Search

Gimeracil (5-chloro-2, 4-dihydroxypyridine) is an inhibitor of dihydropyrimidine dehydrogenase (DPYD), which degrades pyrimidine including 5-fluorouracil in the blood. Gimeracil was originally added to an oral fluoropyrimidine derivative S-1 to yield prolonged 5-fluorouracil concentrations in serum and tumor tissues. We have already reported that gimeracil had radiosensitizing effects by partially inhibiting homologous recombination (HR) in the repair of DNA double strand breaks. We investigated the mechanisms of gimeracil radiosensitization. Comet assay and radiation-induced focus formation of various kinds of proteins involved in HR was carried out. siRNA for DPYD were transfected to HeLa cells to investigate the target protein for radiosensitization with gimeracil. SCneo assay was carried out to examine whether DPYD depletion by siRNA inhibited HR repair of DNA double strand breaks. Tail moments in neutral comet assay increased in gimeracil-treated cells. Gimeracil restrained the formation of foci of Rad51 and replication protein A (RPA), whereas it increased the number of foci of Nbs1, Mre11, Rad50, and FancD2. When HeLa cells were transfected with the DPYD siRNA before irradiation, the cells became more radiosensitive. The degree of radiosensitization by transfection of DPYD siRNA was similar to that of gimeracil. Gimeracil did not sensitize DPYD-depleted cells. Depletion of DPYD by siRNA significantly reduced the frequency of neopositive clones in SCneo assay. Gimeracil partially inhibits the early step in HR. It was found that DPYD is the target protein for radiosensitization by gimeracil. The inhibitors of DPYD, such as gimeracil, could enhance the efficacy of radiotherapy through partial suppression of HR-mediated DNA repair., (© 2011 Japanese Cancer Association.)

Purpose: The aim of this study was to develop a dose calculation method which is applicable to the interseed attenuation and the geometry lacking the equilibrium radiation scatter conditions in brachytherapy., Methods: The dose obtained from measurement with a radiophotoluminescent glass rod dosimeter (GRD) was compared to the dose calculated with the Monte Carlo (MC) code "EGS5," using the 125I source structure detailed in by Kennedy et al. The GRDs were irradiated with 125I Oncoseed 6711 in a human head phantom. The phantom was a cylinder made of 2 mm thick PMMA with a diameter of 18 cm and length of 16 cm. Some of the GRD positions were so close to the phantom surface that the backscatter margin was less than 5 cm, insufficient for photons., Results: The EGS5 simulations were found to reproduce the relative dose distributions as measured with the GRDs to within 25% uncertainty in the geometry lacking the equilibrium radiation scatter conditions. The absolute value of the GRD measurement agreed with the American Association of Physicist in Medicine Task Group No 43 Updated Protocol (AAPM-TG43U1) formalism to within 3% of the reference point (r = 1 cm, theta = 90 degrees), where the TG43U1 is especially reliable because of the abundant data accumulation in composing the formalism. The factor to normalize the measured or calculated dose to the TG43U1 estimate at the reference point was evaluated to be 0.97 for the GRD measurement and 1.8 for the MC calculation, which uses the integration of the apparent activity with the time as the amount of disintegration during the irradiation. Also, F(r,theta) and g(r) estimated by this calculation method were consistent with those proposed in the TG43U1., Conclusions: The results of this investigation support the validity of both the MC calculation method and GRD measurement in this study as well as the TG-43U1 formalism. Also, this calculation is applicable to interseed attenuation and the geometry lacking the equilibrium radiation scatter.

Background: Repair of various types of DNA damages is critical for genomic stability. DNA-dependent protein kinase (DNA-PK) has an important role in DNA double-strand break repair. We examined whether there may be a correlation between DNA-PK activity in peripheral blood lymphocytes (PBLs) and survival percentages in various cancer patients. We also investigated the changes of DNA-PK activity in PBLs after radiotherapy., Methods: A total of 167 of untreated cancer patients participated in this study. Peripheral blood was collected, separated, and centrifuged. DNA-PK activity was measured by DNA-pull-down assay. Chromosomal aberrations were examined by cytogenetic methods., Results: DNA-PK activity of PBLs in advanced cancer patients was significantly lower than that in early stage. The patients with lower DNA-PK activity in PBLs tended to have the lower disease-specific survivals and distant metastasis-free survivals than those with higher DNA-PK activity in advanced stages. There was also a tendency of inverse correlation between DNA-PK activity and excess fragments. The DNA-PK activity of PBLs in most patients decreased in response to radiation as the equivalent whole-body dose increased., Conclusion: Cancer patients in advanced stage, with lower DNA-PK activity of PBLs might have higher distant metastasis and exhibit poorer prognosis. Therefore, DNA-PK activity in PBLs could be used as a marker to predict the chromosomal instability and poorer prognosis.

Background and Purpose: The structure of radiation oncology in designated cancer care hospitals in Japan was investigated in terms of equipment, personnel, patient load, and geographic distribution. The effect of changes in the health care policy in Japan on radiotherapy structure was also examined., Material and Methods: The Japanese Society of Therapeutic Radiology and Oncology surveyed the national structure of radiation oncology in 2007. The structures of 349 designated cancer care hospitals and 372 other radiotherapy facilities were compared., Results: Respective findings for equipment and personnel at designated cancer care hospitals and other facilities included the following: linear accelerators/facility: 1.3 and 1.0; annual patients/linear accelerator: 296.5 and 175.0; and annual patient load/full-time equivalent radiation oncologist was 237.0 and 273.3, respectively. Geographically, the number of designated cancer care hospitals was associated with population size., Conclusion: The structure of radiation oncology in Japan in terms of equipment, especially for designated cancer care hospitals, was as mature as that in European countries and the United States, even though the medical costs in relation to GDP in Japan are lower. There is still a shortage of manpower. The survey data proved to be important to fully understand the radiation oncology medical care system in Japan.

Gandolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) is a hepatobiliary contrast agent for MRI. It was reported that Gd-EOB-DTPA is useful to detect liver tumors and differentially diagnose benign and malignant pathologies in the liver. Since Gd-EOB-DTPA partially accumulates in the hepatocytes and bile via various transporters after intravenous injection, signal intensity in the liver increases on T1-weighted images. The signal intensity of the liver after Gd-EOB-DTPA injection depends on the Gd-EOB-DTPA uptake by hepatocytes and bile excretion. It is known tha the Gd-EOB-DTPA accumulating in the kidney is excreted to the urine through glomerular filtration. Because Gd-DTPA is concentrated in the renal tubules after being filtered at the Bowman's capsule, and since it is neither secreted nor reabsorbed the concentrating and diluting function of the renal tubules can be studied by imaging techniques. since renal function can be evaluated with Gd-EOB-DTPA can also be used to evaluate renal function. Eith the development of MRI equipment and rapid imaging techniques, temporal resolution had improved greatly. However, no previous study has been carried out on renal function using Gd-EOB-DTPA dynamic MR study that was correlated with estimated glomerular filtration rate (eGFR) and stage of chronic kidney disease (CKD) in the Japan Association of chronic kidney disease initiative.

Purpose: To evaluate the ongoing structure of radiation oncology in Japan in terms of equipment, personnel, patient load, and geographic distribution to identify and improve any deficiencies., Methods and Materials: A questionnaire-based national structure survey was conducted from March to December 2008 by the Japanese Society of Therapeutic Radiology and Oncology (JASTRO). These data were analyzed in terms of the institutional stratification of the Patterns of Care Study., Results: The total numbers of new cancer patients and total cancer patients (new and repeat) treated with radiation in 2007 were estimated at 181,000 and 218,000, respectively. There were 807 linear accelerator, 15 telecobalt, 46 Gamma Knife, 45 (60)Co remote-controlled after-loading, and 123 (192)Ir remote-controlled after-loading systems in actual use. The linear accelerator systems used dual-energy function in 539 units (66.8%), three-dimensional conformal radiation therapy in 555 (68.8%), and intensity-modulated radiation therapy in 235 (29.1%). There were 477 JASTRO-certified radiation oncologists, 826.3 full-time equivalent (FTE) radiation oncologists, 68.4 FTE medical physicists, and 1,634 FTE radiation therapists. The number of interstitial radiotherapy (RT) administrations for prostate, stereotactic body radiotherapy, and intensity-modulated radiation therapy increased significantly. Patterns of Care Study stratification can clearly identify the maturity of structures based on their academic nature and caseload. Geographically, the more JASTRO-certified physicians there were in a given area, the more RT tended to be used for cancer patients., Conclusions: The Japanese structure has clearly improved during the past 17 years in terms of equipment and its use, although a shortage of personnel and variations in maturity disclosed by Patterns of Care Study stratification were still problematic in 2007., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Background and Purpose: 5-Chloro-2,4-dihydroxypyridine (Gimeracil) is a component of an oral fluoropyrimidine derivative S-1. Gimeracil is originally added to S-1 to yield prolonged 5-FU concentrations in tumor tissues by inhibiting dihydropyrimidine dehydrogenase, which degrades 5-FU. We found that Gimeracil by itself had the radiosensitizing effect., Methods and Materials: We used various cell lines deficient in non-homologous end-joining (NHEJ) or homologous recombination (HR) as well as DLD-1 and HeLa in clonogenic assay. gamma-H2AX focus formation and SCneo assay was performed to examine the effects of Gimeracil on DNA double strand break (DSB) repair mechanisms., Results: Results of gamma-H2AX focus assay indicated that Gimeracil inhibited DNA DSB repair. It did not sensitize cells deficient in HR but sensitized those deficient in NHEJ. In SCneo assay, Gimeracil reduced the frequency of neo-positive clones. Additionally, it sensitized the cells in S-phase more than in G0/G1., Conclusions: Gimeracil inhibits HR. Because HR plays key roles in the repair of DSBH caused by radiotherapy, Gimeracil may enhance the efficacy of radiotherapy through the suppression of HR-mediated DNA repair pathways., (Copyright 2010 Elsevier Ireland Ltd. All rights reserved.)

Purpose: The aim of this study was to evaluate the accuracy of dynamic gadolinium (Gd)-enhanced magnetic resonance imaging (MRI) with endorectal coil for assessing tumor invasion based on simple classification criteria., Materials and Methods: A total of 58 patients with operable primary rectal cancer underwent preoperative MRI. An enhancement pattern in Gd-enhanced dynamic MRI with regard to tumor penetration was clarified. Retrospectively, two observers independently scored T2-weighted MRI and T2-weighted MRI combined with Gd-enhanced dynamic MRI for tumor penetration using the following criteria: With Gd-enhanced dynamic MRI, T1 tumors showed an early enhanced line around the tumor as rim enhancement; T2 tumors appeared as black lines or double layers, as the muscularis propria kept its integrity; T3 tumors showed partial discontinuity of the muscularis propria as a dotted line and a perforated area as an interrupted line. A confidence level scoring system was used, and receiver operating characteristic curves were generated., Results: There were no significant differences at the T1 stage. There were significant differences for observer 1 (P = 0.001 for observer 1) at the T2 stage. There were significant differences for both observers (P = 0.001 for observer 1 and P = 0.005 for observer 2) at the T3 stage., Conclusion: Our criteria for Gd-enhanced dynamic MRI were effective for T3 stage tumors.

Purpose: The purpose of the present study is to investigate anticancer efficacy and apoptosis confirmed by caspase under several exposure conditions of high-intensity focused ultrasound (HIFU)., Materials and Methods: Twenty-five rats with KDH-8 hepatoma were treated by HIFU at several acoustic energies to evaluate treatment efficacy. Apoptosis was examined by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) and Hoechst 33258 staining, and caspase 3, 8, and 9/6 activity was respectively assayed., Results: The KDH-8 subcutaneous tumors were reduced by HIFU, and these rats survived longer than the nontreatment rats (P < 0.01). The minimal threshold of HIFU energy was 30 W × 1.0 s for tumor control and long-term survival. The tumors exposed to HIFU exhibited marked apoptotic features under conditions of less than 10 W × 1.0 s. In cultured KDH-8 cells, apoptosis was caused at less than 30 W × 1.0 s (P < 0.01), and more was induced as the energy went down. Caspase 3, 8, and 9/6 were more activated at low energy under 10 W × 1.0 s (P < 0.01), and caspase 8, which is death receptor dependent, was significantly more activated than caspase 9/6, which is mitochondria dependent (P < 0.01)., Conclusion: HIFU-induced apoptosis in vivo and in vitro is one of the mechanisms for tumor control and is mediated by caspase 3, 8, and 9/6. The significantly greater activation of caspase 8 than of caspase 9/6 suggests that the apoptosis pathway induced by HIFU might be more mitochondria dependent than death receptor dependent. However, further examination will be needed.

Purpose: Image-guided biopsy occasionally fails to diagnose small lung lesions, which are highly suggestive of primary lung cancer. The aim of the present study was to evaluate the outcome of stereotactic body radiotherapy (SBRT) for small lung lesions that were clinically diagnosed as primary lung cancer without pathologic confirmation., Methods and Materials: A total of 115 patients were treated with SBRT in 12 institutions. Tumor size ranged from 5 to 45 mm in diameter, with a median of 20 mm., Results: The 3-year and 5-year overall survival rates for patients with a tumor size < or =20 mm in diameter (n = 58) were both 89.8%, compared with 60.7% and 53.1% for patients with tumors >20 mm (n = 57) (p <0.0005), respectively. Local progression occurred in 2 patients (3.4%) with a tumor size < or =20 mm and in 3 patients (5.3%) with tumors >20 mm. Among the patients with a tumor size < or =20 mm, Grade 2 pulmonary complications were observed in 2 (3.4%), but no Grade 3 to 5 toxicity was observed. In patients with a tumor size >20 mm, Grades 2, 3, and 5 toxicity were observed in 5 patients (8.8%), 3 patients (5.3%), and 1 patient (1.8%), respectively., Conclusion: In patients with a tumor < or =20 mm in diameter, SBRT was reasonably safe in this retrospective study. The clinical implications of the high local control rate depend on the accuracy of clinical/radiologic diagnosis for small lung lesions and are to be carefully evaluated in a prospective study.

Purpose: The purpose of this study was to assess the control of nidus blood flow and the association between such control and clinical outcomes after ethanolamine oleate (EO) sclerotherapy for vascular malformations., Materials and Methods: Morphological grades on magnetic resonance (MR) images (grades 1-3), preprocedure nidus blood flow control, and clinical results in 22 cases of vascular malformation were reviewed., Results: Cases were subdivided by MR morphological grade as follows: grade 1, 3 patients; grade 2A, 6 patients; grade 3, 13 patients. Responses to EO sclerotherapy were as follows: excellent, 3 patients; good, 5 patients; poor, 14 patients. An excellent response was achieved in one grade 1 case, one grade 2A case, and one grade 3 case. Preprocedure nidus flow was controlled in 8 lesions (type A) and not controlled in 14 lesions (type B). Three (37.5%) type A lesions had an excellent response, five had a good response; and none had a poor response. All type B lesions had a poor response. Flow control predicted an excellent result (P < 0.05)., Conclusion: Preprocedure nidus blood flow control (versus lack of control) is associated with a significantly higher incidence of favorable clinical responses to EO sclerotherapy for vascular malformations.

Antioxidant molecules reduce oxidative stress and protect cells from reactive oxygen species (ROS)-mediated cellular damage and probably the development of cancer. We have investigated the contribution of X-box-binding protein (XBP1), a major endoplasmic reticulum stress-linked transcriptional factor, to cellular resistance to oxidative stress. After exposure to hydrogen peroxide (H(2)O(2)) or a strong ROS inducer parthenolide, loss of mitochondrial membrane potential (MMP) and subsequent cell death occurred more extensively in XBP1-deficient cells than wild-type mouse embryonic fibroblast cells, whereas two other anticancer agents induced death similarly in both cells. In XBP1-deficient cells, H(2)O(2) exposure induced more extensive ROS generation and prolonged p38 phosphorylation, and expression of several antioxidant molecules including catalase was lower. Knockdown of XBP1 decreased catalase expression, enhanced ROS generation and MMP loss after H(2)O(2) exposure, but extrinsic catalase supply rescued them. Overexpression of XBP1 recovered catalase expression in XBP1-deficient cells and diminished ROS generation after H(2)O(2) exposure. Mutation analysis of the catalase promoter region suggests a pivotal role of CCAAT boxes, NF-Y-binding sites, for the XBP1-mediated enhancing effect. Taken together, these results indicate a protective role of XBP1 against oxidative stress, and its positive regulation of catalase expression may at least in part account for this function.

Background: Secondary cancers are severe complications in patients who have had allogeneic bone marrow transplantation for childhood leukemia. We describe here a case of squamous cell carcinoma (SCC) of the buccal mucosa in a young adult patient who had had allogeneic bone marrow transplantation for childhood acute leukemia., Methods and Results: The primary tumor was treated with interstitial brachytherapy, and lymph node metastasis was treated by supraomohyoid neck dissection. The patient had a history of acute lymphoblastic leukemia (ALL) at 11 years of age and had received an allogeneic bone marrow transplant from a female donor. Further investigation of the tissue specimens by fluorescent in situ hybridization (FISH) revealed that an XX chromosome pattern was dominant in the tumor region, and this suggested that donor-derived cells might affect carcinogenesis in the recipient., Conclusions: This case presents an incidence of secondary oral cancer associated with allogeneic bone marrow transplantation.

The purpose of this study is to evaluate tumor vascularity of pancreatic carcinoma noninvasively by contrast-enhanced ultrasound (US) and clarify the diagnostic value of tumor vascularity in subjects with nonresectable advanced pancreatic carcinoma. The study was approved by our institutional review board and written informed consent was obtained from all subjects. Twenty-seven subjects with advanced pancreatic ductal carcinoma were treated by chemoradiotherapy. Contrast-enhanced US, US guided biopsies and dynamic computed tomography (CT) were performed before and after the therapy. We assigned the intratumoral enhancement pattern of US as an enhanced ultrasound (EU) score, from 1 to 4, according to the degree of enhancement area. Intratumoral microvessel density (IMD) and average vessel diameter (AVD) were calculated by means of CD 34 immunostaining. Vascular endothelial growth factor (VEGF) staining was graded on a scale of 1 to 3. EU scores before chemoradiotherapy were compared with IMD, AVD, VEGF, histological grading and hepatic metastasis. After the therapy, local treatment response was evaluated by dynamic CT calculating the maximum area of the tumor, by comparing it with its size in pre- therapy. Subjects who had at least a 50% or more decrease of tumor size lasting more than 4 wk were estimated as partial response (PR), more than a 50% of increase progressive disease (PD) and if neither PR nor PD criteria were met, they were classified as stabled disease (SD). Next, EU scores were compared with IMD, AVD, VEGF and treatment response. Statistically significant differences were evaluated by Pearson's correlation, post-hoc, Spearman's rank correlation, Wilcoxon rank sum and Student's t-test. A p < 0.05 was defined as being statistically significant. Before the therapy, the EU score and IMD were significantly correlated (r = 0.50, p < 0.02), as was VEGF (r = 0.45, p < 0.05). The EU score and AVD were negatively correlated (r = - 0.56, p < 0.02). Significant correlation was found between the EU score and histological grading (p < 0.004). The EU score was higher in subjects who had hepatic metastasis compared with subjects who had no hepatic metastasis (p < 0.05). After chemoradiotherapy, 14 subjects exhibited PR, while 13 showed SD. None of the subjects showed PD. The EU score was smaller in PR than SD (p < 0.05). The EU score significantly decreased after the therapy in PR (p < 0.01) but not in SD. IMD and AVD did not significantly decrease in either PR or SD; however, VEGF decreased significantly in PR (p < 0.01) but not in SD. Contrast-enhanced US could reveal tumor vascularity of pancreatic ductal carcinoma and could be potentially useful to evaluate treatment effect of subjects who receive chemoradiotherapy. Further investigation will be needed to prove the usefulness of contrast-enhanced US.

Purpose: We evaluated the efficacy of magnetic resonance angiography (MRA) for detecting the artery of Adamkiewicz (AKA) and the vertebral level of its feeding arteries branching from the aorta., Materials and Methods: Eighty-two patients (67 men, 15 women; aged 34 to 86 years, mean age 68.6 years) with thoracic descending and thoracoabdominal aortic lesions (aneurysm in 55, dissection in 25, coarctation in 2) underwent MRA to detect AKA. MRA was performed using 6-phase, dynamic-enhanced, 3-dimensional, fast spoiled gradient recalled acquisition in steady state (GRASS) on a 1.5-tesla (T) system, with double-dose bolus contrast injection. The vertebral levels of AKA branching and the AKA feeder artery branching from the aorta were determined., Results: The AKA was detected in 67 patients (81.7%). Branching of AKA occurred at levels T7 to T12 on the left side (n=52) and on the right (n=15). Vascular continuity from the aorta to the anterior spinal artery was demonstrated in 55 patients (67.1%). Comparing the vertebral level of arterial branching from the aorta to that of the AKA at the intervertebral foramen, the AKA branched at the same vertebral level in 44 patients (80.0%), one vertebral level above/below in 10 (18.2%), and 2 vertebral levels above in one (1.8%)., Conclusion: MRA can be useful in the preoperative work-up of patients with thoracoabdominal aortic lesions to localize AKA and the segmental trajectories of vessels supplying blood to the AKA.

Background: Treatment outcome was evaluated in patients who underwent breast-conserving therapy and tangential irradiation. After verifying background factors including systemic therapy, the clinical efficacy of postoperative irradiation was investigated., Method: There were 708 study subjects, all of whom had early breast cancer treated between 1992 and 2002. The median follow-up period was 83 months. After breast-conserving surgery, in patients with negative surgical margins, only tangential irradiation at 48 Gy/24 fr was performed. In contrast, in those with positive surgical margins, 10 Gy of radiation boost to the tumor bed with electrons was administered after tangential irradiation with 50 Gy/25 fr. Treatment outcome was analyzed using the Kaplan-Meier method and Cox's proportional hazards regression model., Results: The disease-free survival and no-recurrence rates within the ipsilateral breast after 5 years were 93.4 and 97.2%, respectively. Risk factors for recurrence within the ipsilateral breast included younger age of patient, the number of positive lymph nodes, and no endocrine therapy. However, the surgical margin was not a risk factor. Risk factors for relapse outwith the ipsilateral breast included younger age, the number of positive lymph nodes, and recurrence within the ipsilateral breast., Conclusions: From our analysis of 708 Japanese women who received breast-conserving therapy, which can be regarded as a standard method in Japan, the treatment outcome was compatible with previous reports from other countries.

Altered fractionation schedules are based on two different concepts of radiobiology. One concept is that the radiation repair capability of cells in late responding tissues is higher than that of cells in acute responding tissues which include tumor tissues. Hyperfractionation utilizes this concept. The other concept is that accelerated repopulation of tumor cells occurs in a later period of radiation therapy. In order to overcome repopulation of tumor cells, accelerated hyperfractionation is proposed. These two concepts are independent and some fractionation methods include both concepts. Clinical results of altered fractionation schedules of radiation therapy could be predicted with a biological model (the linear quadratic model theory)for fractionated radiation. When this biological model is applied to tumors in which the tumor cell repopulation during radiotherapy period is negligible, the correction for tumor proliferation is required. Since the calculation of the biological effect dose with this model uses several assumptions, we should consider the biological effect dose as a crude approximation. Especially, in case of concomitant chemotherapy and altered fractionation, it is difficult to predict its results with a simple radiobiology model. The randomized trial is required to examine the significance of chemoradiotherapy using altered fractionation.

Purpose: Severe acute radiation dermatitis is observed in approximately 5% to 10% of patients who receive whole-breast radiotherapy. Several factors, including treatment-related and patient-oriented factors, are involved in susceptibility to severe dermatitis. Genetic factors are also thought to be related to a patient's susceptibility to severe dermatitis. To elucidate genetic polymorphisms associated with a susceptibility to radiation-induced dermatitis, a large-scale single-nucleotide polymorphism (SNP) analysis using DNA samples from 156 patients with breast cancer was conducted., Experimental Design: Patients were selected from more than 3,000 female patients with early breast cancer who received radiotherapy after undergoing breast-conserving surgery. The dermatitis group was defined as patients who developed dermatitis at a National Cancer Institute Common Toxicity Criteria grade of > or =2. For the SNP analysis, DNA samples from each patient were subjected to the genotyping of 3,144 SNPs covering 494 genes., Results: SNPs that mapped to two genes, ABCA1 and IL12RB2, were associated with radiation-induced dermatitis. In the ABCA1 gene, one of these SNPs was a nonsynonymous coding SNP causing R219K (P = 0.0065). As for the IL12RB2 gene, the strongest association was observed at SNP-K (rs3790568; P = 0.0013). Using polymorphisms of both genes, the probability of severe dermatitis was estimated for each combination of genotypes. These analyses showed that individuals carrying a combination of genotypes accounting for 14.7% of the Japanese population have the highest probability of developing radiation-induced dermatitis., Conclusion: Our results shed light on the mechanisms responsible for radiation-induced dermatitis. These results may also contribute to the individualization of radiotherapy.

Background and Purpose: Flow voids within the cavernous sinuses and/or certain venous drainage on spin-echo MR imaging and time-of-flight (TOF) flow enhancement on MR angiography (MRA) have indicated high-velocity shunt flow and have been used for screening patients with dural arteriovenous fistulas (DAVFs) of the cavernous sinuses. In this investigation, the capabilities of 3D dynamic MRA as a flow-independent approach and those of conventional MR imaging techniques were compared with selective angiography for the diagnosis of DAVFs of the cavernous sinuses., Materials and Methods: This retrospective study involved 18 patients with angiographically proved DAVFs of the cavernous sinuses and 12 control subjects. Sixteen partially overlapping sequential MR images were acquired on contrast-enhanced 3D dynamic MRA between the petrosal bone and the orbital roof. Two experienced observers blinded to the clinical data and results of angiography independently graded 3D dynamic MRA, fast spin-echo T2-weighted imaging (FSE T2WI), and TOF MRA., Results: The average area under the receiver operating characteristic curve values and interobserver kappa scores for the diagnosis of DAVFs on 3D dynamic MRA, FSE T2WI, and TOF MRA were 0.99, 0.89, and 0.95; and 0.92, 0.71, and 0.73, respectively. Those for the diagnosis of anterior, posterior, and retrograde cortical venous drainage on 3D dynamic MRA were 0.72, 0.95, and 0.81; and 0.56, 0.50, and 0.49, respectively., Conclusion: In this small series, screening 3D dynamic MRA directly demonstrates DAVFs of the cavernous sinuses and has improved diagnostic capability.

Purpose: The purpose of this study was to elucidate the wall layer appearance of the human hepatic artery shown by intravascular ultrasound (IVUS)., Methods: We evaluated the wall layer appearance of 57 human hepatic arteries from 36 cadavers. The thickness of the inner high-echoic layer and the second low-echoic layer of the arteries was measured by IVUS, and it was compared with that of the arterial intima and media, respectively., Results: The thickness of the inner high-echoic layer was 0.2 ± 0.1 mm and that of the second low-echoic layer was 0.4 ± 0.1 mm, on IVUS. However, the histological thickness of the intima was 120 ± 45 μm and that of the media was 258 ± 71 μm. The media of the hepatic artery correlated significantly with the second low-echoic layer on IVUS (r = 0.62, P < 0.01). The diameter of the vessels measured on IVUS correlated significantly with that of the histological specimens (r = 0.89, P < 0.01)., Conclusion: From our results, the three layers of the hepatic artery detected with IVUS may correspond to the intima, media, and adventitia, respectively.

Background and Purpose: Hyperfractionated accelerated radiotherapy without a split (AF) has been performed to improve the local control probability of early glottic carcinomas since 1990 in the authors' institution. Here, they report their experience treating early glottic cancer patients with AF in a single institution who have a long follow-up period., Patients and Methods: 131 T1 N0 M0 glottic cancers and 65 T2 N0 M0 glottic cancers were treated with conventional fractionation (CF) from 1984 to 1989 and with AF since 1990. CF consisted of five daily fractions of 2 Gy per week, to a total dose of 64 Gy. AF consisted of 1.72 Gy per fraction, two fractions per day, 5 days a week, to a total dose of 55 or 58.5 Gy., Results: The 5-year local control probability for T1 tumors was 94% with 58.5 Gy and 87% with 55 Gy of AF, whereas it amounted to 80% with CF. For T2 tumors, it was 56% with 58.5 Gy and 68% with 55 Gy of AF, whereas it amounted to 64% with CF. The data of T2 should be evaluated with caution due to the small number of patients. Patients with AF had more severe mucosal reactions but no severe late reactions., Conclusion: AF significantly improved the local control rates for T1 glottic cancer.

In this study, we examined the ability of an L-EPID to verify rectangular and irregular fields and to measure the transmitted exit doses. With respect to the beam profile of rectangular and irregular fields and the doses transmitted through an inhomogeneous phantom, the L-EPID dose obtained from the L-EPID measurement was compared with the conventional dose measured by use of a 0.12-cc ionization chamber and a 3D water phantom. In the comparison of the rectangular and irregular fields, the difference in the off-center ratio (OCR) between the L-EPID dose and the conventional dose was approximately 3% in the steep-dose-gradient region (penumbra regions, >30%/cm) and approximately +/-0.5% in the gentle-dose-gradient region (5%/cm). On the other hand, the dose differences between the L-EPID and the measured doses were less than approximately 2% in the gentle-dose-gradient region. In addition, in the steep-dose-gradient region, the maximum difference was 30%. However, the differences in the distance-to-agreement (DTA) were less than approximately +/-1 mm and were unrelated to the dose gradient. These results suggest that dose verification by L-EPID is very useful in clinical applications.

Objective: Low-dose-rate (LDR) brachytherapy is an effective treatment for tongue cancer. However, little is known about the biological mechanism underlying this therapy, characterized by delivery of continuous exposures of LDR irradiation. It is reported that lower microvessel density (MVD), lower Ki-67 index or higher expression of endogenous hypoxic markers such as carbonic CA IX and Glut-1 are related to the poor control of tumors treated with external irradiation. To elucidate the biological characteristics of LDR brachytherapy, we analyzed our results in cases of tongue cancer treated with LDR brachytherapy by using immunohistochemical stainings with antibodies against Ki-67 and MVD, Glut-1 and CA IX., Methods: The prognostic value of Ki-67 index, MVD and the expression of CA IX and Glut-1 was assessed in 68 tongue cancers treated with LDR brachytherapy. The specimens were taken from tongue cancers before radiation therapy and immunohistochemical staining was performed., Results: The local recurrence-free survival rates were significantly different between T1+T2 and T3 (P = 0.00067), but not between low and high Ki-67 indexes (P = 0.54), between low and high MVD (P = 0.071), low and high CA IX indexes (P = 0.062) or low and high Glut-1 indexes (P = 0.107). T stage, the size of the tumor was the only significant factor for local control in multivariate analyses (P = 0.0377)., Conclusion: LDR could overcome the radioresistence of non-cycling and hypoxic cells; however, we cannot draw firm conclusions due to the limited number of patients.

Purpose: The goal of this study was to clarify the dynamics of oxygenation (partial pressure of oxygen, pO(2)) in SCC VII murine tumors in mice after X-ray irradiation., Materials and Methods: Changes in pO(2) in tumors were measured by 1.2-GHz electron paramagnetic resonance (EPR) spectroscopy after they were exposed to various doses of irradiation. The pO(2) in tumors was followed for up to six days after irradiation at doses of 0, 5, 10, 15, and 20 Gy. Paramagnetic crystals were used as an oximetry probe and implanted into normal or tumor tissues in mice for prolonged periods., Results: The pattern of tumor oxygen after a single dose of radiation with the 5-Gy dose was different from those with other doses (10, 15, and 20 Gy). After 5 Gy, pO(2) increased rapidly (P<0.01, Student's t test) and then returned to the level observed before irradiation by 12h (P<0.01). In contrast, after 10, 15, or 20 Gy, pO(2) increased rapidly by 6h after irradiation, continued to increase until at least 24h (P<0.01), and then gradually decreased., Conclusions: In tumors that received 5 Gy, post-irradiation increases in pO(2) at 4h after irradiation were detected by EPR oximetry (P<0.01) noninvasively.

Background: Nasal NK/T cell lymphoma is an aggressive disease and has a poor prognosis. Nasal NK/T cell lymphoma is refractory to conventional chemotherapy and has strong tendency of widespread relapse or dissemination into distant sites., Methods: We immunohistochemically studied nasal NK/T-cell lymphoma to elucidate the unique characteristics of nasal NK/T-cell lymphoma, such as its higher metastatic tendency and its vast necrosis which leads to destruction of the involved tissues. The expression of P-glycoprotein and MMP-9 was evaluated in the 20 patients with nasal NK/T-cell lymphoma and 25 with nasal non-NK/T-cell lymphoma and the relationship between expression of these proteins and clinical results were analyzed in this report., Results: Overall 5-year survival rates for patients with nasal NK/T cell lymphoma, and nasal non-NK/T cell lymphoma were 51%, and 84%. Distant involvement free 5-year survival rates for patients with nasal NK/T cell lymphoma, and nasal non-NK/T cell lymphoma were 53%, and 79%. Overall positivity for P-glycoprotein was observed in 10 of 19 patients with NTL and in 13 of 23 patients with non-NTL. When the overall survival rate was compared between patients with P-glycoprotein positive and negative, there was no difference between them. Sixteen of the 19 patients with nasal NK/T cell lymphoma expressed MMP-9. In contrast, only 8 of the 22 patients with nasal non-NK/T cell lymphoma expressed MMP-9. Distant involvement free 5-year survival rates for patients with MMP-9 negative, and MMP-9 positive were 92%, and 61%, respectively. The difference was statistically significant (p = 0.027)., Conclusion: Positive immunoreactivity for P-glycoprotein was not an independent prognostic factor in nasal NK/T-cell lymphomas, which stresses the importance of exploring other mechanisms of drug resistance. The strong expression of MMP-9 is uniquely characteristic of nasal NK/T cell lymphoma and may contribute to its strong tendency to disseminatate and the extensive necrosis which is always seen. However, our results are based on univariate comparisons, and as such, should be viewed with some caution.

DNA-dependent protein kinase (DNA-PK) has an important role in DNA double-strand break repair. We previously demonstrated the association of DNA-PK activity in peripheral blood lymphocytes (PBL) with incidence of chromosomal aberrations and risk of cancer. In this study, we examined the expression of Ku70 and Ku86 in breast cancer tissue and normal breast tissue with immunohistochemistry. We also measured the DNA-PK activity in PBL of the same patient. One hundred and ten breast cancer patients were included in this study. The expression of Ku70, and Ku86 in normal mammary epithelial cells and breast cancer cells obtained from surgical specimens was immunohistochemically examined. DNA-PK activity of PBL was measured by DNA-pull-down assay. The expression of Ku70 and that of Ku86 tended to parallel each other in normal and cancer tissues. There was also a relationship in the expression of Ku70 and Ku86 between cancer tissues and normal tissues in the same samples. Lower expression of Ku70 or Ku86 tended to be associated with higher malignant nuclear grade of cancer cells and higher frequency of axillary lymph node metastasis. The staining score of Ku70 or Ku86 of normal mammary epithelial cells or breast cancer cells had no significant relationship with DNA-PK activity of PBL. In conclusion, breast cancer cells inherited the characteristics of expression of Ku proteins from original mammary epithelial cells. The staining score of Ku70 or Ku86 of normal or cancer cells had no significant relationship with DNA-PK activity of PBL. This may be due to limitations in the assay sensitivity of immunohistochemistry.

Traditional radiobiology has aimed at elucidating the mechanism of radiosensitivity of cancer cells and normal cells. Because the mechanism of DNA double-strand break (DSB) repair, which is inherently important to radiosensitivity, was unknown, it has been difficult to obtain results applicable to clinical radiotherapy from traditional radiobiology research. Today, however, the molecular mechanism of DNA DSB repair has been elucidated because of the rapid advances in molecular biology. In DNA DSB repair, at least two major repair mechanisms, homologous recombination and nonhomologous end joining (NHEJ) have been reported. In the NHEJ pathway, DSBs are directly, or after processing of the DNA ends, rejoined at an appropriate chromosomal end. DNA-dependent protein kinase (DNA-PK) plays an important role in DNA DSB repair by NHEJ. We have investigated how the ability of repair of DNA DSB influences cancer susceptibility and the radiosensitivity of tumors and normal tissues by focusing on the activity of DNA-PK. In the near future, research on DNA DSB repair mechanism will be able to be applied to research on carcinogenesis, prediction of radiosensitivity of tumors and normal cells, and sensitization of tumor cells.

DNA double-strand break (DSB) is one of the most deleterious lesions induced by DNA damaging agents. DSB repair pathway is implicated in maintaining genomic integrity via suppression of genetic instability and neoplastic transformation. DNA-dependent protein kinase (DNA-PK) has a pivotal role in DNA DSB repair. The Nijmegen breakage syndrome protein (NBS1), essential for DSB repair, re-localizes into subnuclear structures upon induction of DNA damage by ionizing radiation, forming so-called ionizing radiation-induced foci (IRIF), which is visualized by immunostaining. We measured DNA-PK activity and the number of persistent NBS1 IRIF per nucleus 24 h after irradiation of peripheral blood lymphocytes (PBL) from patients with sporadic breast cancer. Chromosomal aberrations were examined by cytogenetic methods. We examined the relationship between these measurements and clinical characteristics of patients such as tumor size, lymph node metastasis and nuclear grade of cancer cells. A higher number of NBS1 IRIF or lower DNA-PK activity correlated with higher chromosome instability. Patients whose PBL had lower DNA-PK or higher NBS1 IRIF had aggressive cancer phenotypes such as a larger tumor, higher nuclear grade and positive axillary lymph node metastasis. The combination of DNA-PK activity and NBS1 IRIF were useful for predicting lymph node metastasis. The ability of DSB repair in PBL is related to aggressive breast cancer phenotypes. Axillary lymph node dissection can be avoided by examining DNA-PK activity and NBS1 IRIF of PBL, which can contribute to improving the quality of life of breast cancer patients.

Objective: To explore the effect of the number of two-dimensional (2D) images and x-ray projection angles on the resolution of reconstructed three-dimensional (3D) volumes of intracochlear electrode arrays in cadaveric cat temporal bones using Tuned Aperture Computed Tomography (TACT)., Design: Multiple 2D radiographs (basis images (BI)) of implanted cadaveric cat temporal bones were acquired using a range of projection angles, and imported into the TACT workbench. 3D volumes were reconstructed using varying numbers of BIs. Contrast resolution in the image was determined by comparing the contrast ratio (using maximum and minimum grayscale values) in specified anatomic areas of interest., Results: Systematically increasing the number of BIs used in the reconstruction process resulted in a systematic increase in contrast resolution. Likewise, increasing the range of effective projection angles, as also the number of such angles used in the TACT computation also increased the contrast resolution of the resulting images., Conclusions: Precise determination of the location of cochlear implant electrodes in situ is critical to understanding the factors influencing efficacy of electrical stimulation of the deaf ear. Renderings generated with the TACT algorithm produce 3D images permitting visualization of implant electrode features and anatomic details with resolution sufficient to accurately localize electrode contacts within scala tympani. The quality of resulting images, evaluated as a function of image contrast, improved with a larger number of BIs in the reconstruction. Wider projection angles also improved image detail in addition to generating thinner slices. Any loss in contrast was compensated for by the number of BIs. TACT can thus be optimized to provide useful data to help characterize the location of intracochlear electrode arrays.

Purpose: To evaluate the efficacy of double-subtraction magnetic resonance angiography (MRA) (subtraction of the subtracted venous phase image from the subtracted arterial dominant phase image) for depicting the artery of Adamkiewicz and differentiating it from the drainage vein., Materials and Methods: A total of 170 patients (123 men, 47 women; aged 17-84 years, mean = 67 years), with a thoracoabdominal vascular lesion underwent MRA for detection of the artery of Adamkiewicz. MRA was performed as a five-phase dynamic-enhanced three-dimensional (3D) fast spoiled gradient recalled acquisition in steady state (GRASS) sequence on a 1.5-T system, with double-dose bolus contrast and saline injection. The levels at which the artery of Adamkiewicz and drainage vein originated were determined. Signal intensities of the two vessels were measured with source images to assess the signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), and necessity of the double-subtraction technique., Results: The artery of Adamkiewicz was detected in 140 patients (82.4%). Branching occurred at levels T8-T12 on the left and T8-T11 on the right. An additional anterior radiculomedullary artery was detected in 18 patients. The drainage vein was detected in 133 patients (78.2%). It merged at the T9-L2 level on both sides. In six of the 133 patients (4.5%), the drainage vein branched upwardly. Neither SNR nor CNR differed significantly between the artery of Adamkiewicz and the drainage vein in the arterial phase; but on the subtraction image, signal intensity of the artery was higher than that of the drainage vein (P < 0.05)., Conclusion: Double-subtraction MRA is useful for detecting the artery of Adamkiewicz when it is necessary to differentiate it from the drainage vein., ((c) 2007 Wiley-Liss, Inc.)

Objective: To determine the suitability of Tuned Aperture Computed Tomography (TACT) to generate high-resolution images of intracochlear electrode arrays, in situ, with sufficient anatomic and electrode detail to relate the location of individual electrode contacts to important anatomic landmarks in cat cadaveric temporal bones. The ultimate objective is to develop an imaging technology whereby variations in electrode location, relative to the target neural tissues, can be accurately determined and related to variations in performance with the cochlear implant., Design: Cat temporal bones were implanted with an experimental scala tympani electrode array and an external fiducial landmark. A series of conventional 2D digital radiographs were collected from a variety of x-ray source projection angles and served as for generation of 3D volume renderings using the TACT software toolbox. The 3D renderings were then reoriented and resliced interactively to view the cochlear and electrode features of interest., Results: Significant electrode and anatomical details could be visualized including the course of the electrode wires (<40 microm diameter), the location of all electrode contacts and the outline of the scala tympani., Conclusions: TACT generates high-resolution 3D images from 2D conventional radiographs. With TACT, the 3D renderings can be interactively reoriented and resectioned to permit visualization of any cochlear or electrode feature. In the present study, this aspect of TACT affords the opportunity to view of the location of each electrode contact relative to the adjacent cochlear features, such as the scalar walls. Because TACT uses conventional radiographic images to generate the volume renderings, the quality and resolution of the resulting 2D images do not suffer from artifacts characteristic of CT. These findings suggest that TACT may be a powerful tool for understanding the contribution of electrode placement to perceptual performance with the cochlear implant.

Introduction: Hypofractionated stereotactic radiotherapy (HypoFXSRT) has recently been used for the treatment of small lung tumors. We retrospectively analyzed the treatment outcome of HypoFXSRT for stage I non-small cell lung cancer (NSCLC) treated in a Japanese multi-institutional study., Methods: This is a retrospective study to review 257 patients with stage I NSCLC (median age, 74 years: 164 T1N0M0, 93 T2N0M0) were treated with HypoFXSRT alone at 14 institutions. Stereotactic three-dimensional treatment was performed using noncoplanar dynamic arcs or multiple static ports. A total dose of 18 to 75 Gy at the isocenter was administered in one to 22 fractions. The median calculated biological effective dose (BED) was 111 Gy (range, 57-180 Gy) based on alpha/beta = 10., Results: During follow-up (median, 38 months), pulmonary complications of above grade 2 arose in 14 patients (5.4%). Local progression occurred in 36 patients (14.0%), and the local recurrence rate was 8.4% for a BED of 100 Gy or more compared with 42.9% for less than 100 Gy (p < 0.001). The 5-year overall survival rate of medically operable patients was 70.8% among those treated with a BED of 100 Gy or more compared with 30.2% among those treated with less than 100 Gy (p < 0.05)., Conclusions: Although this is a retrospective study, HypoFXSRT with a BED of less than 180 Gy was almost safe for stage I NSCLC, and the local control and overall survival rates in 5 years with a BED of 100 Gy or more were superior to the reported results for conventional radiotherapy. For all treatment methods and schedules, the local control and survival rates were better with a BED of 100 Gy or more compared with less than 100 Gy. HypoFXSRT is feasible for curative treatment of patients with stage I NSCLC.

Background: Clivus epidural hematoma (CEH) is reported to be extremely rare. However, we consider that CEH may not be as rare as commonly thought, and that it may often go unrecognized because of diagnostic problems. The aim of this study was to evaluate the value of multidetector row computed tomography (MDCT) in the diagnosis of CEH., Methods: Twenty-seven children aged less than 16 years who had experienced traffic crashes or falls were retrospectively evaluated with MDCT including sagittal reconstruction of the cervical spine., Results: Sagittal reconstructed images showed definitive findings of CEH in 3 (13%) of the 24 traffic-crash patients., Conclusion: MDCT can show definitive findings of CEH, and diagnostic problems can be solved through the utilization of MDCT. We consider that CEH may be more common than previously thought.

To reappraise the cutoff level of abdominal circumference (AC) for diagnosis of visceral obesity in Japanese, we examined the association of visceral fat deposition with other constituents of metabolic syndrome and atherosclerotic cardiovascular disease (ASCD). CT was used for determination of visceral-fat area (VFA), subcutaneous-fat area (SFA) and AC on CT (AC(CT)) in 420 Japanese patients with (n=180) or without ASCD (n=240). VFA cutoff levels were calculated by receiver operating characteristic (ROC) analysis. AC(CT) correlated with VFA (r=0.828), SFA (r=0.795), and AC measured with an anthropometric tape (AC(M), r=0.96). The VFA cutoff levels yielding the maximum sensitivity and specificity to predict two or more components of metabolic syndrome were 92 cm(2) in males and 63 cm(2) in females, which correspond to AC(M) values of 83 cm and 78 cm, respectively. The male AC(M) cutoff level was similar to the AC in current Japanese criteria (85 cm), but the female AC(M) cutoff level was considerably smaller than the criteria, and this change in cutoff level increased the prevalence of metabolic syndrome in females three-fold. The cutoff levels of VFA for predicting presence of ASCD were 98 cm(2) in males and 75 cm(2) in females, corresponding to AC(M) values of 84 cm and 80 cm, respectively. The present results obtained by CT support the validity of the current Japanese criteria for visceral obesity in males but not in females. AC(M) of 78 cm appears to be a cutoff level suitable for diagnosing visceral obesity in Japanese females, though further confirmation is needed.

DNA-dependent protein kinase (DNA-PK) is thought to play a pivotal role in DNA double-strand break repair. We recently demonstrated the association of DNA-PK activity in peripheral blood lymphocytes (PBL) with the incidence of chromosomal aberrations and the risk of cancer. In this study, we applied cDNA array technology to find the expression of genes which are associated with DNA-PK activity in PBLs with various levels of DNA-PK activity. Most genes correlated with DNA-PK activity involved cell cycle regulation. Moreover, the transcription factor E2F1, which plays an important role in cell cycle progression, exhibited strong correlation with the DNA-PK activity and Rbp130, which is considered a negative regulator of E2F, showed inverse correlation with DNA-PK activity. In silico promoter analyses showed the presence of at least one E2F binding site in the promoter regions of Ku70, Ku86, DNA-PKcs and genes associated with DNA-PK activity. In order to examine the relationship among the E2F1 expression, the expression of genes related with DNA-PK activity, and DNA-PK activity, we activated PMLs by PHA to progress the cell cycle. After PHA activation of PML, the expression of E2F1 and DNA-PK activity increased. The expression of most genes in PHA-stimulated PBLs had a similar relationship with DNA-PK activity to that without PHA stimulation. These results indicate that the E2F transcription factor may regulate the concerted expression of genes related with DNA-PK activity.

Purpose: To determine the recommended dose (RD) of cis-diammine-glycolatoplatinum (nedaplatin) when given concurrently with 5-FU and high dose radiation therapy in the treatment of esophageal cancer. The purpose of the phase II trial is to determine efficacy and further define the side effect profile., Methods: Twenty-six patients with clinical stage I to IVA squamous cell carcinoma of the esophagus were enrolled in a non-surgical treatment comprised of a fixed dose of fluorouracil (400 mg/m2 administered as continuous intravenous infusion on days 1-5 and days 8-12) plus escalating doses of nedaplatin (40 mg/m2 in level 1, 50 mg/m2 in level 2, or 60 mg/m2 in level 3 on days 1 and 8), repeated twice every 3 weeks with concurrent radiotherapy (60 Gy)., Results: Between July 1998 and February 2004, a total of 26 patients entered this trial, all of whom were considered evaluable for toxicity assessment. In phase I of the study, 12 patients were treated in sequential cohorts of three to six patients per dose level. The maximum tolerated dose was reached at level 3 with two grade 4 neutropenia and one grade 4 thrombocytopenia. Thus, the recommended dosing schedule is level 2. Of the 20 patients treated at the RD level 2, including 6 patients of the RD phase I portion, 8 out of 20 patients (40%) had grade 3-4 neutropenia, 5 patients (25.0%) had grade 3-4 thrombocytopenia, 4 patients (20.0%) had grade 3 anemia and 4 patients (20.0%) had grade 3-4 esophagitis. Other toxicities were relatively mild and usually of grade 2 or less. Objective responses were noted in the 26 patients (overall response rate, 88.5%) including 11 (42.3%) complete remissions. The 1- and 3-year survival rates were 65.1 and 37.2%, respectively, with a median survival time of 21.2 months., Conclusions: The combination of nedaplatin and 5-FU with radiation is a feasible regimen that shows promising antitumor activity with an acceptable safety profile in patients with esophageal cancer.

Purpose: 2-Methoxyestradiol (2ME), an estrogen metabolite, induces apoptosis in various cell types. We investigated whether 2ME pretreatment can radiosensitize colon adenocarcinoma cells., Experimental Design: Radiosensitizing effects of 2ME were evaluated by cell death, clonogenic assay, nuclear fragmentation, and tumor progression of xenografts. Ionizing radiation-induced DNA damage was evaluated by histone H2AX phosphorylation and its foci. The c-Jun NH2-terminal kinase (JNK) activation was evaluated by anti-phosphorylated JNK antibody and inhibited by the JNK-specific inhibitor SP600125 or dominant-negative SEK1 expression., Results: Clonogenic assays revealed that 2ME, but not estradiol, radiosensitized three colon carcinoma cells, DLD-1, HCT-8, and HCT-15, and strongly suppressed tumor progression of DLD-1 xenografts. Gene transfer-mediated Bcl-xL overexpression largely abolished both augmented apoptosis and reduced survival fractions. Pretreatment with 2ME enhanced H2AX phosphorylation, its foci, and phosphorylation of ATM kinase and delayed re-entry of cell cycle progression after ionizing radiation. Augmentation of both radiosensitivity and H2AX phosphorylation was substantially reduced by SP600125 or overexpression of a dominant-negative mutant SEK1., Conclusion: 2ME radiosensitized colon carcinoma cells through enhanced DNA damage via JNK activation, thereby representing a novel radiosensitizing therapy against colon cancer.

Background: A previous meta-analysis investigated the role of chemotherapy in head and neck locally advanced carcinoma. This work had not been performed on nasopharyngeal carcinoma., Objectives: The aim of the project was to study the effect of adding chemotherapy to radiotherapy on overall survival (OS) and event-free survival (EFS) in patients with nasopharyngeal carcinoma., Search Strategy: We searched MEDLINE (1966 to October 2003), EMBASE (1980 to October 2003) and the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, Issue 3, 2003) and trial registers. Handsearches of meeting abstracts, references in review articles and of the Chinese medical literature were carried out. Experts and pharmaceutical companies were asked to identify trials., Selection Criteria: Randomised trials comparing chemotherapy plus radiotherapy to radiotherapy alone in locally advanced nasopharyngeal carcinoma were included., Data Collection and Analysis: The meta-analysis was based on updated individual patient data. The log rank test, stratified by trial, was used for comparisons and the hazard ratios (HR) of death and failure (loco-regional/distant failure or death) were calculated., Main Results: Eight trials with 1753 patients were included. One trial with a 2 x 2 design was counted twice in the analysis. The analysis was performed including 11 comparisons based on 1975 patients. The median follow up was six years. The pooled hazard ratio of death was 0.82 (95% confidence interval (CI) 0.71 to 0.95; P = 0.006) corresponding to an absolute survival benefit of 6% at five years from chemotherapy (from 56% to 62%). The pooled hazard ratio of tumour failure or death was 0.76 (95% CI 0.67 to 0.86; P < 0.00001) corresponding to an absolute event-free survival benefit of 10% at five years from chemotherapy (from 42% to 52%). A significant interaction was observed between chemotherapy timings and overall survival (P = 0.005), explaining the heterogeneity observed in the treatment effect (P = 0.03) with the highest benefit from concomitant chemotherapy., Authors' Conclusions: Chemotherapy led to a small but significant benefit for overall survival and event-free survival. This benefit was essentially observed when chemotherapy was administered concomitantly with radiotherapy.

NBS1, a protein essential for DNA double-strand break repair, relocalizes into subnuclear structures upon induction of DNA damage by ionizing radiation, forming ionizing radiation-induced foci. We compared radiation-induced NBS1 foci in peripheral blood lymphocytes (PBLs) from 46 sporadic breast cancer patients and 30 healthy cancer-free volunteers. The number of persistent radiation-induced NBS1 foci per nucleus at 24 h after irradiation for patients with invasive cancer was significantly higher than for normal healthy volunteers. The frequency of spontaneous chromosome aberration increased as the number of persistent radiation-induced NBS1 foci increased, indicating that the number of persistent radiation-induced NBS1 foci might be associated with chromosome instability. There was also an inverse correlation between the number of radiation-induced NBS1 foci and the activity of DNA-dependent protein kinase (DNA-PK), which plays an important role in the nonhomologous end-joining (NHEJ) pathway, another mechanism of DNA DSB repair, indicating a close interrelationship between homologous recombination (HR) and NHEJ in DNA DSB repair. In conclusion, the number of persistent radiation-induced NBS1 foci is associated with chromosomal instability and risk of sporadic breast cancer and hence might be used to select individuals for whom a detailed examination is necessary because of their increased susceptibility to breast cancer, although refinement of the techniques for technical simplicity and accuracy will be required for clinical use.

Purpose: To examine various kinds of endogenous hypoxia markers' expression in the tissues of uterine cervix cancer and to elucidate the characteristics and pitfalls when they are used as a hypoxia marker, by comparing these expressions with tumor oxygen partial pressure (pO2) values., Patients and Methods: Assessment of pO2 using polarographic oxygen electrodes was performed in 69 patients with cervix carcinomas. Biopsies were taken from the region of electrode measurements. Expression of endogenous hypoxic markers in biopsy specimens such as vascular endothelial growth factor, glucose transporter-1 (GLUT-1), involucrin, and osteopontin was detected by immunohistochemistry. A double immunolabeling technique with GLUT-1 and MIB-1 as a marker of proliferation was also performed., Results: There was no significant correlation between expression of endogenous hypoxic markers and pO2. The only significant association seen was between the fraction of necrosis and pO2. A significant but weak correlation was found among expression of endogenous hypoxic markers. The levels of necrosis were related negatively with levels of expression of endogenous hypoxic markers. The double immunolabeling technique with GLUT-1 and MIB-1 indicated that there were about 20% MIB-1-positive tumor cells without GLUT-1 expression in tissues adjacent to areas of necrosis., Conclusion: The existence of necrosis affected the expression of endogenous hypoxic markers. Some hypoxic tumor cells without expressions of hypoxia markers can maintain clonogenicity and influence the treatment results. The combined use of hypoxic markers is recommended because their expression is influenced by factors other than hypoxia.

Histone deacetylase (HDAC) inhibitors augment ionizing radiation (IR)-induced apoptosis in several cancer cells by undefined mechanism(s). We recently found that the HDAC inhibitors induce a BH3-only protein Bmf in human squamous carcinoma SAS cells. We extended this study and found that 2.5 nM FK228 pretreatment could not induce apoptosis but augmented IR-induced death. The FK228 pretreatment increased Bmf expression level, and siRNA-mediated knockdown of Bmf transcripts strongly inhibited its augmentation of IR-induced cell death, disruption of mitochondrial membrane potential and DNA fragmentation. Another HDAC inhibitor CBHA pretreatment similarly augmented IR-induced apoptosis, and this effect was also inhibited by Bmf knockdown. Bmf overexpression augmented IR-induced death, and the augmented effects of FK228 were similarly observed in another squamous carcinoma HSC2 cells. Overexpression of histone acetyltransferase p300 mimicked the effects of the HDAC inhibitors, i.e., it enhanced IR-induced death, which was mostly abolished by Bmf knockdown. Taken together, histone hyperacetylation may enhance IR-induced death via activation of Bmf transcription, thereby implying Bmf as a key molecule for HDAC inhibitors (FK228 and CBHA)-mediated enhancing effect on IR-induced cell death.

Purpose: To analyze the outcomes of patients with early hypopharyngeal cancer treated with radical radiotherapy (RT)., Methods and Materials: Ten institutions combined the data from 115 patients with Stage I-II hypopharyngeal squamous cell carcinoma treated with definitive RT between 1990 and 2001. The median patient age was 67 years; 99 patients were men and 16 were women. Of the 115 patients, 39 had Stage I and 76 had Stage II disease. Conventional fractionation was used in 98 patients and twice-daily RT in 17 patients; chemotherapy was combined with RT in 57 patients. The median follow-up period was 47 months., Results: The overall and disease-specific 5-year survival rate for 95 patients without synchronous malignancies was 66.0% and 77.4%, respectively. The 5-year disease-specific survival rate by T stage was 95.8% for patients with T1 disease and 70.1% for patients with T2 disease (p=0.02). Of the 115 patients, local control with laryngeal voice preservation was achieved in 34 of 39 patients with T1 lesions, including 7 patients successfully salvaged, and in 56 of 76 patients with T2 lesions. Sixty-five patients (56.5%) had synchronous or metachronous cancers. Of the 115 patients, 19 died of hypopharyngeal cancer, 10 died of second primary cancers, and 14 died of other causes during the study and follow-up periods., Conclusions: Patients with early hypopharyngeal cancer tended to have a good prognosis after RT. However, second malignancies had an adverse effect on the overall outcomes of patients with early hypopharyngeal cancer.

Purpose: Histone deacetylase (HDAC) inhibitors are believed to be promising radiosensitizers. To explore their effects on ionizing radiation (IR), we examined whether the HDAC inhibitors m-carboxycinnamic acid bis-hydroxamide (CBHA) and depsipeptide FK228 affect H2AX phosphorylation (gamma-H2AX), a landmark of DNA double-strand breaks after IR exposure., Methods and Materials: We evaluated the effects of the HDAC inhibitors on clonogenic assay in human lung carcinoma A549 cells and progression of A549 xenograft tumors. IR-induced DNA damage was evaluated by histone gamma-H2AX. Histone hyperacetylation was induced by overexpression of histone acetyltransferase p300 and evaluated by Western blots., Results: M-carboxycinnamic acid bishydroxyamide pretreatment radiosensitized A549 cells and strongly inhibited A549 xenograft tumor progression. CBHA and FK228, but not 5-fluorouracil, enhanced IR-induced gamma-H2AX in A549 and other cancer cell lines. Overexpression of p300 similarly augmented IR-induced gamma-H2AX., Conclusion: The results of this study suggest that HDAC inhibitors enhance IR-induced gamma-H2AX, most likely through histone hyperacetylation, and radiosensitize various cancers.

The prognosis of stage IV malignant rhabdoid tumor of the kidney (MRTK) has been extremely poor. However, a combination of ICE (ifosfamide, carboplatin, and etoposide) and VDCy (vincristine, doxorubicin, and cyclophosphamide) was recently reported to be effective for metastatic MRTK. We describe a 21-month-old girl with stage IV MRTK who was successfully treated with ICE, VDCy, and radiotherapy. She remained well, without recurrence, 24 months after diagnosis. Alternating therapy with ICE and VDCy might become a standard regimen for stage IV MRTK, although further study is required to confirm its effectiveness.

Background and Purpose: This study was conducted to analyze the influence of radiotherapy doses and chemotherapy doses and clinical parameters on in-field disease control in order to assess the optimal radiation doses for treatment of mature T/NK-cell lymphomas according to the newly proposed WHO classification., Patients and Methods: Subjects consisted of 62 patients with mature T/NK-cell lymphomas treated with radiotherapy at four Japanese institutions between 1983 and 2002. We reevaluated all histopathological specimens of non-Hodgkin's lymphomas (NHL), using the WHO classification. Radiation therapy was usually delivered to the involved field. The majority of patients also received adriamycin-based chemotherapy such as CHOP, modified CHOP, or more intensive chemotherapy., Results: There were no significant differences in radiosensitivity among subtypes of mature T/NK-cell lymphomas, at least between extranodal NK/T-cell lymphomas, nasal type and peripheral T-cell lymphomas, unspecified. There was a radiation dose-response in non-bulky mature T/NK-cell lymphomas, indicating that radiation doses of more than 52 Gy may be required to obtain in-field control. However, it was difficult to obtain local control of bulky T-cell lymphomas, even with high doses of irradiation., Conclusions: Mature T/NK-cell lymphomas were more radioresistant than B-cell lymphomas such as diffuse large B-cell lymphomas (DLBCL). The chemotherapy including adriamycin did not improve the in-field control of mature T/NK-cell lymphomas. These results were obtained by using non-randomized data and the significance of these results is limited by bias in data. However, our results suggest that the treatment strategy which is usually used for DLBCL, that is, a combined modality of CHOP and around 40 Gy of radiotherapy, may not be sufficiently effective for mature T/NK-cell lymphomas.

The DNA double-strand breaks (DSBs) repair pathway has been implicated in maintaining genomic integrity via suppression of chromosomal rearrangements. DNA-dependent protein kinase (DNA-PK) has an important role with DNA DSBs repair. In this study, 93 of untreated cancer patients and 41 of cancer-free healthy volunteers were enrolled. Peripheral blood was collected, separated and centrifuged; DNA-PK activity was measured by DNA-pull-down assay. The expressions of DNA-PKcs, Ku70 and Ku86 were examined by RT-PCR assay and western blotting. Chromosomal aberrations were examined by cytogenetic methods. DNA-PK activities of peripheral blood lymphocytes (PBL) in patients with uterine cervix or breast cancer were significantly lower than those in normal volunteers. Age and smoking had no association with DNA-PK activity, whereas DNA-PK activity and the expression of Ku70, Ku86 and DNA-PKcs in RT-PCR were interrelated. A similar tendency was seen in western blot assay but less clear than in RT-PCR. Therefore, the association between DNA-PK activity and expression of DNA-PK in protein level could not be concluded. The frequency of chromosome aberration, such as dicentric chromosomes and excess fragment increased as the DNA-PK activity decreased. In conclusion, DNA-PK activity is associated with chromosomal instability. DNA-PK activity in PBL is associated with risk of breast and uterine cervix cancer. DNA-PK activity in PBL can be used to select individuals for whom an examination should be performed because of their increased susceptibility to breast and uterine cervix cancer.

In the relation between the pixel values of the electronic portal imaging device (EPID) and dose rate, pixel values have been reported to be proportional to the square roots of the dose rates although some researchers have reported that each EPID pixel value was almost proportional to the dose rates when they were more than 1 Gy/min. To resolve this contradiction, in this study we have investigated the dosimetric properties of the liquid ionization chamber EPID based on a two-dimensional matrix of liquid- filled ionization chambers. Our results show that the pixel values of this EPID were proportional to the square roots of the dose rates when they were less than 0.5 Gy/min, and the values were proportional to the dose rates when they were more than that. In addition, the survival time of electrons in the liquid of the EPID is reportedly dependent on the amount of impurities in the liquid ionizing chamber of EPID. The pixel values of the EPID acquired in rapid succession, increased. In the results, the pixel values were constantly increased to approximately 0.2% of pre-images for less than 15 s of the rest interval. When changes in the sensitivity of each pixel value were approximately 1%, approximately 5% changes were observed against the transformed dose rate. To avoid this difference, we developed the following formula relating the pixel value, P, and dose rate, D. P=a D + b radicalD - k h (a, b, h: constants, k : variable).

Objectives: To study the effect of adding chemotherapy to radiotherapy (RT) on overall survival and event-free survival for patients with nasopharyngeal carcinoma., Methods and Materials: This meta-analysis used updated individual patient data from randomized trials comparing chemotherapy plus RT with RT alone in locally advanced nasopharyngeal carcinoma. The log-rank test, stratified by trial, was used for comparisons, and the hazard ratios of death and failure were calculated., Results: Eight trials with 1753 patients were included. One trial with a 2 x 2 design was counted twice in the analysis. The analysis included 11 comparisons using the data from 1975 patients. The median follow-up was 6 years. The pooled hazard ratio of death was 0.82 (95% confidence interval, 0.71-0.94; p = 0.006), corresponding to an absolute survival benefit of 6% at 5 years from the addition of chemotherapy (from 56% to 62%). The pooled hazard ratio of tumor failure or death was 0.76 (95% confidence interval, 0.67-0.86; p < 0.0001), corresponding to an absolute event-free survival benefit of 10% at 5 years from the addition of chemotherapy (from 42% to 52%). A significant interaction was observed between the timing of chemotherapy and overall survival (p = 0.005), explaining the heterogeneity observed in the treatment effect (p = 0.03), with the highest benefit resulting from concomitant chemotherapy., Conclusion: Chemotherapy led to a small, but significant, benefit for overall survival and event-free survival. This benefit was essentially observed when chemotherapy was administered concomitantly with RT.