Extended Measurement of the Cosmic-Ray Electron and Positron Spectrum from 11 GeV to 4.8 TeV with the Calorimetric Electron Telescope on the International Space Station.

Extended results on the cosmic-ray electron + positron spectrum from 11 GeV to 4.8 TeV are presented based on observations with the Calorimetric Electron Telescope (CALET) on the International Space Station utilizing the data up to November 2017. The analysis uses the full detector acceptance at high energies, approximately doubling the statistics compared to the previous result. CALET is an all-calorimetric instrument with a total thickness of 30 X_{0} at normal incidence and fine imaging capability, designed to achieve large proton rejection and excellent energy resolution well into the TeV energy region. The observed energy spectrum in the region below 1 TeV shows good agreement with Alpha Magnetic Spectrometer (AMS-02) data. In the energy region below ∼300 GeV, CALET's spectral index is found to be consistent with the AMS-02, Fermi Large Area Telescope (Fermi-LAT), and Dark Matter Particle Explorer (DAMPE), while from 300 to 600 GeV the spectrum is significantly softer than the spectra from the latter two experiments. The absolute flux of CALET is consistent with other experiments at around a few tens of GeV. However, it is lower than those of DAMPE and Fermi-LAT with the difference increasing up to several hundred GeV. The observed energy spectrum above ∼1 TeV suggests a flux suppression consistent within the errors with the results of DAMPE, while CALET does not observe any significant evidence for a narrow spectral feature in the energy region around 1.4 TeV. Our measured all-electron flux, including statistical errors and a detailed breakdown of the systematic errors, is tabulated in the Supplemental Material in order to allow more refined spectral analyses based on our data.

Energy Spectrum of Cosmic-Ray Electron and Positron from 10 GeV to 3 TeV Observed with the Calorimetric Electron Telescope on the International Space Station.

First results of a cosmic-ray electron and positron spectrum from 10 GeV to 3 TeV is presented based upon observations with the CALET instrument on the International Space Station starting in October, 2015. Nearly a half million electron and positron events are included in the analysis. CALET is an all-calorimetric instrument with total vertical thickness of 30 X_{0} and a fine imaging capability designed to achieve a large proton rejection and excellent energy resolution well into the TeV energy region. The observed energy spectrum over 30 GeV can be fit with a single power law with a spectral index of -3.152±0.016 (stat+syst). Possible structure observed above 100 GeV requires further investigation with increased statistics and refined data analysis.

Preliminary results of proton-beam therapy for stage III non-small-cell lung cancer.

BACKGROUND: We conducted a preliminary retrospective evaluation of the efficacy and toxicity of proton-beam therapy (pbt) for stage iii non-small-cell lung cancer. METHODS: Between January 2009 and August 2013, 27 patients (26 men, 1 woman) with stage iii non-small-cell lung cancer underwent pbt. The relative biologic effectiveness value of the proton beam was defined as 1.1. The beam energy and spread-out Bragg peak were fine-tuned such that the 90% isodose volume of the prescribed dose encompassed the planning target volume. Of the 27 patients, 11 underwent neoadjuvant chemotherapy. Cumulative survival curves were calculated using the Kaplan-Meier method. Treatment toxicities were evaluated using version 4 of the Common Terminology Criteria for Adverse Events. RESULTS: Median age of the patients was 72 years (range: 57-91 years), and median follow-up was 15.4 months (range: 7.8-36.9 months). Clinical stage was iiia in 14 patients (52%) and iiib in 13 (48%). The median dose of pbt was 77 GyE (range: 66-86.4 GyE). The overall survival rate in the cohort was 92.3% at 1 year and 51.1% at 2 years. Locoregional failure occurred in 7 patients, and distant metastasis, in 10. In 2 patients, initial failure was both locoregional and distant. The 1-year and 2-year rates of local control were 68.1% and 36.4% respectively. The 1-year and 2-year rates of progression-free survival were 39.9% and 21.4% respectively. Two patients experienced grade 3 pneumonitis. CONCLUSIONS: For patients with stage iii non-small-cell lung cancer, pbt can be an effective and safe treatment option.

The combination of hyperthermia or chemotherapy with gimeracil for effective radiosensitization.

PURPOSE: 5-chloro-2,4-dihydroxypyridine (gimeracil) is a component of the oral fluoropyrimidine derivative S-1. Gimeracil was originally added to S-1 to yield prolonged 5-fluorouracil (5-FU) concentrations in serum and tumor tissues by inhibiting dihydropyrimidine dehydrogenase, which degrades 5-FU. We previously demonstrated that gimeracil enhances the efficacy of radiotherapy through the suppression of homologous recombination (HR) in DNA double strand repair. The goal of this paper was to examine the effects of gimeracil on the sensitivity of anticancer drugs and hyperthermia in order to obtain effective radiosensitization. MATERIALS AND METHODS: Various cell lines, including DLD 1 (human colon carcinoma cells) and cells deficient in HR or nonhomologous end-joining (NHEJ), were used in clonogenic assays. The survival of these cells after various treatments (e.g., drug treatment, heat treatment, and radiation) was determined based on their colony-forming ability. RESULTS: Gimeracil enhanced cell-killing effects of camptothecin (CPT), 5-FU, and hydroxyurea. Gimeracil sensitized effects of CPT or 5-FU to cells deficient in HR or NHEJ to a similar extent as in other cells (DLD1 and a parent cell), indicating that its sensitizing mechanisms may be different from inhibition of HR or NHEJ. Combination of gimeracil and CPT or 5-FU sensitized radiation more effectively than each modality alone. Gimeracil also enhanced heat sensitivity at 42°C or more. The degree of heat sensitization with gimeracil increased as the temperature increased, and the combination of gimeracil and heat-sensitized radiation was more effective than each modality alone. CONCLUSION: Gimeracil enhanced sensitivity of CPT, 5-FU, and hyperthermia. Combination of these modalities sensitized radiation more efficiently than each modality alone.

The association of DNA-dependent protein kinase activity of peripheral blood lymphocytes with prognosis of cancer.

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.

Preventing oxidative stress: a new role for XBP1.

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.

Assessment of dural arteriovenous fistulas of the cavernous sinuses on 3D dynamic MR angiography.

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.

Chemotherapy as an adjunct to radiotherapy in locally advanced nasopharyngeal carcinoma.

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.

MEK/ERK pathway protects ionizing radiation-induced loss of mitochondrial membrane potential and cell death in lymphocytic leukemia cells.

MEK/ERK-mediated signals have recently been found to inhibit Fas-mediated cell death through inhibition of caspase-8 activity. It remains unknown whether MEK/ERK-mediated signals affect ionizing radiation (IR)-induced cell death. Here we demonstrate that MEK/ERK-mediated signals selectively inhibit IR-induced loss of mitochondrial membrane potential (DeltaPsi(m)) and subsequent cell death. In Jurkat cells, TPA strongly activated ERK and inhibited the IR-induced caspase-8/Bid cleavage and the loss of DeltaPsi(m). The inhibitory effect of TPA was mostly abrogated by pretreatment of a specific MEK inhibitor PD98059, indicating that the effect depends upon MEK/ERK-mediated signals. Moreover, BAF-B03 transfectants expressing IL-2 receptor (IL-2R) beta(c) chain lacking the acidic region, which is responsible for MEK/ERK-mediated signals, revealed higher sensitivity to IR than the transfectants expressing wild-type IL-2R. Interestingly, the signals could neither protect the DeltaPsi(m) loss nor cell death in UV-irradiated cells. These data imply that the anti-apoptotic effect of MEK/ERK-mediated signals appears to selectively inhibit the IR-induced cell death through protection of the DeltaPsi(m) loss. Our data enlighten an anti-apoptotic function of MEK/ERK pathway against IR-induced apoptosis, thereby implying its contribution to radioresistance.

Spiral CT venography of the lower extremities by injection via an arm vein in patients with leg swelling.

The purpose of this prospective study was to assess the role of spiral CT venography (CTV) via an arm vein injection in the detection of causes of leg swelling. 42 consecutive patients with leg swelling were studied with indirect spiral CTV and ultrasound (US). CT parameters were as follows: 5 mm beam collimation; 7-10 mm s(-1) table speed; and 2-3 mm reconstruction. Two consecutive spiral scans with a 40 s exposure time were performed from the pelvis to the knee. One bolus of 150 ml non-ionic contrast medium was injected at a rate of 3 ml s(-1) by a power injector via an arm vein. The delay times to the first and second scans were 120 s and 180 s, respectively. Spiral CTV demonstrated not only deep vein thrombosis (DVT) (n=12) but also other abnormalities (n=25). US showed DVT (n=10) and some other abnormalities (n=5). The sensitivity and specificity of spiral CTV for femoropopliteal DVT, as compared with US, were both 100%. Two cases of DVT in the left common-external iliac vein (iliac vein compression syndrome) detected by spiral CTV were not confirmed by US. We were able to evaluate DVT above the knee with this method. Indirect spiral CTV showed promise for the diagnosis of DVT and other soft tissue diseases in patients with leg swelling.

Virtual CT cholangioscopy: comparison with fiberoptic cholangioscopy.

BACKGROUND AND STUDY AIMS: No studies comparing virtual computed tomography (CT) cholangioscopy of the common bile duct compared with fiberoptic cholangioscopy are available. The aim of our study was to evaluate the feasibility of virtual CT cholangioscopy of the common bile duct. PATIENTS AND METHODS: The study population comprised 52 patients (25 women, 27 men; mean age 56.5, range 32 - 81) with biliopancreatic disorders. Endoscopic images were produced by a volume-rendering method and a perspective projection. The ability to detect the endoluminal view and abnormalities of the common bile duct by virtual CT cholangioscopy and fiberoptic cholangioscopy was evaluated. RESULTS: Except for two cases (4 %), virtual CT cholangioscopy revealed excellent and moderate endoluminal visualization. There was no significant difference between the techniques (virtual CT cholangioscopy vs. fiberoptic cholangioscopy: excellent, 73 % vs. 85 %, P = 0.149; moderate 23 % vs. 15 % (P = 0.319); poor, 4 % vs. 0 %, P = 0.153). Virtual CT cholangioscopy revealed no significantly different ability to detect stenosis and obstruction of the common bile duct, compared with fiberoptic cholangioscopy. However, the ability of virtual CT cholangioscopy to detect minute papillary tumors (virtual CT cholangioscopy 30 % vs. fiberoptic cholangioscopy 100 %, P = 0.001) and stones smaller than 5 mm (virtual CT cholangioscopy 25 % vs. fiberoptic cholangioscopy 100 %; P = 0.002 was significantly less than that of fiberoptic cholangioscopy. CONCLUSIONS: Virtual CT cholangioscopy cannot replace fiberoptic cholangioscopy completely. However, the use of this technique, instead of fiberoptic cholangioscopy, may be feasible for following up patients after biliary intervention.

Supratentorial astrocytomas and oligodendrogliomas treated in the MRI era.

BACKGROUND: There is at present no consensus on the policy for the treatment of patients with low-grade gliomas (LGGs). METHODS: This report is a retrospective multi-institutional study of 100 patients (ages 16-65 years) with astrocytoma (grade II), oligodendroglioma, anaplastic oligodendroglioma and anaplastic oligoastrocytoma of the supratentorial areas which were treated with surgery and postoperative radiotherapy at five university hospitals in northern Japan between 1990 and 1997 when MRI was routinely used to determine the target volume. Most patients were irradiated with 50-60 Gy. The target volume usually covered the areas with T2 prolongation of MRI with a margin of 2 cm. RESULTS: The disease-specific 5-year survival rate was 87.4% for patients with oligodendroglioma and 75.3% for patients with astrocytoma. Survival for patients with astrocytoma in the MRI era appears to be improved compared with historical controls in the literature. Patients with astrocytoma aged 40 years and under had a significantly better disease-specific survival rate than those over 40 years (P < 0.05) and patients with oligodendroglioma and oligoastrocytoma showed a similar tendency. Patients with astrocytoma who had over 50% of their tumor removed had a significantly better survival rate than those who had less than 50% removed (P < 0.05). Chemotherapy appeared to improve the disease-specific survival rate of patients with oligodendroglioma but not that of patients with astrocytoma. CONCLUSION: Oligodendroglioma has a more protracted course of disease progression than astrocytoma. This particular feature and the sensitivity of LGGs to chemotherapy as well as their relevant prognostic factors, such as age, histopathology and amount of tumor removal, should be taken into account before any decision on treatment methods for LGGs is made.

Radiation therapy for superficial esophageal cancer: a comparison of radiotherapy methods.

PURPOSE: A comparison of treatment outcomes in response to various methods of radiotherapy for superficial esophageal cancer (SEC) was carried out for a large series of patients. METHODS AND MATERIALS: During the period from March 1987 to November 1998, 147 patients with superficial esophageal cancer received definitive radiation therapy at nine radiotherapy institutions in Japan. Fifty-five patients were treated with external radiation therapy alone, 69 with high-dose-rate intracavitary radiation therapy with or without external radiation therapy, and 23 with low-dose-rate intracavitary radiation therapy and external radiation therapy. RESULTS: The 5-year survival rates for mucosal and submucosal cancer patients were 62% and 42%, respectively. The 5-year cause-specific survival rates for mucosal and submucosal cancer patients were 81% and 64%, respectively (p = 0.013). There was no statistically significant difference in the survival rates for either mucosal or submucosal cancer patients between treatment groups. Metastasis was observed only in submucosal cancer patients. Esophageal ulcers developed only in patients who received intracavitary radiation therapy, and were especially common in patients treated with a fraction size of 5 Gy or more. CONCLUSIONS: The use of intracavitary radiation therapy does not influence the survival or local control rate of SEC. Optimal radiotherapy methods for SEC should be determined by a randomized clinical trial.

Clinical studies of immunohistochemical staining of DNA-dependent protein kinase in oropharyngeal and hypopharyngeal carcinomas.

PURPOSE: DNA-dependent protein kinase (DNA-PK), a serine/threonine kinase composed of p470 catalytic subunit (DNA-PKcs) and p85/p70 heterodimer (Ku antigen), is considered a critical enzyme in the repair of the DNA double-strand breaks (DSB) that are the major lethal lesions induced by ionizing radiation. We investigated the expression of DNA-PK subunits in human tumors. MATERIALS AND METHODS: We examined immunohistochemically the biopsy specimens of 44 patients with oropharyngeal carcinoma and 32 patients with hypopharyngeal carcinoma who had been treated with radiotherapy. RESULTS: Immunopositivity to Ku85 and DNA-PKcs was found in all patients. The staining of Ku85 and DNA-PKcs was nuclear, with none of the normal epithelial cells or malignant cells exhibiting cytoplasmic or membrane immunoreactivity. Normal epithelial cells were all stained intensely. In tumors, intense nuclear staining of DNA-PKcs was seen in 75 of 76 tumors, while that of Ku85 was seen in all 76 patients. The radiation responses of a primary tumor that was stained weakly with DNA-PKcs were excellent. CONCLUSION: Our results suggest the possibility of predicting the intrinsic radiosensitivity of human tumors in clinics able to perform immunohistochemical analysis of DNA-PK.

Usefulness of magnetic resonance imaging for surgical management of extravasation of an antitumor agent: a case report.

We report a case of extravasation of an antitumor agent by preoperative magnetic resonance (MR) imaging. MR studies demonstrated a decreased signal intensity on T1- and T2-weighted images and a strong enhancement of contrast media in injured tissue, including subcutaneous adipose tissue and deep fascia, which was cicatrical macroscopically. The MR findings were in good agreement with the macroscopic findings. We believe that MR imaging is useful for estimating deep tissue damage due to extravasation of an antitumor agent.

Pancreas: imaging diagnosis with color/power Doppler ultrasonography, endoscopic ultrasonography, and intraductal ultrasonography.

Recent advances of ultrasound imaging have made possible to depict various diseases and conditions of the pancreas. Color/power Doppler ultrasonography, endoscopic ultrasonography, and intraductal ultrasonography are feasible to show vascular abnormalities, differentiate the solid and cystic tumors, decide tumor extent, and help to perform interventional treatments of the pancreatic diseases. Those techniques will contribute to the more precise and easier diagnosis and to prompt decision of the treatments of the pancreatic disorders. Radiologists should recognize the diagnostic feasibility and limitations of those techniques in order to avoid unnecessary examinations on the patients, and obtain precise diagnostic images.

[Model of biological equivalent dose distribution modified by volume effect in radiotherapy].

This paper demonstrates that a biologically equivalent dose distribution including volume effect can be generated. Since the time-dose-fractionation (TDF) concept is convenient for comparing various radiation treatment schedules, TDF distribution maps are made on the basis of the physical dose distribution. On the other hand, the dose volume histogram is useful to evaluate volume effect, but is not necessarily an easy approach owing to the absence of spatial linkage. If distribution maps also representing the volume effect could actually be made, it would become easier to simultaneously predict both tumor control probability and the normal tissue complication rate. Because such tools should be very useful for planning radiotherapy, we proposed an experimental volume effect model. In this, one pixel is affected by all its surrounding pixels and the effect depends on the distance between pixels, volume, and the irradiated dose of another pixel. When the model was adapted to the conventional power law model, we could acquire a new equation with mathematical analysis. This permitted us to calculate the volume effect on each voxel within the treatment volume. Using a personal computer and treatment planning system, we calculated the "TDF-volume" distribution and drew maps based on this equation and the TDF values of each voxel for radiotherapy of a pelvic tumor.

Congenital arteriovenous malformation of the pancreas: its diagnostic features on images.

To analyze diagnostic features on images of congenital arteriovenous malformation (AVM) of the pancreas, we analyzed the diagnostic findings in six patients with the disease, using gray-scale ultrasonography (US), color Doppler US, computed tomography, and angiography and analyzed previously reported cases. AVM characteristic findings on images were multiple, small hypoechoic nodules on US, mosaic appearance of the lesion and pulsatile wave form in the portal vein on color Doppler US, conglomerated small nodular enhancement of the lesion and early appearance of the portal vein on CT, and a racemose network and early appearance of the portal vein on angiography. Five of the six patients underwent surgery, and all resected specimens were histologically found to be AVMs of the pancreas; however, one with developed portal hypertension at surgery died of repeated bleeding from esophageal varices. From analysis of total of 35 cases including our six cases, a mosaic appearance of the lesion was found in 100% and a pulsatile wave form in the portal vein in 77.8% on color Doppler US. Color Doppler US is noninvasive and useful for detecting congenital AVM of the pancreas at an early stage, preventing the portal hypertension causing esophageal varices and their rupture.