceptable toxicity for primary sacral chordoma and has the potential to reduce pain.

Multilingualization of geographical name information has been required to support foreign visitors to the Olympic Games and the Paralympic Games to be held in Tokyo in 2020 and to correspond to the rapid increase of foreign visitors in recent years. GSI has prepared geographical name information in English and it has been already released. To expand this effort, we have conducted the experiment to translate geographical name information in Japanese and English into French, Korean, Simplified Chinese, and Traditional Chinese automatically and to prepare a multilingual map using vector tile format. To be specific, we prepared transformation rules for translation of geographical name information, and implemented the Javascript codes of transformation rules to deploy in combination with the existing Javascript library group which controls display on the web map. Thus, we developed a web map system which automatically generates geographical name information in these targeted languages on web browsers.

Case series Patients: Male, 73-year-old • Female, 79-year-old • Male, 45-year-old • Male, 76-year-old • Female, 63-year-old • Male, 43-year-old Final Diagnosis: Aspergillus fumigatus infection • hereditary haemorrhagic telangiectasia • lymphangioleiomyomatosis • tuberculosis Symptoms: Hemoptysis Medication: — Clinical Procedure: Angiography • CT scan • embolization Specialty: Pulmonology • Radiology Objective: Unusual clinical course Background: Although bronchial arteries are the most common cause of hemoptysis, other systemic arteries can cause hemoptysis and are potential pitfalls for successful embolization. Case Reports: We present 6 cases of hemoptysis showing vascularization from systemic arteries other than bronchial arteries that presented to our department between 2013 and 2020. Chronic inflammatory diseases such as tuberculosis and pulmonary aspergillosis were the underlying diseases in 4 of the 6 cases. In all 6 cases, the lesions were close to the pleura. The abnormal non-bronchial systemic arteries were the internal thoracic artery in 4 cases, intercostal artery in 2 cases, lateral thoracic artery in 2 cases, and the subclavian, thyrocervical, and inferior phrenic arteries in 1 case each, all of which formed a shunt with the pulmonary artery. Additionally, depending on the location of the lesion, the non-bronchial systemic arteries near the lesion proliferated into the lung parenchyma through the adherent pleura. Conclusions: When lesions are in contact with the pleura, various non-bronchial systemic arteries near the lesion can develop in the pulmonary parenchyma via the adherent pleura, which can cause hemoptysis. In patients with hemoptysis, it may be useful to evaluate chest contrast-enhanced computed tomography and angiography, while always accounting for the potential involvement of non-bronchial systemic arteries to ensure a safer and more reliable treatment.

Pulmonary endometriosis (PEM) is a rare disease characterized by the proliferation of ectopic endometrial tissue in the lungs, which presents as catamenial hemoptysis. A 20-year-old-woman was admitted for repeated hemoptysis. Chest CT revealed a ground-glass opacity that appeared consistently with her menstrual cycle. Our detailed inquiry revealed a history of artificial abortion, which was followed by the use of oral contraceptives and catamenial hemoptysis after the discontinuation of these medications. Surgical removal was performed and histopathological examinations confirmed PEM. This clinical course suggested hematogenous metastasis. An inquiry regarding the patient's history of uterine procedures and use of oral contraceptives was suggestive for the diagnosis of this disease.

Background The primary definitive treatment for abdominopelvic sarcomas (APSs) is resection, although incomplete resection has a negative prognostic impact. Although the effectiveness of particle therapy (PT) as a treatment for APS has already been demonstrated, its application for tumors adjacent to the gastrointestinal tract is frequently restricted, due to extremely low tolerance. Space-making PT, consisting of surgical spacer placement and subsequent PT, has been developed to overcome this limitation. Materials and methods Between June 2006 and June 2018, a total of 75 patients with 12 types of APS underwent space-making PT. Results The 3-year local control rate of all patients was 90.3%. Fourteen surgery-related complications were observed in 12 patients (16%), and complications of Grade 3b or higher were observed in 3 patients. Ninety-five PT-related complications were seen in 66 patients (88.0%), and 13 patients (17.3%) had complications of Grade 3 or higher. The median V95% (volume irradiated with 95% of the treatment planning dose) of the gross tumor volume and clinical target volume were 99.9% and 99.5%, respectively. The median D95% (dose intensity covering 95% of the target volume) of the gross tumor volume/planned dose and clinical target volume/planned dose were 99.4%, and 99.1%, respectively. Conclusion The feasibility and effectiveness of space-making PT have been demonstrated via dosimetric evaluation, and our results indicate that this new strategy may potentially provide an effective and innovative treatment option for advanced APS.

Pulmonary intimal sarcoma (PIS) constitutes a rare sarcoma originating from the intimal cells of pulmonary arteries. The pathogenesis of PIS remains to be elucidated and specific treatments have not been established; therefore, prognosis is generally poor. The purpose of our study was to isolate and characterize PIS cells from a specimen resected from a patient with PIS. The surgical specimen was minced and incubated, and spindle-shaped and small cells were successfully isolated and designated as PIS-1. PIS-1 cells at passages 8–9 were used for all in vitro and in vivo experiments. Immunocytochemistry showed that PIS-1 cells were positive for vimentin, murine double minute 2, and CD44 and negative for α-smooth muscle actin, CD31, von Willebrand factor, and desmin. PIS-1 cells exhibited the hallmarks of malignant cells including the potential for autonomous proliferation, anchorage-independent growth, invasion, genetic instability, and tumorigenicity in severe combined immunodeficiency mice. The PIS-1 cells highly expressed tyrosine kinase receptors such as platelet-derived growth factor receptor, and vascular endothelial growth factor receptor 2. Pazopanib, a multi-targeted tyrosine kinase inhibitor, suppressed the proliferation of PIS-1 cells in vitro and the growth of tumors formed from xenografted PIS-1 cells. A PIS cell line was thus successfully established. The PIS-1 cells highly expressed tyrosine kinase receptors, which may be a target for treatment of PIS.

Background Medium‐dose (25 gray) x‐ray radiation therapy has recently been performed on patients with refractory ventricular tachyarrhythmias. Unlike x‐ray, carbon ion and proton beam radiation can deliver most of their energy to the target tissues. This study investigated the electrophysiological and pathological changes caused by medium‐dose carbon ion and proton beam radiation in the left ventricle (LV). Methods and Results External beam radiation in the whole LV was performed in 32 rabbits. A total of 9 rabbits were not irradiated (control). At the 3‐month or 6‐month follow‐up, the animals underwent an open‐chest electrophysiological study and were euthanized for histological analyses. No acute death occurred. Significant LV dysfunction was not seen. The surface ECG revealed a significant reduction in the P and QRS wave voltages in the radiation groups. The electrophysiological study showed that the local conduction times in each LV site were significantly longer and that the local LV bipolar voltages were significantly lower in the radiation groups than in the control rabbits. Histologically, apoptosis, fibrotic changes, and a decrease in the expression of the connexin 43 protein were seen in the LV myocardium. These changes were obvious at 3 months, and the effects were sustained 6 months after radiation. No histological changes were seen in the coronary artery and esophagus, but partial radiation pneumonitis was observed. Conclusions Medium‐dose carbon ion and proton beam radiation in the whole LV resulted in a significant electrophysiological disturbance and pathological changes in the myocardium. Radiation of the arrhythmogenic substrate would modify the electrical status and potentially induce the antiarrhythmic effect.

An asymptomatic 70-year-old woman presented with a nodular lesion overlapping the pulmonary artery at the right hilar region on a chest X-ray. Bronchial arteriography revealed an aneurysmal dilation of the long segment of the right bronchial artery and a shunt from the right bronchial artery to the right lower pulmonary artery. She was diagnosed with primary racemose hemangioma of the bronchial artery (RHBA). Considering the risk of hemoptysis, we performed a bronchial arterial embolization (BAE) using coils and N-butyl-2-cyanoacrylate. She had no complication after the BAE and no recurrences of hemoptysis at the 36-month follow-up. RHBA should be considered in case of aneurysmal dilation in the long segment of the bronchial artery, and BAE should be considered as a treatment strategy despite the absence of symptoms., Highlights • Primary racemose hemangioma of the bronchial artery (RHBA) has a risk of hemoptysis. • RHBA should be included in differential diagnosis as a nodular lesion overlapping the pulmonary artery at the hilar region. • Computed tomography and bronchial arteriography aids in the diagnosis of RHBA. • Bronchial arterial embolization should be considered in asymptomatic RHBA patients.

Background/aim Carbon-ion beam is one of the most advanced radiations used for cancer treatment. However, there are tumors that are difficult to suppress with carbon-ion beam alone, thus necessitating development of drugs that can enhance its therapeutic effect. In this regard, the radiosensitizing effect of 5-aminolevulinic acid (ALA) and protoporphyrin IX (PpIX), that is a metabolic intermediate of ALA, on carbon-ion beam was investigated. Materials and methods Radiosensitizing activity, mitochondrial ROS and DNA double-strand break production of ALA and PpIX were evaluated by irradiation with 1.0 or 1.5-Gy carbon-ion beam to mouse mammary EMT6 tumor cells. Results Combination of carbon-ion beam and ALA or PpIX showed a significant enhancement of its cytotoxic activity through a significant increase in ROS production in mitochondria. Furthermore, the combined activity of carbon-ion beam and ALA resulted in a significant increase in DNA double-strand breakage. Conclusion ALA selectively accumulates in the mitochondria and PpIX synthesized from ALA reacts with carbon-ion beam to produce ROS that exert antitumor activity.

Pulmonary arteriovenous malformation (PAVM) is an abnormal blood vessel connecting a pulmonary artery and a vein, and is accompanied by paradoxical embolism to other organs due to a right-to-left shunt. We report the case of a 66-year-old woman with PAVM complicated by splenic infarction and abscess. Although the PAVM had been detected on a chest image 2 years previously, and she had been advised to have further investigations, she decided not to follow this further at the time. She then visited our hospital complaining of worsening dyspnoea on exertion. Detailed examinations revealed splenic infarction and abscessation due to PAVM. PAVM embolization was performed after antibiotic treatment. It is very rare for PAVM to be complicated by splenic infarction and abscess. Regardless of its size, embolization of a PAVM as soon as possible can reduce not only the risk of central nervous system complications, but also the risk of splenic infarction and abscess.

Trifluoperazine (TFP) has been widely studied in relation to its mode of binding and its inactivation of calmodulin (CaM). Most studies in solution have indicated that CaM has two high-affinity binding sites for TFP. The crystal structure of the 1:4 CaM-TFP complex (CaM-4TFP) shows that three TFP molecules bind to the C-domain of CaM, and that one TFP molecule binds to the N-domain. In contrast, the crystal structure of the 1:1 CaM-TFP complex (CaM-1TFP) shows that one TFP molecule binds to the C-domain. It has been thought that the binding of one TFP molecule to the C-domain is followed by binding to the N-domain. The crystal structure of the 1:2 CaM-TFP complex (CaM-2TFP), moreover, has recently been determined, showing that two TFP molecules bind to the C-domain. In order to determine the structure of the CaM-TFP complex and to clarify the interaction between CaM and TFP in solution, we performed a molecular dynamics simulation of the CaM-TFP complex in aqueous solution starting from the CaM-4TFP crystal structure. The obtained solution structure is very similar to the CaM-2TFP crystal structure. The computer simulation showed that the binding ability of the secondary binding site of the C-domain is higher than that of the primary binding site of the N-domain. © 2001 John Wiley & Sons, Inc. Biopolymers 58: 410–421, 2001