白井 克幸

近年、口腔癌を含む頭頸部扁平上皮癌の放射線治療においてIMRTが普及し、口内乾燥などの副作用が少ない効果的な治療法として確立されてきた。根治照射および術後照射ともにIMRTは有効であり、本稿にて概説する。(著者抄録)

耳下腺癌は多彩な病理組織像を呈し、しばしば治療に難渋する。治療の第一選択は手術だが、切除不能例や顔面神経麻痺などの合併症の問題がある。当科では耳下腺癌症例の一部に重粒子線治療を行っている。重粒子線は強い殺細胞効果と優れた線量分布を持ち、重要臓器の隣接する頭頸部領域で従来の放射線抵抗性の高い悪性腫瘍に有用とされている。今回、2011年8月から2016年8月までに当科で初期治療として手術治療を施行した22症例(9例早期癌、13例進行癌)と重粒子線治療を行った11症例(2例早期癌、9例進行癌)の計33症例について比較検討を行った。その結果、無増悪生存期間および全生存期間は、手術群と重粒子線治療群で有意差を認めなかった(無増悪生存期間、p=0.147;全生存期間、p=0.580)。重粒子線治療群では、1例で永続的な顔面神経麻痺を治療後に認めたが、治療前に麻痺を認めた4例中3例で麻痺の部分改善を認めた。一方、重粒子線治療に特有の有害事象として全例に放射線皮膚炎(Grade 2以下)、また9例に外耳道炎、5例に滲出性中耳炎、1例に脳障害を認めた。進行癌の比率が多いにもかかわらず、重粒子線治療は手術療法とほぼ同等の有効性が示唆され、有害事象では手術と異なる特徴が認められた。(著者抄録)

Background/Aim: The aim of this study was to assess the feasibility and safety of hypofractionated carbon-ion radiotherapy (C-ion RT) in patients with stage III non-small cell lung cancer (NSCLC). Patients and Methods: Patients with untreated, histologically proven, unresectable stage III NSCLC and not candidates for chemotherapy were included in this study. C-ion RT was planned and administered with 4 Gy (relative biological effectiveness (RBE)) in daily fractions for a total dose of 64 Gy (RBE) without combined chemotherapy. Dose-limiting toxicity (DLT) was defined as suspension of C-ion RT treatment for 2 weeks due to ≥ grade 2 pneumonitis, or any other ≥ grade 3 adverse event, or as any ≥ grade 4 adverse event within 3 months from the start of treatment. Results: Six patients were treated between June 2013 and December 2014. The planned full dose of C-ion RT (64 Gy (RBE)) was completed in all patients. No patient developed DLT, and no patient experienced toxicities of ≥grade 3 severity. The overall response rate was 100%, and local tumor control was achieved in all patients during the survival period. Conclusion: Hypofractionated C-ion RT of patients with stage III NSCLC was feasible and well tolerated. Although the number of patients in this study was small, the results support further investigations to confirm the long-term therapeutic efficacy of this treatment.

To evaluate the efficacy and safety of carbon-ion radiotherapy for non-squamous cell carcinoma of the head and neck, 35 patients were enrolled in this prospective study. The primary end-point was the 3-year local control rate, and the secondary end-points included the 3-year overall survival rate and adverse events. Acute and late adverse events were evaluated according to the Common Terminology Criteria for Adverse Events, version 4.0. The median follow-up time for all patients was 39months. Thirty-two and three patients received 64.0Gy (relative biological effectiveness) and 57.6Gy (relative biological effectiveness) in 16 fractions, respectively. Adenoid cystic carcinoma was dominant (60%). Four patients had local recurrence and five patients died. The 3-year local control and overall survival rates were 93% and 88%, respectively. Acute grade 2-3 radiation mucositis (65%) and dermatitis (31%) was common, which improved immediately with conservative therapy. Late mucositis of grade 2, grade 3, and grade 4 were observed in 11, one, and no patients, respectively. There were no adverse events of grade 5. Carbon-ion radiotherapy achieved excellent local control and overall survival rates for non-squamous cell carcinoma. However, the late mucosal adverse events were not rare, and meticulous treatment planning is required. Trial registration no. UMIN000007886.

To evaluate the efficacy and safety of carbon-ion radiotherapy for non-squamous cell carcinoma of the head and neck, 35 patients were enrolled in this prospective study. The primary end-point was the 3-year local control rate, and the secondary end-points included the 3-year overall survival rate and adverse events. Acute and late adverse events were evaluated according to the Common Terminology Criteria for Adverse Events, version 4.0. The median follow-up time for all patients was 39 months. Thirty-two and three patients received 64.0 Gy (relative biological effectiveness) and 57.6 Gy (relative biological effectiveness) in 16 fractions, respectively. Adenoid cystic carcinoma was dominant (60%). Four patients had local recurrence and five patients died. The 3-year local control and overall survival rates were 93% and 88%, respectively. Acute grade 2-3 radiation mucositis (65%) and dermatitis (31%) was common, which improved immediately with conservative therapy. Late mucositis of grade 2, grade 3, and grade 4 were observed in 11, one, and no patients, respectively. There were no adverse events of grade 5. Carbon-ion radiotherapy achieved excellent local control and overall survival rates for non-squamous cell carcinoma. However, the late mucosal adverse events were not rare, and meticulous treatment planning is required. Trial registration no. UMIN000007886.

Background and purpose: We aimed to evaluate the relationship between brainstem necrosis and dose volume histograms in patients with head and neck tumors after carbon-ion radiotherapy. Material and methods: We evaluated 85 patients with head and neck tumors who underwent carbon-ion radiotherapy and were followed-up for >= 12 months. Brainstem necrosis was evaluated using the Common Terminology Criteria for Adverse Events (version 4.0). Results: The median follow-up was 24 months, and four patients developed grade 1 brainstem necrosis, with 2-year and 3-year cumulative rates of 2.8% and 6.5%, respectively. Receiver operating characteristic curve analysis revealed the following significant cut-off values: a maximum brainstem dose of 48 Gy (relative biological effectiveness [RBE]), D1 cm(3) of 27 Gy (RBE), V40 Gy (RBE) of 0.1 cm(3), V30 Gy (RBE) of 0.7 cm(3), and V20 Gy (RBE) of 1.4 cm(3). Multivariate analysis revealed that V30 Gy (RBE) was most significantly associated with brainstem necrosis. The 2-year cumulative rates were 33% and 0% for V30 Gy (RBE) of >= 0.7 cm(3) and <0.7 cm(3), respectively (p < 0.001). Conclusions: The present study indicated that the dose constraints might help minimize brainstem necrosis after carbon-ion radiotherapy. (C) 2017 The Author(s). Published by Elsevier Ireland Ltd.

Background/Aim: To analyze the accuracy of patient positioning and dose distribution quality using a fiducial marker-matching technique in carbon-ion radiotherapy (C-ion RT) for stage I lung cancer. Patients and Methods: Thirteen patients with 26 fiducial markers and 104 radiation fields were examined. Change in the fiducial marker position coordinates from the gross tumor volume center (Delta m), and change in the water-equivalent path length of the chest wall (Delta WEL) were measured in each radiation field. Criterion for an acceptable change in dose distribution was defined as the percentage of D95 (% D95) at gross tumor volume greater than 90% of the prescribed dose. Results: Thirteen radiation fields (12.5%) were classified as unacceptable. Delta m and Delta WEL had significant negative correlations with % D95 and thus were significant factors related to unacceptable irradiation fields. Conclusion: Patient positioning using a fiducial marker-matching technique resulted in 12.5% of radiation fields demonstrating unacceptable degradation due to Delta m and Delta WEL.

This study aimed to evaluate the clinical outcomes of patients with mucoepidermoid carcinomas in the head and neck treated with carbon-ion radiotherapy. Data from 26 patients who underwent carbon-ion radiotherapy in four facilities were analyzed in this multi-institutional retrospective study: the Japan Carbon-ion Radiation Oncology Study Group. The median follow-up time was 34 months. One patient experienced local recurrence, and the 3-year local control rate was 95%. One patient developed lymph node recurrence and five developed distant metastases. The 3-year progression-free survival rate was 73%. Five patients died, two of mucoepidermoid carcinoma and three of intercurrent disease. The 3-year overall survival rate was 89%. Acute mucositis and dermatitis of grade 3 or higher were experienced by 19% and 8% of patients, respectively; these improved with conservative therapy. Late mucositis and osteonecrosis of jaw were observed in 12% and 23% of patients, respectively. The 3-year cumulative rate of any late adverse event of grade 3 or higher was 14%. None of the patients died of the acute or late adverse events. Carbon-ion radiotherapy was efficacious and safe for treating mucoepidermoid carcinoma in this multi-institutional retrospective study (registration no. UMIN000024473). We are currently undertaking a prospective multicenter study.

This study aimed to evaluate the clinical outcomes of patients with mucoepidermoid carcinomas in the head and neck treated with carbon-ion radiotherapy. Data from 26 patients who underwent carbon-ion radiotherapy in four facilities were analyzed in this multi-institutional retrospective study: the Japan Carbon-ion Radiation Oncology Study Group. The median follow-up time was 34 months. One patient experienced local recurrence, and the 3-year local control rate was 95%. One patient developed lymph node recurrence and five developed distant metastases. The 3-year progression-free survival rate was 73%. Five patients died, two of mucoepidermoid carcinoma and three of intercurrent disease. The 3-year overall survival rate was 89%. Acute mucositis and dermatitis of grade 3 or higher were experienced by 19% and 8% of patients, respectively these improved with conservative therapy. Late mucositis and osteonecrosis of jaw were observed in 12% and 23% of patients, respectively. The 3-year cumulative rate of any late adverse event of grade 3 or higher was 14%. None of the patients died of the acute or late adverse events. Carbon-ion radiotherapy was efficacious and safe for treating mucoepidermoid carcinoma in this multi-institutional retrospective study (registration no. UMIN000024473). We are currently undertaking a prospective multicenter study.

The present study (University Hospital Medical Information Network study no. UMIN000003797) aimed to evaluate whether the maximum standardized uptake value (SUVmax) of pretreatment F-18-fluorodeoxyglucose-positron emission tomography (FDG-PET) is prognostic factor for stage I non-small cell lung cancer (NSCLC) treated with carbon ion radiotherapy (C-ion RT). Patients treated between June 2010 and June 2013 at Gunma University Heavy Ion Medical Center (Maebashi, Japan) on a prospective protocol were included in the present study. Patients with T1a-b and T2a NSCLC were treated with C-ion RT at a dose of 52.8 Gy [relative biological effectiveness (RBE)] and 60.0 Gy (RBE), respectively, in four fractions. Prior to treatment, all patients underwent FDG-PET, in which the SUVmax of primary tumors was evaluated. Local control, progression-free survival (PFS), and overall survival (OS) were calculated. A total of 45 patients were analyzed and the median follow-up period was 28.9 months. The 2-year local control, PFS and OS rates for all patients were 93, 78 and 89%, respectively. The mean SUVmax of primary tumors was 5.5, and patients were divided into higher (>= 5.5) and lower (<5.5) SUVmax groups. The 2-year PFS rates were 61 and 89% for the higher and lower SUVmax groups, respectively (P=0.01), and the 2-year OS rates for the higher and lower SUVmax groups were 76 and 96%, respectively (P=0.01). The higher SUVmax group exhibited a significantly worse PFS and OS compared with the lower SUVmax group; however, the SUVmax was not associated with the local control rate. In total, 2 patients (4%) experienced grade 2 or 3 radiation pneumonitis, with their symptoms improved through conservative treatment. No patients experienced any grade 4 or 5 toxicities. The results of the present study indicate that pretreatment SUVmax is a prognostic indicator for outcomes in patients with stage I NSCLC treated with C-ion RT.

The safety and efficacy of carbon-ion radiotherapy for advanced non-small cell lung cancer have not been established. We evaluated the clinical outcomes and dose-volume histogram parameters of carbon-ion radiotherapy compared with photon therapy in T2b-4N0M0 non-small cell lung cancer. Twenty-three patients were treated with carbon-ion radiotherapy between May 2011 and December 2015. Seven, 14, and 2 patients had T2b, T3, and T4, respectively. The median age was 78 (range, 53-91) years, with 22 male patients. There were 12 adenocarcinomas, 8 squamous cell carcinomas, 1 non-small cell lung carcinoma, and 2 clinically diagnosed lung cancers. Eleven patients were operable, and 12 patients were inoperable. Most patients (91%) were treated with carbon-ion radiotherapy of 60.0 Gy relative biological effectiveness (RBE) in 4 fractions or 64.0 Gy (RBE) in 16 fractions. Local control and overall survival rates were calculated. Dose-volume histogram parameters of normal lung and tumor coverages were compared between carbon-ion radiotherapy and photon therapies, including three-dimensional conformal radiotherapy (3DCRT) and intensity-modulated radiotherapy (IMRT). The median follow-up of surviving patients was 25 months. Three patients experienced local recurrence, and the 2-year local control rate was 81%. During follow-up, 5 patients died of lung cancer, and 1 died of intercurrent disease. The 2-year overall survival rate was 70%. Operable patients had a better overall survival rate compared with inoperable patients (100% vs. 43%; P = 0.04). There was no grade >= 2 radiation pneumonitis. In dose-volume histogram analysis, carbon-ion radiotherapy had a significantly lower dose to normal lung and greater tumor coverage compared with photon therapies. Carbon-ion radiotherapy was effectively and safely performed for T2b-4N0M0 non-small cell lung cancer, and the dose distribution was superior compared with those for photon therapies. A Japanese multi-institutional study is ongoing to prospectively evaluate these patients and establish the use of carbon-ion radiotherapy.

Background: To assess the efficacy of concurrent chemoradiotherapy (CCRT) with daily low-dose cisplatin (CDDP) plus weekly docetaxel (DTX) for patients with T2N0 glottic cancer. Methods: Between January 2004 and December 2013, 62 treatment-naive patients with histologically proven T2N0 glottic cancer were treated with concurrent chemoradiotherapy. Radiation therapy (RT; 2 Gy daily fractions up to a total dose of 66 Gy) was administered in combination with daily low-dose CDDP (6 mg/m(2), five times a week), plus weekly DTX (10 mg/m(2)) for up to 4 weeks from the commencement of RT. Results: Median duration of follow-up was 70 months. The actuarial 3-year and 5-year overall survival rates were 95% and 93%. The 3-year and 5-year cause-specific survival rates were both 100%. The actuarial 3-year and 5-year local control rates were 94% and 94%, respectively. Hematologic toxicity (neutoropenia of severity >= Grade 3) was observed in 8% of the patients, and non-hematologic toxicity (radiation mucositis of severity >= Grade 3) developed in one patient (2%). Radiation dermatitis of severity >= Grade 3 and laryngeal necrosis developed in one patient. Conclusion: CCRT with weekly DTX and low-dose CDDP appears to be a practical and safe modality and is expected to improve local control.

Purpose: To evaluate robustness of dose distribution of carbon-ion radiation therapy (C-ion RT) in non-small cell lung cancer (NSCLC) and to identify factors affecting the dose distribution by simulated dose distribution. Methods and Materials: Eighty irradiation fields for delivery of C-ion RT were analyzed in 20 patients with stage I NSCLC. Computed tomography images were obtained twice before treatment initiation. Simulated dose distribution was reconstructed on computed tomography for confirmation under the same settings as actual treatment with respiratory gating and bony structure matching. Dose-volume histogram parameters, such as %D95 (percentage of D95 relative to the prescribed dose), were calculated. Patients with any field for which the %D95 of gross tumor volume (GTV) was below 90% were classified as unacceptable for treatment, and the optimal target margin for such cases was examined. Results: Five patients with a total of 8 fields (10% of total number of fields analyzed) were classified as unacceptable according to %D95 of GTV, although most patients showed no remarkable change in the dose-volume histogram parameters. Receiver operating characteristic curve analysis showed that tumor displacement and change in water-equivalent pathlength were significant predictive factors of unacceptable cases (P<.001 and P=.002, respectively). The main cause of degradation of the dose distribution was tumor displacement in 7 of the 8 unacceptable fields. A 6-mm planning target volume margin ensured a GTV %D95 of >90%, except in 1 extremely unacceptable field. Conclusions: According to this simulation analysis of C-ion RT for stage I NSCLC, a few fields were reported as unacceptable and required resetting of body position and reconfirmation. In addition, tumor displacement and change in water-equivalent

Background: Hypopharyngeal cancer is relatively rare disease and continues to have a poor prognosis. This study analyzed the efficacy and safety of radiotherapy for stage I-IVB hypopharyngeal cancer. Patients and Methods: Between 2000 and 2015, 72 patients were treated with definitive radiotherapy and 29 patients with stage IVA were treated with postoperative radiotherapy. Results: With definitive radiotherapy, the 3-year locoregional control rates for stage I-II, III, IVA, and IVB disease were 89%, 74%, 51% and 0%, respectively. The 3-year overall survival rates for patients with stage I-II, III, IVA and IVB disease were 84%, 89%, 55% and 15%, respectively. In patients with stage IVA disease treated with postoperative radiotherapy, 3-year locoregional control and overall survival rates were 83% and 75%, respectively, which were significantly better than those treated with definitive radiotherapy. Conclusion: Definitive radiotherapy was effective for stage I-III disease. Surgery and postoperative radiotherapy improved the survival rate of patients with stage IVA hypopharyngeal cancer.

The present study compared the dose-volume histograms of patients with Stage IIIA non-small cell lung cancer (NSCLC) treated with carbon ion radiotherapy with those of patients treated with X-ray radiotherapy. Patients with Stage IIIA NSCLC (n = 10 patients for each approach) were enrolled. Both radiotherapy plans were calculated with the same targets and organs at risk on the same CT. The treatment plan for the prophylactic lymph node and primary tumor (PTV1) delivered 40 Gy for X-ray radiotherapy and 40 Gy (relative biological effectiveness RBE) for carbon ion radiotherapy. The total doses for the primary tumor and clinically positive lymph nodes (PTV2) were 60 Gy for X-ray radiotherapy and 60 Gy (RBE) for carbon ion radiotherapy. The homogeneity indexes for PTV1 and PTV2 were superior for carbon ion radiotherapy in comparison with X-ray radiotherapy (PTV1, 0.57 vs 0.65, P = 0.009 PTV2, 0.07 vs 0.16, P = 0.005). The normal lung mean dose, V5, V10 and V20 for carbon ion radiotherapy were 7.7 Gy (RBE), 21.4%, 19.7% and 17.0%, respectively, whereas the corresponding doses for X-ray radiotherapy were 11.9 Gy, 34.9%, 26.6% and 20.8%, respectively. Maximum spinal cord dose, esophageal maximum dose and V50, and bone V10, V30 and V50 were lower with carbon ion radiotherapy than with X-ray radiotherapy. The present study indicates that carbon ion radiotherapy provides a more homogeneous target dose and a lower dose to organs at risk than X-ray radiotherapy for Stage IIIA non-small cell lung cancer.

Background: The purpose of this study was to assess the incidence, risk factors, and dose-volume relationship of radiation-induced rib fracture (RIRF) after carbon ion radiotherapy for lung cancer.Material and methods: Fifty-seven ribs of 18 patients with peripheral stage I non-small cell lung cancer treated with carbon ion radiotherapy were analyzed on rib fracture. The patients were treated at a total dose of 52.8 Gy [relative biologic effectiveness (RBE)] or 60.0 Gy (RBE) in 4 fractions and were followed at least six months. Patient characteristics and dosimetric parameters were analyzed for associations with RIRF.Results: Eighteen patients and 57 ribs were included in this study. The median length of follow-up was 36.5 months. RIRF was observed in seven (39%) of the 18 patients, and in 11 (19%) of 57 ribs. Only one patient developed symptomatic fracture. The distance from the ribs to the tumor site was significantly shorter in fractured ribs than in non-fractured ribs (1.40.3cm vs. 2.5 +/- 0.3cm). Receiver operating characteristic curve analysis showed that D-1cm (3) as a cut-off value for discriminating RIRF had the largest area under the curve (AUC=0.78). Comparison of the two-year cumulative incidence of RIRF among two groups as determined by cut-off values, yielded the following result: 53% vs. 4% [D-1cm (3) >= 38.2 Gy (RBE) or less]. Results from the two groups were significantly different (p<0.05).Conclusion: The crude incidence of RIRF after carbon ion radiotherapy was 39% but incidence of symptomatic fracture was low. The D-1cm (3) as cut-off values may be helpful for discriminating the risk of RIRF.

Purpose To evaluate the dose-response relationship for development of acute radiation mucositis (ARM) using an oral mucosal dose surface model (OMDS-model) in carbon ion radiotherapy (C-ion RT) for head and neck tumors. Methods Thirty-nine patients receiving C-ion RT for head and neck cancer were evaluated for ARM (once per week for 6 weeks) according to the Common Terminology Criteria for Adverse Events (CTCAE), version 4.0, and the Radiation Therapy Oncology Group (RTOG) scoring systems. The irradiation schedule typically used was 64 Gy [relative biological effectiveness (RBE)] in 16 fractions for 4 weeks. Maximum point doses in the palate and tongue were compared with ARM in each patient. Results The location of the ARM coincided with the high-dose area in the OMDS-model. There was a clear dose-response relationship between maximum point dose and ARM grade assessed using the RTOG criteria but not the CTCAE. The threshold doses for grade 2-3 ARM in the palate and tongue were 43.0 Gy(RBE) and 54.3 Gy(RBE), respectively. Conclusions The OMDS-model was useful for predicting the location and severity of ARM. Maximum point doses in the model correlated well with grade 2-3 ARM.

Background: The purpose of this study was to compare carbon ion radiotherapy (C-ion RT) and stereotactic radiotherapy (SBRT) with photon beams for the treatment of hepatocellular carcinoma (HCC), specifically with regard to the dose volume parameters for target coverage and normal tissue sparing. Methods: Data of 10 patients who were treated using C-ion RT with a total dose of 60 Gy(RBE) in four fractions were used. The virtual plan of SBRT was simulated on the treatment planning computed tomography images of C-ion RT. Dose volume parameters such as minimum dose covering 90 % of the planning target volume (PTV D90), homogeneity index (HI), conformity index (CI), mean liver dose (MLD), volume of the liver receiving 5 to 60 Gy (V5-60), and max point dose (Dmax) of gastrointestinal (GI) tract were calculated from both treatment plans. Results: The PTV D90 was 59.6 +/- 0.2 Gy(RBE) in C-ion RT, as compared to 56.6 +/- 0.3 Gy in SBRT (p < 0.05). HI and CI were 1.19 +/- 0.03 and 0.79 +/- 0.06, respectively in C-ion RT, as compared to 1.21 +/- 0.01 and 0.37 +/- 0.02, respectively in SBRT. Only CI showed a significant difference between two modalities. Mean liver dose was 8.1 +/- 1.4 Gy(RBE) in C-ion RT, as compared to 16.1 +/- 2.5 Gy in SBRT (p < 0.05). V5 to V50 of liver were higher in SBRT than C-ion RT and significant differences were observed for V5, V10 and V20. Dmax of the GI tract was higher in SBRT than C-ion RT, but did not show a significantly difference. Conclusions: C-ion RT provides an advantage in both target conformity and normal liver sparing compared with SBRT.

Glioblastoma multiforme(GBM) is the most common primary brain tumor in adults, and it is associated with poor survival. The standard therapy for newly-diagnosed GBM is radiotherapy with concurrent temozolomide following maximal surgical resection. To improve the outcome of these patients, combinations of the standard therapy plus molecular-targeted agents have been tested in clinical trials. However, the addition of gefitinib to the standard therapy did not appear to improve clinical outcome, and the standard therapy plus bevacizumab showed no improvement in overall survival, although a 4-month improvement in progression-free survival (PFS) was observed. Phase II data have indicated the potential efficacy of talampanel combined with the standard therapy for patients with newly-diagnosed GBM, and these findings are awaiting validation in phase III trials. In addition, phase II trials have demonstrated that adjuvant immunotherapy is effective and tolerable for treatment of patients with GBM. In this article, we discuss topics in chemotherapy, molecular-targeted therapy, and immunotherapy for patients with newly-diagnosed GBM.

Non-proliferating cell, such as mature neurons, are generally believed to be more resistant to X-rays than proliferating cells, such as glial and vascular endothelial cells. Therefore, the late adverse effects of radiotherapy on the brain have been attributed to the radiation-induced damage of glial and vascular endothelial cells. However, little is known about the radiosensitivities of neurons and glial cells due to difficulties in culturing these cells, particularly neurons, independently. In the present study, primary dissociated neurons and glial cultures were prepared separately from the hippocampi and cerebrum, respectively, which had been obtained from the same fetal rat on embryonic day 18. X-irradiations of 50 Gy were performed on the cultured neurons and glial cells at 7 and 21 days in vitro (DIV). The cells were fixed at 24 h after irradiation. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling was then performed to measure the apoptotic indices (AIs). The AIs of non-irradiated and irradiated neurons at 7 DIV were 23.7 +/- 6.7 and 64.9 +/- 4.8%, and those at 21 DIV were 52.1 +/- 17.4 and 44.6 +/- 12.5%, respectively. The AIs of non-irradiated and irradiated glial cells at 7 DIV were 5.8 +/- 1.5 and 78.4 +/- 3.3% and those at 21 DIV were 9.6 +/- 2.6 and 86.3 +/- 4.9%, respectively. Glial cells and neurons were radiosensitive at 7 DIV. However, while glial cells were radiosensitive at 21 DIV, neurons were not.

Aim: To evaluate dosimetric differences between carbon ion radiotherapy (C-ion RT) and stereotactic body radiotherapy (SBRT) for stage I non-small cell lung cancer (NSCLC). Patients and Methods: Thirteen stage I NSCLC cases were planned with C-ion RT and SBRT. Prescription of the dose and fractionation (fr) for stage IA and IB in C-ion RT were 52.8 Gy (RBE)/4fr and 60.0 Gy (RBE)/4fr, respectively and those in SBRT were 52.8 Gy/4fr and 60.0 Gy/4fr, respectively. Results: The conformity index (CI) for planning target volume of C-ion RT was significantly lower than that of SBRT. The normal lung doses in C-ion RT were significantly lower those that in SBRT. In particularly, for a larger tumor, C-ion RT was lower CI and normal lung dose than SBRT. Conclusion: C-ion RT has an advantage in both target conformity and sparing of normal lung in stage I NSCLC.

Purpose: To determine the efficacy and safety of oral S-1 in combination with cisplatin and thoracic radiotherapy in patients with unresectable stage III non-small-cell lung cancer (NSCLC). Methods and materials: S-1 (50 mg/m(2)) was administered orally twice daily for 14 days, with cisplatin (40 mg/m(2)) on days 1 and 8 of each cycle every 3 weeks, for 2-4 cycles. Thoracic radiation therapy was administered in 2 Gy fractions five times weekly for a total dose of 60 Gy. The primary endpoint was the response rate, and secondary endpoints included progression-free survival, overall survival and safety. Results: Forty-one patients were enrolled in this study. The objective response rate was 87.8% (98% CI: 77.8-97.8%). The median progression-free survival was 467 days (15.4 months), and the median survival time was 904 days (29.7 months). The overall survival rates at 1- and 2-years were 85.7% and 52.9%, respectively. Hematological toxicities included grade 3/4 neutropenia (17%) and grade 3/4 leukopenia (27%). No grade 3 febrile neutropenia was detected, and grade 3/4 non-hematological toxicities were also mild. A grade 3 gastrointestinal hemorrhage was observed in one patient. Conclusions: The combination of oral S-1 plus cisplatin with concurrent radiotherapy is a promising treatment with a high efficacy and lower toxicity in patients with locally advanced NSCLC. (C) 2013 Elsevier Ireland Ltd. All rights reserved.

This study was conducted to investigate the feasibility and survival benefits of combined treatment with radiotherapy and temozolomide (TMZ), which has been covered by the national health insurance in Japanese patients with glioblastoma since September 2006. Between September 2006 and December 2011, 47 patients with newly diagnosed and histologically confirmed glioblastoma received radiotherapy for 60 Gy in 30 fractions. Among them, 45 patients (TMZ group) received concomitant TMZ (75 mg/m2/day, every day) and adjuvant TMZ (200 mg/m2/day, 5 days during each 28-days). All 36 of the glioblastoma patients receiving radiotherapy between January 1988 and August 2006 were analyzed as historical controls (control group). All patients were followed for at least 1 year or until they died. The median survival was 15.8 months in the TMZ group and 12.0 months in the control group after a median follow-up of 14.0 months. The hazard ratio for death in the TMZ group relative to the control group was 0.52 (P&lt 0.01) the 2-year survival rate was 27.7% in the TMZ group and 14.6% in the control group. Hematologic toxicity of grade 3 and higher was observed in 20.4% in the TMZ group. Multivariate analysis showed that extent of surgery had the strongest impact on survival (P&lt 0.01), while the use of TMZ had the second largest impact on survival (P = 0.035). The results indicate that combined treatment with radiotherapy and TMZ has a significant survival benefit for Japanese patients with newly diagnosed glioblastoma with slightly higher toxicities than previously reported. © 2013 Oike et al.

Esophageal cancer patients are often associated with multiple primary cancers (MPC). The aim of this study is to evaluate the effect of MPC on prognosis in esophageal cancer patients treated by radiotherapy. Between 2001 and 2008, esophageal cancer patients treated by definitive radiotherapy at Gunma Cancer Center were retrospectively reviewed. Exclusion criteria were preoperative or postoperative radiotherapy, palliative radiotherapy, follow-up of < 6 months, radiation dose of < 50 Gy and no information on MPC. We analyzed 167 esophageal cancer patients and 56 (33.5%) were associated with MPC. Gastric cancer was the most frequent tumor (38.2%), followed by head and neck cancer (26.5%). Median follow-up time was 31.5 months (range 6.1-87.3 months). Patients with MPC included more stage I/II esophageal cancer than those without MPC (66.1% vs. 36.9%, P < 0.01). The 5-year overall survival rate for esophageal cancer with MPC was relatively better than those without MPC (46.1% vs. 26.7%), although the difference did not reach statistical significance in univariate analysis (P = 0.09). Stage I/II esophageal cancer patients had a significantly better overall survival than stage III/IV patients (P < 0.01). Among esophageal cancer patients with MPC, there was no difference in overall survival between antecedent and synchronous cancer (P = 0.59). Our study indicated that the prognosis of esophageal cancer patients treated by radiotherapy was primarily determined by the clinical stage itself, but not the presence of MPC.

Neurons are essential components of neural circuits and provide brain function organization. We previously reported that X irradiation induces apoptosis in immature neurons. To the best of our knowledge, there have been few reports investigating the effects of X irradiation on mature neurons. We analyzed the effects of X irradiation on the morphology, density and cytoskeletal proteins in dendritic spines on mature neurons. We prepared developing hippocampal neurons from 18 days embryo by using Banker's method. Neurons at 21 days in vitro were X irradiated at several doses and were immediately fixed. To evaluate the dendritic spine morphology and density, the neurons were transfected with a reporter plasmid for enhanced green fluorescent protein (GFP). Changes in the dendritic spines as a result of X irradiation were evaluated using electron microscopy. To analyze the cytoskeletal proteins within the dendritic spines, we performed immunocytochemistry to detect filamentous actin (F-actin), drebrin and PSD-95. X irradiation immediately changed the dendritic spine morphology, and the irradiated spines were significantly thinner and longer than the nonirradiated spines. X irradiation decreased the dendritic spine density in a dose-dependent manner. Electron microscopy confirmed these changes of dendritic spines by X irradiation. Immunohistochemical studies showed that X irradiation decreased the accumulation of drebrin and F-actin, but not PSD-95, within the dendritic spines. These results suggest that X irradiation immediately decreases the dendritic spine density and changes the morphology of mature neurons by reducing the abundance of cytoskeletal proteins. The abnormal dendritic spines may be associated with acute adverse effects after X irradiation in a clinical setting, although further investigations are warranted to validate these findings. (C) 2013 by Radiation Research Society

PURPOSE: To compare the efficacy and the incidence of complications of high-dose-rate (HDR) and low-dose-rate (LDR) intraluminal brachytherapy (IBT) boost after external beam radiation therapy in patients with superficial esophageal cancer. METHODS AND MATERIALS: Fifty-four consecutive patients with Stage I thoracic esophageal squamous cell carcinoma who were treated with definitive radiotherapy using 1BT between 1991 and 2007 were studied retrospectively. LDR-IBT and HDR-IBT were performed for 19 and 35 patients, respectively. After external beam radiation therapy of 56-60 Gy with a conventional fractionation, LDR-IBT (5 Gy x 2) or HDR-IBT (3 Gy x 3) was given within 2 weeks. The median follow-up was 47 months (7-151 months). RESULTS: Overall, the 5-year overall survival, cause-specific survival (CSS), and locoregional control (LRC) rates were 61%, 86%, and 79%, respectively. The 5-year overall survival, CCS, and LRC rates did not differ significantly between the LDR-IBT and HDR-IBT groups (68% vs. 58% (p = 0.50), 83% vs. 85% (p = 0.63), and 84% vs. 75% (p = 0.42), respectively). Salvage treatment was given in 8 locally recurrent patients, and 6 patients were rescued. The Grade >= 2 late morbidities of esophagus and heart/lung were observed in 5 patients (4 in the LDR-IBT group and 1 in the HDR-IBT group) and 2 patients (one from each group), respectively. CONCLUSIONS: In view of the safety profile and effectiveness, our results encourage the continued adoption of HDR-IBT as radiation boost in medically inoperable or elderly superficial esophageal cancer patients undergoing definitive radiotherapy. (C) 2012 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.

To clarify the relative biological effectiveness (RBE) values of carbon ion (C) beams in normal brain tissues, a rat organotypic slice culture system was used. The cerebellum was dissected from 10-day-old Wistar rats, cut parasagittally into approximately 600-mu m-thick slices and cultivated using a membrane-based culture system with a liquid-air interface. Slices were irradiated with 140 kV X-rays and 18.3 MeV/amu C-beams (linear energy transfer = 108 keV/mu m). After irradiation, the slices were evaluated histopathologically using hematoxylin and eosin staining, and apoptosis was quantified using the TdT-mediated dUTP-biotin nick-end labeling (TUNEL) assay. Disorganization of the external granule cell layer (EGL) and apoptosis of the external granule cells (EGCs) were induced within 24 h after exposure to doses of more than 5 Gy from C-beams and X-rays. In the early postnatal cerebellum, morphological changes following exposure to C-beams were similar to those following exposure to X-rays. The RBEs values of C-beams using the EGL disorganization and the EGC TUNEL index endpoints ranged from 1.4 to 1.5. This system represents a useful model for assaying the biological effects of radiation on the brain, especially physiological and time-dependent phenomena.

Survivin is a critical regulator of mitosis, and an inhibitor of apoptosis which is overexpressed in almost all cancers. In the current study, cell cycle profiles of normal proliferating human umbilical vein endothelial cells, prostate cancer, and lung cancer cell lines expressing varying levels of survivin and its splice variants were compared using a novel functional complementation assay. Defects in chromosome segregation and cytokinesis that were observed after depletion of endogenous survivin were not complemented by any of the survivin splice variants: survivin-2B, survivin-3B, survivin-Ex3, or survivin-2A when expressed exogenously at a level comparable to endogenous full-length survivin. Survivin variants were not detectable at the endogenous protein level. Cancer cells with higher levels of full-length survivin and survivin-2B expression, exhibited reduced caspase-3 activation following doxorubicin treatment and radiation. Whereas earlier studies focused on function and expression levels of survivin specific to cancer cells, the current study brings forward the essential role of survivin in normal dividing cells. Full-length survivin was found to be associated with Aurora-B kinase in the chromosomal passenger complex and depletion of survivin mimics mitotic phenotypes observed after Aurora-B kinase inhibition, in cancer as well as normal proliferating cells. Thus, our study establishes survivin as a marker of proliferation, rather than a cancer specific marker. Therefore, systemic therapeutic interventions targeting survivin will affect cancer as well as normal proliferating cells.

Combined therapy with temozolomide and radiotherapy is a standard treatment and improves the survival for patients with newly diagnosed glioblastoma. However, the prognosis remains poor, with a median survival time of 12-15 months. Currently, several clinical trials of dose-dense temozolomide regimen or molecular-targeting therapies have been performed to overcome the resistance of glioblastoma. In these therapies, rational prognostic biomarkers have also been investigated to predict their outcome and response to treatment. This advanced understanding of the biological markers can help to develop personalized therapies for glioblastoma patients. Generally, due to a reduced tolerance, elderly patients do not seem to benefit from intensive treatment. This population needs individual treatments depended on their age or performance status. In this article, we review the recent studies that can provide personalized therapy for glioblastoma, based on molecular tumor profiling or patients' physical status.

Gliomas account for the vast majority of malignant adult brain tumors. Even though tremendous effort has been made to optimize treatment of patients with high-grade glioma, the prognosis remains poor, especially for patients with glioblastoma. The dismal prognosis conferred by these tumors is in part caused by the tendency to diffusely infiltrate into neighboring brain tissue, but also by the inherent resistance of these tumors to both chemotherapy and radiation. This article reviews the recent advancements in multimodality treatment of patients with gliomas, both in the primary and recurrent setting, with an emphasis on the emerging targeted therapies. Moreover, the external beam radiotherapy options, including intensity modulated radiotherapy and particle (proton and carbon ion) radiotherapy are reviewed.

Purpose: To investigate the dose volume histogram parameters and clinical factors as predictors of pleural effusion in esophageal cancer patients treated with concurrent chemoradiotherapy (CRT). Methods and Materials: Forty-three esophageal cancer patients treated with definitive CRT from January 2001 to March 2007 were reviewed retrospectively on the basis of the following criteria: pathologically confirmed esophageal cancer, available computed tomography scan for treatment planning, 6-month follow-up after CRT, and radiation dose >= 50 Gy. Exclusion criteria were lung metastasis, malignant pleural effusion, and surgery. Mean heart dose, mean total lung dose, and percentages of heart or total lung volume receiving >= 10-60 Gy (Heart-V-10 to V-60 and Lung-V-10 to V-60, respectively) were analyzed in relation to pleural effusion. Results: The median follow-up time was 26.9 months (range, 6.7-70.2) after CRT. Of the 43 patients, 15(35%) developed pleural effusion. By univariate analysis, mean heart dose, Heart-V-10 to V-60, and Lung-V-50 to V-60 were significantly associated with pleural effusion. Poor performance status, primary tumor of the distal esophagus, and age years were significantly related with pleural effusion. Multivariate analysis identified Heart-V-50 as the strongest predictive factor for pleural effusion (p = 0.01). Patients with Heart-V-50 <20%, 20% Heart-V-50 <40%, and Heart-V5(0_) >= 40% had 6%, 44%, and 64% of pleural effusion, respectively (p < 0.01). Conclusion: Heart-V-50 is a useful parameter for assessing the risk of pleural effusion and should be reduced to avoid pleural effusion. (C) 2011 Elsevier Inc.

Despite the wide use of definitive chemoradiotherapy (CRT) for locally advanced esophageal adenocarcinoma, there is little evidence that CRT improves the survival of patients with esophageal adenocarcinoma compared with radiotherapy (RT) alone. Therefore, we retrospectively evaluated the outcome of patients with esophageal adenocarcinoma treated by CRT and RT alone. Patients were treated at the Gunma Prefectural Cancer Center (Ota, Japan) and the Gunma University Hospital (Maebashi, Japan). Patients provided written informed consent before treatment. Patients with distant metastases were excluded. CRT consisting of RT, nedaplatin, and 5-fluorouracil has been performed since 2002 when patients have adequate bone marrow, liver, and renal function. Between November 1993 and April 2006, 8 patients were treated by CRT and 12 were RT alone. The median follow-up period of surviving patients was 19 months. CRT group had a significantly higher complete response rate than those RT alone group (87% vs. 33%, P = 0.05). Of all patients, 2-year overall survival rate was 41% and the median survival time was 18 months. The 2-year overall survival of patients treated by CRT was 58%, significantly better than 24% of those with RT alone (P = 0.02). CRT can improve outcomes of patients with esophageal adenocarcinoma compared with RT alone.

The direct biological effects of radiation, particularly accelerated heavy particle ions, on neurons are not fully known. Hence, the direct effect of carbon-ion beams on immature neurons was investigated by comparing to the effect of X-rays in vitro using primary hippocampal neurons. Primary neurons were prepared from hippocampi of fetal rats at embryonic day 18 from timed pregnant Wistar rats and cultured with Banker's methods. At 7 Days In Vitro (DIV), the cells were irradiated with 140 kV X-ray and 18.3 MeV/amu carbon-ion beams (LET = 108 keV/mu m). The cells were fixed with 4% paraformaldehyde at 12 hours after irradiation. Then, the cells were treated with terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) and DAPI staining for measuring the percentage of apoptosis (apoptotic index: Al). Al in sham-irradiated hippocampal neurons was 18%. The value of Al (Als) of the cells irradiated with X-rays at 10 or 30 Gy were 15% or 23%, respectively. Al in cells irradiated with carbon-ion beams at 1 Gy, 3 Gy, 5 Gy and 10 Gy were 22%, 23%, 24% and 33%, respectively. Al was significantly increased by carbon-ion beams at 10 Gy (p < 0.001). The apoptosis of hippocampal neurons increased in a dose-dependent manner following both X-ray and carbon-ion beams irradiation. Carbon-ion beams were about 10-fold more effective than X-rays for apoptosis induction in immature hippocampal neurons.

World Health Organization (WHO) grade 3 glioma is one of the common brain tumors and has three main histological subtypes, including anaplastic astrocytoma (AA), anaplastic oligoastrocytoma (AOA) and anaplastic oligodendroglioma (AO). However, most previous studies have considered AOA and AO as one group because of the difficult differential diagnosis between AOA and AO. Therefore the prognostic difference among patients with these histological subtypes has been unclear. In this study, 68 patients with histologically proven WHO grade 3 glioma, consecutively received postoperative radiotherapy at the Gunma University Hospital, Japan, between 1983 and 2005, were investigated to assess the impact of histological subtype on the survival. The number of AA, AOA and AO patients was 41, 16 and 11, respectively. The mean and median follow-up periods were 72 and 48 months, respectively. The number of patients treated with gross total resection, partial resection and biopsy was 14, 38 and 16, respectively. The mean and median radiation doses were 58 +/- 5 Gy and 60 Gy, respectively. The 5-year overall survival rates of AA, AOA and AO were 21%, 38% and 80%, and median survival period were 16 months, 58 months and not reached, respectively. Univariate analysis showed that the histological subtype (P < 0.01) and extent of surgery (P < 0.01) were significant prognostic factors for survival. Selective comparison showed that overall survival of patients with AA was significantly worse than for those with AOA (P = 0.01) and AO (P < 0.01). The overall survival of patients with AO was better than for those with AOA; however, the difference was not statistically significant (P = 0.14). Multivariate analysis demonstrated that histological subtype, age and extent of surgery were the significant independent variable for survival (P < 0.01, P <0.01 and P = 0.04). In our study, histological subtype was one of the most important prognostic factors of WHO grade 3 glioma.

phosphorylated-Akt (pAkt) plays an important role in tumorigenesis through promotion of cell survival by inhibiting apoptosis and mediating cell proliferation Higher expression of pAkt has been reported to be associated with an unfavorable prognosis in several malignant tumors In this study, the prognostic value of pAkt expression was investigated in glioblastomas by using immunohistochemical methods Tissue sections obtained from 64 patients with glioblastoma were evaluated The mean and median follow-up period was 16 2 +/- 12 4 and 12 months. respectively (range. from 1 to 62 months) pAkt expression levels were determined by immunohistochemical staining and evaluated for cell positivity Positive staining was defined when more than 50% of the tumor cells were stained in each section The correlation between expression of pAkt and overall survival rate was assessed. Glioblastomas showed either or both cytoplasmic and nuclear positive findings for pAkt A total of 29 7% (19/64) of tissue specimens had greater than 50% positivity The median survival periods of the patients with pAkt positive and negative tumor were 10 and 14 months. respectively Two years overall survival rate of the pAkt positive and negative patients were 0% and 24 4%. respectively Survival rate of the patients with pAkt positive tumor was significantly lower than that of the patients with pAkt negative tumors (p = 0 004) Multivariate analysis showed that extent of surgery was the strongest factor for survival (p = 0 01) and the pAkt expression was the secondly strongest factor (p = 0.06) These results suggest that the higher expression of pAkt the poorer prognosis in patients with glioblastoma

Purpose: To assess the efficacy of radiation therapy (RT) by using intraluminal brachytherapy (IBT) combined with external beam RT (EBRT) for submucosal esophageal cancer. Methods and Materials: Between 1991 and 2005,59 consecutive patients received definitive RT without chemotherapy. IBT was performed after patients completed EBRT as a booster therapy for 17 patients, using low-dose-rate Cs-137 sources until 1997, and for 19 patients, using high-dose-rate Ir-192 sources thereafter. The long-term outcomes were investigated with a median follow-up time of 61 months. Results: Logoregional recurrences and distant metastases were observed in 14 patients and in 2 patients in the lung, respectively, and 5 patients were rescued by salvage treatments. The 5-year logoregional control and cause-specific survival rates were 75% and 76%, respectively. The 5-year cause-specific survival rate in the EBRT group was 62%, whereas the corresponding rate in the IBT group was 86% (p=0.04). Multivariate analysis revealed that IBT was the most powerful predictor of survival but did not reach a significant level (p=0.07). There were five esophageal ulcers in the IBT group, but no ulcers developed with small fractions of 3 Gy. Grade 2 or higher cardiorespiratory complications developed in 2 patients (5.6%) in the IBT group and in 3 patients (13.0%) in the EBRT group. Conclusions: Combining IBT with EBRT is suggested to be one of the preferable treatment modalities for medically inoperable submucosal esophageal cancer because of its preferable local control and survival probabilities, with appreciably less morbidity. (C) 2010 Elsevier Inc.