[Show abstract][Hide abstract] ABSTRACT: Non-proliferating cells, 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.
Experimental and therapeutic medicine 09/2014; 8(3):754-758. · 0.34 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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).
Anticancer research 09/2014; 34(9):5099-104. · 1.71 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: 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.
Journal of Radiation Research 02/2013; · 1.45 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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/m(2)/day, every day) and adjuvant TMZ (200 mg/m(2)/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<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<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.
PLoS ONE 01/2013; 8(11):e78943. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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/m2) was administered orally twice daily for 14 days, with cisplatin (40 mg/m2) 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.
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.
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.
Lung Cancer 01/2013; 82(3):449–454. · 3.39 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Malignant gliomas have a poor prognosis despite advances in diagnosis and therapy. Although postoperative temozolomide and radiotherapy improve overall survival in glioblastoma patients, most patients experience a recurrence. The prognosis of recurrent malignant gliomas is dismal, and more effective therapeutic strategies are clearly needed. Antiangiogenesis is currently considered an attractive targeting therapy for malignant gliomas due to its important role in tumor growth. Clinical trials using bevacizumab have been performed for recurrent glioblastoma, and these studies have shown promising response rates along with progression-free survival. Based on the encouraging results, bevacizumab was approved by the FDA for the treatment of recurrent glioblastoma. In addition, bevacizumab has shown to be effective for recurrent anaplastic gliomas. Large phase III studies are currently ongoing to demonstrate the efficacy and safety of the addition of bevacizumab to temozolomide and radiotherapy for newly diagnosed glioblastoma. In contrast, several other antiangiogenic drugs have also been used in clinical trials. However, previous studies have not shown whether antiangiogenesis improves the overall survival of malignant gliomas. Specific severe side effects, difficult assessment of response, and lack of rational predictive markers are challenging problems. Further studies are warranted to establish the optimized antiangiogenesis therapy for malignant gliomas.
[Show abstract][Hide abstract] ABSTRACT: 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-µm-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/µm). 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.
Journal of Radiation Research 01/2012; 53(1):87-92. · 1.45 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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-ΔEx3, 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.
OncoTargets and Therapy 01/2012; 5:7-20. · 2.07 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Conventional treatment of glioblastoma has advanced only incrementally in the last 30 years and still yields poor outcomes. The current strategy of surgery, radiation, and chemotherapy has increased median survival to approximately 15 months. With the advent of molecular biology and consequent improved understanding of basic tumor biology, targeted therapies have become cornerstones for cancer treatment. Many pathways (RTKs, PI3K/AKT/mTOR, angiogenesis, etc.) have been identified in GBM as playing major roles in tumorigenesis, treatment resistance, or natural history of disease. Despite the growing understanding of the complex networks regulating GBM tumors, many targeted therapies have fallen short of expectations. In this paper, we will discuss novel therapies and the successes and failures that have occurred. One clear message is that monotherapies yield minor results, likely due to functionally redundant pathways. A better understanding of underlying tumor biology may yield insights into optimal targeting strategies which could improve the overall therapeutic ratio of conventional treatments.
Neurology research international. 01/2012; 2012:428565.
[Show abstract][Hide abstract] ABSTRACT: Radiotherapy plays an important role in the treatment for thoracic cancers. Accurate diagnosis is essential to correctly perform curative radiotherapy. Tumor delineation is also important to prevent geographic misses in radiotherapy planning. Currently, planning is based on computed tomography (CT) imaging when radiation oncologists manually contour the tumor, and this practice often induces interobserver variability. F-18 fluorodeoxyglucose positron emission tomography (FDG-PET) has been reported to enable accurate staging and detect tumor extension in several thoracic cancers, such as lung cancer and esophageal cancer. FDG-PET imaging has many potential advantages in radiotherapy planning for these cancers, because it can add biological information to conventional anatomical images and decrease the inter-observer variability. FDG-PET improves radiotherapy volume and enables dose escalation without causing severe side effects, especially in lung cancer patients. The main advantage of FDG-PET for esophageal cancer patients is the detection of unrecognized lymph node or distal metastases. However, automatic delineation by FDG-PET is still controversial in these tumors, despite the initial expectations. We will review the role of FDG-PET in radiotherapy for thoracic cancers, including lung cancer and esophageal cancer.
International journal of molecular imaging. 01/2012; 2012:609545.
[Show abstract][Hide abstract] ABSTRACT: Recently, it has become clear that acute hypoxia affecting radioresistance exists widely in tumor tissues. Concurrently, hypoxia-inducible factor-1α (HIF-1α) is recognized as an essential transcriptional factor, enabling cells to survive through hypoxia. However, it is unclear as to whether HIF-1α plays a direct role in the radioresistance caused by acute hypoxia. Therefore, in this study, we investigated the in vitro response of the human lung adenocarcinoma cell line, A549, to ionizing radiation in an experimental model that imitates acute hypoxia in the presence and absence of HIF-1α expression, using the HIF-1α inhibitor 5-[1-(phenylmethyl)-1H-indazol-3-yl]-2-furanmethanol (YC-1). Cells were treated with or without 10 μM YC-1 for 2 h. Cells were exposed to either 95% N(2) and 5% CO(2) (hypoxic condition of <0.1 mmHg) or atmospheric air (normoxic condition) for 1 h, and irradiated with 2, 5 and 10 Gy. Western blot analysis revealed that, without YC-1, cells exposed to hypoxic conditions expressed increased levels of HIF-1α compared with those exposed to normoxic conditions. Under hypoxic conditions, HIF-1α expression was suppressed by YC-1 to the same extent as that observed in cells exposed to normoxic conditions without YC-1. Clonogenic survival assay revealed that under hypoxic conditions there was no significant difference between the surviving fraction of cells treated with YC-1 and without YC-1 at any dose point examined. The oxygen enhancement ratio at 10% surviving fraction was calculated as 2.7 and 2.6 in the presence and the absence of YC-1, respectively. These results indicate that HIF-1α itself is not an immediate cause of acute hypoxia-induced radioresistance in A549 cells.
Experimental and therapeutic medicine 01/2012; 3(1):141-145. · 0.34 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: To investigate the dose-volume histogram parameters and clinical factors as predictors of pleural effusion in esophageal cancer patients treated with concurrent chemoradiotherapy (CRT).
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.
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 ≥ 65 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-V(50) ≥ 40% had 6%, 44%, and 64% of pleural effusion, respectively (p < 0.01).
Heart-V(50) is a useful parameter for assessing the risk of pleural effusion and should be reduced to avoid pleural effusion.
International journal of radiation oncology, biology, physics 07/2011; 80(4):1002-7. · 4.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
Fifty-four consecutive patients with Stage I thoracic esophageal squamous cell carcinoma who were treated with definitive radiotherapy using IBT 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 × 2) or HDR-IBT (3 Gy × 3) was given within 2 weeks. The median follow-up was 47 months (7-151 months).
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.
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.
[Show abstract][Hide abstract] ABSTRACT: 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.
Journal of Radiation Research 02/2011; 52(3):264-9. · 1.45 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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/µm). 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: AI). AI in sham-irradiated hippocampal neurons was 18%. The value of AI (AIs) of the cells irradiated with X-rays at 10 or 30 Gy were 15% or 23%, respectively. AI in cells irradiated with carbon-ion beams at 1 Gy, 3 Gy, 5 Gy and 10 Gy were 22%, 23%, 24% and 33%, respectively. AI 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.
Journal of Radiation Research 10/2010; 51(6):627-31. · 1.45 Impact Factor