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In order to enhance J c in (Ba,Na)Fe2As2 wires and tapes further by improving texturing, we examined the following approaches; (1) Ag-sheathed HIP tapes, (2) AgSn-sheathed cold-pressed tapes, and (3) multifilamentary HIP wires with each filament having tape-like cross section. In addition, we attempted to increase I c by fabricating (Ba,Na)Fe2As2 wires with larger core areas, and constructed a small demo coil using one of these wires with length up to 9 m. J c characteristics of these new wires and the performance of the demo coil with and without an electrical insulation are reported.

Aim:CyberKnife is the most advanced form of stereotactic body radiotherapy (SBRT) system that uses a robotic arm to deliver highly focused beams of radiation; however, a limitation is that it only irradiates from ceiling to floor direction. In patients with posterior lungs tumour who are positioned supine, normal lung tissue may suffer undesirable radiation injuries. This study compares the treatment planning between the prone set-up and the supine set-up for lung cancer in CyberKnife SBRT to decrease normal lung dose to avoid radiation side effects.Materials and methods:A human phantom was used to generate 108 plans (54 for prone and 54 for supine) using the CyberKnife planning platform. The supine and prone plans were compared in terms of the dosimetric characteristics, delivery efficiency and plan efficiency.Results:For posterior targets, the area of low-dose exposure to normal lungs was smaller in the prone set-up than in the supine set-up. V10 of the lungs was 7·53% and 10·47% (p < 0·001) in the anterior region, and 10·78% and 8·03% (p < 0·001) in the posterior region in the supine and prone set-up plans, respectively.Conclusions:The comparison between the prone set-up and the supine set-up was investigated with regard to target coverage and dose to organs at risk. Our results may be deployed in CyberKnife treatment planning to monitor normal tissue dose by considering patient positioning. This may assist in the design of better treatment plans and prevention of symptomatic radiation pneumonitis in lung cancer patients.

Background: Metal nanoparticles have been proposed as potential radiosensitizers. Among those, titanium nanoparticles are attractive candidates for application as radiosensitizers. We have newly established and evaluated titanium peroxide nanoparticles (TiOxNPs). The TiOxNPs are generated from titanium dioxide nanoparticles (TiO2NPs), manufactured via direct reaction of TiO2NPs with hydrogen peroxide. Distinguished characteristics of the TiOxNPs are continuous generation of reactive oxygen species (ROS) by X-ray irradiation. Bio-availabilities and safety was previously reported (Nanoparticles, 2020; 10(6): 1125). Materials and Methods: Characteristics of TiOxNPs were determined following experiments. Dynamic light scattering analysis was used to measure the diameter and Z-potential of the NPs. Transmission electron microscope (TEM) observation revealed the detailed topology of the NPs. X-ray irradiation was performed using the X-ray generator at a voltage of 150 kV and a current of 5 mA with a 1-mm thick aluminum filter in vitro and in vivo. Reactive oxygen species (ROS) generation was evaluated using human pancreatic cancer cells, named MIAPaCa-2. The cells were stained with 50 μM carboxy-20,70-dichlorofluorescein (C-H2DCF) incubated for 45 min, and then stained with Hoechst for nuclear staining. The degree of fluorescence of C-H2DCF was detected using the fluorescence microscope. To evaluate cytotoxic effects of TiOxNPs, a colony-formation assay was performed. For xenograft experiments, the MIAPaCa-2 cells (2 x 106 cells) were injected subcutaneously into the hind legs of the BALB/cAJcl nude mice. Once the tumor volume reached 100-200 mm3, mice were randomly assigned into six groups: the control group, TiOxNPs alone, 5 Gy alone, and TiOxNPs combined with 5 Gy. Tumor size, body weight, and health condition of all mice were followed every two to three days for 55 days post-treatment. Results: Primary particles smaller than 10 nm gathered and formed secondary particles that were approximately 50 nm in diameter, and their Z-potential was -30 mV. TEM observation revealed the detailed topology of the NPs. The TiOxNPs enhanced H2O2 production more than 7-folds compared to X-ray irradiation alone in MIA PaCa-2 cells. In xenografts, combination effects of the TiOxNPs and X-ray irradiation were significantly greater than X-ray irradiation (5 Gy) alone. Conclusions: The TiOxNPs revealed to be powerful radiosensitizers in pancreatic cancer model. Clinical tests are warranted to clarify the application of TiOxNPs in the nearest future. Citation Format: Ryohei Sasaki, Hiroaki Akasaka, Masao Nakayama, Yoshiko Fujita, Hikaru Kubota, Kenta Morita, Mennaallah Hassan, Mohammed Salah, Yuya Nishimura, Naritoshi Mukumoto, Takeaki Ishihara, Daisuke Miyawaki, Chiaki Ogino. A novel radiosensitizer of titanium peroxide nanoparticles (TiOxNPs) through continuous ROS generation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2837.

Background: Colorectal cancer (CRC) is a major cause of cancer-related deaths in Japan and worldwide. Since CRC has been reported to have close relationship with diet, it seems significant to identify dietary constituents that might suppress occurrence of CRC. Recently, an epidemiological investigation for cancer incidence in Japan revealed that consumptions of black soybeans seem to reduce incidence of several cancers, especially colorectal cancer. Black soybeans coat extract (BE) is known to contain rich procyanidins which have many beneficial physiological activities such as anticancer effects. Therefore, we hypothesized that BE may have inhibitory effects to intestinal tumorigenesis and investigated using APCmin/+ mice models. Materials and Methods: APCmin/+ male mice in the C57BL/6 genetic background were obtained from Jackson Laboratories. APCmin/+ genotypes of each mouse were confirmed by polymerase chain reaction analysis (PCR) using DNA extracted from the tip of mouse tails. Mice were weighed weekly once and monitored regularly for any signs of weight loss. APC min/+ mice at 4 weeks of age were randomly divided into three groups with 5 mice, and fed by either AIN-76A diet, AIN-76A diet containing 0.05% or 0.05% BE for 8 weeks. At 12 weeks of age, intestines were removed from each mouse and then sliced longitudinally. The small intestine was cut into three equally parts: proximal, middle, and distal. Numbers and sizes of intestinal polyps in each portion were evaluated under Video-Zoom-microscope XV-440. Intestinal polyps were categorized by size into 1-2 mm, 2-3 mm and >3 mm. Other parts of the intestines were placed in 10% phosphate-buffered formalin for histopathology and immunohistochemical (PCNA, β-catenin, and MUC2) analyses. Results: Numbers of polyps in mice fed with containing 0.05% or 0.5% BE diet were significantly smaller than in mice fed without BE (P < 0.05). As for size of polyps, the number of polyps of 1 to 3 mm in size was decreased in mice with BE, however, there were no significant difference for numbers of polyps more than 3 mm in size regarding diets with or without BE. With 0.05% BE diet, reduction rates for occurrence of polyps were 81% for proximal, 48% for middle, and 47% for distal positions, while in with 0.5% BE diet, those reduction rates were 71% for proximal, 59% for middle, and 58% for distal positions, respectively. From these results, the BE, either 0.05% or 0.05% concentration, showed inhibitory effects for tumorigeneses in the small intestine of APC min/+ mice. In histological analyses, the BE was induced higher expression of MUC2-positive cells in normal intestinal lesions and lower expression of β-catenin in tumor sites Conclusions: The BE showed inhibitory effects in occurrence and growth of intestinal polyps in APCmin/+ mice models. With further evaluation of mechanisms, the BE could be a promising nutrition for prevention of CRC in human. Citation Format: Yasuyuki Shimizu, Shunta Hirano, Yoko Yamashita, Tsuyoshi Fukumoto, Naritoshi Mukumoto, Ai Nakaoka, Namiko Hoshi, Takeaki Ishihara, Daisuke Miyawaki, Ashida Hitoshi, Ryohei Sasaki. Black soybean seed coat extract suppress intestinal tumorigenesis in APCmin mice. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4244.

Introduction: Pancreatic cancer (PC) is believed to be a difficult disease because of its radio-resistance and metastases. Radiotherapy reported to modify tumor microenvironment (TME) and to affect PC progression. Exosomes containing such as microRNAs (miRNAs), messenger RNAs (mRNAs), and proteins of cells, play essential roles in cell-to-cell communications. However, characteristics and mechanisms for radiation responsive exosomes remain unclear. Here, we first report mechanisms of exosomes-mediated radiation response and regulation in PC metastasis with focusing on intra/intercellular communications via miRNA. Methods: MIAPaCa-2 cells, human pancreatic carcinoma, was used. To isolate exosomes, cell culture media was ultracentrifuged at 100,000 x g for 90 min at 4°C. Exosomes derived from non-irradiated culture media was named ‘0 Gy-Exo’ and those from irradiated with 5 Gy culture media is called ‘5 Gy-Exo’. Exosome sizes and features were evaluated by transmission electron microscopy (TEM). Intracellular reactive oxygen species (ROS) levels induced by exosomes and by X-ray irradiation were evaluated by the C-H2DCF dye staining. To detect DNA damage, cells were fixed and stained by γ-H2AX antibody. The expression of superoxide dismutase 1 (SOD1) was evaluated by using immunoblots. Total RNA was extracted from 0 Gy-Exo and 5 Gy-Exo, and then comprehensive miRNA expression analysis was performed to analyze 2,565 human miRNA sequences. The Gene Expression Omnibus database (GSE163133) and the TargetScan were used for specific miRNAs identification. Living MIAPaCa-2 cells in the presence or absence of those exosomes were injected in the spleen of Balb/c nude mice to establish liver metastatic models. Eight weeks after the injection, mice were sacrificed, and then the spleen and the liver were harvested as a whole organ. H-E staining and immunohisitochemical analyses using S100A4 and SMAD4 antibodies were performed to detect liver metastases. Results: Isolated exosomes were shaped in the form of closed, round vesicles with a diameter of 10~100 nm. Intracellular ROS levels and the numbers of γ-H2AX foci in the cells with 5 Gy-Exo were significantly increased compared to those the control (without adding exosomes, p Conclusion: Exosomes increased radiation sensitivity through increase of intracellular ROS levels via exosomal miRNAs and also could affect liver metastases in pancreatic cancer models. Citation Format: Ai Nakaoka, Makiko Nakahana, Sachiko Inubushi, Yasuyuki Shimizu, Kazuma Iwashita, Naritoshi Mukumoto, Kana Kobayashi, Takeaki Ishihara, Daisuke Miyawaki, Ryohei Sasaki. Exosomes enhance the radiation sensitivity via miR-6823-5p and modulate metastases in pancreatic cancer model. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3796.

Background/aim We aimed to investigate the dosimetric effects of a spacer placed between the pancreas and surrounding gastrointestinal structures in intensity-modulated radiation therapy (IMRT) planning to provide more effective radiation therapy for locally advanced pancreatic cancer (LAPC). Patients and methods Treatment planning was performed for six patients with LAPC based on computed tomography images without spacers and with 5-mm or 10-mm spacers virtually inserted under the supervision of a hepatobiliary pancreatic surgeon. The prescription dose was 63 Gy in 28 fractions. Results With the exception of one case of pancreatic head cancer, planning target volume receiving ≥95% of the prescribed dose (PTV V95) was achieved by 90% or more by inserting a spacer, and by 95% or more in all 3 cases of pancreatic body and tail cancer by inserting a 10-mm spacer. Conclusion IMRT with appropriate spacer placement may help provide high-dose treatment for LAPC and improve associated patient outcomes.

Background/aim: We aimed to investigate the dosimetric effects of a spacer placed between the pancreas and surrounding gastrointestinal structures in intensity-modulated radiation therapy (IMRT) planning to provide more effective radiation therapy for locally advanced pancreatic cancer (LAPC). Patients and methods: Treatment planning was performed for six patients with LAPC based on computed tomography images without spacers and with 5-mm or 10-mm spacers virtually inserted under the supervision of a hepatobiliary pancreatic surgeon. The prescription dose was 63 Gy in 28 fractions. Results: With the exception of one case of pancreatic head cancer, planning target volume receiving ≥95% of the prescribed dose (PTV V95) was achieved by 90% or more by inserting a spacer, and by 95% or more in all 3 cases of pancreatic body and tail cancer by inserting a 10-mm spacer. Conclusion: IMRT with appropriate spacer placement may help provide high-dose treatment for LAPC and improve associated patient outcomes.

Aim:To modify the final dose delivered to superficial tissues and to modulate dose distribution near irradiated surface, different boluses are used. Air gaps often form under the bolus affecting dose distribution. This study aimed to evaluate the effect of an air gap under the bolus radiation on dose delivery.Materials and methods:To evaluate the impact of the air gap, both helical tomotherapy (HT) and direct tomotherapy (DT) were performed in a simulation study.Results:The maximum dose to bolus in DT plans was bigger than that used in HT plans. The maximum dose delivered to the bolus depended on the air gap size. However, the maximum dose to bolus in all HT plans was within the acceptable value range. Acceptable value was set to up to 107% of the prescription dose. In the simulation performed in this study, the acceptable air gap under bolus was up to 15 mm and below 5 mm in HT and DT plans, respectively.Conclusions:HT technique is a good choice, but DT technique can be also used if the bolus position can be reproduced accurately. Thus, the reproducibility of the bolus position between planning and treatment is very important.

We retrospectively reviewed the effect of stereotactic body radiation therapy (SBRT) in patients with stage I lung cancer whose lung tumor showed a nodular appearance of ground glass opacity, so-called ground glass nodule (GGN). A total of 84 patients (42 men, 42 women; mean age, 75 years) with stage I lung cancer with GGN accompanying a solid component

Recently, the introduction of various novel technologies in clinical settings has improved the accuracy of radiation therapy. Stereotactic body radiation therapy (SBRT) involves the delivery of an accurate radiation dose to the tumor with a minimal impact on normal tissues using various measures to address changes in the tumor position due to respiratory displacement. The SyncTraX FX4 real-time tumor tracking system (Shimadzu Corporation) introduced in our hospital tracks the actual tumor location by radioscopically monitoring a metallic marker that is placed in the vicinity of the tumor. However, there have been no reports yet on respiratory-gated volumetric modulated arc therapy (VMAT)-SBRT using a real-time tumor tracking system. This study aimed to develop an irradiation procedure for respiratory-gated VMAT-SBRT using a real-time tumor tracking system and to evaluate radiation doses therein. In this study, we found that absolute doses with respiratory gating did not deviate by more than ±1.0% from those without respiratory gating. In addition, the pass rate in gamma analysis using GAFCHROMIC EBT3 was ³95% with the pass criteria in dose difference, distance to agreement, and threshold being 2%, 2 mm, and 10%, respectively. Furthermore, a trajectory log file analysis did not reveal any significant error causes. Thus, these data indicate that respiratory-gated VMAT-SBRT can be applied clinically.

Depression is an independent risk factor for cardiovascular disease and is significantly associated with the prevalence of abdominal aortic aneurysm (AAA). We investigated the effect of repeated social defeat (RSD) on AAA development. Eight-week-old male wild-type mice were exposed to RSD by being housed with larger CD-1 mice in a shared cage. They were subjected to vigorous physical contact. After the confirmation of depressive-like behavior, calcium chloride was applied to the infrarenal aorta of the mice. At one week, AAA development was comparable between the defeated and control mice, without any differences being observed in the accumulated macrophages or in the matrix metalloproteinase activity. At two weeks, the maximum diameter and circumference of the aneurysm were significantly increased in the defeated mice, and a significant decrease in periaortic fibrosis was also observed. Consistently, the phosphorylation of the extracellular signal-regulated kinase and the incorporation of 5-bromo-2'-deoxyuridine in the primarily cultured aortic vascular smooth muscle cells were significantly reduced in the defeated mice, which was accompanied by a substantial increase in mitogen-activated protein kinase phosphatase-1 (MKP-1). The MKP-1 mRNA and protein expression levels during AAA were much higher in the defeated mice than they were in the control mice. Our findings demonstrate that RSD enhances AAA development by suppressing periaortic fibrosis after an acute inflammatory response and imply novel mechanisms that are associated with depression-related AAA development.

Maternal high-fat diet (HFD) is associated with the development of cardiovascular disease (CVD) in adult offspring. Atherosclerotic vascular calcification is well documented in patients with CVD. We examined the effect of maternal HFD on calcified plaque formation.Seven-week-old female apo-EOur findings indicate that maternal HFD accelerates the expansion of atherogenic calcification independent of plaque progression. In vitro phosphate- and IL-1β-induced osteochondrocytic transformation of VSMCs was augmented in O-HFD. Inhibition of VSMCs, skewing toward osteochondrocytic-like cells, might be a potential therapeutic strategy for preventing maternal HFD-associated CVD development.

Depression is an independent risk factor for cardiovascular disease (CVD). We have previously shown that repeated social defeat (RSD) exaggerates atherosclerosis development by enhancing neutrophil extracellular trap (NET) formation. In this study, we investigated the impact of RSD on arterial thrombosis. Eight-week-old male wild-type mice (C57BL/6J) were exposed to RSD by housing with larger CD-1 mice in a shared home cage. They were subjected to vigorous physical contact daily for 10 consecutive days. After confirming depression-like behaviors, mice underwent FeCl3-induced carotid arterial injury and were analyzed after 3 h. Although the volume of thrombi was comparable between the two groups, fibrin(ogen)-positive areas were significantly increased in defeated mice, in which Ly-6G-positive cells were appreciably co-localized with Cit-H3-positive staining. Treatment with DNase I completely diminished exaggerated fibrin-rich clot formation in defeated mice. Flow cytometric analysis showed that neutrophil CD11b expression before FeCl3 application was significantly higher in defeated mice than in control mice. In vitro NET formation induced by activated platelets was significantly augmented in defeated mice, which was substantially inhibited by anti-CD11b antibody treatment. Our findings demonstrate that RSD enhances fibrin-rich clot formation after arterial injury by enhancing NET formation, suggesting that NET can be a new therapeutic target in depression-related CVD.

Background The purpose of this study was to investigate the effectiveness of dental intervention before and after radiation therapy (RT) for head and neck malignancy on prevention of osteoradionecrosis (ORN) of the jaws. Methods This is a single-arm prospective study according to intervention protocol of prophylactic dental extraction before RT and routine follow-up after RT. The primary endpoint was the occurrence of jawbone exposure during the first 2 years after RT. Results Sixty-seven patients were assessed. Before RT, 144 teeth among 39 patients (58%) were prophylactically extracted. The occurrence of transient jawbone exposure during the first 2 years after RT was 7%. Because those jawbone exposures healed with intervention after RT, no jawbone exposure was found at 2 years after RT. Conclusions Dental intervention both before and after RT seemed to be important to prevent ORN development. Further studies in larger cohorts are necessary.

Na-substituted 122-type iron-based superconductors were synthesized and fabricated into superconducting tapes and wires. Good J c performance of Ag-sheathed Sr0.45Na0.55Fe2As2 pressed tapes was demonstrated, and it was further improved by using AgSn as a sheath material. The improved J c characteristics are due to the reduction of the optimum sintering temperature by ∼100 °C, which suppressed the reaction between the sheath and the core. However, the fabrication of good Sr0.45Na0.55Fe2As2 round wire using the hot isostatic press method failed, due possibly to the segregation of Na in the core. To avoid the segregation of Na, we fabricated round wires employing (Ba,Na)Fe2As2 rather than underdoped (Sr,Na)Fe2As2. J c in Ba0.6Na0.4Fe2As2 round wire processed 700 °C under the pressure of 175 MPa reached 1.5 × 105 and 2.0 × 104 A/cm2 at self-field and 100 kOe, respectively. These values are more than fifty percent of the largest J c in (Ba,K)Fe2As2 round wires, demonstrating the excellent performance of (Ba,Na)Fe2As2 wires.

Purpose Surgical spacer placement (SSP) is useful in particle therapy (PT) for patients with abdominal or pelvic tumors located adjacent to normal organs. We developed a nonwoven fabric bioabsorbable spacer made of polyglycolic acid (PGA) sutures that degrades via hydrolysis. We then conducted this first-in-human phase 1 study of the combination of SSP and PT using the PGA spacer, which we termed space-making PT (SMPT). This study aimed to evaluate the safety and efficacy of SMPT in patients with unresectable malignant tumor located adjacent to normal organs. Methods and Materials The eligibility criteria included histologically proven malignant abdominal or pelvic tumor adjacent to the intestines, no metastasis, and no previous radiation therapy. Periodic computed tomography (CT) images were obtained before SSP and before, during, and after PT until the spacer disappeared. Treatment planning was performed for each CT image set until the end of PT, and doses for the planning target volume and organs at risk were analyzed. The thickness and volume of the PGA spacer were measured in each CT image set. Adverse events were evaluated according to the Common Terminology Criteria for Adverse Events version 4.0. Results Five patients were enrolled in this study. All patients received 70.4 Gy (relative biological effectiveness) of irradiation. V95% of the planning target volume before SSP, at the beginning of PT, and at the end of PT was 82.1% ± 11.3%, 98.1% ± 1.1%, and 97.1% ± 0.8%, respectively. The PGA spacers maintained enough thickness (≥1 cm) until the end of PT and disappeared within 8 months after SSP in all patients. No grade ≥3 acute adverse events were observed. Conclusions The SMPT is feasible and useful for abdominal or pelvic tumors adjacent to the intestines. This method may be applicable to unresectable tumors located adjacent to normal organs and may expand the indications of PT.

Purpose: Effective methods to ameliorate radiation enteropathy have not been developed. To address this issue, we investigated the reduced form of coenzyme Q10 (rCoQ10) as a potential radioprotector in a mouse model. Methods and Materials: rCoQ10 was added to a standard laboratory mouse diet at a final concentration of 1.0% 9 days before irradiation and 30 days thereafter or dissolved in corn oil and administered transorally. Accumulated amounts of coenzyme Q10 (CoQ10) or coenzyme Q9 in the intestine were measured by high-performance liquid chromatography. Reactive oxygen species (ROS), apoptosis, and morphologic changes in the intestine were assessed by immunohistochemistry after administration of 13 Gy of x-ray to the mouse abdomen. Body weight and survival were monitored for 30 days after irradiation. Cytotoxicity using 3 human cancer cell lines and the tumor growth-inhibiting effect in a xenograft were investigated to determine whether rCoQ10 interferes with radiation-specific cytotoxic effects on tumor growth. Results: CoQ10 was greatly accumulated in all sections of the intestine after both massive transoral dosing and dietary administration, whereas coenzyme Q9 was not. Administration of rCoQ10 suppressed ROS production and inhibited apoptosis in the crypts, resulting in preservation of villi structures after irradiation. Notably, 92% of mice fed the rCoQ10-supplemented diet were healthy and alive 30 days after irradiation, whereas 50% of control mice died (P < .05). Moreover, rCoQ10 did not interfere with radiation-specific cytotoxic effects on tumors either in vitro or in vivo. Conclusions: Administration of rCoQ10 led to its accumulation in the intestine and induced radioprotective effects by inhibiting ROS-mediated apoptosis, thereby preserving intestinal structures. Our results indicated that rCoQ10 supplementation effectively ameliorated radiation enteropathy.

Background Vascular closure devices have been widely used to achieve rapid hemostasis after percutaneous catheterization procedures via the common femoral artery. The EXOSEAL vascular closure device is a device that can deliver a bioabsorbable polyglycolic acid plug to fill the subcutaneous puncture route at the groin for rapid hemostasis, and this device has a lower risk of arterial occlusion than other vascular closure devices. Case presentation An 83-year-old Japanese man underwent percutaneous coronary intervention for a proximal stenosis in his left circumflex artery through a 7-Fr sheath from his right common femoral artery. We encountered acute popliteal artery occlusion associated with EXOSEAL vascular closure device. We detected the plug material of this device at the occluded lesion by intravascular ultrasound, and performed successful bailout stenting after pulling the embolus with an inflated balloon catheter up to the superficial femoral artery from the popliteal artery. Conclusion Acute limb ischemia caused by an EXOSEAL vascular closure device is a very rare complication. Balloon angioplasty and stenting are considered to be effective options to deal with the plug dislodgement of an EXOSEAL vascular closure device. We must be prepared for every rare complication during endovascular treatment.

Purpose: Chemoradiotherapy with docetaxel (DOC), cisplatin (CDDP), and 5-FU (TPF-CRT) for locally advanced external auditory canal cancer (EACC) has favorable oncological and functional outcomes. To establish TPF-CRT as a standard of care for advanced EACC, we conducted this study to determine the maximum tolerated (MTD) and recommended dose (RD) of DOC in TPF-CRT for locally advanced EACC. Methods: To determine the recommended (RD) and maximum tolerated dose (MTD) of DOC in TPF-CRT for EACC, a phase I trial was conducted using the standard “3 + 3” design for maximum dose finding. DOC was administered twice every 4 weeks, CDDP at 70 mg/m² and 5-FU at 700 mg/m²; patients were also receiving radiotherapy (66 Gy). Eight patients with T3 or T4 EACC were prospectively enrolled. Results: Two patients treated with DOC, 50 mg/m², and one out of six patients treated with DOC, 40 mg/m², had dose-limiting toxicities. Prolonged febrile neutropenia was observed in three patients. Grade 3 non-hematological toxicities were observed in only three patients. At study completion, six patients survived, five of whom were disease free. Conclusion: The RD and MTD of DOC in TPF-CRT for locally advanced EACC are 40 mg/m² when doses of CDDP and 5-FU are 70 mg/m² and 700 mg/m², respectively.

BackgroundThe prognosis of patients with advanced squamous cell carcinoma of the external auditory canal and middle ear has been improved by advances in skull base surgery and multidrug chemoradiotherapy during the last two decades.MethodsNinety-five patients with squamous cell carcinoma of the external auditory canal and middle ear who were treated between 1998 and 2017 were enrolled. The number of patients with tumour stages T1, T2, T3 and T4 was 15, 22, 24 and 34, respectively. Oncological outcomes and prognostic factors were retrospectively investigated.ResultsAmong patients with T4 disease, invasion of the brain (p = 0.024), carotid artery (p = 0.049) and/or jugular vein (p = 0.040) were significant predictors of poor prognosis. The five-year overall survival rate of patients with at least one of these factors (T4b) was significantly lower than that of patients without these factors (T4a) (25.5 vs 65.5 per cent, p = 0.049).ConclusionIt is proposed that stage T4 be subclassified into T4a and T4b according to the prognostic factors.

Background and Objective: Depression is an independent risk factor of cardiovascular disease and significantly associated with the prevalence of abdominal aortic aneurysm (AAA). We investigated the impact of repeated social defeat (RSD) on AAA formation. Methods and Results: Eight-week-old male WT mice were exposed to RSD by housing with a larger CD-1 mouse in a shared cage. They were subjected to vigorous physical contact daily for 10 consecutive days. Control mice were housed in the same cage without physical contact. After social interaction test to confirm depressive-like behaviors, mice underwent application of 0.5M calcium chloride (CaCl 2 ) on the infrarenal aorta. At one-week, maximum diameter and circumference of external elastic membrane were comparable between the two groups. The number of F-4/80 and MMP-9-positive cells in immunofluorescent images were also comparable. Consistently, fluorescent image taken by IVIS revealed no difference in MMP activity, suggesting that acute inflammatory response was comparable between the two groups. In contrast, at two weeks, maximum diameter and circumference of external elastic membrane were significantly increased in defeated mice ( p < 0.01). Intriguingly, periaortic fibrotic area in aneurysmal portion was markedly decreased in defeated mice (12.5х10 3 μm 2 vs. 3.7х10 3 μm 2 , Control vs. Defeat, p < 0.01). Consistently, accumulation of α-SMA-positive cells in adventitia of aneurysmal portion was much lesser in defeated mice (876 cells/mm 2 vs. 319 cells/mm 2 , Control vs. Defeat, p < 0.05), whereas those in tunica media of non-aneurysmal portion did not show any difference between the two groups. LPS-induced iNOS gene and protein expressions in bone marrow-derived macrophages (BMDMs) were significantly decreased in defeated mice, whereas the TGF-β-induced phosphorylation of Smad2 and ERK1/2 in primary cultured aortic VSMCs were comparable between the two groups. Conclusions: Our findings demonstrate that RSD enhances AAA expansion by suppressing the periaortic fibrosis following inflammatory response, and suggest that decreased NO production from accumulated macrophages contributes to the reduced VSMCs proliferation and collagen deposition.

Background and Objective: Depression is an independent risk factor of cardiovascular disease (CVD). We have recently shown that repeated social defeat (RSD) exaggerates atherosclerosis development by enhancing neutrophil extracellular traps (NETs) formation. Here, we investigated the impact of RSD on arterial thrombosis. Methods and Results: Eight-week-old male WT mice were exposed to RSD by housing with a larger CD-1 mouse in a shared home cage. They were subjected to vigorous physical contact daily for 10 consecutive days. Control mice were housed in the same gage without physical contact. After social interaction test to confirm depressive-like behaviors, defeated mice (19 of 31) and control mice (12 of 14) were underwent arterial injury at 10 wks of age. A filter paper saturated with 10% FeCl3 was applied on the adventitial surface of left carotid artery for 3 min and analyzed 3 hrs later. The volume of thrombi was comparable between the two groups. However, fibrinogen/fibrin-positive areas in immunofluorescent images significantly increased in defeated mice (48.8% vs. 27.8%, p < 0.01). The number of Ly-6G-positive cells in thrombi was markedly higher in defeated mice (878/mm2 vs. 144/mm2, p < 0.05). Further, Ly-6G-positive cells were co-localized with neutrophil elastase, Cit-H3, and CD42b-positive staining. Percentage of CD42b-positive area in thrombi and in vitro platelets aggregations induced by ADP or collagen were comparable between the two groups. Treatment with DNase I completely diminished the exaggerated fibrin-rich clot formation in defeated mice to an extent similar to that in control mice (22.3% vs. 25.7%, p = ns), although the number of Ly-6G-positive cells in thrombi was not affected. We therefore examined the vulnerability to NETs formation induced by thrombin-activated platelets. Flow cytometric analysis showed that in vitro NETs formation assessed by Cit-H3/MPO double-positive cells was significantly higher in defeated mice (20.7% vs 12.5%, p < 0.01). Conclusions: Our findings demonstrate that RSD enhances fibrin-rich clot formation after arterial injury by enhancing NETs formation via platelet-neutrophil interactions, suggesting that NETosis could be a new therapeutic target in depression-related CVD development.

Background and objective Maternal high-fat diet (HFD) has been shown to modulate vascular function and remodeling in adult offspring. Atherosclerotic vascular calcification is closely associated with the onset of cardiovascular event. We therefore investigated the impact of maternal HFD on calcification of atherogenic plaques. Methods and results Eight-week-old female apo-E−/− mice (C57BL/6) were fed an HFD or a normal diet (ND) one week prior to mating, and the diet was continued throughout gestation and lactation. Offspring of both groups were fed a high-cholesterol diet (HCD) from 8 weeks of age. Ex vivo osteogenic activity of aortic root and aortic arch was analyzed using in vivo imaging system (IVIS) with OsteoSense 680. Sixteen-week-old male offspring of HFD-fed dams (O-HFD) showed a 1.4-fold increase in fluorescent intensity compared with those of ND-fed dams (O-ND) (p Conclusion Our findings demonstrate that maternal HFD accelerates the development of atherogenic calcification independent of plaque size. In vitro transformation to osteochondrocytic-like cells is enhanced in VSMCs from offspring of HFD-fed dams. Inhibition of VSMCs skewing toward osteochondrocytic-like cells could be a potential therapeutic target for preventing the development of atherosclerotic vascular calcification. Funding Acknowledgement Type of funding source: None

Background and objective Maternal high-fat diet (HFD) has been shown to modulate vascular function and remodeling in adult offspring. Here, we investigated the impact of maternal HFD on abdominal aortic aneurysm (AAA) formation. Methods and results Eight-week-old female wild-type mice (C57BL/6) were fed a HFD or normal diet (ND) one week prior to mating, and the diet was continued throughout gestation and lactation. In eight-week-old male offspring, AAA was induced with the application of 0.5 M calcium chloride (CaCl2) on the infrarenal aorta. Offspring of HFD-fed dams (O-HFD) showed a significant increase in maximum outer diameter of AAA at 1, 4 and 8 weeks after surgery compared with offspring of ND-fed dams (O-ND). The lengths of outer circumference assessed by histological analysis were increased in O-HFD (p Conclusion Our findings demonstrate that maternal HFD accelerates CaCl2-induced AAA expansion, accompanied by the exaggerated accumulation of osteoclast-like macrophages and augmented activity of MMPs. Inhibition of macrophages skewing toward osteoclast-like cells could be a potential therapeutic target for preventing AAA development. Funding Acknowledgement Type of funding source: None

Background and objective Depression is an independent risk factor of cardiovascular disease (CVD) and significantly associated with the prevalence of abdominal aortic aneurysm (AAA). We have recently shown that repeated social defeat (RSD) precipitates depressive-like behaviors in apoE−/− mice and exaggerates atherosclerosis development by enhancing leukocyte activation. Here, we investigated the impact of RSD on AAA formation. Methods and results Eight-week-old male WT mice were exposed to RSD by housing with a larger CD-1 mouse in a shared home cage. They were subjected to vigorous physical contact daily for 10 consecutive days. Control mice were housed in the same gage without physical contact. After social interaction test to confirm depressive-like behaviors, defeated mice (28 of 48) and control mice (31 of 36) underwent application of 0.5 M calcium chloride (CaCl2) on the infrarenal aorta to induce AAA. At 1 week after application, maximum diameter and circumference of external elastic membrane were comparable between the two groups. The number of F-4/80, MMP-9, and TNF-α-positive cells in immunofluorescent images were also comparable. Further, in vitro bone marrow derived macrophages stimulation by LPS did not show any difference in mRNA expression levels of inflammatory cytokines, suggesting no discernable difference in acute inflammatory response between the two groups. In contrast, at 2 weeks after application, at the time point when MMP-9 and TNF-α-positive cells were scarcely observed, maximum diameter and circumference of external elastic membrane were significantly increased in defeated mice (0.72 mm vs. 0.90 mm, 1.59 mm vs. 2.00 mm, respectively, Control vs. Defeat, p Conclusions Our findings demonstrate for the first time that RSD enhances AAA expansion by eliminating periaortic fibrosis in tissue repair phase, suggesting that the impaired resolution of acute inflammation after CaCl2 application contributes, at least in part, to the augmented expansion of AAA in defeated mice. Funding Acknowledgement Type of funding source: None

Background and objective Depression is an independent risk factor of cardiovascular disease (CVD). We have recently shown that repeated social defeat (RSD) precipitates depressive-like behaviors in apoE−/− mice and exaggerates atherosclerosis development by enhancing neutrophil extracellular traps (NETs) formation. Here, we investigated the impact of RSD on arterial thrombosis. Methods and results Eight-week-old male WT mice were exposed to RSD by housing with a larger CD-1 mouse in a shared home cage. They were subjected to vigorous physical contact daily for 10 consecutive days. Control mice were housed in the same gage without physical contact. After social interaction test to confirm depressive-like behaviors, defeated mice (19 of 31) and control mice (12 of 14) were underwent arterial injury at 10 wks of age. A filter paper saturated with 10% FeCl3 was applied on the adventitial surface of left carotid artery for 3 min and analyzed 3 hrs later. The volume of thrombi was comparable between the two groups. However, fibrinogen/fibrin-positive areas in immunofluorescent images significantly increased in defeated mice (27.8% vs. 48.8%, p Conclusions Our findings demonstrate for the first time that repeated social defeat enhances fibrin-rich clot formation after arterial injury by enhancing NETs formation via modulation of neutrophil functional properties, suggesting that NETosis could be a new therapeutic target in depression-related CVD development. Funding Acknowledgement Type of funding source: None

The development of potentially safe radiosensitizing agents is essential to enhance the treatment outcomes of radioresistant cancers. The titanium peroxide nanoparticle (TiOxNP) was originally produced using the titanium dioxide nanoparticle, and it showed excellent reactive oxygen species (ROS) generation in response to ionizing radiation. Surface coating the TiOxNPs with polyacrylic acid (PAA) showed low toxicity to the living body and excellent radiosensitizing effect on cancer cells. Herein, we evaluated the mechanism of radiosensitization by PAA-TiOxNPs in comparison with gold nanoparticles (AuNPs) which represent high-atomic-number nanoparticles that show a radiosensitizing effect through the emission of secondary electrons. The anticancer effects of both nanoparticles were compared by induction of apoptosis, colony-forming assay, and the inhibition of tumor growth. PAA-TiOxNPs showed a significantly more radiosensitizing effect than that of AuNPs. A comparison of the types and amounts of ROS generated showed that hydrogen peroxide generation by PAA-TiOxNPs was the major factor that contributed to the nanoparticle radiosensitization. Importantly, PAA-TiOxNPs were generally nontoxic to healthy mice and caused no histological abnormalities in the liver, kidney, lung, and heart tissues.

Purpose/Objectives: The mechanism of intercellular communication after radiation exposure in cancer cells remains fully undetermined. Exosomes are lipid bilayer-constituted, membrane-enclosed small vesicles that are recognized as mediators transporting a variety of intracellular components including miRNA. Here we identified the novel role of exosomes released from irradiated cells to neighboring cancer cells. Materials/Methods: Human pancreatic cancer cell line MIAPaCa-2 was used in this study. Purified exosome product (PEP) was obtained from cultured media by ultra-centrifugation. PEP was morphologically confirmed by transmission electron microscopy (TEM), and analyzed by NanoSight. Exosome-specific surface markers CD9 and CD63 were evaluated by western blotting. Endocytosis of irradiated exosomes was confirmed by fluorescent microscopy by using the PKH26 dye. Cell survival after irradiation was evaluated by a colony-forming assay. Intracellular reactive oxygen species (ROS) levels were determined using the oxidation-sensitive fluorescent probe dye C-H 2 DCF, and DNA damage was evaluated by detecting phosphorylated histone 2AX (γ-H2AX) foci by immunocytochemistry. MiRNAs were isolated from the exosomes after 5 Gy or 8 Gy of irradiation and comprehensive miRNA expression analysis was performed by miRNA microarray analyses. Expressions of Cu/Zn superoxide dismutase enzyme (SOD1) or Mn superoxide dismutase enzyme (SOD2), catalase, and glutathione peroxidase were studied to determine whether the exosomes received by the neighboring cells may have influence to them and lead to production of ROS or not. Results: Exosome characteristics were confirmed by multiple methods. The uptake of irradiated exosomes was significantly higher than that of nonirradiated exosomes. Notably, nonirradiated neighboring cells with irradiated exosomes induced higher intracellular levels of ROS, and a higher frequency of DNA damage. These neighboring cells also showed greater sensitivity to radiation. Seven upregulated and 5 downregulated miRNAs were identified that correlated with the miRNA microarray analyses results obtained after 5 Gy and 8 Gy radiation. Among them, miR-6823-5p was identified as a possible candidate for SOD1 inhibition, leading to intracellular ROS production and DNA damage. Conclusions : This is the first study to determine that irradiated exosomes can enhance the radiation effect via ROS production in cancer cells. This novel finding may lead to the understanding of the bystander effect of neighboring cancer cells.

Purpose To develop a novel biocompatible solid fiducial marker that prevents radiopaque imaging artifacts and also maintains high imaging contrast for kilovoltage x-ray image-guided radiation therapy. Methods The fiducial marker was made of pure zinc. An in-house water-equivalent phantom was designed to evaluate artifacts and visibility under various simulated treatment scenarios. Image artifacts were quantitatively assessed in terms of the metal artifact index (MAI) on kilovoltage computed tomography (CT) and cone-beam CT (CBCT) scans. Marker visibility was evaluated on two types of kilovoltage planar x-ray images in terms of the contrast-to-background ratio (CBR). Comparisons with a conventional gold fiducial marker were conducted. Results The use of zinc rather than a gold marker mitigates imaging artifacts. The MAI near the zinc marker decreased by 76, 79, and 77 % in CT, and by 77 (81), 74 (80), and 79 (85) % in CBCT full-fan (half-fan) scans, when using one-, two-, and three-marker phantom settings, respectively. The high-contrast part of the zinc marker exhibited CBRs above 2.00 for 28/32 exposures under four (lung, tissue, low-density bone, and high-density bone) different simulation scenarios, making its visibility comparable to that of the gold marker (30/32 exposures with CBRs > 2.00). Conclusions We developed a biocompatible, artifact-robust, and highly visible solid zinc fiducial marker. Although further evaluation is needed in clinical settings, our findings suggest its feasibility and benefits for kilovoltage x-ray image-guided radiation therapy.