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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.

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

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.

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.

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.

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. 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

Enhancing the antitumor effect of radiation, while reducing damage to organs, is a significant challenge in radiation therapy for head and neck malignancies. One promising radiosensitizer is gold. The present study aimed to determine whether gold nanoparticles (AuNPs) have the potential to enhance the effects of X-ray irradiation on head and neck cancer cells. The human head and neck carcinoma cell line HSC-3 was used. Total cell number and the levels of cell proliferation and apoptosis were compared between control cells and cells treated with 5-nm AuNPs alone at four concentrations (0.1, 0.4, 1.0 and 10.0 nM), X-ray irradiation alone at three doses (2, 4 and 8 Gy), or a combination of 4 Gy X-ray irradiation and 1.0 nM AuNPs. Analysis of variance and Tukey-Kramer testing were performed to compare the different groups. The total number of cells significantly decreased following 4 and 8 Gy X-ray irradiation, compared with in the control group (control vs. 4Gy, P=2.19×10−4; control vs. 8Gy, P=1.28×10−6). The combination of 4 Gy X-ray irradiation and 1.0 nM AuNPs significantly reduced the total number of cells compared with 4 Gy X-ray irradiation alone (P=2.95×10−4). Cell proliferation was not affected by AuNP treatment alone, 4 Gy X-ray irradiation alone or the combination of X-ray irradiation and AuNPs. The combination of 4 Gy irradiation and 1.0 nM AuNPs significantly increased the number of apoptotic cells compared with 4 Gy irradiation alone (P=0.0261). In conclusion, AuNPs combined with X-ray irradiation enhanced the cytotoxic effect on human head and neck cancer cells in vitro, through the induction of apoptosis, but not inhibition of cell proliferation.

Micro-slit-beam radiation therapy (MRT) using synchrotron-generated X-ray beams allows for extremely high-dose irradiation. However, the toxicity of MRT in central nervous system (CNS) use is still unknown. To gather baseline toxicological data, we evaluated mortality in normal mice following CNS-targeted MRT. Male C57BL/6 J mice were head-fixed in a stereotaxic frame. Synchrotron X-ray-beam radiation was provided by the SPring-8 BL28B2 beam-line. For MRT, radiation was delivered to groups of mice in a 10 × 12 mm unidirectional array consisting of 25-μm-wide beams spaced 100, 200 or 300 μm apart; another group of mice received the equivalent broad-beam radiation therapy (BRT) for comparison. Peak and valley dose rates of the MRT were 120 and 0.7 Gy/s, respectively. Delivered doses were 96–960 Gy for MRT, and 24–120 Gy for BRT. Mortality was monitored for 90 days post-irradiation. Brain tissue was stained using hematoxylin and eosin to evaluate neural structure. Demyelination was evaluated by Klüver–Barrera staining. The LD50 and LD100 when using MRT were 600 Gy and 720 Gy, respectively, and when using BRT they were 80 Gy and 96 Gy, respectively. In MRT, mortality decreased as the center-to-center beam spacing increased from 100 μm to 300 μm. Cortical architecture was well preserved in MRT, whereas BRT induced various degrees of cerebral hemorrhage and demyelination. MRT was able to deliver extremely high doses of radiation, while still minimizing neuronal death. The valley doses, influenced by beam spacing and irradiated dose, could represent important survival factors for MRT.

Background Maternal high-fat diet (HFD) has been shown to promote the development of insulin resistance (IR) in adult offspring; however, the underlying mechanisms remain unclear. Approach 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 received during pregnancy and lactation. Eight-week-old male offspring of both groups were fed a HFD for 8 weeks. Offspring of HFD-fed dams (O-HFD) showed significantly enhanced IR compared with offspring of ND-fed dams (O-ND). There was no difference in body weight, epidydimal white adipose tissue (eWAT) weight, and cumulative caloric intake between the 2 groups. However, eWAT adipocyte size was significantly increased in O-HFD, accompanied by the abundant crown-like structures. Flow cytometric analysis revealed an increased percentage of M1, but not M2, macrophages. Serum and eWAT concentrations of IL-1β, but not TNF-α, were significantly higher in O-HFD than O-ND (3.7-fold and 2.0-fold, respectively, P Conclusions Our findings demonstrate that maternal HFD exaggerates diet-induced insulin resistance in adult offspring by enhancing pyroptosis through augmented GSDM-D-mediated pore formation.

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 received during pregnancy and lactation. In eight-week-old offspring of both genders, AAA was induced with the application of 0.5M calcium chloride (CaCl2) on the infrarenal aorta. Male 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) (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.

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 behaviorsin apoE−/− mice and exaggerates atherosclerosis development by enhancing neutrophil extracellular traps (NETs) formation (BBRC 2018; 500:490). Here, we investigated the impact of RSD on arterial thrombosis. Methods and results Eight-week-old male WT mice were exposed to RSDby 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 testto 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% FeCl3was applied on the adventitial surface of left carotid artery for 3 min and analyzed 3 hrs later. The volume of thrombi calculated by summing8–15 frozen cross-sectional images, each separated by 200 μm, was comparable between the 2 groups. However, fibrinogen/fibrin-positive areas in immunofluorescent images were significantly increased in defeated mice (27.8% vs. 48.8%, Control vs. Defeat, 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, suggesting that NETosis could be a new therapeutic target in depression-related CVD development.

Highlights • Prognostic factors: primary tumor, visceral metastases, and surgical procedure. • PS, BI, EQ-5D, and NRS improved at 3 months after surgery. • The improvements of PS, BI, EQ-5D, and NRS were maintained for 6 M after surgery. • The management of bone metastases must be decided by a multidisciplinary team. • The proper management of bone metastasis will reduce postoperative complications., Background Skeletal related events due to metastatic bone tumors markedly affect the activities of daily living (ADL) and quality of life (QOL) in cancer patients. We focused on multidisciplinary therapy for metastatic bone tumors. This study aimed to evaluate the outcomes of surgical treatment for metastatic bone tumors in the extremities. Methods We retrospectively reviewed 114 patients who underwent surgical treatment for metastatic bone tumors of the extremities between 2008 and 2019 and 69 patients were reassessed for more than 6 months after surgery. The most common primary tumor was renal, followed by lung, thyroid, and breast cancers. We assessed 69 patients’ performance status (PS), Barthel Index (BI) for ADL, EuroQol 5 Dimensions (EQ-5D) for QOL, and numerical rating scale (NRS) for pain and analyzed these postoperative values relative to preoperative values using Friedman’s test. The postoperative overall survival and the prognostic factors were evaluated using the Kaplan-Meier method, the log-rank test and Cox proportional hazards analysis. Results The 1-year overall survival rate was 59%, and the median survival time after surgery was 20 months. Primary tumor, visceral metastasis, and surgical procedure were risk factors correlated with overall survival. PS, BI, EQ-5D, and NRS improved at 3 months after surgery and these improvements were maintained for 6 months after surgery regardless of the surgical procedure. Conclusions The significant factors affecting survival after surgical treatment for bone metastases included the primary tumor, presence of visceral metastases, and internal fixation without tumor resection or curettage. Surgical treatment for metastatic bone tumors effectively reduced pain and improved PS, ADL, and QOL postoperatively after 3 months.

Background To evaluate factors associated with osteoradionecrosis of the jaw (ORNJ) in patients with head and neck squamous cell carcinoma (HNSCC), focusing on jaw-related dose–volume histogram (DVH) parameters. Methods We retrospectively reviewed the medical records of 616 patients with HNSCC treated with curative-intent or postoperative radiation therapy (RT) during 2008–2018. Patient-related (age, sex, history of smoking or alcohol use, diabetes mellitus, performance status, pre-RT dental evaluation, pre- or post-RT tooth extraction), tumor-related (primary tumor site, T-stage, nodal status), and treatment-related (pre-RT surgery, pre-RT mandible surgery, induction or concurrent chemotherapy, RT technique) variables and DVH parameters (relative volumes of the jaw exposed to doses of 10 Gy–70 Gy [V10–70]) were investigated and compared between patients with and without ORNJ. The Mann–Whitney U test was used to compare RT dose parameters. Univariate and multivariate Cox regression analyses were used to assess factors associated with ORNJ development. Kaplan–Meier analyses were performed for cumulative ORNJ incidence estimation. Results Forty-six patients (7.5%) developed ORNJ. The median follow-up duration was 40 (range 3–145) months. The median time to ORNJ development was 27 (range 2–127) months. DVH analysis revealed that V30–V70 values were significantly higher in patients with than in those without ORNJ. In univariate analyses, primary tumor site, pre-RT mandible surgery, post-RT tooth extraction, and V60 > 14% were identified as important factors. In multivariate analyses, V60 > 14% (p = 0.0065) and primary tumor site (p = 0.0059) remained significant. The 3-year cumulative ORNJ incidence rates were 2.5% and 8.6% in patients with V60 ≤ 14% and > 14%, respectively (p p Conclusions V60 > 14% and oropharyngeal or oral cancer were found to be independent risk factors for ORNJ. These findings might be useful to minimize ORNJ incidence in HNSCC treated with curative RT.

We encountered a case of blow-out type coronary perforation at the calcified stenosis of left anterior descending artery. First, we started immediate balloon tamponade through the initial guiding catheter (GC) with a GuideLiner® catheter. Next, we introduced a second GC with a GuideLiner® catheter and successfully deployed a covered stent. Two sets of the GC with GuideLiner® catheter facilitated us to simultaneously perform temporary hemostasis with balloon tamponade and rapid delivery of a covered stent. To alternately manipulate the GuideLiner® catheters, back and forth with seesaw-like motion enabled us to minimize the interruption of balloon tamponade.

This study aimed to evaluate the efficacy of stereotactic body radiotherapy (SBRT) compared with three-dimensional conformal radiotherapy (3DCRT). Forty-three patients with portal vein tumor thrombosis (PVTT)/inferior vena cava tumor thrombosis (IVCTT) treated with SBRT (27 with CyberKnife (CK) and 16 with TrueBeam (TB)) from April 2013 to December 2014, and 54 treated with 3DCRT from June 2008 to March 2013 were evaluated. Dosimetric parameters, response to radiotherapy (RT) and survival outcomes were compared in total SBRT vs. 3DCRT, CK vs. 3DCRT and TB vs. 3DCRT, respectively. The median biologically effective dose 10 (BED10) values in total SBRT, CK, TB and 3DCRT were 73.4 Gy10, 75.0 Gy10, 60.5 Gy10 and 58.5 Gy10, respectively (P < 0.001 in total SBRT vs. 3DCRT, P < 0.001 in CK vs. 3DCRT, P = 0.004 in TB vs. 3DCRT). The tumor response rates were 67%, 70%, 62% and 46%, respectively (P = 0.04, P = 0.04, P = 0.25). The 1-year overall survival rates were 49.3%, 56.7%, 38.1% and 29.3%, respectively (P = 0.02, P = 0.02, P = 0.30), and the 1-year local progression rates were 20.4%, 21.9%, 18.8% and 43.6%, respectively (P = 0.01, P = 0.04, P = 0.10). The use of SBRT made it possible to achieve a higher BED10 compared with the use of 3DCRT. Improvements in local control and survival were achieved in the CK group and the total SBRT group. Our results suggest that SBRT may have the potential to be the standard RT technique for the treatment of PVTT/IVCTT.

To evaluate the efficacy and toxicity of hypofractionated stereotactic radiotherapy (HSRT) for brain metastases (BMs) from lung cancer, and to explore prognostic factors associated with local control (LC) and indication. We evaluated patients who were treated with linac-based HSRT for BMs from lung cancer. Lesions treated with stereotactic radiosurgery (SRS) in the same patients during the same periods were analysed and compared with HSRT in terms of LC or toxicity. There were 53 patients with 214 lesions selected for this analysis (HSRT: 76 lesions, SRS: 138 lesions). For HSRT, the median prescribed dose was 35 Gy in 5 fractions. The 1‑year LC rate was 83.6 % in HSRT; on multivariate analysis, a planning target volume (PTV) of

Aim To evaluate the treatment results of radiotherapy (RT) in children and adults with brainstem gliomas (BSGs) and review the previous literature. Methods Thirty patients (14 children, 16 adults) with BSG treated using RT were retrospectively evaluated. The median ages of the children and adults were 8 years (range: 2–16 years) and 49 years (range: 19–75 years), respectively. A histological diagnosis was obtained in 11 patients. The median total radiation dose was 56 Gy (range: 50–70 Gy) with a single fraction size of 1.8–2.0 Gy. Temozolomide was administered concurrently with RT in 14 patients. Results Tumor progression after RT occurred in 26 patients (14 children and 12 adults). Four adults survived without tumor progression. The median survival times for children and adults were 8.5 and 39 months, respectively. The 1-, 2- and 3-year overall survival rates for children/adults were 29%/75%, 14%/68% and 0%/53%, respectively (P = 0.001), and the 1-, 2- and 3-year progression-free survival rates for children/adults were 14%/69%, 0%/49% and 0%/35%, respectively (P < 0.001). Grade 3 or higher acute and late toxicities did not occur. Conclusion In this study, the prognosis of children with BSGs was considerably poorer than that of adults, and our results are consistent with those of previous studies. Efforts should be made to improve the survival outcomes of patients with BSGs, especially children.

A 77-year-old Japanese woman underwent bioprosthetic aortic valve replacement (AVR) and the Maze procedure for severe aortic valve disease and paroxysmal atrial fibrillation (AF), and one year after the AVR, she also underwent a permanent pacemaker implantation for sick sinus syndrome. At two postoperative years, a large mural mass happened to be detected in her left atrium on routine trans-thoracic echocardiography. The cardiac rhythm records produced by the implanted pacemaker demonstrated the recurrence of AF. As anticoagulant therapy was not effective at reducing the size of the mass, surgery was performed and organized thrombus was detected on the ablation line made at the Maze procedure.

Objectives This study aimed to investigate the practical usefulness of dual lumen catheter-facilitated reverse wire technique. Background We sometimes encounter difficulty in introducing a guidewire to the highly angulated side branch. In those cases, the reverse wire technique is considered as a last resort to overcome the situation. Methods Between January 2013 and June 2015, we performed the reverse wire technique for guidewire crossing into an extremely angulated side branch in consecutive seven cases with true bifurcated lesions. We retrospectively evaluated patients’ backgrounds, lesion characteristics, and details of the percutaneous coronary intervention (PCI) procedures. Results Three interventional cardiologists with various levels of experience in coronary intervention performed this technique. A polymer-jacket hydrophilic-coated guidewire was used for the reverse wire system excluding in one case, and we adopted a sharp curve for the tip shape in all cases. After crossing the reverse wire into a highly angulated side branch, we usually deliver a flexible micro catheter over the guidewire for the purpose of guidewire exchange. We deployed a stent in the side branch in three cases. We successfully performed all PCI procedures without any complications and no major adverse cardiac event was observed during hospitalization. Conclusions We could safely and effectively perform the reverse wire technique for guidewire crossing into a markedly angulated side branch. We recommend a polymer-jacket hydrophilic-coated guidewire with a sharp curve in the tip shape for this technique. All interventional cardiologists should acquire knowledge and skills regarding this guidewire manipulation technique. (J Interven Cardiol 2015;28:544–550)

Objective Maternal high-fat diet (HFD) has been shown to promote the development of insulin resistance (IR) in adult offspring; however, the underlying mechanisms remain unclear. Methods Eight-week-old female wild-type mice (C57BL/6) were fed either an HFD or a normal diet (ND), one week prior to mating, and the diet was continued throughout gestation and lactation. Eight-week-old male offspring of both groups were fed an HFD for 8 weeks. Results Offspring of HFD-fed dams (O-HFD) exhibited significantly impaired insulin sensitivity compared with the offspring of ND-fed dams (O-ND). The adipocyte size of the eWAT increased significantly in O-HFD and was accompanied by abundant crown-like structures (CLSs), as well as a higher concentration of interleukin 1β (IL-1β) in the eWAT. Treatment with an inflammasome inhibitor, MCC950, completely abrogated the enhanced IR in O-HFD. However, ex vivo caspase-1 activity in eWAT revealed no difference between the two groups. In contrast, noncanonical inflammasome activation of caspase-11 was significantly augmented in O-HFD compared with O-ND, suggesting that membrane pore formation, but not cleavage of pro-IL-1β by caspase-1, is augmented in O-HFD. To examine the membrane pore formation, we performed metabolic activation of bone marrow-derived macrophages (BMDMs). The percentage of pore formation assessed by ethidium bromide staining was significantly higher in BMDMs of O-HFD, accompanied by an enhanced active caspase-11 expression. Consistently, the concentration of IL-1β in culture supernatants was significantly higher in the BMDMs from O-HFD than those from O-ND. Conclusions These findings demonstrate that maternal HFD exaggerates diet-induced IR in adult offspring by enhancing noncanonical caspase-11-mediated inflammasome activation., Highlights • Maternal HFD increases the vulnerability to HFD-induced IR in adult offspring. • Maternal HFD augments inflammasome activation in eWAT in adult offspring. • Treatment with an inflammasome inhibitor abrogates IR in offspring of HFD-fed dam. • Maternal HFD augments the noncanonical inflammasome activation pathway of caspase-11. • Maternal HFD augments IL-1β release from BMDMs by enhancing membrane pore formation.

In practical settings of percutaneous coronary intervention (PCI), we sometimes encounter difficulty in introducing a guidewire (GW) to the markedly angulated side branch (SB), and the reverse wire technique is considered as a last resort to overcome such a situation. We analyzed 12 cases that underwent PCI with dual-lumen microcatheter-facilitated reverse wire technique between January 2013 and July 2016. We retrospectively investigated the lesion's characteristics and the details of the PCI procedures, and discussed tips about the use of this technique. The SB that exhibits both a smaller take-off angle and a larger carina angle is considered to be the most suitable candidate for this technique. The first step of this technique involves the delivery of the reverse wire system to the target bifurcation. However, most cases exhibit significant stenosis proximal to the bifurcation, which often hampers the delivery of the reverse wire system. Because the sharply curved reverse wire system is easier to pass the stenosis as compared to the roundly curved system, we recommend a sharp curve should be adopted for this technique. On the other hand, it is sure that device delivery is much easier on the GW with a round curve as compared to that with a sharp curve. Therefore, it is important to modify the details of this procedure on a case-by-case basis according to the lesion's characteristics.

A 74-year-old woman underwent percutaneous coronary intervention (PCI) for a severe stenotic lesion in the left anterior descending coronary artery. We deployed a SYNERGY drug-eluting stent (Boston Scientific, Natick, Massachusetts) there over a Sion blue guidewire through the diagonal branch ([

The prognosis of patients who have hepatocellular carcinoma (HCC) associated with inferior vena cava tumor thrombus (IVCTT) is very poor, and effective treatment modalities are extremely limited. The objective of this study was to determine the therapeutic efficacy of particle radiotherapy for HCC with IVCTT. Between June 2001 and January 2009, 16 evaluable patients who had HCC with IVCTT were treated with particle radiotherapy. They were divided into 2 groups: 6 were treated with curative intent; 10 with palliative intent. The local tumor control rates, overall survival rates, and toxicities were evaluated. All tumors treated with particle radiotherapy remained controlled without local recurrence at the last follow-up. The overall survival rates for the 16 patients at 1 and 3 years were 61.1 and 36.7%, respectively. We observed a significant difference in the survival rates according to treatment policy. The median survival time was 25.4 months for patients treated with curative intent and 7.7 months for those treated with palliative intent. The one-year survival rates were 100.0 and 33.3%, respectively. No Grade 3 or higher treatment-related toxicities were observed. Particle radiotherapy is thought to be potentially effective and safe for HCC with IVCTT. Considering the current lack of effective and less-invasive local therapy for HCC with IVCTT, particle radiotherapy may therefore be an attractive new therapeutic approach for this type of HCC.

BACKGROUND: The objective of this study was to evaluate the clinical outcome of proton and carbon ion therapy for hepatocellular carcinoma (HCC). METHODS: In total, 343 consecutive patients with 386 tumors, including 242 patients (with 278 tumors) who received proton therapy and 101 patients (with 108 tumors) who received carbon ion therapy, were treated on 8 different protocols of proton therapy (52.8-84.0 gray equivalents [GyE] in 4-38 fractions) and on 4 different protocols of carbon ion therapy (52.8-76.0 GyE in 4-20 fractions). RESULTS: The 5-year local control and overall survival rates for all patients were 90.8% and 38.2%, respectively. Regarding proton and carbon ion therapy, the 5-year local control rates were 90.2% and 93%, respectively, and the 5-year overall survival rates were 38% and 36.3%, respectively. These rates did not differ significantly between the 2 therapies. Univariate analysis identified tumor size as an independent risk factor for local recurrence in proton therapy, carbon ion therapy, and in all patients. Multivariate analysis identified tumor size as the only independent risk factor for local recurrence in proton therapy and in all patients. Child-Pugh classification was the only independent risk factor for overall survival in proton therapy, in carbon ion therapy, and in all patients according to both univariate and multivariate analyses. No patients died of treatment-related toxicities. CONCLUSIONS: Proton and carbon ion therapies for HCC were comparable in terms of local control and overall survival rates. These therapies may represent innovative alternatives to conventional local therapies for HCC. Cancer 2011;. © 2011 American Cancer Society.

The present study aimed to investigate the effect of heterogeneity correction (HC) on dosimetric parameters in 3-dimensional conformal radiotherapy planning for patients with thoracic esophageal cancer. We retrospectively analyzed 20 patients. Two treatment plans were generated for each patient using a superposition algorithm on the Xio radiotherapy planning system. The first plan was calculated without HC. The second was a new plan calculated with HC, using identical beam geometries and maintaining the same number of monitor units as the first. With regard to the planning target volume (PTV), the overall mean differences in the prescription dose, maximum dose, mean dose, and dose that covers 95% of the PTV between the first and second plans were 1.10 Gy (1.8%), 1.35 Gy (2.2%), 1.10 Gy (1.9%), and 0.56 Gy (1.0%), respectively. With regard to parameters related to the organs at risk (OARs), the mean differences in the absolute percentages of lung volume receiving greater than 5, 10, 20, and 30 Gy (lung V 5 , V 10 , V 20 , and V 30 ) between the first and second plans were 7.1%, 2.7%, 0.4%, and 0.5%, respectively. These results suggest that HC might have a more pronounced effect on the percentages of lung volume receiving lower doses ( e.g., V 5 and V 10 ) than on the dosimetric parameters related to the PTV and other OARs.

Purpose To examine the preliminary survival outcomes and treatment-related toxicity for elderly patients with cervical cancer treated with radiotherapy (RT). Methods Forty patients ≥75 years old with cervical cancer who were treated with RT were evaluated. Of these 40 patients, 25 were classified as FIGO stage I or II and 15 as stage III or IVA. Thirty-five patients were treated with radical RT (RRT), and five were treated with surgery plus adjuvant RT (S + ART). External beam radiotherapy combined with high-dose-rate intracavitary brachytherapy was performed on 31 patients who were treated with RRT and on 2 patients who were treated with S + ART because of positive vaginal surgical margins. The patients’ median age was 78 years (range 75–89 years). Concurrent chemotherapy (CCT) was performed on five patients (RRT: 3, S + ART: 2). Results The median follow-up period was 20 months (range 1–85 months). Only one patient could not complete RT. The 3-year overall and disease-specific survival (OS and DSS) rates for all patients were 58 and 80%, respectively. Five patients experienced Grade 3 acute toxicity; two were treated with RRT (2/35), and three were treated with S + ART (3/5, 2 of them with CCT). Two patients experienced Grade 3 late toxicity; one was treated with RRT (1/35, with CCT) and the other was treated with S + ART (1/5). No Grade 4 or higher toxicity was experienced. Conclusions RRT for elderly patients with cervical cancer is generally effective and safe, but severe toxicity may occur with more aggressive treatment modalities.

Purpose: To assess the incident rates of vision loss (VL; based on counting fingers or more severe) caused by radiation-induced optic neuropathy (RION) after particle therapy for tumors adjacent to optic nerves (ONs), and to evaluate factors that may contribute to VL. Methods and Materials: From August 2001 to August 2006, 104 patients with head-and-neck or skull-base tumors adjacent to ONs were treated with carbon ion or proton radiotherapy. Among them, 145 ONs of 75 patients were irradiated and followed for greater than 12 months. The incident rate of VL and the prognostic factors for occurrence of VL were evaluated. The late effects of carbon ion and proton beams were compared on the basis of a biologically effective dose at alpha/beta = 3 gray equivalent (GyE{sub 3}). Results: Eight patients (11%) experienced VL resulting from RION. The onset of VL ranged from 17 to 58 months. The median follow-up was 25 months. No significant difference was observed between the carbon ion and proton beam treatment groups. On univariate analysis, age (>60 years), diabetes mellitus, and maximum dose to the ON (>110 GyE{sub 3}) were significant, whereas on multivariate analysis only diabetes mellitus was found to be significant for VL. Conclusions:more » The time to the onset of VL was highly variable. There was no statistically significant difference between carbon ion and proton beam treatments over the follow-up period. Based on multivariate analysis, diabetes mellitus correlated with the occurrence of VL. A larger study with longer follow-up is warranted.« less

Proton therapy is a sophisticated treatment modality for prostate cancer. We investigated how physiologic factors affected the distribution of autoactivation as detected by positron emission tomography (PET) after proton beam therapy.Autoactivation was evaluated in 59 patients treated with a 210-MeV proton beam. Data acquisition for autoactivation by PET started 5 minutes after proton irradiation to assess activation. In the first 29 patients, five regions of interest were evaluated: planning target volume (PTV) center, urinary bladder inside the PTV, urinary bladder outside the PTV, rectum (outside the PTV), and contralateral femoral bone head (outside the PTV). In the remaining 30 patients, urine activity was measured directly. In a phantom study autoactivation and its diffusion after proton beam irradiation were evaluated with water or an ice block.Mean activities calculated by use of PET were 629.3 Bq in the PTV center, 555.6 Bq in the urinary bladder inside the PTV, 332.5 Bq in the urinary bladder outside the PTV, 88.4 Bq in the rectum, and 23.7 Bq in the femoral bone head (p0.001). Mean urine activity was 679.4 Bq, recorded 10 minutes after therapy completion, and the half-life for urine autoactivation was 4.5 minutes.Urine is a major diffusion mediator of autoactivation after proton beam therapy. Our results indicate that physiologic factors can influence PET images of autoactivation in the context of proton beam therapy verification.

Purpose: To investigate the incidence and influencing factors of acute genitourinary (GU) and gastrointestinal morbidities in patients with prostate cancer treated with proton therapy. Methods and Materials: A total of 287 patients with histologically proven Stage cT1-T4N0M0 prostate cancer were treated with proton therapy between 2003 and 2004. Of these, 204 (71%) received neoadjuvant androgen suppression therapy. The patients were treated with 190–230-MeV protons using lateral-opposed techniques to a dose of 74 GyE. Dose–volume histogram analyses were performed. The incidence of acute morbidity was evaluated using the National Cancer Institute Common Toxicity Criteria, version 2.0. Clinical factors, including age, clinical target volume, initial prostate-specific antigen level, T stage, presence of diabetes mellitus, and the use of androgen suppression therapy, were investigated to determine whether those affected the incidence of acute GU morbidity. Results: None developed Grade 2 or higher acute gastrointestinal morbidity. In contrast, 111 (39%) and 4 (1%) patients experienced acute Grade 2 and Grade 3 GU morbidities, respectively. However, 87% of the patients were successfully relieved by the administration of a selective α-1 blocker. Multivariate analysis showed that a larger clinical target volume ( p = 0.001) and the use of androgen suppression therapy ( p = 0.017) were significant factors for the prediction of acute Grade 2-3 GU morbidity. Conclusion: In our experience with proton therapy, a low incidence of acute gastrointestinal morbidity was observed. In contrast, the incidence of acute GU morbidity was similar to that in other reports of photon radiotherapy. Additional follow-up is warranted to elucidate the long-term safety and efficacy of proton therapy for prostate cancer.

Objective This retrospective study analyzed the oncological and treatment outcomes of the patients with T1-T2N0 glottic cancer, who were treated with radiotherapy as initial treatment and salvaged by conservative surgery for radiation failure. Methods Between May 1999 and December 2010, 115 patients with glottic laryngeal cancer were treated at Kobe University Hospital. At presentation, 54 patients had stage T1a disease, 26 had stage T1b disease and 35 had stage T2 disease. Seventy-nine patients were treated with conventional radiotherapy and 36 patients were treated with hyperfractionated radiotherapy as initial treatment. Results Median duration of follow-up was 61 months. Five-year local control rates of radiotherapy were 92% in T1a, 83% in T1b and 86% in T2. Of 12 patients who developed local recurrence, larynx was successfully preserved in 3 patients by laryngomicrosurgery, 7 patients by vertical partial laryngectomy and one patient by subtotal laryngectomy. Ultimate 5-year laryngeal preservation rate and local control rate of all cases were 99 and 100%, respectively. Conclusions Present results suggest that initial treatment with radiotherapy salvaged by organ preservation surgery is an effective strategy for laryngeal preservation in the treatment of T1-T2N0 glottic laryngeal cancer.

Introduction: In practical settings of endovascular treatment,wesometimes encounter difficulties in treating lesions with massive thrombi, which may cause distal thromboembolism. Case Presentation: We encountered a case of severe critical limb ischemia involving in-stent iliac occlusion with massive thrombi. We had to overcome the critical issue of how to treat the massive thrombi in the iliac artery while avoiding thromboembolism. Therefore, we devised a very simple but possibly very useful protection system without any special devices based on the concept of the Optimo® balloon-tipped occlusion catheter. Conclusions: Although various endovascular treatment (EVT) devices and techniques have since been developed, little tips and tricks during EVT procedures are sometimes markedly useful.

The aim of our study was to analyze changes over time in the characteristics, treatment, and outcome of patients with primary central nervous system lymphoma (PCNSL). Data on 315 patients with histologically proven PCNSL undergoing radiotherapy between 2005 and 2009 were collected from 20 Japanese institutions using a questionnaire. These data were then compared with data on 273 patients treated during the period 1995–2004 and those on 466 patients treated during the period 1985–1994. In terms of patient and tumor characteristics, we found a significant increase in mean patient age in the 2005–2009 period compared to the 1985–2004 period (63 vs. 58–59 years, respectively) and in the percentage of patients with better performance status (PS) during the 2005–2009 period compared with the 1995–2004 period (World Health Organization PS 0–2: 73 vs. 65 %, respectively). Regarding treatment, relative to the 1995–2004 period, significant changes in the 2005–2009 period were (1) decreased rate of attempting tumor resection (23 vs. 44 %); (2) increased use of chemotherapy (78 vs. 68 %), and (3) increased use of methotrexate (MTX)-containing regimens (84 vs. 53 %). The 5-year overall survival rates were 15.3, 30.1, and 36.5 % for patients seen during the 1985–1994, 1995–2004, and 2005–2009 periods, respectively, but relapse-free survival did not improve between the 1995–2004 and 2005–2009 periods (26.7 vs. 25.7 % at 5 years, respectively). Patients receiving MTX-containing chemotherapy had 5-year survival rates of 19, 50, and 44 % during these three periods, respectively. Although patient backgrounds differed among the study periods, recent trends were a high patient age, better PS, avoidance of extensive tumor resection, more frequent use of chemotherapy, and improved survival. The recent improvement in survival may be due to improvements in second-line treatment and supportive care.

Purpose To evaluate the long-term treatment outcome and disease behavior of primary ocular adnexal MALT (mucosa-associated lymphoid tissue) lymphoma (POAML) after treatment with radiotherapy. Methods and Materials Seventy-eight patients (42 male, 36 female) diagnosed with stage I POAML between 1991 and 2010 at Kobe University Hospital were included. The median age was 60 years (range, 22–85 years). The median radiation dose administered was 30.6 Gy. Rituximab-based targeted therapy and/or chemotherapy was performed in 20 patients (25.6%). Local control (LC), recurrence-free survival (RFS), and overall survival (OS) rates were calculated using the Kaplan-Meier method. Results The median follow-up duration was 66 months. Major tumor sites were conjunctiva in 37 patients (47.4%), orbita in 29 (37.2%), and lacrimal glands in 12 (15.4%). The 5- and 10-year OS rates were 98.1% and 95.3%, respectively. The 5- and 10-year LC rates were both 100%, and the 5- and 10-year RFS rates were 88.5% and 75.9%, respectively. Patients treated with a combination of radiotherapy and targeted therapy and/or chemotherapy had a trend for a better RFS compared with those treated with radiotherapy alone ( p = 0.114). None developed greater than Grade 2 acute morbidity. There were 14 patients who experienced Grade 2 morbidities (cataract: 14; retinal disorders: 7; dry eye: 3), 23 patients who had Grade 3 morbidities (cataract: 23; dry eye: 1), and 1 patient who had Grade 4 glaucoma. Conclusions Radiotherapy for POAML was shown to be highly effective and safe for LC and OS on the basis of long-term observation. The absence of systemic relapse in patients with combined-modality treatment suggests that lower doses of radiation combined with targeted therapy may be worth further study.

HIBMC is the world’s first facility to be able to use both proton (PRT) and carbon‐ion radiotherapy (CiRT). The medically dedicated synchrotron can accelerate protons up to 230 MeV and carbon ions up to 320 MeV. From April 2001 to March 2010, the facility treated 3275 patients, with 2487 patients treated using PRT and 788 using CiRT. Particle radiotherapy was delivered to patients suffering from malignant tumors originating in the head and neck (502 patients), lungs (330), liver (539), prostate (1283), and the bone & soft tissue (130). The clinical results are as follows: (1) H & N tumors: The 2‐year overall survival (OS) rates of patients with olfactory neuroblastoma, mucoepidermoid cancer, adenoid cystic cancer, adenocarcinoma, squamous cell carcinoma, and malignant melanoma was 100%, 86%, 78%, 78%, 66%, and 62%, respectively. (2) Lung cancer: For all 80 patients, the 3‐year OS rate was 75% (Stage IA: 74%; Stage IB: 76%) and local control (LC) rate was 82% (IA: 87%; IB: 77%). Grade 3 pulmonary toxicity was observed in only 1 patient. These results are comparable to those obtained by surgery, and indicate proton therapy and carbon‐ion therapy are safe and effective for stage I lung cancer. (3) Liver cancer: The 5‐year LC rate for 429 tumor patient was 90%, and the 5‐year OS rate for 364 patients was 38%. These results seem equivalent to those obtained by surgery or radio‐frequency ablation. (4) Prostate cancer: In 290 patients treated by proton radiotherapy, five patients died from other disease in the median follow‐up period of 62 months. Biochemical disease‐free survival and OS rate at 5 years was 88.2% and 96.5%, respectively. Our proton radiotherapy showed excellent OS and biochemical disease‐free survival rates with minimum late morbidities. PRT VS CiRT: From our retrospective analysis, it seems that there is no significant difference in the LC and OS rate in H&N, lung and liver cancer between PRT and CiRT.

BACKGROUND: A study was undertaken to evaluate the clinical outcome of particle therapy for stage I nonsmall cell lung cancer (NSCLC). METHODS: From April 2003 to April 2007, 80 patients with stage I NSCLC were treated with proton therapy or carbon-ion therapy (57 with proton therapy and 23 with carbon-ion therapy) using 3 treatment protocols. In the first protocol, 80 gray equivalents (GyE) of proton therapy was given in 20 fractions, and the second proton therapy protocol used 60 GyE in 10 fractions. For carbon-ion therapy, 52.8 GyE was given in 4 fractions. After achieving promising preliminary results for the first protocol, the authors started to use the second proton therapy protocol to shorten the overall treatment time. Carbon-ion therapy was started in 2005, and thereafter, both proton and carbon-ion therapy plans were made for each patient, and the 1 that appeared superior was adopted. Patient age ranged from 48 to 89 years (median, 76 years). Thirty-seven patients were medically inoperable, and 43 refused surgery. Forty-two patients had T1 tumors, and 38 had T2 tumors. RESULTS: The median follow-up period for living patients was 35.5 months. For all 80 patients, the 3-year overall survival, cause-specific survival, and local control rates were 75% (IA: 74%; IB: 76%), 86% (IA: 84%; IB: 88%), and 82% (IA: 87%; IB: 77%), respectively. There were no significant differences in treatment results among the 3 protocols. Grade 3 pulmonary toxicity was observed in only 1 patient. CONCLUSIONS: Proton therapy and carbon-ion therapy are safe and effective for stage I NSCLC. Further investigation of particle therapy for stage I NSCLC is warranted. Cancer 2010. © 2010 American Cancer Society.

The proton radiotherapy (PRT) has been spreading, since 1990 when 250 MeV proton beams with rotation gantry was developed for medical use. On the other hand, carbon‐ion radiotherapy (CRT) that has both physical and biological features is available at 4 facilities in the world. HIBMC is the only facility to be able to use both particles. From Apr 2001 to Dec 2008, 2486 patients were treated with PRT in 2030 patients or with CRT in 456. Treatment to the Head and Neck (H&N: in 405 patients), the lung (245), the liver (371), and the prostatic carcinoma (1059) was a major subject. The 2‐year local control rates is 72% in H&N (n = 163, T1:9, T2:18, T3:36, T4:79, malignant melanoma 48, adenoid cystic carcinoma 35, squamous cell carcinoma (SCC) 32, adenocarcinoma 14, others 34), 88% in lung (n = 116, T1:59, T2:42, T3:4, T4:6, SCC 30, adenocarcinoma 59, others 27), and 89% in liver cancer (n = 153, Proton: 130, carbon: 23). Biochemical disease free 3‐year survival of 291 prostate cancer is 100% in 9 patients with ...

Purpose To assess the incidence of early delayed or late morbidity of the brain after particle therapy for skull base tumors and head-and-neck cancers. Methods and Materials Between May 2001 and December 2005, 59 patients with cancerous invasion of the skull base were treated with proton or carbon ion therapy at the Hyogo Ion Beam Medical Center. Adverse events were assessed according to the magnetic resonance imaging findings (late effects of normal tissue-subjective, objective, management, analytic [LENT-SOMA]) and symptoms (Common Terminology Criteria for Adverse Events [CTCAE], version 3.0). Dose–volume histograms were used to analyze the relationship between the dose and volume of the irradiated brain and the occurrence of brain injury. The median follow-up time was 33 months. Results Of the 48 patients treated with proton therapy and 11 patients treated with carbon ion radiotherapy, 8 (17%) and 7 (64%), respectively, developed radiation-induced brain changes (RIBCs) on magnetic resonance imaging (LENT-SOMA Grade 1-3). Four patients (7%) had some clinical symptoms, such as vertigo and headache (CTCAE Grade 2) or epilepsy (CTCAE Grade 3). The actuarial occurrence rate of RIBCs at 2 and 3 years was 20% and 39%, respectively, with a significant difference in the incidence between the proton and carbon ion radiotherapy groups. The dose–volume histogram analyses revealed significant differences between the brain lobes with and without RIBCs in the actuarial volume of brain lobes receiving high doses. Conclusion Particle therapies produced minimal symptomatic brain toxicities, but sequential evaluation with magnetic resonance imaging detected a greater incidence of RIBCs. Significant differences were observed in the irradiated brain volume between the brain lobes with and without RIBCs.