Non-DBS DNA Repair Genes Regulate Radiation-induced Cytogenetic Damage Repair and Cell Cycle Progression

NASA Technical Reports Server (NTRS)

Zhang, Ye; Rohde, Larry H.; Emami, Kamal; Casey, Rachael; Wu, Honglu

2008-01-01

Changes of gene expression profile are one of the most important biological responses in living cells after ionizing radiation (IR) exposure. Although some studies have shown that genes up-regulated by IR may play important roles in DNA damage repair, the relationship between the regulation of gene expression by IR, particularly genes not known for their roles in DSB repair, and its impact on cytogenetic responses has not been systematically studied. In the present study, the expression of 25 genes selected on the basis of their transcriptional changes in response to IR was individually knocked down by transfection with small interfering RNA in human fibroblast cells. The purpose of this study is to identify new roles of these selected genes on regulating DSB repair and cell cycle progression , as measured in the micronuclei formation and chromosome aberration. In response to IR, the formation of MN was significantly increased by suppressed expression of 5 genes: Ku70 in the DSB repair pathway, XPA in the NER pathway, RPA1 in the MMR pathway, and RAD17 and RBBP8 in cell cycle control. Knocked-down expression of 4 genes (MRE11A, RAD51 in the DSB pathway, SESN1, and SUMO1) significantly inhibited cell cycle progression, possibly because of severe impairment of DNA damage repair. Furthermore, loss of XPA, P21, or MLH1 expression resulted in both significantly enhanced cell cycle progression and increased yields of chromosome aberrations, indicating that these gene products modulate both cell cycle control and DNA damage repair. Most of the 11 genes that affected cytogenetic responses are not known to have clear roles influencing DBS repair. Nine of these 11 genes were up-regulated in cells exposed to gamma radiation, suggesting that genes transcriptionally modulated by IR were critical to regulate the biological consequences after IR.

Effect of radiation therapy on bronchial obstruction due to bronchogenic carcinoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chetty, K.G.; Moran, E.M.; Sassoon, C.S.

1989-03-01

We evaluated the effect of radiation therapy in 57 patients with obstruction of a large bronchus with NSCC. Response with aeration of the atelectatic lung was seen in 12 patients (21 percent). Three patients (5 percent) showed partial response with persistent partial atelectasis, and nine patients (16 percent) showed good response with complete aeration of the atelectatic lung. In these patients the response appeared to be related to the dose of radiation. All of the patients who responded received more than 50 Gy. The difference in the response rate related to the dose of radiation was statistically significant (p lessmore » than 0.05). The rates were similar with all histologic types of NSCC. Regardless of the clinical response observed, bronchoscopy performed two to four months after completion of radiation therapy in 14 patients revealed persistent endobronchial tumor. There was no significant relationship between the persistence of endobronchial tumor, the dose of radiation therapy, and the tumor's histologic type. Of the 12 patients with radiographic improvement in atelectasis, fibrotic changes developed in four (33 percent) patients and pneumonitis in two (17 percent). Progression of disease with distant metastases occurred in 58 percent (seven) of the 12 patients who showed a clinical response of their bronchial obstruction. The median time to survival was nearly identical in responders and nonresponders.« less

A Multicenter Phase II Trial of S-1 With Concurrent Radiation Therapy for Locally Advanced Pancreatic Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ikeda, Masafumi, E-mail: masikeda@east.ncc.go.jp; Ioka, Tatsuya; Ito, Yoshinori

2013-01-01

Purpose: The aim of this trial was to evaluate the efficacy and toxicity of S-1 and concurrent radiation therapy for locally advanced pancreatic cancer (PC). Methods and Materials: Locally advanced PC patients with histologically or cytologically confirmed adenocarcinoma or adenosquamous carcinoma, who had no previous therapy were enrolled. Radiation therapy was delivered through 3 or more fields at a total dose of 50.4 Gy in 28 fractions over 5.5 weeks. S-1 was administered orally at a dose of 80 mg/m{sup 2} twice daily on the day of irradiation during radiation therapy. After a 2- to 8-week break, patients received amore » maintenance dose of S-1 (80 mg/m{sup 2}/day for 28 consecutive days, followed by a 14-day rest period) was then administered until the appearance of disease progression or unacceptable toxicity. The primary efficacy endpoint was survival, and the secondary efficacy endpoints were progression-free survival, response rate, and serum carbohydrate antigen 19-9 (CA19-9) response; the safety endpoint was toxicity. Results: Of the 60 evaluable patients, 16 patients achieved a partial response (27%; 95% confidence interval [CI], 16%-40%). The median progression-free survival period, overall survival period, and 1-year survival rate of the evaluable patients were 9.7 months (95% CI, 6.9-11.6 months), 16.2 months (95% CI, 13.5-21.3 months), and 72% (95%CI, 59%-82%), respectively. Of the 42 patients with a pretreatment serum CA19-9 level of {>=}100 U/ml, 34 (81%) patients showed a decrease of greater than 50%. Leukopenia (6 patients, 10%) and anorexia (4 patients, 7%) were the major grade 3-4 toxicities with chemoradiation therapy. Conclusions: The effect of S-1 with concurrent radiation therapy in patients with locally advanced PC was found to be very favorable, with only mild toxicity.« less

Evaluation of the response to selective internal radiation therapy in patients with hepatocellular cancer according to pretreatment (99m)Tc-MAA uptake.

PubMed

Kucuk, Ozlem N; Soydal, Cigdem; Araz, Mine; Ozkan, Elgin; Aras, Gulseren

2013-04-01

The aim of the study was to evaluate if there is a prognostic importance of pretreatment Tc-MAA uptake of liver lesion of patients who received Y selective internal radiation therapy (SIRT) treatment for hepatocellular cancer (HCC) or not. Nineteen patients (5 female and 14 male patients; mean age, 64.5 ± 14.7 years; range, 57-73 years) who received SIRT treatment in our department for HCC between June 2008 and May 2011 were included in the study. All the patients have undergone Tc-MAA scintigraphy within 2 weeks' period before treatment for evaluation of presence of extrahepatic uptake. Patients were evaluated according to their lesions' Tc-MAA uptake patterns. Response to the treatment, presence of progression after treatment, and progression-free survival of all the patients were calculated. Treatment has been administered on the right and left lobes of the liver in 18 and 1 patient, respectively. The mean treatment dose was estimated as 1.4 + 1.0 GBq. In the pretreatment Tc-MAA scintigraphy, liver lesions of 5 patients were hypoactive, and 14 patients were hyperactive. In the hypoactive group, whereas 2 patients (40%) were responders to treatment, 3 were nonresponders (60%). In the hyperactive group, 8 (58%) and 6 (42%) patients were responders and nonresponders, respectively (P = 0.51). Disease progression was seen in 4 (80%) and 8 patients (58%) in the hypoactive group and hyperactive groups, respectively (P = 0.36). Progression-free survival of the hypoactive group was calculated as 8 ± 4.3 months and of the hyperactive group 11 ± 4.7 months (P = 0.22). Despite the small number of patients, this study revealed that there is no significance between tumor response and progression rates of patients who received SIRT for HCC with or without pretreatment Tc-MAA uptake in liver lesions. Selective internal radiation therapy could be safely performed in patients who have hypoactive lesions in Tc-MAA scintigraphy.

[Personal experience with VP-16 in the treatment of malignant lymphomas at the Chemotherapy Clinic of the Oncology Center--M. Skłodowskiej-Curie Institute in Warsaw].

PubMed

Pałucka, A; Walewski, J; Siedlecki, P; Zborzil, J

1990-01-01

Eighteen patients with advanced malignant lymphomas who had progressed with previous chemotherapy were treated with LEPP (chlorambucil, VP-16, procarbazine, prednisone). One complete response and 5 partial remissions were observed, yielding an overall response rate of 33%, with median response duration of about 2 months. Twenty three patients with advanced Hodgkin's disease all who had progressed with previous chemotherapy (MOPP and ABVD) and 19 of them also after radiation therapy were treated with third line salvage chemotherapy consisting of OPEC (VP- 16, chlorambucil, vincristine and prednisone). Two complete response and 3 partial remissions were obtained for overall response rate of 21% with median duration of about 9 months.

The Peripheral Myeloid Expansion Driven by Murine Cancer Progression Is Reversed by Radiation Therapy of the Tumor

PubMed Central

Crittenden, Marka R.; Savage, Talicia; Cottam, Benjamin; Bahjat, Keith S.; Redmond, William L.; Bambina, Shelly; Kasiewicz, Melissa; Newell, Pippa; Jackson, Andrew M.; Gough, Michael J.

2013-01-01

Expansion of myeloid-lineage leukocytes in tumor-bearing mice has been proposed as a cause of systemic immunosuppression. We demonstrate that radiation therapy of tumors leads to a decline in myeloid cell numbers in the blood and a decrease in spleen size. The frequency of myeloid cells does not decline to the level seen in tumor-free mice: we demonstrate that metastatic disease can prevent myeloid cell numbers from returning to baseline, and that tumor recurrence from residual disease correlates with re-expansion of myeloid lineage cells. Radiation therapy results in increased proliferation of T cells in the spleen and while T cell responses to foreign antigens are not altered by tumor burden or myeloid cell expansion, responses to tumor-associated antigens are increased after radiation therapy. These data demonstrate that myeloid cell numbers are directly linked to primary tumor burden, that this population contracts following radiation therapy, and that radiation therapy may open a therapeutic window for immunotherapy of residual disease. PMID:23936036

What Drives the Outflows in Broad Absorption Line QSOs?

NASA Technical Reports Server (NTRS)

Begelman, Mitchell C.

1997-01-01

We have made progress in the areas related to the propulsion and confinement of gas responsible for broad absorption troughts in QSOs: Radiative Acceleration in BALQSOs; The "Ghost" of Lyman (alpha); and Magnetic Confinement of Absorbing Gas.

Gamma Low-Dose-Rate Ionizing Radiation Stimulates Adaptive Functional and Molecular Response in Human Aortic Endothelial Cells in a Threshold-, Dose-, and Dose Rate–Dependent Manner

PubMed Central

Vieira Dias, Juliana; Gloaguen, Celine; Kereselidze, Dimitri; Manens, Line; Tack, Karine; Ebrahimian, Teni G

2018-01-01

A central question in radiation protection research is whether low-dose and low-dose-rate (LDR) exposures to ionizing radiation play a role in progression of cardiovascular disease. The response of endothelial cells to different LDR exposures may help estimate risk of cardiovascular disease by providing the biological mechanism involved. We investigated the effect of chronic LDR radiation on functional and molecular responses of human aorta endothelial cells (HAoECs). Human aorta endothelial cells were continuously irradiated at LDR (6 mGy/h) for 15 days and analyzed at time points when the cumulative dose reached 0.05, 0.5, 1.0, and 2.0 Gy. The same doses were administered acutely at high-dose rate (HDR; 1 Gy/min). The threshold for the loss of angiogenic capacity for both LDR and HDR radiations was between 0.5 and 1.0 Gy. At 2.0 Gy, angiogenic capacity returned to normal only for HAoEC exposed to LDR radiation, associated with increased expression of antioxidant and anti-inflammatory genes. Pre-LDR, but not pre-HDR, radiation, followed by a single acute 2.0 Gy challenge dose sustained the expression of antioxidant and anti-inflammatory genes and stimulated angiogenesis. Our results suggest that dose rate is important in cellular response and that a radioadaptive response is involved for a 2.0 Gy dose at LDR. PMID:29531508

Gamma Low-Dose-Rate Ionizing Radiation Stimulates Adaptive Functional and Molecular Response in Human Aortic Endothelial Cells in a Threshold-, Dose-, and Dose Rate-Dependent Manner.

PubMed

Vieira Dias, Juliana; Gloaguen, Celine; Kereselidze, Dimitri; Manens, Line; Tack, Karine; Ebrahimian, Teni G

2018-01-01

A central question in radiation protection research is whether low-dose and low-dose-rate (LDR) exposures to ionizing radiation play a role in progression of cardiovascular disease. The response of endothelial cells to different LDR exposures may help estimate risk of cardiovascular disease by providing the biological mechanism involved. We investigated the effect of chronic LDR radiation on functional and molecular responses of human aorta endothelial cells (HAoECs). Human aorta endothelial cells were continuously irradiated at LDR (6 mGy/h) for 15 days and analyzed at time points when the cumulative dose reached 0.05, 0.5, 1.0, and 2.0 Gy. The same doses were administered acutely at high-dose rate (HDR; 1 Gy/min). The threshold for the loss of angiogenic capacity for both LDR and HDR radiations was between 0.5 and 1.0 Gy. At 2.0 Gy, angiogenic capacity returned to normal only for HAoEC exposed to LDR radiation, associated with increased expression of antioxidant and anti-inflammatory genes. Pre-LDR, but not pre-HDR, radiation, followed by a single acute 2.0 Gy challenge dose sustained the expression of antioxidant and anti-inflammatory genes and stimulated angiogenesis. Our results suggest that dose rate is important in cellular response and that a radioadaptive response is involved for a 2.0 Gy dose at LDR.

Rates and Durability of Response to Salvage Radiation Therapy Among Patients With Refractory or Relapsed Aggressive Non-Hodgkin Lymphoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tseng, Yolanda D., E-mail: ydt2@uw.edu; Chen, Yu-Hui; Catalano, Paul J.

Purpose: To evaluate the response rate (RR) and time to local recurrence (TTLR) among patients who received salvage radiation therapy for relapsed or refractory aggressive non-Hodgkin lymphoma (NHL) and investigate whether RR and TTLR differed according to disease characteristics. Methods and Materials: A retrospective review was performed for all patients who completed a course of salvage radiation therapy between January 2001 and May 2011 at Brigham and Women's Hospital/Dana-Farber Cancer Institute. Separate analyses were conducted for patients treated with palliative and curative intent. Predictors of RR for each subgroup were assessed using a generalized estimating equation model. For patients treatedmore » with curative intent, local control (LC) and progression-free survival were estimated with the Kaplan-Meier method; predictors for TTLR were evaluated using a Cox proportional hazards regression model. Results: Salvage radiation therapy was used to treat 110 patients to 121 sites (76 curative, 45 palliative). Salvage radiation therapy was given as part of consolidation in 18% of patients treated with curative intent. Median dose was 37.8 Gy, with 58% and 36% of curative and palliative patients, respectively, receiving 39.6 Gy or higher. The RR was high (86% curative, 84% palliative). With a median follow-up of 4.8 years among living patients, 5-year LC and progression-free survival for curative patients were 66% and 34%, respectively. Refractory disease (hazard ratio 3.3; P=.024) and lack of response to initial chemotherapy (hazard ratio 4.3; P=.007) but not dose (P=.93) were associated with shorter TTLR. Despite doses of 39.6 Gy or higher, 2-year LC was only 61% for definitive patients with refractory disease or disease that did not respond to initial chemotherapy. Conclusions: Relapsed or refractory aggressive NHL is responsive to salvage radiation therapy, and durable LC can be achieved in some cases. However, refractory disease is associated with a shorter TTLR, suggesting that radiation dose escalation, addition of radiosensitizers, or a combination of both may be indicated in these patients.« less

Arterial Perfusion Imaging–Defined Subvolume of Intrahepatic Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Hesheng, E-mail: hesheng@umich.edu; Farjam, Reza; Feng, Mary

2014-05-01

Purpose: To assess whether an increase in a subvolume of intrahepatic tumor with elevated arterial perfusion during radiation therapy (RT) predicts tumor progression after RT. Methods and Materials: Twenty patients with unresectable intrahepatic cancers undergoing RT were enrolled in a prospective, institutional review board–approved study. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was performed before RT (pre-RT), after delivering ∼60% of the planned dose (mid-RT) and 1 month after completion of RT to quantify hepatic arterial perfusion. The arterial perfusions of the tumors at pre-RT were clustered into low-normal and elevated perfusion by a fuzzy clustering-based method, and the tumor subvolumesmore » with elevated arterial perfusion were extracted from the hepatic arterial perfusion images. The percentage changes in the tumor subvolumes and means of arterial perfusion over the tumors from pre-RT to mid-RT were evaluated for predicting tumor progression post-RT. Results: Of the 24 tumors, 6 tumors in 5 patients progressed 5 to 21 months after RT completion. Neither tumor volumes nor means of tumor arterial perfusion at pre-RT were predictive of treatment outcome. The mean arterial perfusion over the tumors increased significantly at mid-RT in progressive tumors compared with the responsive tumors (P=.006). From pre-RT to mid-RT, the responsive tumors had a decrease in the tumor subvolumes with elevated arterial perfusion (median, −14%; range, −75% to 65%), whereas the progressive tumors had an increase of the subvolumes (median, 57%; range, −7% to 165%) (P=.003). Receiver operating characteristic analysis of the percentage change in the subvolume for predicting tumor progression post-RT had an area under the curve of 0.90. Conclusion: The increase in the subvolume of the intrahepatic tumor with elevated arterial perfusion during RT has the potential to be a predictor for tumor progression post-RT. The tumor subvolume could be a radiation boost candidate for response-driven adaptive RT.« less

So You Want to Go to Mars: Bones and Matters of the Heart

NASA Technical Reports Server (NTRS)

Tahimic, Candice; Globus, Ruth; Torres, Samantha; Steczina, Sonette

2017-01-01

There is evidence that weightlessness and radiation, two elements of the spaceflight environment, can lead to detrimental changes in human musculoskeletal tissue, including bone loss and muscle atrophy. This bone loss is thought to be brought about by the increased activity of bone-resorbing osteoclasts and functional changes in bone-forming osteoblasts, cells that give rise to mature osteocytes. Collectively, our research team aims to understand the molecular mechanisms underlying the responses of mammalian tissue to the spaceflight environment using earth-based animal and cellular models. The overarching goal is to identify molecular targets to prevent tissue decrements induced by spaceflight and earth-based scenarios of radiotherapy, accidental radiation exposure and reduced mobility. In this talk, I will provide an overview of skeletal and cardiovascular responses to spaceflight and will highlight our research progress on understanding the role of reactive oxygen species (ROS) signaling in skeletal responses to radiation and simulated weightlessness.

Prospective evaluation of a 5 × 4 Gy prescription for palliation of canine nasal tumors.

PubMed

Tan-Coleman, Birgitte; Lyons, Jarred; Lewis, Craig; Rosenberg, Mona; Ruiz, Azucena

2013-01-01

We evaluated the efficacy of palliative radiation therapy using 5 × 4 Gy given daily in 18 dogs with nasal tumors. Dogs with malignant nasal tumors were evaluated for response rate, response duration, and survival. Seventy-eight percent of the dogs achieved complete resolution of clinical signs, and 16.5% had partial resolution of their signs. Overall median response duration for all dogs was 178 days after one course of radiation therapy. Six dogs received a second course of therapy when their disease progressed using the same daily 5 × 4 Gy scheme, and all six responded for a median time of 129.5 days for an overall median survival time in these six dogs of 309 days. Based on these results, a radiation prescription of 5 × 4 Gy appears to be useful palliatively in dogs with a malignant nasal tumor. © 2012 Veterinary Radiology & Ultrasound.

Impaired Cytogenetic Damage Repair and Cell Cycle Regulation in Response to Ionizing Radiation in Human Fibroblast Cells with Individual Knock-down of 25 Genes

NASA Technical Reports Server (NTRS)

Zhang, Ye; Rohde, Larry; Emami, Kamal; Hammond, Dianne; Casey, Rachael; Mehta, Satish; Jeevarajan, Antony; Pierson, Duane; Wu, Honglu

2008-01-01

Changes of gene expression profile are one of the most important biological responses in living cells after ionizing radiation (IR) exposure. Although some studies have demonstrated that genes with upregulated expression induced by IR may play important roles in DNA damage sensing, cell cycle checkpoint and chromosomal repair, the relationship between the regulation of gene expression by IR and its impact on cytogenetic responses to ionizing radiation has not been systematically studied. In our present study, the expression of 25 genes selected based on their transcriptional changes in response to IR or from their known DNA repair roles were individually knocked down by siRNA transfection in human fibroblast cells. Chromosome aberrations (CA) and micronuclei (MN) formation were measured as the cytogenetic endpoints. Our results showed that the yield of MN and/or CA formation were significantly increased by suppressed expression of 5 genes that included Ku70 in the DSB repair pathway; XPA in the NER pathway; RPA1 in the MMR pathway; RAD17 and RBBP8 in cell cycle control. Knocked-down expression of 4 genes including MRE11A, RAD51 in the DSB pathway, and SESN1 and SUMO1 showed significant inhibition of cell cycle progression, possibly because of severe impairment of DNA damage repair. Furthermore, loss of XPA, p21 and MLH1 expression resulted in both enhanced cell cycle progression and significantly higher yield of cytogenetic damage, indicating the involvement of these gene products in both cell cycle control and DNA damage repair. Of these 11 genes that affected the cytogenetic response, 9 were up-regulated in the cells exposed to gamma radiation, suggesting that genes transcriptionally modulated by IR were critical to regulating the biological consequences after IR. Failure to express these IR-responsive genes, such as by gene mutation, could seriously change the outcome of the post IR scenario and lead to carcinogenesis.

Hypofractionated Image-guided Radiation Therapy (3Gy/fraction) in Patients Affected by Inoperable Advanced-stage Non-small Cell Lung Cancer After Long-term Follow-up.

PubMed

Agolli, Linda; Valeriani, Maurizio; Bracci, Stefano; Nicosia, Luca; DE Sanctis, Vitaliana; Enrici, Riccardo Maurizi; Osti, Mattia Falchetto

2015-10-01

We conducted long-term follow-up analysis of the outcomes for patients affected by advanced-stage non-small cell lung cancer (NSCLC) treated with hypofractionated radiotherapy (RT). Sixty patients with advanced-stage NSCLC (IIIA-IV) treated with hypofractionated radiotherapy (60Gy/20 fractions) were analyzed. Radiation was delivered using an image-guided RT technique to verify the correct position. Toxicities were graded according to the Common Toxicity Criteria for Adverse Effects v4.0 scale. Overall, six patients achieved a complete response and 46 patients had a partial response (tumor response rate 86%). After a median follow-up of 30 months, locoregional progression occurred in 23 patients and distant progression occurred in 38. The 1-year and 2-years overall survival were 57% and 40%, respectively. The 1-year and 2-years progression-free survival (PFS) were 47.1% and 33.5%, respectively. The median duration of OS and PFS was 13 months and 12 months, respectively. The 2-year local PFS and metastases-free survival (MFS) were 53% and 40.3%, respectively. On univariate analysis, the T-size (≥5 cm), and type of response to RT (non-response/progressive disease) were significantly associated with worse OS. Type of response was identified as significant prognostic factors for PFS (p<0.01) local PFS (p=0.015) and MFS (p<0.01). Acute grade 3 esophagitis and pneumonitis occurred in three patients (5%) and four patients (6%), respectively. Late grade 3 esophagitis and pneumonitis occurred in 2% (one patient) and 3% (two patients), respectively. No patient experienced grade 4 acute or late RT-related toxicities. Hypofractionated RT offers good disease control for patients with advanced-stage NSCLC with acceptable toxicity rates. Phase III randomized trials are necessary to compare hypofractionated RT with conventional RT. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Stereotactic Radiation Therapy can Safely and Durably Control Sites of Extra-Central Nervous System Oligoprogressive Disease in Anaplastic Lymphoma Kinase-Positive Lung Cancer Patients Receiving Crizotinib

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gan, Gregory N., E-mail: gregory.gan@ucdenver.edu; Weickhardt, Andrew J.; Scheier, Benjamin

Purpose: To analyze the durability and toxicity of radiotherapeutic local ablative therapy (LAT) applied to extra-central nervous system (eCNS) disease progression in anaplastic lymphoma kinase-positive non-small cell lung cancer (NSCLC) patients. Methods and Materials: Anaplastic lymphoma kinase-positive NSCLC patients receiving crizotinib and manifesting ≤4 discrete sites of eCNS progression were classified as having oligoprogressive disease (OPD). If subsequent progression met OPD criteria, additional courses of LAT were considered. Crizotinib was continued until eCNS progression was beyond OPD criteria or otherwise not suitable for further LAT. Results: Of 38 patients, 33 progressed while taking crizotinib. Of these, 14 had eCNS progressionmore » meeting OPD criteria suitable for radiotherapeutic LAT. Patients with eCNS OPD received 1-3 courses of LAT with radiation therapy. The 6- and 12-month actuarial local lesion control rates with radiation therapy were 100% and 86%, respectively. The 12-month local lesion control rate with single-fraction equivalent dose >25 Gy versus ≤25 Gy was 100% versus 60% (P=.01). No acute or late grade >2 radiation therapy-related toxicities were observed. Median overall time taking crizotinib among those treated with LAT versus those who progressed but were not suitable for LAT was 28 versus 10.1 months, respectively. Patients continuing to take crizotinib for >12 months versus ≤12 months had a 2-year overall survival rate of 72% versus 12%, respectively (P<.0001). Conclusions: Local ablative therapy safely and durably eradicated sites of individual lesion progression in anaplastic lymphoma kinase-positive NSCLC patients receiving crizotinib. A dose–response relationship for local lesion control was observed. The suppression of OPD by LAT in patients taking crizotinib allowed an extended duration of exposure to crizotinib, which was associated with longer overall survival.« less

On the Development of a Deterministic Three-Dimensional Radiation Transport Code

NASA Technical Reports Server (NTRS)

Rockell, Candice; Tweed, John

2011-01-01

Since astronauts on future deep space missions will be exposed to dangerous radiations, there is a need to accurately model the transport of radiation through shielding materials and to estimate the received radiation dose. In response to this need a three dimensional deterministic code for space radiation transport is now under development. The new code GRNTRN is based on a Green's function solution of the Boltzmann transport equation that is constructed in the form of a Neumann series. Analytical approximations will be obtained for the first three terms of the Neumann series and the remainder will be estimated by a non-perturbative technique . This work discusses progress made to date and exhibits some computations based on the first two Neumann series terms.

TOPK modulates tumour-specific radiosensitivity and correlates with recurrence after prostate radiotherapy

PubMed Central

Pirovano, Giacomo; Ashton, Thomas M; Herbert, Katharine J; Bryant, Richard J; Verrill, Clare L; Cerundolo, Lucia; Buffa, Francesca M; Prevo, Remko; Harrap, Iona; Ryan, Anderson J; Macaulay, Valentine; McKenna, William G; Higgins, Geoff S

2017-01-01

Background: Tumour-specific radiosensitising treatments may enhance the efficacy of radiotherapy without exacerbating side effects. In this study we determined the radiation response following depletion or inhibition of TOPK, a mitogen-activated protein kinase kinase family Ser/Thr protein kinase that is upregulated in many cancers. Methods: Radiation response was studied in a wide range of cancer cell lines and normal cells using colony formation assays. The effect on cell cycle progression was assessed and the relationship between TOPK expression and therapeutic efficacy was studied in a cohort of 128 prostate cancer patients treated with radical radiotherapy. Results: TOPK knockdown did not alter radiation response in normal tissues, but significantly enhanced radiosensitivity in cancer cells. This result was recapitulated in TOPK knockout cells and with the TOPK inhibitor, OTS964. TOPK depletion altered the G1/S transition and G2/M arrest in response to radiation. Furthermore, TOPK depletion increased chromosomal aberrations, multinucleation and apoptotic cell death after irradiation. These results suggest a possible role for TOPK in the radiation-induced DNA damage checkpoints. These findings have clinical relevance, as elevated TOPK protein expression was associated with poorer clinical outcomes in prostate cancer patients treated with radical radiotherapy. Conclusions: This study demonstrates that TOPK disruption may cause tumour-specific radiosensitisation in multiple different tumour types. PMID:28677687

TOPK modulates tumour-specific radiosensitivity and correlates with recurrence after prostate radiotherapy.

PubMed

Pirovano, Giacomo; Ashton, Thomas M; Herbert, Katharine J; Bryant, Richard J; Verrill, Clare L; Cerundolo, Lucia; Buffa, Francesca M; Prevo, Remko; Harrap, Iona; Ryan, Anderson J; Macaulay, Valentine; McKenna, William G; Higgins, Geoff S

2017-08-08

Tumour-specific radiosensitising treatments may enhance the efficacy of radiotherapy without exacerbating side effects. In this study we determined the radiation response following depletion or inhibition of TOPK, a mitogen-activated protein kinase kinase family Ser/Thr protein kinase that is upregulated in many cancers. Radiation response was studied in a wide range of cancer cell lines and normal cells using colony formation assays. The effect on cell cycle progression was assessed and the relationship between TOPK expression and therapeutic efficacy was studied in a cohort of 128 prostate cancer patients treated with radical radiotherapy. TOPK knockdown did not alter radiation response in normal tissues, but significantly enhanced radiosensitivity in cancer cells. This result was recapitulated in TOPK knockout cells and with the TOPK inhibitor, OTS964. TOPK depletion altered the G 1 /S transition and G 2 /M arrest in response to radiation. Furthermore, TOPK depletion increased chromosomal aberrations, multinucleation and apoptotic cell death after irradiation. These results suggest a possible role for TOPK in the radiation-induced DNA damage checkpoints. These findings have clinical relevance, as elevated TOPK protein expression was associated with poorer clinical outcomes in prostate cancer patients treated with radical radiotherapy. This study demonstrates that TOPK disruption may cause tumour-specific radiosensitisation in multiple different tumour types.

Hypofractionated Radiotherapy Is Superior to Conventional Fractionation in an Orthotopic Model of Anaplastic Thyroid Cancer.

PubMed

Oweida, Ayman; Phan, Andy; Vancourt, Benjamin; Robin, Tyler; Hararah, Mohammad K; Bhatia, Shilpa; Milner, Dallin; Lennon, Shelby; Pike, Laura; Raben, David; Haugen, Bryan; Pozdeyev, Nikita; Schweppe, Rebecca; Karam, Sana D

2018-06-01

Anaplastic thyroid cancer (ATC) is an aggressive and highly lethal disease with poor outcomes and resistance to therapy. Despite multimodality treatment, including radiation therapy and chemotherapy, response rates remain <15%, with a median time to progression of less than three months. Recent advances in radiotherapy (RT) delivery and gene-expression profiling may help guide patient selection for personalized therapy. The purpose of this study was to characterize the response to radiation in a panel of ATC cell lines and to test alternative RT fractionation schedules for overcoming radioresistance. The cellular response to radiation was characterized based on clonogenic assays. Radiation response was correlated with microarray gene-expression data. Hypofractionated and conventional RT was tested in an orthotopic ATC tumor model, and tumor growth was assayed locally and distantly with in vivo and ex vivo bioluminescence imaging. A spectrum of radiosensitivities was observed in ATC cell lines. Radioresistant cell lines had higher levels of CXCR4 compared to radiosensitive cell lines. Compared to conventionally fractionated RT, hypofractionated RT resulted in significantly improved tumor growth delay, decreased regional and distant metastases, and improved overall survival. The findings demonstrate the heterogeneity of response to radiation in ATC tumors and the superiority of hypofractionated RT in improving local control, metastatic spread, and survival in preclinical models. These data support the design of clinical trials targeting radioresistant pathways in combination with hypofractionated RT.

The mechanism of action of radiosensitization of conventional chemotherapeutic agents.

PubMed

Lawrence, Theodore S; Blackstock, A William; McGinn, Cornelius

2003-01-01

It is not an exaggeration to state that most of the advances in curing cancer in the last decade have come from successful combinations of conventional chemotherapeutic agents with radiation therapy. Further improvements in therapy will depend on understanding the mechanisms by which chemotherapy improves the effectiveness of radiation in model systems and in patients. In this review, we discuss the mechanisms of action of the fluoropyrimidines, gemcitabine, and the platinums. The fluoropyrimidines (5-fluorouracil and fluorodeoxyuridine) increase the effectiveness of radiation chiefly when given before and during radiation. Increased radiation sensitivity occurs in cells that progress inappropriately into S phase in the presence of drug, suggesting a key role for dysregulation of S-phase checkpoints. Gemcitabine may radiosensitize by a similar mechanism, although the relative roles of specific DNA repair pathways (such as homologous end rejoining) and of apoptosis remain to be determined. For both of these categories of drugs, sensitization probably results when cells that are progressing inappropriately through S phase misrepair DNA damage inflicted by radiation. Thus, loss of the S-phase checkpoint in cancer cells may provide the molecular basis for selective killing of tumors compared with normal tissues. Cisplatin has multiple effects on cells, such as adduct formation and DNA damage repair inhibition, but the mechanism for selectivity against cancer cells compared with normal cells is not yet determined. The identification of the enzymatic targets for these drugs offers the potential to develop predictive assays for response and to develop methods of imaging the progress of therapy. Copyright 2003, Elsevier Science (USA). All rights reserved.

Lobulated Enhancement Evaluation in the Follow-Up of Liver Metastases Treated by Stereotactic Body Radiation Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jarraya, Hajer, E-mail: h-jarraya@o-lambret.fr; Borde, Paul; Mirabel, Xavier

Objective: The Response Evaluation Criteria in Solid Tumors (RECIST) can have limitations when used to evaluate local treatments for cancer, especially for liver malignancies treated by stereotactic body radiation therapy (SBRT). The aim of this study was to validate the relationship between the occurrence of lobulated enhancement (LE) and local relapse and to evaluate the utility of this relationship for predicting local progression. Patients and Methods: Imaging data of 59 lesions in 46 patients, including 281 computed tomographic (CT) scans, were retrospectively and blindly reviewed by 3 radiologists. One radiologist measured the lesion size, for each CT and overall, tomore » classify responses using RECIST threshold criteria. The second studied LE occurrence. A third radiologist was later included and studied LE occurrence to evaluate the interobserver consistency for LE evaluation. Results: The mean duration of follow-up was 13.6 months. LE was observed in 16 of 18 progressive lesions, occurring before size-based progression in 50% of cases, and the median delay of LE detection was 3.2 months. The sensitivity of LE to predict progression was 89%, and its specificity was 100%. The positive predictive value was 100%, the negative predictive value was 95.3%, and the overall accuracy was 97%. The probability of local progression-free survival at 12 months was significantly higher for lesions without LE compared with all lesions: 0.80 (CI 95%: 0.65-0.89) versus 0.69 (CI 95%: 0.54-0.80), respectively. The overall concordance rate between the 2 readers of LE was 97.9%. Conclusion: Response assessment of liver metastases treated by SBRT can be improved by including LE. This study demonstrates the diagnostic and predictive utility of LE for assessing local progression at a size still eligible for local salvage treatment.« less

Response of antioxidant defense system to laser radiation apical meristem of Isatis indigotica seedlings exposed to UV-B.

PubMed

Chen, Yi-Ping

2009-07-01

To determine the response of antioxidant defense system to laser radiation apical meristem of Isatis indigotica seedlings, Isatis indigotica seedlings were subjected to UV-B radiation (10.08 kJ m(-2)) for 8 h day(-1) for 8 days (PAR, 220 micromol m(-2) s(-1)) and then exposed to He-Ne laser radiation (633 nm; 5.23 mW mm(-2); beam diameter: 1.5 mm) for 5 min each day without ambient light radiation. Changes in free radical elimination systems were measured, the results indicate that: (1) UV-B radiation enhanced the concentration of Malondialdahyde (MDA) and decreased the activities of superoxide dismutase (SOD), catalase (CAT) and peroxidase (POD) in seedlings compared with the control. The concentration of MDA was decreased and the activities of SOD, CAT and POD were increased when seedlings were subjected to elevated UV-B damage followed by laser; (2) the concentration of UV absorbing compounds and proline were increased progressively with UV-B irradiation, laser irradiation and He-Ne laser irradiation plus UV-B irradiation compared with the control. These results suggest that laser radiation has an active function in repairing UV-B-induced lesions in seedlings.

Complete intracranial response to talimogene laherparepvec (T-Vec), pembrolizumab and whole brain radiotherapy in a patient with melanoma brain metastases refractory to dual checkpoint-inhibition.

PubMed

Blake, Zoë; Marks, Douglas K; Gartrell, Robyn D; Hart, Thomas; Horton, Patti; Cheng, Simon K; Taback, Bret; Horst, Basil A; Saenger, Yvonne M

2018-04-06

Immunotherapy, in particular checkpoint blockade, has changed the clinical landscape of metastatic melanoma. Nonetheless, the majority of patients will either be primary refractory or progress over follow up. Management of patients progressing on first-line immunotherapy remains challenging. Expanded treatment options with combination immunotherapy has demonstrated efficacy in patients previously unresponsive to single agent or alternative combination therapy. We describe the case of a patient with diffusely metastatic melanoma, including brain metastases, who, despite being treated with stereotactic radiosurgery and dual CTLA-4/PD-1 blockade (ipilimumab/nivolumab), developed systemic disease progression and innumerable brain metastases. This patient achieved a complete CNS response and partial systemic response with standard whole brain radiation therapy (WBRT) combined with Talimogene laherparepvec (T-Vec) and pembrolizumab. Patients who do not respond to one immunotherapy combination may respond during treatment with an alternate combination, even in the presence of multiple brain metastases. Biomarkers are needed to assist clinicians in evidence based clinical decision making after progression on first line immunotherapy to determine whether response can be achieved with second line immunotherapy.

Membrane Signaling Induced by High Doses of Ionizing Radiation in the Endothelial Compartment. Relevance in Radiation Toxicity

PubMed Central

Corre, Isabelle; Guillonneau, Maëva; Paris, François

2013-01-01

Tumor areas can now be very precisely delimited thanks to technical progress in imaging and ballistics. This has also led to the development of novel radiotherapy protocols, delivering higher doses of ionizing radiation directly to cancer cells. Despite this, radiation toxicity in healthy tissue remains a major issue, particularly with dose-escalation in these new protocols. Acute and late tissue damage following irradiation have both been linked to the endothelium irrigating normal tissues. The molecular mechanisms involved in the endothelial response to high doses of radiation are associated with signaling from the plasma membrane, mainly via the acid sphingomyelinase/ceramide pathway. This review describes this signaling pathway and discusses the relevance of targeting endothelial signaling to protect healthy tissues from the deleterious effects of high doses of radiation. PMID:24252908

Circadian light

PubMed Central

2010-01-01

The present paper reflects a work in progress toward a definition of circadian light, one that should be informed by the thoughtful, century-old evolution of our present definition of light as a stimulus for the human visual system. This work in progress is based upon the functional relationship between optical radiation and its effects on nocturnal melatonin suppression, in large part because the basic data are available in the literature. Discussed here are the fundamental differences between responses by the visual and circadian systems to optical radiation. Brief reviews of photometry, colorimetry, and brightness perception are presented as a foundation for the discussion of circadian light. Finally, circadian light (CLA) and circadian stimulus (CS) calculation procedures based on a published mathematical model of human circadian phototransduction are presented with an example. PMID:20377841

Neuroimaging classification of progression patterns in glioblastoma: a systematic review.

PubMed

Piper, Rory J; Senthil, Keerthi K; Yan, Jiun-Lin; Price, Stephen J

2018-03-30

Our primary objective was to report the current neuroimaging classification systems of spatial patterns of progression in glioblastoma. In addition, we aimed to report the terminology used to describe 'progression' and to assess the compliance with the Response Assessment in Neuro-Oncology (RANO) Criteria. We conducted a systematic review to identify all neuroimaging studies of glioblastoma that have employed a categorical classification system of spatial progression patterns. Our review was registered with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) registry. From the included 157 results, we identified 129 studies that used labels of spatial progression patterns that were not based on radiation volumes (Group 1) and 50 studies that used labels that were based on radiation volumes (Group 2). In Group 1, we found 113 individual labels and the most frequent were: local/localised (58%), distant/distal (51%), diffuse (20%), multifocal (15%) and subependymal/subventricular zone (15%). We identified 13 different labels used to refer to 'progression', of which the most frequent were 'recurrence' (99%) and 'progression' (92%). We identified that 37% (n = 33/90) of the studies published following the release of the RANO classification were adherent compliant with the RANO criteria. Our review reports significant heterogeneity in the published systems used to classify glioblastoma spatial progression patterns. Standardization of terminology and classification systems used in studying progression would increase the efficiency of our research in our attempts to more successfully treat glioblastoma.

Salate derivatives found in sunscreens block experimental autoimmune encephalomyelitis in mice

PubMed Central

Wang, Yanping; Marling, Steven J.; Plum, Lori A.; DeLuca, Hector F.

2017-01-01

UV light suppresses experimental autoimmune encephalomyelitis (EAE), a widely used animal model of MS, in mice and may be responsible for the decreased incidence of MS in equatorial regions. To test this concept further, we applied commercially available sunblock preparations to mice before exposing them to UV radiation. Surprisingly, some of the sunblock preparations blocked EAE without UV radiation. Furthermore, various sunblock preparations had variable ability to suppress EAE. By examining the components of the most effective agents, we identified homosalate and octisalate as the components responsible for suppressing EAE. Thus, salates may be useful in stopping the progression of MS, and may provide new insight into mechanisms of controlling autoimmune disease. PMID:28739922

The efficacy and safety of simultaneous integrated boost intensity-modulated radiation therapy for esophageal squamous cell carcinoma in Chinese population: A single institution experience.

PubMed

Xu, Yujin; Wang, Zhun; Liu, Guan; Zheng, Xiao; Wang, Yuezhen; Feng, Wei; Lai, Xiaojing; Zhou, Xia; Li, Pu; Ma, Honglian; Wang, Jin; Hu, Xiao; Chen, Ming

2016-10-01

To evaluate the clinical efficacy and toxicity of simultaneous integrated boost intensity-modulated radiotherapy (SIB-IMRT) in patients with esophageal squamous cell carcinoma (ESCC) in Chinese population. Patients with ESCC, who received SIB-IMRT from September 2011 to January 2013 were retrospectively analyzed. The SIB-IMRT plans were designed to deliver primary gross tumor volume at 60-64.4 Gy in 28-30 fractions, and planning target volume at 50.4-56 Gy in 28-30 fractions. Treatment-related toxicities were estimated based on Common Terminology Criteria for Adverse Events version 4.0, and tumor response after the treatment was estimated according to Response Evaluation Criteria in Solid Tumors version 1.0. Overall survival (OS), locoregional progression-free survival (LPFS), and progression-free survival (PFS) were estimated with Kaplan-Meier. All patients completed definitive radiotherapy, 54 (78.3%) received combined chemotherapy, of which 31 (44.9%) were concurrent chemoradiotherapy and 23 (33.3%) were sequential chemotherapy. The objective response rate is 82.6% (56/69), with complete response 11 (15.9%), partial response 45 (65.2%), stable disease 8 (11.6%), and progressive disease 5 (7.2%). The 1-, 2- and 3-year LPFS was 74.4%, 57.8%, and 55.6%, respectively. The 1-, 2- and 3-year PFS was 62.3%, 41.0%, and 34.2%, respectively, and the 1-, 2-, and 3-year OS was 73.8%, 57.4%, and 41.0%, respectively, with a median OS of 27.1 months (4.5-54.9 m). For those who received concurrent chemotherapy, the 1-, 2-, and 3-year OS was 75.9%, 69.0%, and 55.2%, respectively, better than those who had sequential chemotherapy or radiotherapy alone (χ2 = 3.115, P = 0.078). Radiation esophagitis occurred in 63.8% and 14.5% with Grade 2 and 3, respectively. No patients occurred ≥ Grade 3 radiation pneumonia. It is safe and effective using SIB-IMRT technology to treat patients with ESCC. More prospective clinical studies should be needed.

Multifunctional albumin-MnO₂ nanoparticles modulate solid tumor microenvironment by attenuating hypoxia, acidosis, vascular endothelial growth factor and enhance radiation response.

PubMed

Prasad, Preethy; Gordijo, Claudia R; Abbasi, Azhar Z; Maeda, Azusa; Ip, Angela; Rauth, Andrew Michael; DaCosta, Ralph S; Wu, Xiao Yu

2014-04-22

Insufficient oxygenation (hypoxia), acidic pH (acidosis), and elevated levels of reactive oxygen species (ROS), such as H2O2, are characteristic abnormalities of the tumor microenvironment (TME). These abnormalities promote tumor aggressiveness, metastasis, and resistance to therapies. To date, there is no treatment available for comprehensive modulation of the TME. Approaches so far have been limited to regulating hypoxia, acidosis, or ROS individually, without accounting for their interdependent effects on tumor progression and response to treatments. Hence we have engineered multifunctional and colloidally stable bioinorganic nanoparticles composed of polyelectrolyte-albumin complex and MnO2 nanoparticles (A-MnO2 NPs) and utilized the reactivity of MnO2 toward peroxides for regulation of the TME with simultaneous oxygen generation and pH increase. In vitro studies showed that these NPs can generate oxygen by reacting with H2O2 produced by cancer cells under hypoxic conditions. A-MnO2 NPs simultaneously increased tumor oxygenation by 45% while increasing tumor pH from pH 6.7 to pH 7.2 by reacting with endogenous H2O2 produced within the tumor in a murine breast tumor model. Intratumoral treatment with NPs also led to the downregulation of two major regulators in tumor progression and aggressiveness, that is, hypoxia-inducible factor-1 alpha and vascular endothelial growth factor in the tumor. Combination treatment of the tumors with NPs and ionizing radiation significantly inhibited breast tumor growth, increased DNA double strand breaks and cancer cell death as compared to radiation therapy alone. These results suggest great potential of A-MnO2 NPs for modulation of the TME and enhancement of radiation response in the treatment of cancer.

Research progress in radiation detectors, pattern recognition programs, and radiation damage determination in DNA

NASA Technical Reports Server (NTRS)

Baily, N. A.

1973-01-01

The radiological implications of statistical variations in energy deposition by ionizing radiation were investigated in the conduct of the following experiments: (1) study of the production of secondary particles generated by the passage of the primary radiation through bone and muscle; (2) the study of the ratio of nonreparable to reparable damage in DNA as a function of different energy deposition patterns generated by X rays versus heavy fast charged particles; (3) the use of electronic radiography systems for direct fluoroscopic tomography and for the synthesis of multiple planes and; (4) the determination of the characteristics of systems response to split fields having different contrast levels, and of minimum detectable contrast levels between the halves under realistic clinical situations.

Multiagent chemotherapy and deferred radiotherapy in infants with malignant brain tumors: a report from the Children's Cancer Group.

PubMed

Geyer, J Russell; Sposto, Richard; Jennings, Mark; Boyett, James M; Axtell, Richard A; Breiger, David; Broxson, Emmett; Donahue, Bernadine; Finlay, Jonathan L; Goldwein, Joel W; Heier, Linda A; Johnson, Dennis; Mazewski, Claire; Miller, Douglas C; Packer, Roger; Puccetti, Diane; Radcliffe, Jerilynn; Tao, May Lin; Shiminski-Maher, Tania

2005-10-20

To evaluate response rate, event-free survival (EFS), and toxicity of two chemotherapeutic regimens for treatment of children younger than 36 months with malignant brain tumors and to estimate control intervals without irradiation in children with no residual tumor after initial surgery and induction chemotherapy and with delayed irradiation in patients with residual tumor or metastatic disease at diagnosis. Patients were randomly assigned to one of two regimens of induction chemotherapy (vincristine, cisplatin, cyclophosphamide, and etoposide v vincristine, carboplatin, ifosfamide, and etoposide). Maintenance chemotherapy began after induction in children without progressive disease. Children with no residual tumors after induction therapy and no metastatic disease at diagnosis were not to receive radiation therapy unless their tumors progressed. Two hundred ninety-nine infants were enrolled. Forty-two percent of patients responded to induction chemotherapy. At 5 years from study entry, the EFS rate was 27% +/- 3%, and the survival rate was 43% +/- 3%. There was no significant difference between the two arms in terms of response rate or EFS. For medulloblastoma, supratentorial primitive neuroectodermal tumor, ependymoma, and rhabdoid tumors, 5-year EFS rates were 32% +/- 5%, 17% +/- 6%, and 32% +/- 6%, and 14% +/- 7%, respectively. Fifty-eight percent of patients who were alive 5 years after study entry had not received radiation therapy. Intensified induction chemotherapy resulted in a high response rate of malignant brain tumors in infants. Survival was comparable to that of previous studies, and most patients who survived did not receive radiation therapy.

Current trends in gamma radiation detection for radiological emergency response

NASA Astrophysics Data System (ADS)

Mukhopadhyay, Sanjoy; Guss, Paul; Maurer, Richard

2011-09-01

Passive and active detection of gamma rays from shielded radioactive materials, including special nuclear materials, is an important task for any radiological emergency response organization. This article reports on the current trends and status of gamma radiation detection objectives and measurement techniques as applied to nonproliferation and radiological emergencies. In recent years, since the establishment of the Domestic Nuclear Detection Office by the Department of Homeland Security, a tremendous amount of progress has been made in detection materials (scintillators, semiconductors), imaging techniques (Compton imaging, use of active masking and hybrid imaging), data acquisition systems with digital signal processing, field programmable gate arrays and embedded isotopic analysis software (viz. gamma detector response and analysis software [GADRAS]1), fast template matching, and data fusion (merging radiological data with geo-referenced maps, digital imagery to provide better situational awareness). In this stride to progress, a significant amount of inter-disciplinary research and development has taken place-techniques and spin-offs from medical science (such as x-ray radiography and tomography), materials engineering (systematic planned studies on scintillators to optimize several qualities of a good scintillator, nanoparticle applications, quantum dots, and photonic crystals, just to name a few). No trend analysis of radiation detection systems would be complete without mentioning the unprecedented strategic position taken by the National Nuclear Security Administration (NNSA) to deter, detect, and interdict illicit trafficking in nuclear and other radioactive materials across international borders and through the global maritime transportation-the so-called second line of defense.

Cloud Feedbacks in the Climate System: A Critical Review.

NASA Astrophysics Data System (ADS)

Stephens, Graeme L.

2005-01-01

This paper offers a critical review of the topic of cloud-climate feedbacks and exposes some of the underlying reasons for the inherent lack of understanding of these feedbacks and why progress might be expected on this important climate problem in the coming decade. Although many processes and related parameters come under the influence of clouds, it is argued that atmospheric processes fundamentally govern the cloud feedbacks via the relationship between the atmospheric circulations, cloudiness, and the radiative and latent heating of the atmosphere. It is also shown how perturbations to the atmospheric radiation budget that are induced by cloud changes in response to climate forcing dictate the eventual response of the global-mean hydrological cycle of the climate model to climate forcing. This suggests that cloud feedbacks are likely to control the bulk precipitation efficiency and associated responses of the planet's hydrological cycle to climate radiative forcings.The paper provides a brief overview of the effects of clouds on the radiation budget of the earth-atmosphere system and a review of cloud feedbacks as they have been defined in simple systems, one being a system in radiative-convective equilibrium (RCE) and others relating to simple feedback ideas that regulate tropical SSTs. The systems perspective is reviewed as it has served as the basis for most feedback analyses. What emerges is the importance of being clear about the definition of the system. It is shown how different assumptions about the system produce very different conclusions about the magnitude and sign of feedbacks. Much more diligence is called for in terms of defining the system and justifying assumptions. In principle, there is also neither any theoretical basis to justify the system that defines feedbacks in terms of global-time-mean changes in surface temperature nor is there any compelling empirical evidence to do so. The lack of maturity of feedback analysis methods also suggests that progress in understanding climate feedback will require development of alternative methods of analysis.It has been argued that, in view of the complex nature of the climate system, and the cumbersome problems encountered in diagnosing feedbacks, understanding cloud feedback will be gleaned neither from observations nor proved from simple theoretical argument alone. The blueprint for progress must follow a more arduous path that requires a carefully orchestrated and systematic combination of model and observations. Models provide the tool for diagnosing processes and quantifying feedbacks while observations provide the essential test of the model's credibility in representing these processes. While GCM climate and NWP models represent the most complete description of all the interactions between the processes that presumably establish the main cloud feedbacks, the weak link in the use of these models lies in the cloud parameterization imbedded in them. Aspects of these parameterizations remain worrisome, containing levels of empiricism and assumptions that are hard to evaluate with current global observations. Clearly observationally based methods for evaluating cloud parameterizations are an important element in the road map to progress.Although progress in understanding the cloud feedback problem has been slow and confused by past analysis, there are legitimate reasons outlined in the paper that give hope for real progress in the future.

Positron emission tomography-guided conformal fast neutron therapy for glioblastoma multiforme

PubMed Central

Stelzer, Keith J.; Douglas, James G.; Mankoff, David A.; Silbergeld, Daniel L.; Krohn, Kenneth A.; Laramore, George E.; Spence, Alexander M.

2008-01-01

Glioblastoma multiforme (GBM) continues to be a difficult therapeutic challenge. Our study was conducted to determine whether improved survival and tumor control could be achieved with modern delivery of fast neutron radiation using three-dimensional treatment planning. Ten patients were enrolled. Eligibility criteria included pathologic diagnosis of GBM, age ≥ 18 years, and KPS ≥60. Patients underwent MRI and 18F-fluorodeoxyglucose PET (FDG PET) as part of initial three-dimensional treatment planning. Sequential targets were treated with noncoplanar fields to a total dose of 18 Gy in 16 fractions over 4 weeks. Median and 1-year overall survival were 55 weeks and 60%, respectively. One patient remains alive at last follow-up 255 weeks after diagnosis. Median progression-free survival was 16 weeks, and all patients had tumor progression by 39 weeks. Treatment was clinically well tolerated, but evidence of mild to moderate gliosis and microvascular sclerosis consistent with radiation injury was observed at autopsy in specimens taken from regions of contralateral brain that received approximately 6–10 Gy. Fast neutron radiation using modern imaging, treatment planning, and beam delivery was feasible to a total dose of 18 Gy, but tumor control probability was poor in comparison to that predicted from a dose-response model based on older studies. Steep dose-response curves for both tumor control and neurotoxicity continue to present a challenge to establishing a therapeutic window for fast neutron radiation in GBM, even with modern techniques. PMID:18055860

Safety and Efficacy of High-Dose Tamoxifen and Sulindac for Desmoid Tumor in Children: Results of a Children’s Oncology Group (COG) Phase II Study

PubMed Central

Skapek, Stephen X.; Anderson, James R.; Hill, D. Ashley; Henry, David; Spunt, Sheri L.; Meyer, William; Kao, Simon; Hoffer, Fredric A.; Grier, Holcombe E.; Hawkins, Douglas S.; Raney, R. Beverly

2015-01-01

Background Desmoid fibromatosis (desmoid tumor, DT) is a soft tissue neoplasm prone to recurrence despite complete surgical resection. Numerous small retrospective reports suggest that non-cytotoxic chemotherapy using tamoxifen and sulindac may be effective for DT. We evaluated the safety and efficacy of tamoxifen and sulindac in a prospective phase II study within the Children’s Oncology Group. Procedures Eligible patients were <19 years of age who had measurable DT that was recurrent or not amenable to surgery or radiation. The primary objective was to estimate progression-free survival (PFS). Patients received tamoxifen and sulindac daily for 12 months or until disease progression or intolerable toxicity occurred. Response was assessed by magnetic resonance imaging. Results Fifty-nine eligible patients were enrolled from 2004 to 2009; 78% were 10–18 years old. Twenty-two (38%) were previously untreated; 15 (41%) of the remaining 37 enrolling with recurrent DT had prior systemic chemotherapy and six (16%) had prior radiation. No life-threatening toxicity was reported. Twelve (40%) of 30 females developed ovarian cysts, which were asymptomatic in 11 cases. Ten patients completed therapy without disease progression or discontinuing treatment. Responses included four partial and one complete (5/59, 8%). The estimated 2-year PFS and survival rates were 36% (95% confidence interval: 0.23–0.48) and 96%, respectively. All three deaths were due to progressive DT. Conclusions Tamoxifen and sulindac caused few serious side effects in children with DT, although ovarian cysts were common. However, the combination showed relatively little activity as measured by response and PFS rates. PMID:23281268

Safety and efficacy of high-dose tamoxifen and sulindac for desmoid tumor in children: results of a Children's Oncology Group (COG) phase II study.

PubMed

Skapek, Stephen X; Anderson, James R; Hill, D Ashley; Henry, David; Spunt, Sheri L; Meyer, William; Kao, Simon; Hoffer, Fredric A; Grier, Holcombe E; Hawkins, Douglas S; Raney, R Beverly

2013-07-01

Desmoid fibromatosis (desmoid tumor, DT) is a soft tissue neoplasm prone to recurrence despite complete surgical resection. Numerous small retrospective reports suggest that non-cytotoxic chemotherapy using tamoxifen and sulindac may be effective for DT. We evaluated the safety and efficacy of tamoxifen and sulindac in a prospective phase II study within the Children's Oncology Group. Eligible patients were <19 years of age who had measurable DT that was recurrent or not amenable to surgery or radiation. The primary objective was to estimate progression-free survival (PFS). Patients received tamoxifen and sulindac daily for 12 months or until disease progression or intolerable toxicity occurred. Response was assessed by magnetic resonance imaging. Fifty-nine eligible patients were enrolled from 2004 to 2009; 78% were 10-18 years old. Twenty-two (38%) were previously untreated; 15 (41%) of the remaining 37 enrolling with recurrent DT had prior systemic chemotherapy and six (16%) had prior radiation. No life-threatening toxicity was reported. Twelve (40%) of 30 females developed ovarian cysts, which were asymptomatic in 11 cases. Ten patients completed therapy without disease progression or discontinuing treatment. Responses included four partial and one complete (5/59, 8%). The estimated 2-year PFS and survival rates were 36% (95% confidence interval: 0.23-0.48) and 96%, respectively. All three deaths were due to progressive DT. Tamoxifen and sulindac caused few serious side effects in children with DT, although ovarian cysts were common. However, the combination showed relatively little activity as measured by response and PFS rates. Copyright © 2012 Wiley Periodicals, Inc.

A phase II study of nab-paclitaxel plus carboplatin in combination with thoracic radiation in patients with locally advanced non-small-cell lung cancer.

PubMed

Hasegawa, Takaaki; Futamura, Yohei; Horiba, Akane; Yoshida, Tsutomu; Suzuki, Toshitaka; Kato, Tatsuo; Kaito, Daizo; Ohno, Yasuhi; Iida, Takayoshi; Hayashi, Shinya; Sawa, Toshiyuki

2016-01-01

We investigated the efficacy and safety of albumin-bound paclitaxel (nab-PTX) and carboplatin (CBDCA) with concurrent radiotherapy for unresectable locally advanced non-small-cell lung cancer (NSCLC). Patients with Stage III NSCLC and an Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible. Concurrent chemoradiotherapy consisted of weekly administration of nab-PTX (40 mg/m(2)) plus CBDCA (area under the plasma concentration time curve (AUC) 2) and thoracic radiotherapy (60 Gy/30 fractions) for a total of 6 weeks. After concurrent chemoradiotherapy, patients received an additional two cycles of consolidation phase chemotherapy that consisted of 4-week cycles of nab-PTX (100 mg/m(2) on Days 1, 8 and 15)/CBDCA (AUC 5 mg/ml/min on Day 1). Response was evaluated in accordance with the Response Evaluation Criteria in Solid Tumors. Progression-free survival and overall survival were estimated using the Kaplan-Meier method. Toxicity was graded using the National Cancer Institute Common Terminology Criteria for Adverse Events. A total of 10 patients were enrolled in this trial between September 2013 and January 2014 from three institutes. The overall response rate was 40.0% and the median progression-free survival was 6.7 months. Treatment-related death occurred in two patients. Grade 2 or worse severe radiation pneumonitis was observed in all three patients that had the volume of lung receiving at least 20 Gy (V20) >30%. The results of this study indicate that no further investigation is warranted into nab-PTX and CBDCA with concurrent thoracic radiation for Stage III NSCLC with V20 > 30% due to severe toxicity. © The Author 2015. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.

Current concepts for the combined treatment modality of ionizing radiation with anticancer agents.

PubMed

Oehler, Christoph; Dickinson, Daniel J; Broggini-Tenzer, Angela; Hofstetter, Barbara; Hollenstein, Andreas; Riesterer, Oliver; Vuong, Van; Pruschy, Martin

2007-01-01

In current applied radiobiology, there exists a tremendous effort in basic and translational research to identify novel treatment modalities combining ionizing radiation with anticancer agents. This is mainly due to the highly improved molecular understanding of intrinsic radioresistance and the profiling of cellular stress responses to irradiation during recent years. Ionizing radiation not only damages DNA but also affects multiple cellular components that induce a multi-layered stress response. The treatment responses can be restricted to the individual cell level but might also be part of an intercellular stress communication network. Both DNA damage-induced signaling (which results in cell cycle arrest and induction of the DNA-repair machinery) and also ionizing radiation-induced signal transduction cascades, which are generated at cellular sites distant from and independent of DNA-damage, represent interesting targets for anticancer treatment modalities to sensitize for ionizing radiation. Due to the lack of molecular knowledge classic radiobiology assembled the cellular and tissue responses into four groups (4 R's of radiotherapy) which describe biological factors influencing the treatment response to fractionated radiotherapy. These classic 4 R's are Repair, Reassortment, Repopulation and Reoxygenation. With the tremendous progress in molecular oncology we now begin to understand theses factors on the molecular level. At the same time this classification may guide modern molecular radiobiologists to identify novel pharmaceuticals and antisignaling agents which can modulate the treatment response to irradiation. In this review we describe current approaches to sensitize tumor cells with novel anticancer agents along the lines of these 4 R's.

Clustered DNA damages induced in human hematopoietic cells by low doses of ionizing radiation

NASA Technical Reports Server (NTRS)

Sutherland, Betsy M.; Bennett, Paula V.; Cintron-Torres, Nela; Hada, Megumi; Trunk, John; Monteleone, Denise; Sutherland, John C.; Laval, Jacques; Stanislaus, Marisha; Gewirtz, Alan

2002-01-01

Ionizing radiation induces clusters of DNA damages--oxidized bases, abasic sites and strand breaks--on opposing strands within a few helical turns. Such damages have been postulated to be difficult to repair, as are double strand breaks (one type of cluster). We have shown that low doses of low and high linear energy transfer (LET) radiation induce such damage clusters in human cells. In human cells, DSB are about 30% of the total of complex damages, and the levels of DSBs and oxidized pyrimidine clusters are similar. The dose responses for cluster induction in cells can be described by a linear relationship, implying that even low doses of ionizing radiation can produce clustered damages. Studies are in progress to determine whether clusters can be produced by mechanisms other than ionizing radiation, as well as the levels of various cluster types formed by low and high LET radiation.

Simultaneous measurement of multiple radiation-induced protein expression profiles using the Luminex(TM) system

NASA Technical Reports Server (NTRS)

Desai, N.; Wu, H.; George, K.; Gonda, S. R.; Cucinotta, F. A.; Cucniotta, F. A. (Principal Investigator)

2004-01-01

Space flight results in the exposure of astronauts to a mixed field of radiation composed of energetic particles of varying energies, and biological indicators of space radiation exposure provides a better understanding of the associated long-term health risks. Current methods of biodosimetry have employed the use of cytogenetic analysis for biodosimetry, and more recently the advent of technological progression has led to advanced research in the use of genomic and proteomic expression profiling to simultaneously assess biomarkers of radiation exposure. We describe here the technical advantages of the Luminex(TM) 100 system relative to traditional methods and its potential as a tool to simultaneously profile multiple proteins induced by ionizing radiation. The development of such a bioassay would provide more relevant post-translational dynamics of stress response and will impart important implications in the advancement of space and other radiation contact monitoring. c2004 COSPAR. Published by Elsevier Ltd. All rights reserved.

Role of Definitive Radiation Therapy in Carcinoma of Unknown Primary in the Abdomen and Pelvis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kelly, Patrick; Das, Prajnan; Varadhachary, Gauri R.

2012-04-01

Objectives: Carcinoma of unknown primary (CUP) in the abdomen and pelvis is a heterogeneous group of cancers with no standard treatment. Considered by many to be incurable, these patients are often treated with chemotherapy alone. In this study, we determined the effectiveness of radiation therapy in combination with chemotherapy in patients with CUP in the abdomen and pelvis. Patients and Methods: Medical records were reviewed for 37 patients with CUP treated with radiation therapy for disease located in the soft tissues and/or nodal basins of the abdomen and pelvis at University of Texas M.D. Anderson Cancer between 2002 and 2009.more » All patients underwent chemotherapy, either before or concurrent with radiation therapy. Patients were selected for radiation therapy on the basis of histologic type, disease extent, and prior therapy response. Twenty patients underwent definitive radiation therapy (defined as radiation therapy targeting all known disease sites with at least 45 Gy) and 17 patients underwent palliative radiation therapy. Only 6 patients had surgical resection of their disease. Patient and treatment characteristics were extracted and the endpoints of local disease control, progression-free survival (PFS), overall survival (OS), and treatment-related toxicity incidence were analyzed. Results: The 2-year PFS and OS rates for the entire cohort were 32% and 57%, respectively. However, in patients treated with definitive radiation therapy, the rates were 48% and 76%, and 7 patients lived more than 3 years after treatment with no evidence of disease progression. Nevertheless, radiation-associated toxicity was significant in this cohort, as 40% experienced Grade 2 or higher late toxicities. Conclusions: The use of definitive radiation therapy should be considered in selected patients with CUP in the soft tissues or nodal basins of the abdomen and pelvis.« less

Pre-irradiation chemotherapy for newly diagnosed high grade astrocytoma.

PubMed

Mathieu, N Tubiana; Genet, D; Labrousse, F; Bouillet, P; Denes, S Lavau; Martin, J; Labourey, J L; Venat, L; Clavere, P; Moreau, J J

2004-01-01

The purpose of this work was to determine the response rate and toxicity of a combination of Carmustine and Cisplatin administered before radiation in patients with newly diagnosed high grade astrocytoma. A good response rate has been published with this association in primary cerebral high grade tumor. This protocol was administered in a homogeneous population of 37 adult patients with measurable tumor on magnetic resonance imaging (MRI) or CT scan. After biopsy or subtotal resection, the patients received BCNU 40 mg/m2/d and CODP 40 mg/m2/d, for 3 days every 28 days for 3 cycles. Evaluation was performed before each cycle. Radiation therapy began 4 weeks after completing the chemotherapy or immediately if there was evidence of tumor progression on chemotherapy. Seven out of 37 (19%) demonstrated tumor regression with a median duration to progression of 11 months. Median survival was 6 months. Myelosuppression was the predominant but manageable toxicity. This work indicated that the first chemotherapy protocol gave poor results in a homogeneous group of patients, with bad prognosis.

Radiation Effects in Advanced Multiple Gate and Silicon-on-Insulator Transistors

NASA Astrophysics Data System (ADS)

Simoen, Eddy; Gaillardin, Marc; Paillet, Philippe; Reed, Robert A.; Schrimpf, Ron D.; Alles, Michael L.; El-Mamouni, Farah; Fleetwood, Daniel M.; Griffoni, Alessio; Claeys, Cor

2013-06-01

The aim of this review paper is to describe in a comprehensive manner the current understanding of the radiation response of state-of-the-art Silicon-on-Insulator (SOI) and FinFET CMOS technologies. Total Ionizing Dose (TID) response, heavy-ion microdose effects and single-event effects (SEEs) will be discussed. It is shown that a very high TID tolerance can be achieved by narrow-fin SOI FinFET architectures, while bulk FinFETs may exhibit similar TID response to the planar devices. Due to the vertical nature of FinFETs, a specific heavy-ion response can be obtained, whereby the angle of incidence becomes highly important with respect to the vertical sidewall gates. With respect to SEE, the buried oxide in the SOI FinFETs suppresses the diffusion tails from the charge collection in the substrate compared to the planar bulk FinFET devices. Channel lengths and fin widths are now comparable to, or smaller than the dimensions of the region affected by the single ionizing ions or lasers used in testing. This gives rise to a high degree of sensitivity to individual device parameters and source-drain shunting during ion-beam or laser-beam SEE testing. Simulations are used to illuminate the mechanisms observed in radiation testing and the progress and needs for the numerical modeling/simulation of the radiation response of advanced SOI and FinFET transistors are highlighted.

Reversible CSF cyst related to a functioning ventriculo-peritoneal shunt.

PubMed

Vajramani, G V; Fugleholm, K

2005-11-01

Although the occurrence of CSF oedema and cyst has been described in presence of a blocked ventriculoperitoneal shunt, especially distal end block, its occurrence in presence of a well functioning shunt has not been described so far. We report a case where a 51-year old lady developed an insidious onset and gradually progressive CSF cyst without any clinical or radiological feature of shunt block over a period of about 2 years. The changes started about 6 months after a course of radiation therapy for an extensive residual supra and infratentorial meningioma. Following surgery, where the cyst was punctured and a new ventricular catheter was inserted, despite well functioning upper and lower end, the cyst gradually disappeared. We review the literature and hypothesize that the radiation-induced changes were responsible for initiation and progression of the cyst.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Galperin, Michael

The progress of experimental techniques at the nanoscale in the last decade made optical measurements in current-carrying nanojunctions a reality, thus indicating the emergence of a new field of research coined optoelectronics. Optical spectroscopy of open nonequilibrium systems is a natural meeting point for (at least) two research areas: nonlinear optical spectroscopy and quantum transport, each with its own theoretical toolbox. We review recent progress in the field comparing theoretical treatments of optical response in nanojunctions as is accepted in nonlinear spectroscopy and quantum transport communities. A unified theoretical description of spectroscopy in nanojunctions is presented. Here, we argue thatmore » theoretical approaches of the quantum transport community (and in particular, the Green function based considerations) yield a convenient tool for optoelectronics when the radiation field is treated classically, and that differences between the toolboxes may become critical when studying the quantum radiation field in junctions.« less

Effect of pulsed progressive fluoroscopy on reduction of radiation dose in the cardiac catheterization laboratory

DOE Office of Scientific and Technical Information (OSTI.GOV)

Holmes, D.R. Jr.; Wondrow, M.A.; Gray, J.E.

1990-01-01

The increased application of therapeutic interventional cardiology procedures is associated with increased radiation exposure to physicians, patients and technical personnel. New advances in imaging techniques have the potential for reducing radiation exposure. A progressive scanning video system with a standard vascular phantom has been shown to decrease entrance radiation exposure. The effect of this system on reducing actual radiation exposure to physicians and technicians was assessed from 1984 through 1987. During this time, progressive fluoroscopy was added sequentially to all four adult catheterization laboratories; no changes in shielding procedures were made. During this time, the case load per physician increasedmore » by 63% and the number of percutaneous transluminal coronary angioplasty procedures (a high radiation procedure) increased by 244%. Despite these increases in both case load and higher radiation procedures, the average radiation exposure per physician declined by 37%. During the same time, the radiation exposure for technicians decreased by 35%. Pulsed progressive fluoroscopy is effective for reducing radiation exposure to catheterization laboratory physicians and technical staff.« less

A review of educational philosophies as applied to radiation safety training at medical institutions.

PubMed

Dauer, Lawrence T; St Germain, Jean

2006-05-01

This paper examines the educational philosophy of radiation safety education programs at medical institutions. The regulatory mandates for radiation safety training have traditionally emphasized competency-based training. This emphasis led to the adoption of a behaviorist philosophy that requires predetermined responses to certain situations. The behaviorist approach determines the roles of teacher and learner as well as the methods to be used. This paper examines these roles and methods and the influence of a highly regulated environment on the adoption of the behaviorist model. The paper also suggests that other educational philosophies, such as the progressive philosophy, should be examined to provide a rich foundation for improving the educational experience and outcomes.

Better Efficacy of Synchrotron Spatially Microfractionated Radiation Therapy Than Uniform Radiation Therapy on Glioma.

PubMed

Bouchet, Audrey; Bräuer-Krisch, Elke; Prezado, Yolanda; El Atifi, Michèle; Rogalev, Léonid; Le Clec'h, Céline; Laissue, Jean Albert; Pelletier, Laurent; Le Duc, Géraldine

2016-08-01

Synchrotron microbeam radiation therapy (MRT) is based on the spatial fractionation of the incident, highly focused synchrotron beam into arrays of parallel microbeams, typically a few tens of microns wide and depositing several hundred grays. This irradiation modality was shown to have a high therapeutic impact on tumors, especially in intracranial locations. However, mechanisms responsible for such a property are not fully understood. Thanks to recent progress in dosimetry, we compared the effect of MRT and synchrotron broad beam (BB) radiation therapy delivered at comparable doses (equivalent to MRT valley dose) on tumor growth control and on classical radiobiological functions by histologic evaluation and/or transcriptomic analysis. MRT significantly improved survival of rats bearing 9L intracranial glioma compared with BB radiation therapy delivered at a comparable dose (P<.001); the efficacy of MRT and BB radiation therapy was similar when the MRT dose was half that of BB. The greater efficacy of MRT was not correlated with a difference in cell proliferation (Mki67 and proliferating cell nuclear antigen) or in transcriptomic stimulation of angiogenesis (vascular endothelial growth factor A or tyrosine kinase with immunoglobulin-like and epidermal growth factor-like domains 2) but was correlated with a higher cell death rate (factor for apoptosis signals) and higher recruitment of macrophages (tyrosine kinase with immunoglobulin-like and epidermal growth factor-like domains 1 and CD68 transcripts) a few days after MRT. These results show the superiority of MRT over BB radiation therapy when applied at comparable doses, suggesting that spatial fractionation is responsible for a specific and particularly efficient tissue response. The higher induction of cell death and immune cell activation in brain tumors treated by MRT may be involved in such responses. Copyright © 2016 Elsevier Inc. All rights reserved.

Better Efficacy of Synchrotron Spatially Microfractionated Radiation Therapy Than Uniform Radiation Therapy on Glioma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bouchet, Audrey, E-mail: audrey.m.bouchet@gmail.com; Biomedical Beamline, European Synchrotron Radiation Facility, Grenoble; Bräuer-Krisch, Elke

Purpose: Synchrotron microbeam radiation therapy (MRT) is based on the spatial fractionation of the incident, highly focused synchrotron beam into arrays of parallel microbeams, typically a few tens of microns wide and depositing several hundred grays. This irradiation modality was shown to have a high therapeutic impact on tumors, especially in intracranial locations. However, mechanisms responsible for such a property are not fully understood. Methods and Materials: Thanks to recent progress in dosimetry, we compared the effect of MRT and synchrotron broad beam (BB) radiation therapy delivered at comparable doses (equivalent to MRT valley dose) on tumor growth control andmore » on classical radiobiological functions by histologic evaluation and/or transcriptomic analysis. Results: MRT significantly improved survival of rats bearing 9L intracranial glioma compared with BB radiation therapy delivered at a comparable dose (P<.001); the efficacy of MRT and BB radiation therapy was similar when the MRT dose was half that of BB. The greater efficacy of MRT was not correlated with a difference in cell proliferation (Mki67 and proliferating cell nuclear antigen) or in transcriptomic stimulation of angiogenesis (vascular endothelial growth factor A or tyrosine kinase with immunoglobulin-like and epidermal growth factor-like domains 2) but was correlated with a higher cell death rate (factor for apoptosis signals) and higher recruitment of macrophages (tyrosine kinase with immunoglobulin-like and epidermal growth factor-like domains 1 and CD68 transcripts) a few days after MRT. Conclusions: These results show the superiority of MRT over BB radiation therapy when applied at comparable doses, suggesting that spatial fractionation is responsible for a specific and particularly efficient tissue response. The higher induction of cell death and immune cell activation in brain tumors treated by MRT may be involved in such responses.« less

Randomized Double-Blind Placebo-Controlled Trial of Bevacizumab Therapy for Radiation Necrosis of the Central Nervous System

DOE Office of Scientific and Technical Information (OSTI.GOV)

Levin, Victor A., E-mail: vlevin49@comcast.ne; Bidaut, Luc; Hou, Ping

Purpose: To conduct a controlled trial of bevacizumab for the treatment of symptomatic radiation necrosis of the brain. Methods and Materials: A total of 14 patients were entered into a placebo-controlled randomized double-blind study of bevacizumab for the treatment of central nervous system radiation necrosis. All patients were required to have radiographic or biopsy proof of central nervous system radiation necrosis and progressive neurologic symptoms or signs. Eligible patients had undergone irradiation for head-and-neck carcinoma, meningioma, or low- to mid-grade glioma. Patients were randomized to receive intravenous saline or bevacizumab at 3-week intervals. The magnetic resonance imaging findings 3 weeksmore » after the second treatment and clinical signs and symptoms defined the response or progression. Results: The volumes of necrosis estimated on T{sub 2}-weighted fluid-attenuated inversion recovery and T{sub 1}-weighted gadolinium-enhanced magnetic resonance imaging scans demonstrated that although no patient receiving placebo responded (0 of 7), all bevacizumab-treated patients did so (5 of 5 randomized and 7 of 7 crossover) with decreases in T{sub 2}-weighted fluid-attenuated inversion recovery and T{sub 1}-weighted gadolinium-enhanced volumes and a decrease in endothelial transfer constant. All bevacizumab-treated patients-and none of the placebo-treated patients-showed improvement in neurologic symptoms or signs. At a median of 10 months after the last dose of bevacizumab in patients receiving all four study doses, only 2 patients had experienced a recurrence of magnetic resonance imaging changes consistent with progressive radiation necrosis; one patient received a single additional dose of bevacizumab and the other patient received two doses. Conclusion: The Class I evidence of bevacizumab efficacy from the present study in the treatment of central nervous system radiation necrosis justifies consideration of this treatment option for people with radiation necrosis secondary to the treatment of head-and-neck cancer and brain cancer.« less

Low-Dose Radiation Cataract and Genetic Determinants of Radiosensitivity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kleiman, Norman Jay

The lens of the eye is one of the most radiosensitive tissues in the body. Ocular ionizing radiation exposure results in characteristic, dose related, progressive lens changes leading to cataract formation. While initial, early stages of lens opacification may not cause visual disability, the severity of such changes progressively increases with dose until vision is impaired and cataract extraction surgery may be required. Because of the transparency of the eye, radiation induced lens changes can easily be followed non-invasively over time. Thus, the lens provides a unique model system in which to study the effects of low dose ionizing radiationmore » exposure in a complex, highly organized tissue. Despite this observation, considerable uncertainties remain surrounding the relationship between dose and risk of developing radiation cataract. For example, a growing number of human epidemiological findings suggest significant risk among various groups of occupationally and accidentally exposed individuals and confidence intervals that include zero dose. Nevertheless, questions remain concerning the relationship between lens opacities, visual disability, clinical cataract, threshold dose and/or the role of genetics in determining radiosensitivity. Experimentally, the response of the rodent eye to radiation is quite similar to that in humans and thus animal studies are well suited to examine the relationship between radiation exposure, genetic determinants of radiosensitivity and cataractogenesis. The current work has expanded our knowledge of the low-dose effects of X-irradiation or high-LET heavy ion exposure on timing and progression of radiation cataract and has provided new information on the genetic, molecular, biochemical and cell biological features which contribute to this pathology. Furthermore, findings have indicated that single and/or multiple haploinsufficiency for various genes involved in DNA repair and cell cycle checkpoint control, such as Atm, Brca1 or Rad9, influence cataract development and thus radiosensitivity. These observations have direct applicability to various human populations including accidentally exposed individuals, interventional medical workers, astronauts and nuclear plant workers.« less

Implications of the Endothelial Cell Response in Glioblastoma to Stimulation by Mesenchymal Stem Cells and Ionizing Radiation

NASA Astrophysics Data System (ADS)

Zhao, Tansy Y.

Heightened angiogenesis is both the pathophysiologic hallmark and the potential cause of therapy resistance for glioblastoma (GBM), a deadly brain tumor. It is thought that mesenchymal stem cells (MSCs) play important roles in neovascularization and tumor progression. We postulated that MSCs protect ECs against radiotherapy, which subsequently enhances tumor angiogenesis, and promotes GBM tumor recurrence following therapy. We therefore sought to establish the in-vitro endothelial cell response to stimulation by MSC condition media and ionizing radiation (IR) treatment. We established the gene expression profiles of endothelial cells in response to IR, MSCs and the combination of both. Within the same gene profiles, we identified a unique gene signature that was highly predictive of response to Bevacizumab for GBM patients. We also demonstrated that MSC increased the viability of ECs in response to IR. Protein analysis in ECs suggested MSC-mediated cell cycle arrest as a mechanism for radio-resistance in ECs.

CDDO-Me protects normal lung and breast epithelial cells but not cancer cells from radiation.

PubMed

El-Ashmawy, Mariam; Delgado, Oliver; Cardentey, Agnelio; Wright, Woodring E; Shay, Jerry W

2014-01-01

Although radiation therapy is commonly used for treatment for many human diseases including cancer, ionizing radiation produces reactive oxygen species that can damage both cancer and healthy cells. Synthetic triterpenoids, including CDDO-Me, act as anti-inflammatory and antioxidant modulators primarily by inducing the transcription factor Nrf2 to activate downstream genes containing antioxidant response elements (AREs). In the present series of experiments, we determined if CDDO-Me can be used as a radioprotector in normal non-cancerous human lung and breast epithelial cells, in comparison to lung and breast cancer cell lines. A panel of normal non-cancerous, partially cancer progressed, and cancer cell lines from both lung and breast tissue was exposed to gamma radiation with and without pre-treatment with CDDO-Me. CDDO-Me was an effective radioprotector when given ∼18 hours before radiation in epithelial cells (average dose modifying factor (DMF) = 1.3), and Nrf2 function was necessary for CDDO-Me to exert these radioprotective effects. CDDO-Me did not protect cancer lines tested from radiation-induced cytotoxicity, nor did it protect experimentally transformed human bronchial epithelial cells (HBECs) with progressive oncogenic manipulations. CDDO-Me also protected human lymphocytes against radiation-induced DNA damage. A therapeutic window exists in which CDDO-Me protects normal cells from radiation by activating the Nrf2 pathway, but does not protect experimentally transformed or cancer cell lines. This suggests that use of this oral available, non-toxic class of drug can protect non-cancerous healthy cells during radiotherapy, resulting in better outcomes and less toxicity for patients.

CDDO-Me Protects Normal Lung and Breast Epithelial Cells but Not Cancer Cells from Radiation

PubMed Central

El-Ashmawy, Mariam; Delgado, Oliver; Cardentey, Agnelio; Wright, Woodring E.; Shay, Jerry W.

2014-01-01

Although radiation therapy is commonly used for treatment for many human diseases including cancer, ionizing radiation produces reactive oxygen species that can damage both cancer and healthy cells. Synthetic triterpenoids, including CDDO-Me, act as anti-inflammatory and antioxidant modulators primarily by inducing the transcription factor Nrf2 to activate downstream genes containing antioxidant response elements (AREs). In the present series of experiments, we determined if CDDO-Me can be used as a radioprotector in normal non-cancerous human lung and breast epithelial cells, in comparison to lung and breast cancer cell lines. A panel of normal non-cancerous, partially cancer progressed, and cancer cell lines from both lung and breast tissue was exposed to gamma radiation with and without pre-treatment with CDDO-Me. CDDO-Me was an effective radioprotector when given ∼18 hours before radiation in epithelial cells (average dose modifying factor (DMF) = 1.3), and Nrf2 function was necessary for CDDO-Me to exert these radioprotective effects. CDDO-Me did not protect cancer lines tested from radiation-induced cytotoxicity, nor did it protect experimentally transformed human bronchial epithelial cells (HBECs) with progressive oncogenic manipulations. CDDO-Me also protected human lymphocytes against radiation-induced DNA damage. A therapeutic window exists in which CDDO-Me protects normal cells from radiation by activating the Nrf2 pathway, but does not protect experimentally transformed or cancer cell lines. This suggests that use of this oral available, non-toxic class of drug can protect non-cancerous healthy cells during radiotherapy, resulting in better outcomes and less toxicity for patients. PMID:25536195

Distinct transcriptome profiles identified in normal human bronchial epithelial cells after exposure to γ-rays and different elemental particles of high Z and energy.

PubMed

Ding, Liang-Hao; Park, Seongmi; Peyton, Michael; Girard, Luc; Xie, Yang; Minna, John D; Story, Michael D

2013-06-01

Ionizing radiation composed of accelerated ions of high atomic number (Z) and energy (HZE) deposits energy and creates damage in cells in a discrete manner as compared to the random deposition of energy and damage seen with low energy radiations such as γ- or x-rays. Such radiations can be highly effective at cell killing, transformation, and oncogenesis, all of which are concerns for the manned space program and for the burgeoning field of HZE particle radiotherapy for cancer. Furthermore, there are differences in the extent to which cells or tissues respond to such exposures that may be unrelated to absorbed dose. Therefore, we asked whether the energy deposition patterns produced by different radiation types would cause different molecular responses. We performed transcriptome profiling using human bronchial epithelial cells (HBECs) after exposure to γ-rays and to two different HZE particles (28Si and 56Fe) with different energy transfer properties to characterize the molecular response to HZE particles and γ-rays as a function of dose, energy deposition pattern, and time post-irradiation. Clonogenic assay indicated that the relative biological effectiveness (RBE) for 56Fe was 3.91 and for 28Si was 1.38 at 34% cell survival. Unsupervised clustering analysis of gene expression segregated samples according to the radiation species followed by the time after irradiation, whereas dose was not a significant parameter for segregation of radiation response. While a subset of genes associated with p53-signaling, such as CDKN1A, TRIM22 and BTG2 showed very similar responses to all radiation qualities, distinct expression changes were associated with the different radiation species. Gene enrichment analysis categorized the differentially expressed genes into functional groups related to cell death and cell cycle regulation for all radiation types, while gene pathway analysis revealed that the pro-inflammatory Acute Phase Response Signaling was specifically induced after HZE particle irradiation. A 73 gene signature capable of predicting with 96% accuracy the radiation species to which cells were exposed, was developed. These data suggest that the molecular response to the radiation species used here is a function of the energy deposition characteristics of the radiation species. This novel molecular response to HZE particles may have implications for radiotherapy including particle selection for therapy and risk for second cancers, risk for cancers from diagnostic radiation exposures, as well as NASA's efforts to develop more accurate lung cancer risk estimates for astronaut safety. Lastly, irrespective of the source of radiation, the gene expression changes observed set the stage for functional studies of initiation or progression of radiation-induced lung carcinogenesis.

Distinct transcriptome profiles identified in normal human bronchial epithelial cells after exposure to γ-rays and different elemental particles of high Z and energy

PubMed Central

2013-01-01

Background Ionizing radiation composed of accelerated ions of high atomic number (Z) and energy (HZE) deposits energy and creates damage in cells in a discrete manner as compared to the random deposition of energy and damage seen with low energy radiations such as γ- or x-rays. Such radiations can be highly effective at cell killing, transformation, and oncogenesis, all of which are concerns for the manned space program and for the burgeoning field of HZE particle radiotherapy for cancer. Furthermore, there are differences in the extent to which cells or tissues respond to such exposures that may be unrelated to absorbed dose. Therefore, we asked whether the energy deposition patterns produced by different radiation types would cause different molecular responses. We performed transcriptome profiling using human bronchial epithelial cells (HBECs) after exposure to γ-rays and to two different HZE particles (28Si and 56Fe) with different energy transfer properties to characterize the molecular response to HZE particles and γ-rays as a function of dose, energy deposition pattern, and time post-irradiation. Results Clonogenic assay indicated that the relative biological effectiveness (RBE) for 56Fe was 3.91 and for 28Si was 1.38 at 34% cell survival. Unsupervised clustering analysis of gene expression segregated samples according to the radiation species followed by the time after irradiation, whereas dose was not a significant parameter for segregation of radiation response. While a subset of genes associated with p53-signaling, such as CDKN1A, TRIM22 and BTG2 showed very similar responses to all radiation qualities, distinct expression changes were associated with the different radiation species. Gene enrichment analysis categorized the differentially expressed genes into functional groups related to cell death and cell cycle regulation for all radiation types, while gene pathway analysis revealed that the pro-inflammatory Acute Phase Response Signaling was specifically induced after HZE particle irradiation. A 73 gene signature capable of predicting with 96% accuracy the radiation species to which cells were exposed, was developed. Conclusions These data suggest that the molecular response to the radiation species used here is a function of the energy deposition characteristics of the radiation species. This novel molecular response to HZE particles may have implications for radiotherapy including particle selection for therapy and risk for second cancers, risk for cancers from diagnostic radiation exposures, as well as NASA’s efforts to develop more accurate lung cancer risk estimates for astronaut safety. Lastly, irrespective of the source of radiation, the gene expression changes observed set the stage for functional studies of initiation or progression of radiation-induced lung carcinogenesis. PMID:23724988

Mesoscopic modeling of the response of human dental enamel to mid-infrared radiation

NASA Astrophysics Data System (ADS)

Vila Verde, Ana; Ramos, Marta; Stoneham, A. M.

2006-03-01

Ablation of human dental enamel, a composite biomaterial with water pores, is of significant importance in minimally invasive laser dentistry but progress in the area is hampered by the lack of optimal laser parameters. We use mesoscopic finite element models of this material to study its response to mid-infrared radiation. Our results indicate that the cost-effective, off-the-shelf CO2 laser at λ = 10.6 μm may in fact ablate enamel precisely, reproducibly and with limited unwanted side effects such as cracking or heating, provided that a pulse duration of 10 μs is used. Furthermore, our results also indicate that the Er:YAG laser (λ = 2.94 μm), currently popular for laser dentistry, may in fact cause unwanted deep cracking in the enamel when regions with unusually high water content are irradiated, and also provide an explanation for the large range of ablation threshold values observed for this material. The model may be easily adapted to study the response of any composite material to infrared radiation and thus may be useful for the scientific community.

A Systems Approach to Radiation Carcinogenesis

NASA Astrophysics Data System (ADS)

Hlatky, Lynn

Understanding carcinogenesis risk is complicated by a number of factors, among these the lack of a common platform to integrate and analyze the available data, and the inherently systemsbiologic nature of the problem. We have investigated mechanistic approaches to radiogenic risk estimation that draw on unifying biological principles and incorporate data from multiscale sources. The resultant modeling takes into account that carcinogenesis is a multi-scale phenomenon, critically influenced by determinants not only at the molecular level, but at the cell and tissue-levels as well. To account for cell-level carcinogenesis progression as influenced by inter-tissue signaling, we have developed a dynamic carrying capacity construct that couples the growth of a tumor with the degree of induced vascularization. We have also characterized the molecular responses to radiation incorporating tissue-level angiogenesis implications, and have found striking radiation-quality-dependent responses. The molecular-level events of initiation and promotion are considered in our Two-Stage Logistic model, while incorporating in a rudimentary way the larger-scale growth-limiting role of cell-cell interactions. These and other recent studies undertaken to elaborate radiation-induced carcinogenesis are discussed, in pursuit of a more complete paradigm for understanding radiation induction of cancer and the consequent risk.

SUV39H1 downregulation induces deheterochromatinization of satellite regions and senescence after exposure to ionizing radiation

PubMed Central

Sidler, Corinne; Li, Dongping; Wang, Bo; Kovalchuk, Igor; Kovalchuk, Olga

2014-01-01

While the majority of cancer patients are exposed to ionizing radiation during diagnostic and therapeutic procedures, age-dependent differences in radiation sensitivity are not yet well understood. Radiation sensitivity is characterized by the appearance of side effects to radiation therapy, such as secondary malignancies, developmental deficits, and compromised immune function. However, the knowledge of the molecular mechanisms that trigger these side effects is incomplete. Here we used an in vitro system and showed that low-senescent normal human diploid fibroblasts (WI-38) senesce in response to 5 Gy IR, while highly senescent cultures do not show changes in cell cycle regulation and only a slight increase in the percentage of senescent cells. Our study shows that this is associated with changes in the expression of genes responsible for cell cycle progression, apoptosis, DNA repair, and aging, as well as transcriptional and epigenetic regulators. Furthermore, we propose a role of the downregulation of SUV39H1 expression, a histone methyltransferase that specifically trimethylates H3K9, and the corresponding reduction in H3K9me3 levels in the establishment of IR-induced senescence. PMID:25484892

Mitotic regulator Nlp interacts with XPA/ERCC1 complexes and regulates nucleotide excision repair (NER) in response to UV radiation.

PubMed

Ma, Xiao-Juan; Shang, Li; Zhang, Wei-Min; Wang, Ming-Rong; Zhan, Qi-Min

2016-04-10

Cellular response to DNA damage, including ionizing radiation (IR) and UV radiation, is critical for the maintenance of genomic fidelity. Defects of DNA repair often result in genomic instability and malignant cell transformation. Centrosomal protein Nlp (ninein-like protein) has been characterized as an important cell cycle regulator that is required for proper mitotic progression. In this study, we demonstrate that Nlp is able to improve nucleotide excision repair (NER) activity and protects cells against UV radiation. Upon exposure of cells to UVC, Nlp is translocated into the nucleus. The C-terminus (1030-1382) of Nlp is necessary and sufficient for its nuclear import. Upon UVC radiation, Nlp interacts with XPA and ERCC1, and enhances their association. Interestingly, down-regulated expression of Nlp is found to be associated with human skin cancers, indicating that dysregulated Nlp might be related to the development of human skin cancers. Taken together, this study identifies mitotic protein Nlp as a new and important member of NER pathway and thus provides novel insights into understanding of regulatory machinery involved in NER. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Low-dose radiation decreases tumor progression via the inhibition of the JAK1/STAT3 signaling axis in breast cancer cell lines

PubMed Central

Kaushik, Neha; Kim, Min-Jung; Kim, Rae-Kwon; Kumar Kaushik, Nagendra; Seong, Ki Moon; Nam, Seon-Young; Lee, Su-Jae

2017-01-01

Breast cancer is a widely distributed type of cancer in women worldwide, and tumor relapse is the major cause of breast cancer death. In breast cancers, the acquisition of metastatic ability, which is responsible for tumor relapse and poor clinical outcomes, has been linked to the acquisition of the epithelial-mesenchymal transition (EMT) program and self-renewal traits (CSCs) via various signaling pathways. These phenomena confer resistance during current therapies, thus creating a major hurdle in radiotherapy/chemotherapy. The role of very low doses of radiation (LDR) in the context of EMT has not yet to be thoroughly explored. Here, we report that a 0.1 Gy radiation dose reduces cancer progression by deactivating the JAK1/STAT3 pathway. Furthermore, LDR exposure also reduces sphere formation and inhibits the self-renewal ability of breast cancer cells, resulting in an attenuated CD44+/CD24− population. Additionally, in vivo findings support our data, providing evidence that LDR is a promising option for future treatment strategies to prevent cancer metastasis in breast cancer cases. PMID:28240233

Abscopal Effect in a Stage IV Melanoma Patient who Progressed on Pembrolizumab.

PubMed

Tsui, James M; Mihalcioiu, Catalin; Cury, Fabio L

2018-02-27

In this case report, we present the clinical course of a woman with locally advanced mucosal melanoma of the oral cavity. She was initially treated with surgery with adjuvant local radiation of 50 Gy in 20 fractions. She quickly relapsed with an aggressive regional recurrence of the disease on the neck and with numerous pulmonary metastases. Immunotherapy with pembrolizumab was started, with initial good response and reduction in the size of the lesion in the neck. The regression, however, was short-lived, as the mass quickly grew at a remarkable rate and the lung lesions progressed significantly. Palliative local radiation of 24 Gy in three fractions delivered at days zero, seven, and 21 to the neck mass was eventually given with the goal to alleviate symptoms. An immediate tumor regression was observed after the first fraction of radiotherapy. Remarkably, the lung lesions had also started regressing following radiation. We believe this to be a case of abscopal effect witnessed during the delivery of radiotherapy. A review of the recent literature is also presented here.

Abscopal Effect in a Stage IV Melanoma Patient who Progressed on Pembrolizumab

PubMed Central

Tsui, James M; Mihalcioiu, Catalin

2018-01-01

In this case report, we present the clinical course of a woman with locally advanced mucosal melanoma of the oral cavity. She was initially treated with surgery with adjuvant local radiation of 50 Gy in 20 fractions. She quickly relapsed with an aggressive regional recurrence of the disease on the neck and with numerous pulmonary metastases. Immunotherapy with pembrolizumab was started, with initial good response and reduction in the size of the lesion in the neck. The regression, however, was short-lived, as the mass quickly grew at a remarkable rate and the lung lesions progressed significantly. Palliative local radiation of 24 Gy in three fractions delivered at days zero, seven, and 21 to the neck mass was eventually given with the goal to alleviate symptoms. An immediate tumor regression was observed after the first fraction of radiotherapy. Remarkably, the lung lesions had also started regressing following radiation. We believe this to be a case of abscopal effect witnessed during the delivery of radiotherapy. A review of the recent literature is also presented here. PMID:29719740

Identifying Urinary and Serum Exosome Biomarkers for Radiation Exposure Using a Data Dependent Acquisition and SWATH-MS Combined Workflow.

PubMed

Kulkarni, Shilpa; Koller, Antonius; Mani, Kartik M; Wen, Ruofeng; Alfieri, Alan; Saha, Subhrajit; Wang, Jian; Patel, Purvi; Bandeira, Nuno; Guha, Chandan; Chen, Emily I

2016-11-01

Early and accurate assessment of radiation injury by radiation-responsive biomarkers is critical for triage and early intervention. Biofluids such as urine and serum are convenient for such analysis. Recent research has also suggested that exosomes are a reliable source of biomarkers in disease progression. In the present study, we analyzed total urine proteome and exosomes isolated from urine or serum for potential biomarkers of acute and persistent radiation injury in mice exposed to lethal whole body irradiation (WBI). For feasibility studies, the mice were irradiated at 10.4 Gy WBI, and urine and serum samples were collected 24 and 72 hours after irradiation. Exosomes were isolated and analyzed using liquid chromatography mass spectrometry/mass spectrometry-based workflow for radiation exposure signatures. A data dependent acquisition and SWATH-MS combined workflow approach was used to identify significantly exosome biomarkers indicative of acute or persistent radiation-induced responses. For the validation studies, mice were exposed to 3, 6, 8, or 10 Gy WBI, and samples were analyzed for comparison. A comparison between total urine proteomics and urine exosome proteomics demonstrated that exosome proteomic analysis was superior in identifying radiation signatures. Feasibility studies identified 23 biomarkers from urine and 24 biomarkers from serum exosomes after WBI. Urinary exosome signatures identified different physiological parameters than the ones obtained in serum exosomes. Exosome signatures from urine indicated injury to the liver, gastrointestinal, and genitourinary tracts. In contrast, serum showed vascular injuries and acute inflammation in response to radiation. Selected urinary exosomal biomarkers also showed changes at lower radiation doses in validation studies. Exosome proteomics revealed radiation- and time-dependent protein signatures after WBI. A total of 47 differentially secreted proteins were identified in urinary and serum exosomes. Together, these data showed the feasibility of defining biomarkers that could elucidate tissue-associated and systemic response caused by high-dose ionizing radiation. This is the first report using an exosome proteomics approach to identify radiation signatures. Copyright © 2016 Elsevier Inc. All rights reserved.

Identifying Urinary and Serum Exosome Biomarkers for Radiation Exposure Using a Data Dependent Acquisition and SWATH-MS Combined Workflow

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kulkarni, Shilpa; Koller, Antonius; Proteomics Shared Resource, Herbert Irving Comprehensive Cancer Center, New York, New York

Purpose: Early and accurate assessment of radiation injury by radiation-responsive biomarkers is critical for triage and early intervention. Biofluids such as urine and serum are convenient for such analysis. Recent research has also suggested that exosomes are a reliable source of biomarkers in disease progression. In the present study, we analyzed total urine proteome and exosomes isolated from urine or serum for potential biomarkers of acute and persistent radiation injury in mice exposed to lethal whole body irradiation (WBI). Methods and Materials: For feasibility studies, the mice were irradiated at 10.4 Gy WBI, and urine and serum samples were collected 24more » and 72 hours after irradiation. Exosomes were isolated and analyzed using liquid chromatography mass spectrometry/mass spectrometry-based workflow for radiation exposure signatures. A data dependent acquisition and SWATH-MS combined workflow approach was used to identify significantly exosome biomarkers indicative of acute or persistent radiation-induced responses. For the validation studies, mice were exposed to 3, 6, 8, or 10 Gy WBI, and samples were analyzed for comparison. Results: A comparison between total urine proteomics and urine exosome proteomics demonstrated that exosome proteomic analysis was superior in identifying radiation signatures. Feasibility studies identified 23 biomarkers from urine and 24 biomarkers from serum exosomes after WBI. Urinary exosome signatures identified different physiological parameters than the ones obtained in serum exosomes. Exosome signatures from urine indicated injury to the liver, gastrointestinal, and genitourinary tracts. In contrast, serum showed vascular injuries and acute inflammation in response to radiation. Selected urinary exosomal biomarkers also showed changes at lower radiation doses in validation studies. Conclusions: Exosome proteomics revealed radiation- and time-dependent protein signatures after WBI. A total of 47 differentially secreted proteins were identified in urinary and serum exosomes. Together, these data showed the feasibility of defining biomarkers that could elucidate tissue-associated and systemic response caused by high-dose ionizing radiation. This is the first report using an exosome proteomics approach to identify radiation signatures.« less

Lnk adaptor suppresses radiation resistance and radiation-induced B-cell malignancies by inhibiting IL-11 signaling

PubMed Central

Louria-Hayon, Igal; Frelin, Catherine; Ruston, Julie; Gish, Gerald; Jin, Jing; Kofler, Michael M.; Lambert, Jean-Philippe; Adissu, Hibret A.; Milyavsky, Michael; Herrington, Robert; Minden, Mark D.; Dick, John E.; Gingras, Anne-Claude; Iscove, Norman N.; Pawson, Tony

2013-01-01

The Lnk (Sh2b3) adaptor protein dampens the response of hematopoietic stem cells and progenitors (HSPCs) to a variety of cytokines by inhibiting JAK2 signaling. As a consequence, Lnk−/− mice develop hematopoietic hyperplasia, which progresses to a phenotype resembling the nonacute phase of myeloproliferative neoplasm. In addition, Lnk mutations have been identified in human myeloproliferative neoplasms and acute leukemia. We find that Lnk suppresses the development of radiation-induced acute B-cell malignancies in mice. Lnk-deficient HSPCs recover more effectively from irradiation than their wild-type counterparts, and this resistance of Lnk−/− HSPCs to radiation underlies the subsequent emergence of leukemia. A search for the mechanism responsible for radiation resistance identified the cytokine IL-11 as being critical for the ability of Lnk−/− HSPCs to recover from irradiation and subsequently become leukemic. In IL-11 signaling, wild-type Lnk suppresses tyrosine phosphorylation of the Src homology region 2 domain-containing phosphatase-2/protein tyrosine phosphatase nonreceptor type 11 and its association with the growth factor receptor-bound protein 2, as well as activation of the Erk MAP kinase pathway. Indeed, Src homology region 2 domain-containing phosphatase-2 has a binding motif for the Lnk Src Homology 2 domain that is phosphorylated in response to IL-11 stimulation. IL-11 therefore drives a pathway that enhances HSPC radioresistance and radiation-induced B-cell malignancies, but is normally attenuated by the inhibitory adaptor Lnk. PMID:24297922

Photonics and spectroscopy in nanojunctions: a theoretical insight

DOE PAGES

Galperin, Michael

2017-04-11

The progress of experimental techniques at the nanoscale in the last decade made optical measurements in current-carrying nanojunctions a reality, thus indicating the emergence of a new field of research coined optoelectronics. Optical spectroscopy of open nonequilibrium systems is a natural meeting point for (at least) two research areas: nonlinear optical spectroscopy and quantum transport, each with its own theoretical toolbox. We review recent progress in the field comparing theoretical treatments of optical response in nanojunctions as is accepted in nonlinear spectroscopy and quantum transport communities. A unified theoretical description of spectroscopy in nanojunctions is presented. Here, we argue thatmore » theoretical approaches of the quantum transport community (and in particular, the Green function based considerations) yield a convenient tool for optoelectronics when the radiation field is treated classically, and that differences between the toolboxes may become critical when studying the quantum radiation field in junctions.« less

Whales Use Distinct Strategies to Counteract Solar Ultraviolet Radiation

PubMed Central

Martinez-Levasseur, Laura M.; Birch-Machin, Mark A.; Bowman, Amy; Gendron, Diane; Weatherhead, Elizabeth; Knell, Robert J.; Acevedo-Whitehouse, Karina

2013-01-01

A current threat to the marine ecosystem is the high level of solar ultraviolet radiation (UV). Large whales have recently been shown to suffer sun-induced skin damage from continuous UV exposure. Genotoxic consequences of such exposure remain unknown for these long-lived marine species, as does their capacity to counteract UV-induced insults. We show that UV exposure induces mitochondrial DNA damage in the skin of seasonally sympatric fin, sperm, and blue whales and that this damage accumulates with age. However, counteractive molecular mechanisms are markedly different between species. For example, sperm whales, a species that remains for long periods at the sea surface, activate genotoxic stress pathways in response to UV exposure whereas the paler blue whale relies on increased pigmentation as the season progresses. Our study also shows that whales can modulate their responses to fluctuating levels of UV, and that different evolutionary constraints may have shaped their response strategies. PMID:23989080

The effect of radiation dose on the onset and progression of radiation-induced brain necrosis in the rat model.

PubMed

Hartl, Brad A; Ma, Htet S W; Hansen, Katherine S; Perks, Julian; Kent, Michael S; Fragoso, Ruben C; Marcu, Laura

2017-07-01

To provide a comprehensive understanding of how the selection of radiation dose affects the temporal and spatial progression of radiation-induced necrosis in the rat model. Necrosis was induced with a single fraction of radiation exposure, at doses ranging between 20 and 60 Gy, to the right hemisphere of 8-week-old Fischer rats from a linear accelerator. The development and progression of necrosis in the rats was monitored and quantified every other week with T1- and T2-weighted gadolinium contrast-enhanced MRI studies. The time to onset of necrosis was found to be dose-dependent, but after the initial onset, the necrosis progression rate and total volume generated was constant across different doses ranging between 30 and 60 Gy. Radiation doses less than 30 Gy did not develop necrosis within 33 weeks after treatment, indicating a dose threshold existing between 20 and 30 Gy. The highest dose used in this study led to the shortest time to onset of radiation-induced necrosis, while producing comparable disease progression dynamics after the onset. Therefore, for the radiation-induced necrosis rat model using a linear accelerator, the most optimum results were generated from a dose of 60 Gy.

NCI–RTOG Translational Program Strategic Guidelines for the Early-Stage Development of Radiosensitizers

PubMed Central

2013-01-01

The addition of chemotherapeutic agents to ionizing radiation has improved survival in many malignancies. Cure rates may be further improved by adding novel targeted agents to current radiotherapy or radiochemotherapy regimens. Despite promising laboratory data, progress in the clinical development of new drugs with radiation has been limited. To define and address the problems involved, a collaborative effort between individuals within the translational research program of the Radiation Oncology Therapy Group and the National Cancer Institute was established. We discerned challenges to drug development with radiation including: 1) the limited relevance of preclinical work, 2) the pharmaceutical industry’s diminished interest, and 3) the important individual skills and institutional commitments required to ensure a successful program. The differences between early-phase trial designs with and without radiation are noted as substantial. The traditional endpoints for early-phase clinical trials—acute toxicity and maximum-tolerated dose—are of limited value when combining targeted agents with radiation. Furthermore, response rate is not a useful surrogate marker of activity in radiation combination trials.Consequently, a risk-stratified model for drug-dose escalation with radiation is proposed, based upon the known and estimated adverse effects. The guidelines discuss new clinical trial designs, such as the time-to-event continual reassessment method design for phase I trials, randomized phase II “screening” trials, and the use of surrogate endpoints, such as pathological response. It is hoped that by providing a clear pathway, this article will accelerate the rate of drug development with radiation. PMID:23231975

Environmental standards for ionizing radiation: theoretical basis for dose-response curves.

PubMed Central

Upton, A C

1983-01-01

The types of injury attributable to ionizing radiation are subdivided, for purposes of risk assessment and radiological protection, into two broad categories: stochastic effects and nonstochastic effects. Stochastic effects are viewed as probablistic phenomena, varying in frequency but not severity as a function of the dose, without any threshold; nonstochastic effects are viewed as deterministic phenomena, varying in both frequency and severity as a function of the dose, with clinical thresholds. Included among stochastic effects are heritable effects (mutations and chromosome aberrations) and carcinogenic effects. Both types of effects are envisioned as unicellular phenomena which can result from nonlethal injury of individual cells, without the necessity of damage to other cells. For the induction of mutations and chromosome aberrations in the low-to-intermediate dose range, the dose-response curve with high-linear energy transfer (LET) radiation generally conforms to a linear nonthreshold relationship and varies relatively little with the dose rate. In contrast, the curve with low-LET radiation generally conforms to a linear-quadratic relationship, rising less steeply than the curve with high-LET radiation and increasing in slope with increasing dose and dose rate. The dose-response curve for carcinogenic effects varies widely from one type of neoplasm to another in the intermediate-to-high dose range, in part because of differences in the way large doses of radiation can affect the promotion and progression of different neoplasms. Information about dose-response relations for low-level irradiation is fragmentary but consistent, in general, with the hypothesis that the neoplastic transformation may result from mutation, chromosome aberration or genetic recombination in a single susceptible cell. PMID:6653536

Low-dose radiation treatment in pulmonary mucosa-associated lymphoid tissue lymphoma: a plausible approach? A single-institution experience in 10 patients.

PubMed

Girinsky, Theodore; Paumier, Amaury; Ferme, Christophe; Hanna, Colette; Ribrag, Vincent; Leroy-Ladurie, François; Ghalibafian, Mithra

2012-07-01

To propose an alternative approach for treatment of pulmonary marginal zone lymphoma, using a very small radiation dose (2 × 2 Gy) delivered exclusively to tumor sites. Patients had localized pulmonary mucosa-associated lymphoid tissue (MALT) lymphoma according to the World Health Organization classification. The 6-MV radiation treatments were delivered using tumor-limited fields, except in cases of diffuse bilateral involvement. Two daily fractions of 2 Gy were delivered to tumor-limited fields using a 6-MV linear accelerator. Ten patients with pulmonary MALT lymphoma entered the study. All but 1 had localized tumor masses. The median follow-up was 56 months (range, 2-103 months). Complete remission or an unconfirmed complete remission was obtained in 60% of patients within the first 2 months, and two additional partial responses were converted into a long-term unconfirmed complete remission. All patients are well and alive, no local progression was observed, and the 5-year progression-free survival rate was 87.5% (95% confidence interval 49%-97%). Our results suggest that extremely low radiation doses delivered exclusively to tumor sites might be a treatment option in pulmonary MALT lymphoma. Copyright © 2012 Elsevier Inc. All rights reserved.

{sup 18}F-Fluorodeoxyglucose Positron Emission Tomography Can Quantify and Predict Esophageal Injury During Radiation Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Niedzielski, Joshua S., E-mail: jsniedzielski@mdanderson.org; University of Texas Houston Graduate School of Biomedical Science, Houston, Texas; Yang, Jinzhong

Purpose: We sought to investigate the ability of mid-treatment {sup 18}F-fluorodeoxyglucose positron emission tomography (PET) studies to objectively and spatially quantify esophageal injury in vivo from radiation therapy for non-small cell lung cancer. Methods and Materials: This retrospective study was approved by the local institutional review board, with written informed consent obtained before enrollment. We normalized {sup 18}F-fluorodeoxyglucose PET uptake to each patient's low-irradiated region (<5 Gy) of the esophagus, as a radiation response measure. Spatially localized metrics of normalized uptake (normalized standard uptake value [nSUV]) were derived for 79 patients undergoing concurrent chemoradiation therapy for non-small cell lung cancer. We usedmore » nSUV metrics to classify esophagitis grade at the time of the PET study, as well as maximum severity by treatment completion, according to National Cancer Institute Common Terminology Criteria for Adverse Events, using multivariate least absolute shrinkage and selection operator (LASSO) logistic regression and repeated 3-fold cross validation (training, validation, and test folds). This 3-fold cross-validation LASSO model procedure was used to predict toxicity progression from 43 asymptomatic patients during the PET study. Dose-volume metrics were also tested in both the multivariate classification and the symptom progression prediction analyses. Classification performance was quantified with the area under the curve (AUC) from receiver operating characteristic analysis on the test set from the 3-fold analyses. Results: Statistical analysis showed increasing nSUV is related to esophagitis severity. Axial-averaged maximum nSUV for 1 esophageal slice and esophageal length with at least 40% of axial-averaged nSUV both had AUCs of 0.85 for classifying grade 2 or higher esophagitis at the time of the PET study and AUCs of 0.91 and 0.92, respectively, for maximum grade 2 or higher by treatment completion. Symptom progression was predicted with an AUC of 0.75. Dose metrics performed poorly at classifying esophagitis (AUC of 0.52, grade 2 or higher mid treatment) or predicting symptom progression (AUC of 0.67). Conclusions: Normalized uptake can objectively, locally, and noninvasively quantify esophagitis during radiation therapy and predict eventual symptoms from asymptomatic patients. Normalized uptake may provide patient-specific dose-response information not discernible from dose.« less

(18)F-Fluorodeoxyglucose Positron Emission Tomography Can Quantify and Predict Esophageal Injury During Radiation Therapy.

PubMed

Niedzielski, Joshua S; Yang, Jinzhong; Liao, Zhongxing; Gomez, Daniel R; Stingo, Francesco; Mohan, Radhe; Martel, Mary K; Briere, Tina M; Court, Laurence E

2016-11-01

We sought to investigate the ability of mid-treatment (18)F-fluorodeoxyglucose positron emission tomography (PET) studies to objectively and spatially quantify esophageal injury in vivo from radiation therapy for non-small cell lung cancer. This retrospective study was approved by the local institutional review board, with written informed consent obtained before enrollment. We normalized (18)F-fluorodeoxyglucose PET uptake to each patient's low-irradiated region (<5 Gy) of the esophagus, as a radiation response measure. Spatially localized metrics of normalized uptake (normalized standard uptake value [nSUV]) were derived for 79 patients undergoing concurrent chemoradiation therapy for non-small cell lung cancer. We used nSUV metrics to classify esophagitis grade at the time of the PET study, as well as maximum severity by treatment completion, according to National Cancer Institute Common Terminology Criteria for Adverse Events, using multivariate least absolute shrinkage and selection operator (LASSO) logistic regression and repeated 3-fold cross validation (training, validation, and test folds). This 3-fold cross-validation LASSO model procedure was used to predict toxicity progression from 43 asymptomatic patients during the PET study. Dose-volume metrics were also tested in both the multivariate classification and the symptom progression prediction analyses. Classification performance was quantified with the area under the curve (AUC) from receiver operating characteristic analysis on the test set from the 3-fold analyses. Statistical analysis showed increasing nSUV is related to esophagitis severity. Axial-averaged maximum nSUV for 1 esophageal slice and esophageal length with at least 40% of axial-averaged nSUV both had AUCs of 0.85 for classifying grade 2 or higher esophagitis at the time of the PET study and AUCs of 0.91 and 0.92, respectively, for maximum grade 2 or higher by treatment completion. Symptom progression was predicted with an AUC of 0.75. Dose metrics performed poorly at classifying esophagitis (AUC of 0.52, grade 2 or higher mid treatment) or predicting symptom progression (AUC of 0.67). Normalized uptake can objectively, locally, and noninvasively quantify esophagitis during radiation therapy and predict eventual symptoms from asymptomatic patients. Normalized uptake may provide patient-specific dose-response information not discernible from dose. Copyright © 2016 Elsevier Inc. All rights reserved.

3D conformal radiation therapy for palliative treatment of canine nasal tumors.

PubMed

Buchholz, Julia; Hagen, Regine; Leo, Chiara; Ebling, Alessia; Roos, Malgorzata; Kaser-Hotz, Barbara; Bley, Carla Rohrer

2009-01-01

We evaluated the response of 38 dogs treated with a coarsely fractionated, palliative radiation protocol based on CT-based 3D treatment planning. Dogs with histologically confirmed malignant nasal tumors were studied. Treatment prescriptions consisted of 3-4 x 8 Gy, 4-5 x 6 Gy, or 10 x 3 Gy fractions. Selected patient and tumor factors were evaluated for an effect on outcome. Resolution of clinical signs was reported after irradiation in all dogs. Acute toxicities were mild and short lived. Thirty-seven of 38 dogs died or were euthanized due to tumor-related disease. Overall median progression-free interval (PFI) was 10 months. Tumor stage affected response, with modified stage 1 patients having a median PFI 21.3 months vs. a median PFI of 8.5 months for modified stage 2 patients (P = 0.0006). Modified stage was the only factor significantly related to outcome. Based on these findings, a palliative radiation prescription based on computerized treatment planning may be justified in some canine nasal tumor patients.

Radiation Therapy Induces Macrophages to Suppress T-Cell Responses Against Pancreatic Tumors in Mice.

PubMed

Seifert, Lena; Werba, Gregor; Tiwari, Shaun; Giao Ly, Nancy Ngoc; Nguy, Susanna; Alothman, Sara; Alqunaibit, Dalia; Avanzi, Antonina; Daley, Donnele; Barilla, Rocky; Tippens, Daniel; Torres-Hernandez, Alejandro; Hundeyin, Mautin; Mani, Vishnu R; Hajdu, Cristina; Pellicciotta, Ilenia; Oh, Philmo; Du, Kevin; Miller, George

2016-06-01

The role of radiation therapy in the treatment of patients with pancreatic ductal adenocarcinoma (PDA) is controversial. Randomized controlled trials investigating the efficacy of radiation therapy in patients with locally advanced unresectable PDA have reported mixed results, with effects ranging from modest benefit to worse outcomes compared with control therapies. We investigated whether radiation causes inflammatory cells to acquire an immune-suppressive phenotype that limits the therapeutic effects of radiation on invasive PDAs and accelerates progression of preinvasive foci. We investigated the effects of radiation therapy in p48(Cre);LSL-Kras(G12D) (KC) and p48(Cre);LSLKras(G12D);LSL-Trp53(R172H) (KPC) mice, as well as in C57BL/6 mice with orthotopic tumors grown from FC1242 cells derived from KPC mice. Some mice were given neutralizing antibodies against macrophage colony-stimulating factor 1 (CSF1 or MCSF) or F4/80. Pancreata were exposed to doses of radiation ranging from 2 to 12 Gy and analyzed by flow cytometry. Pancreata of KC mice exposed to radiation had a higher frequency of advanced pancreatic intraepithelial lesions and more foci of invasive cancer than pancreata of unexposed mice (controls); radiation reduced survival time by more than 6 months. A greater proportion of macrophages from radiation treated invasive and preinvasive pancreatic tumors had an immune-suppressive, M2-like phenotype compared with control mice. Pancreata from mice exposed to radiation had fewer CD8(+) T cells than controls, and greater numbers of CD4(+) T cells of T-helper 2 and T-regulatory cell phenotypes. Adoptive transfer of T cells from irradiated PDA to tumors of control mice accelerated tumor growth. Radiation induced production of MCSF by PDA cells. A neutralizing antibody against MCSF prevented radiation from altering the phenotype of macrophages in tumors, increasing the anti-tumor T-cell response and slowing tumor growth. Radiation treatment causes macrophages murine PDA to acquire an immune-suppressive phenotype and disabled T-cell-mediated anti-tumor responses. MCSF blockade negates this effect, allowing radiation to have increased efficacy in slowing tumor growth. Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.

Modeling Space Radiation with Radiomimetic Agent Bleomycin

NASA Technical Reports Server (NTRS)

Lu, Tao

2017-01-01

Space radiation consists of proton and helium from solar particle events (SPE) and high energy heavy ions from galactic cosmic ray (GCR). This mixture of radiation with particles at different energy levels has different effects on biological systems. Currently, majority studies of radiation effects on human were based on single-source radiation due to the limitation of available method to model effects of space radiation on living organisms. While NASA Space Radiation Laboratory is working on advanced switches to make it possible to have a mixed field radiation with particles of different energies, the radiation source will be limited. Development of an easily available experimental model for studying effects of mixed field radiation could greatly speed up our progress in our understanding the molecular mechanisms of damage and responses from exposure to space radiation, and facilitate the discovery of protection and countermeasures against space radiation, which is critical for the mission to Mars. Bleomycin, a radiomimetic agent, has been widely used to study radiation induced DNA damage and cellular responses. Previously, bleomycin was often compared to low low Linear Energy Transfer (LET) gamma radiation without defined characteristics. Our recent work demonstrated that bleomycin could induce complex clustered DNA damage in human fibroblasts that is similar to DNA damage induced by high LET radiation. These type of DNA damage is difficult to repair and can be visualized by gamma-H2Ax staining weeks after the initial insult. The survival ratio between early and late plating of human fibroblasts after bleomycin treatment is between low LET and high LET radiation. Our results suggest that bleomycin induces DNA damage and other cellular stresses resembling those resulted from mixed field radiation with both low and high LET particles. We hypothesize that bleomycin could be used to mimic space radiation in biological systems. Potential advantages and limitations of using bleomycin to treat biological specimen as an easily available model to study effects of space radiation on biological systems and to develop countermeasures for space radiation associated risks will be discussed.

SU-E-J-04: A Data-Driven, Response-Based, Multi-Criteria Decision Support System for Personalized Lung Radiation Treatment Planning

DOE Office of Scientific and Technical Information (OSTI.GOV)

Luo, Y; McShan, D; Schipper, M

2014-06-01

Purpose: To develop a decision support tool to predict a patient's potential overall survival (OS) and radiation induced toxicity (RIT) based on clinical factors and responses during the course of radiotherapy, and suggest appropriate radiation dose adjustments to improve therapeutic effect. Methods: Important relationships between a patient's basic information and their clinical features before and during the radiation treatment are identified from historical clinical data by using statistical learning and data mining approaches. During each treatment period, a data analysis (DA) module predicts radiotherapy features such as time to local progression (TTLP), time to distant metastases (TTDM), radiation toxicity tomore » different organs, etc., under possible future treatment plans based on patient specifics or responses. An information fusion (IF) module estimates intervals for a patient's OS and the probabilities of RIT from a treatment plan by integrating the outcomes of module DA. A decision making (DM) module calculates “satisfaction” with the predicted radiation outcome based on trade-offs between OS and RIT, and finds the best treatment plan for the next time period via multi-criteria optimization. Results: Using physical and biological data from 130 lung cancer patients as our test bed, we were able to train and implement the 3 modules of our decision support tool. Examples demonstrate how it can help predict a new patient's potential OS and RIT with different radiation dose plans along with how these combinations change with dose, thus presenting a range of satisfaction/utility for use in individualized decision support. Conclusion: Although the decision support tool is currently developed from a small patient sample size, it shows the potential for the improvement of each patient's satisfaction in personalized radiation therapy. The radiation treatment outcome prediction and decision making model needs to be evaluated with more patients and demonstrated for use in radiation treatments for other cancers. P01-CA59827;R01CA142840.« less

A phase II study of nab-paclitaxel plus carboplatin in combination with thoracic radiation in patients with locally advanced non–small-cell lung cancer

PubMed Central

Hasegawa, Takaaki; Futamura, Yohei; Horiba, Akane; Yoshida, Tsutomu; Suzuki, Toshitaka; Kato, Tatsuo; Kaito, Daizo; Ohno, Yasuhi; Iida, Takayoshi; Hayashi, Shinya; Sawa, Toshiyuki

2016-01-01

We investigated the efficacy and safety of albumin-bound paclitaxel (nab-PTX) and carboplatin (CBDCA) with concurrent radiotherapy for unresectable locally advanced non–small-cell lung cancer (NSCLC). Patients with Stage III NSCLC and an Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible. Concurrent chemoradiotherapy consisted of weekly administration of nab-PTX (40 mg/m2) plus CBDCA (area under the plasma concentration time curve (AUC) 2) and thoracic radiotherapy (60 Gy/30 fractions) for a total of 6 weeks. After concurrent chemoradiotherapy, patients received an additional two cycles of consolidation phase chemotherapy that consisted of 4-week cycles of nab-PTX (100 mg/m2 on Days 1, 8 and 15)/CBDCA (AUC 5 mg/ml/min on Day 1). Response was evaluated in accordance with the Response Evaluation Criteria in Solid Tumors. Progression-free survival and overall survival were estimated using the Kaplan–Meier method. Toxicity was graded using the National Cancer Institute Common Terminology Criteria for Adverse Events. A total of 10 patients were enrolled in this trial between September 2013 and January 2014 from three institutes. The overall response rate was 40.0% and the median progression-free survival was 6.7 months. Treatment-related death occurred in two patients. Grade 2 or worse severe radiation pneumonitis was observed in all three patients that had the volume of lung receiving at least 20 Gy (V20) >30%. The results of this study indicate that no further investigation is warranted into nab-PTX and CBDCA with concurrent thoracic radiation for Stage III NSCLC with V20 > 30% due to severe toxicity. PMID:26442970

SI113, a SGK1 inhibitor, potentiates the effects of radiotherapy, modulates the response to oxidative stress and induces cytotoxic autophagy in human glioblastoma multiforme cells

PubMed Central

Talarico, Cristina; Dattilo, Vincenzo; D'Antona, Lucia; Barone, Agnese; Amodio, Nicola; Belviso, Stefania; Musumeci, Francesca; Abbruzzese, Claudia; Bianco, Cataldo; Trapasso, Francesco; Schenone, Silvia; Alcaro, Stefano; Ortuso, Francesco; Florio, Tullio; Paggi, Marco G.; Perrotti, Nicola; Amato, Rosario

2016-01-01

Glioblastoma multiforme (GBM) is the most aggressive CNS tumor and is characterized by a very high frequency of clinical relapse after therapy and thus by a dismal prognosis, which strongly compromises patients survival. We have recently identified the small molecule SI113, as a potent and selective inhibitor of SGK1, a serine/threonine protein kinase, that modulates several oncogenic signaling cascades. The SI113-dependent SGK1 inhibition induces cell death, blocks proliferation and perturbs cell cycle progression by modulating SGK1-related substrates. SI113 is also able to strongly and consistently block, in vitro and in vivo, growth and survival of human hepatocellular-carcinomas, either used as a single agent or in combination with ionizing radiations. In the present paper we aim to study the effect of SI113 on human GBM cell lines with variable p53 expression. Cell viability, cell death, caspase activation and cell cycle progression were then analyzed by FACS and WB-based assays, after exposure to SI113, with or without oxidative stress and ionizing radiations. Moreover, autophagy and related reticulum stress response were evaluated. We show here, that i) SGK1 is over-expressed in highly malignant gliomas and that the treatment with SI113 leads to ii) significant increase in caspase-mediated apoptotic cell death in GBM cell lines but not in normal fibroblasts; iii)enhancement of the effects of ionizing radiations; iv) modulation of the response to oxidative reticulum stress; v) induction of cytotoxic autophagy. Evidence reported here underlines the therapeutic potential of SI113 in GBM, suggesting a new therapeutic strategy either alone or in combination with radiotherapy. PMID:26908461

SI113, a SGK1 inhibitor, potentiates the effects of radiotherapy, modulates the response to oxidative stress and induces cytotoxic autophagy in human glioblastoma multiforme cells.

PubMed

Talarico, Cristina; Dattilo, Vincenzo; D'Antona, Lucia; Barone, Agnese; Amodio, Nicola; Belviso, Stefania; Musumeci, Francesca; Abbruzzese, Claudia; Bianco, Cataldo; Trapasso, Francesco; Schenone, Silvia; Alcaro, Stefano; Ortuso, Francesco; Florio, Tullio; Paggi, Marco G; Perrotti, Nicola; Amato, Rosario

2016-03-29

Glioblastoma multiforme (GBM) is the most aggressive CNS tumor and is characterized by a very high frequency of clinical relapse after therapy and thus by a dismal prognosis, which strongly compromises patients survival. We have recently identified the small molecule SI113, as a potent and selective inhibitor of SGK1, a serine/threonine protein kinase, that modulates several oncogenic signaling cascades. The SI113-dependent SGK1 inhibition induces cell death, blocks proliferation and perturbs cell cycle progression by modulating SGK1-related substrates. SI113 is also able to strongly and consistently block, in vitro and in vivo, growth and survival of human hepatocellular-carcinomas, either used as a single agent or in combination with ionizing radiations. In the present paper we aim to study the effect of SI113 on human GBM cell lines with variable p53 expression. Cell viability, cell death, caspase activation and cell cycle progression were then analyzed by FACS and WB-based assays, after exposure to SI113, with or without oxidative stress and ionizing radiations. Moreover, autophagy and related reticulum stress response were evaluated. We show here, that i) SGK1 is over-expressed in highly malignant gliomas and that the treatment with SI113 leads to ii) significant increase in caspase-mediated apoptotic cell death in GBM cell lines but not in normal fibroblasts; iii)enhancement of the effects of ionizing radiations; iv) modulation of the response to oxidative reticulum stress; v) induction of cytotoxic autophagy. Evidence reported here underlines the therapeutic potential of SI113 in GBM, suggesting a new therapeutic strategy either alone or in combination with radiotherapy.

Long-Term Outcomes of Fractionated Stereotactic Radiation Therapy for Pituitary Adenomas at the BC Cancer Agency

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kim, Julian O.; Ma, Roy; Division of Radiation Oncology and Developmental Radiotherapeutics, University of British Columbia, Vancouver

2013-11-01

Purpose: To assess the long-term disease control and toxicity outcomes of fractionated stereotactic radiation therapy (FSRT) in patients with pituitary adenomas treated at the BC Cancer Agency. Methods and Materials: To ensure a minimum of 5 years of clinical follow-up, this study identified a cohort of 76 patients treated consecutively with FSRT between 1998 and 2007 for pituitary adenomas: 71% (54/76) had nonfunctioning and 29% (22/76) had functioning adenomas (15 adrenocorticotrophic hormone-secreting, 5 growth hormone-secreting, and 2 prolactin-secreting). Surgery was used before FSRT in 96% (73/76) of patients. A median isocenter dose of 50.4 Gy was delivered in 28 fractions,more » with 100% of the planning target volume covered by the 90% isodose. Patients were followed up clinically by endocrinologists, ophthalmologists, and radiation oncologists. Serial magnetic resonance imaging was used to assess tumor response. Results: With a median follow-up time of 6.8 years (range, 0.6 - 13.1 years), the 7-year progression-free survival was 97.1% and disease-specific survival was 100%. Of the 2 patients with tumor progression, both had disease control after salvage surgery. Of the 22 patients with functioning adenomas, 50% (11/22) had complete and 9% (2/22) had partial responses after FSRT. Of the patients with normal pituitary function at baseline, 48% (14/29) experienced 1 or more hormone deficiencies after FSRT. Although 79% (60/76) of optic chiasms were at least partially within the planning target volumes, no patient experienced radiation-induced optic neuropathy. No patient experienced radionecrosis. No secondary malignancy occurred during follow-up. Conclusion: In this study of long-term follow-up of patients treated for pituitary adenomas, FSRT was safe and effective.« less

Radiation Therapy Induces Macrophages to Suppress Immune Responses Against Pancreatic Tumors in Mice

PubMed Central

Seifert, Lena; Werba, Gregor; Tiwari, Shaun; Ly, Nancy Ngoc Giao; Nguy, Susanna; Alothman, Sara; Alqunaibit, Dalia; Avanzi, Antonina; Daley, Donnele; Barilla, Rocky; Tippens, Daniel; Torres-Hernandez, Alejandro; Hundeyin, Mautin; Mani, Vishnu R.; Hajdu, Cristina; Pellicciotta, Ilenia; Oh, Philmo; Du, Kevin; Miller, George

2016-01-01

Background & Aims The role of radiation therapy in the treatment of patients with pancreatic ductal adenocarcinoma (PDA) is controversial. Randomized controlled trials investigating the efficacy of radiation therapy in patients with locally advanced unresectable PDA have reported mixed results, with effects ranging from modest benefit to worse outcome, compared with control therapies. We investigated whether radiation causes inflammatory cells to acquire an immune-suppressive phenotype that limits the therapeutic effects of radiation on invasive PDAs and accelerates progression of pre-invasive foci. Methods We investigated the effects of radiation in p48Cre;LSL-KrasG12D (KC) and p48Cre;LSLKrasG12D;LSL-Trp53R172H (KPC) mice, as well as in C57BL/6 mice with orthotopic tumors grown from FC1242 cells derived from KPC mice. Some mice were given neutralizing antibodies against macrophage colony stimulating factor 1 (CSF1 or MCSF) or F4/80. Pancreata were exposed to doses of radiation ranging from 2–12 Gy and analyzed by flow cytometry. Results Pancreata of KC mice exposed to radiation had a higher frequency of advanced pancreatic intraepithelial lesions and more foci of invasive cancer than pancreata of unexposed mice (controls); radiation reduced survival time by more than 6 months. A greater proportion of macrophages from invasive and pre-invasive pancreatic tumors had an immune-suppressive, M2-like phenotype, compared with control mice. Pancreata from mice exposed to radiation had fewer CD8+ T cells than controls and greater numbers of CD4+ T cells of T-helper 2 and T-regulatory cell phenotypes. Adoptive transfer of T cells from irradiated PDA to tumors of control mice accelerated tumor growth. Radiation induced production of MCSF by PDA cells. An antibody against MCSF prevented radiation from altering the phenotype of macrophages in tumors, increasing the anti-tumor T-cell response and slowing tumor growth. Conclusions Radiation exposure causes macrophages in PDAs of mice to acquire an immune-suppressive phenotype and reduce T-cell mediated anti-tumor responses. Agents that block MCSF prevent this effect, allowing radiation to have increased efficacy in slowing tumor growth. PMID:26946344

Lymphoma cases referred to the radiation oncology service of a tertiary referral university hospital in Karachi, Pakistan: a retrospective study.

PubMed

Abbasi, Ahmed Nadeem; Zahid, Sumaiya; Karsan, Farrok; Ali, Nasir; Bhurgri, Yasmin

2010-01-01

Radiation therapy is an important component of curative therapy for Lymphoma [Hodgkin's disease (HD) and non Hodgkin's Lymphoma (NHL)]. The current study was conducted to give us an overview of lymphoma patients presenting to a tertiary care hospital for complementary adjuvant RT. Data of lymphoma patients who underwent radiotherapy during February 2006 till August 2009 at the department of radiation oncology, Aga Khan University, Hospital, Karachi was retrieved from the medical records and analyzed using SPSS (version 16.0). A total of 1,678 cancer patients were registered, 75 (0.45%) were lymphoma patients (25.3% HD; 74.7% NHL). HD and NHL were both seen predominantly in males, with a male:female ratio of 2 and 3 respectively. Nodal HD comprised 94.7% and nodal NHL comprised 41.1%. Extranodal NHL (EN-NHL) comprised 53.6% whereas 5.4% cases had both nodal and EN-NHL; 6.7% of EN-NHL were primary CNS lymphomas. Stages of presentation for HD were IIA (52.6%), 1A (21.1%), IIB (10.5%) and IB, IIIB and IVA collectively 15.9%. The ages of HD patients ranged from 11 to 54 years (median 23.5 years 13.2 SD). Response to therapy for HD was 52.6% complete remission, 36.8% partial response, and 5.3% each with stable and progressive disease. Almost all patients (94.7%) received radical treatment with radiation doses (between 1950 cG to 5404 cGy) with a median of 40 Grays.Stages at presentation for NHL were II (23.2%), IV (21.4%) and IE (17.9%); I, IIE, and III were found to be 12.5 %. NHL patients ranged from 15 to 88 years. It was more commonly observed amongst the elderly with 25% patients diagnosed in the fifth decade of life; 50% patients aged at or above 50 years, 41.1% belonged to the 25-49 years age group and 8.9% below 25 years of age. Majority of the cases were diffuse NHL (82.1%), follicular NHL (7.1%), Primary CNS unclassified type (8.9%), and unclassified other than CNS variety (1.8%). Response to chemotherapy for NHL was 51.8% complete remission, 25.9% progressive disease, 20.4% partial response. Forty (71.4%) patients with NHL received radical treatment with radiation doses between 2340 cG to 6600 cGy; 28.6% received palliative RT. Radiation therapy though important for curative lymphoma therapy, is relatively underutilized in our population, despite encouraging outcomes.

Clinical outcome and prognosis of carbon ion radiotherapy on thoracic malignant tumors

NASA Astrophysics Data System (ADS)

Li, Sha

Objective To evaluate the therapeutic efficacy and side-response of high-LET carbon ion radiotherapy on thoracic malignant tumors. Methods Ten patients with pathological confirmed thoracic malignant tumors received treatment using heavy ion accelerator, which included 6 cases with non-small lung cancer, one case with small lung cancer, 2 cases with metastatic sarcomas and one case with invasive thymoma. The applied regimen included fractioned dose (5.5-6.8GyE/Fraction), one faction/day, and 7 fractions/week. The total dose ranged from 55 to 70 GyE. Results The short-term results showed that the response rate (the complete response (CR) rate +the partial response (PR) rate) was 10% at the first month, 40% at the third month and 90% at the sixth month. The overall response rate was 90% and the rate of stable disease was 10%. There was no relation between the response rate and tumor pathology (P>0.05) while significance between the response rate and the tumor volume.At median follow-up of 27 months (range, 6 to 36 months), the local control rate and free-disease rate were respectively 100% an 90% at the first year, 90% and 80% at the secondary year, 80% and 70% at the third year. The death rate due to disease progression was 20% and the non-specific death rate was 10%. Side and toxicity effects: Grade I skin effect occurred in three cases and Grade I lung effect occurred in two cases. The blood counts didn’t reach significance among pre-radiation course, peri-radiation course and post-radiation course (P>0.05). The subgoups of T cells detected in humoral immunity and cytoimmunity didn’t change between pre-radiation and post radiation(P>0.05). Conclusions Carbon ion radiotherapy is effective and safe in the management of patients with thoracic malignant tumors. There were no obvious side effects. The long term of clinical outcome and the late effect need to be further observed.

A Dose Escalation and Pharmacodynamic Study of Triapine and Radiation in Patients With Locally Advanced Pancreas Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Martin, Ludmila Katherine; Grecula, John; Jia, Guang

2012-11-15

Purpose: Triapine, a novel inhibitor of the M2 subunit of ribonucleotide reductase (RR), is a potent radiosensitizer. This phase 1 study, sponsored by the National Cancer Institute Cancer Therapy Evaluation Program, assessed the safety and tolerability of triapine in combination with radiation (RT) in patients with locally advanced pancreas cancer (LAPCA). Methods and Materials: We evaluated 3 dosage levels of triapine (24 mg/m{sup 2}, 48 mg/m{sup 2}, 72 mg/m{sup 2}) administered with 50.4 Gy of RT in 28 fractions. Patients with LAPCA received triapine thrice weekly, every other week during the course of RT. Dose-limiting toxicity (DLT) was assessed duringmore » RT and for 4 weeks after its completion. Dynamic contrast-enhanced magnetic resonance imaging and serum RR levels were evaluated as potential predictors for early response. Results: Twelve patients were treated. Four patients (1 nonevaluable) were enrolled at dosage level 1 (DL1), 3 patients at DL2, and 5 patients (2 nonevaluable) at DL3. No DLTs were observed, and the maximum tolerated dose was not reached. Two patients (17%) achieved partial response, and 6 patients (50%) had stable disease. One patient underwent R0 resection after therapy. Ninety-two percent of patients (100% at DL3) experienced freedom from local tumor progression. In 75% of patients who eventually experienced progression, metastases developed without local progression. RR levels did not seem to predict outcome. In 4 patients with available data, dynamic contrast-enhanced magnetic resonance imaging may predict early response or resistance to therapy. Conclusion: The combination of triapine at 72 mg/m{sup 2} 3 times weekly every other week and standard RT is tolerable with interesting activity in patients with LAPCA.« less

A Pilot Study of Hypofractionated Stereotactic Radiation Therapy and Sunitinib in Previously Irradiated Patients With Recurrent High-Grade Glioma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wuthrick, Evan J., E-mail: evan.wuthrick@osumc.edu; Curran, Walter J.; Camphausen, Kevin

Purpose/Objective(s): Angiogenic blockade with irradiation may enhance the therapeutic ratio of radiation therapy (RT) through vascular normalization. We sought to determine the safety and toxicity profile of continuous daily-dosed sunitinib when combined with hypofractionated stereotactic RT (fSRT) for recurrent high-grade gliomas (rHGG). Methods and Materials: Eligible patients had malignant high-grade glioma that recurred or progressed after primary surgery and RT. All patients received a minimum of a 10-day course of fSRT, had World Health Organization performance status of 0 to 1, and a life expectancy of >3 months. During fSRT, sunitinib was administered at 37.5 mg daily. The primary endpoint was acutemore » toxicity, and response was assessed via serial magnetic resonance imaging. Results: Eleven patients with rHGG were enrolled. The fSRT doses delivered ranged from 30 to 42 Gy in 2.5- to 3.75-Gy fractions. The median follow-up time was 40 months. Common acute toxicities included hematologic disorders, fatigue, hypertension, and elevated liver transaminases. Sunitinib and fSRT were well tolerated. One grade 4 mucositis toxicity occurred, and no grade 4 or 5 hypertensive events or intracerebral hemorrhages occurred. One patient had a nearly complete response, and 4 patients had stable disease for >9 months. Two patients (18%) remain alive and progression-free >3 years from enrollment. The 6-month progression-free survival was 45%. Conclusions: Sunitinib at a daily dose of 37.5 mg given concurrently with hypofractionated stereotactic reirradiation for rHGG yields acceptable toxicities and an encouraging 6-month progression-free survival.« less

THE CYTOLOGY AND GENETICS OF RADIATION RESISTANCE IN BACTERIA. Progress Report for the Period of November 1, 1956 to November 1, 1957

DOE Office of Scientific and Technical Information (OSTI.GOV)

None

1960-10-31

>The effects of various chemical mutugens on the radiosensitivity of Nocardia corallina were investigated. The application of the unpaired defect theory of Tobias and the ploidy stute in N. corallina were also studied. Nocardia corallina was used as a diploid cell and Micrococcus aureus and Escherichia coli were used as haploid cells for comparative purposes. Chemicals used included nitrogen mustard, sodium azide, copper sulfate, caffeine, ascorbic acid, mercuric chloride, manganous chloride, and hydrogen peroxide. Data are tabulated on the effects of pretreatment with the chemicals on response to ultraviolet and x radiations. Results are also included from a study ofmore » the effects of ultraviolet radiation on the cytology snd colony development of Nocardia corallina. The effects of pigment on radiosensitivity and factors involved in the development of radiation-resistant strains are discussed. (For preceding period see ORO-283.) (C.H.)« less

Low-dose Photofrin-induced PDT offers excellent clinical response with minimal morbidity in chest wall recurrence of breast cancer

NASA Astrophysics Data System (ADS)

Allison, Ron; Mang, Thomas S.

2000-03-01

Limited therapeutic options exist when chest wall recurrence form breast cancer progresses despite standard salvage treatment. As photodynamic therapy offers excellent response for cutaneous lesions this may be a possible indication for PDT. A total of 102 treatment fields were illuminated on 9 women with biopsy proven chest wall recurrence of breast cancer which was progressing despite salvage surgery, radiation, and chemi-hormonal therapy. PDT consisted of outpatient IV infusion of Photofrin at 0.8 mg/kg followed 48 hours laser by illumination at 140-170 J/cm2 via a KTP Yag laser coupled to a dye unit. No patient was lost to follow up. At 6 months post PDT; complete response, defined as total lesion elimination was 89 percent, partial response 8 percent, and no response 3 percent. No photosensitivity was seen and no patient developed scarring, fibrosis, or healing difficulties. Low dose Photofrin induced PDT is very active against chest wall lesions. Despite fragile and heavily pre-treated tissues, excellent clinical and cosmetic outcome was obtained. PDT is an underutilized modality for this indication.

Role of Salvage Radiation Therapy for Patients With Relapsed or Refractory Hodgkin Lymphoma Who Failed Autologous Stem Cell Transplant

DOE Office of Scientific and Technical Information (OSTI.GOV)

Goda, Jayant S.; Massey, Christine; Kuruvilla, John

2012-11-01

Purpose: To analyze, through chart review, the efficacy of salvage radiation therapy (sRT) for relapsed or progressive Hodgkin lymphoma (HL) patients who failed autologous stem cell transplant (ASCT). Patients and Methods: Among 347 patients with recurrent/refractory HL who received ASCT from 1986-2006, 163 had post-ASCT progression or relapse. Of these, 56 received sRT and form the basis of this report. Median age at sRT was 30 years (range, 17-59 years). Disease was confined to lymph nodes in 27 patients, whereas 24 had both nodal and extranodal disease. Salvage radiation therapy alone was given in 34 patients (61%), and sRT plusmore » chemotherapy was given in 22 (39%). Median interval from ASCT to sRT was 0.8 years (range, 0.1-5.6 years). The median dose was 35 Gy (range, 8-40.3 Gy). The sRT technique was extended-field in 14 patients (25%) and involved-field in 42 (75%). Results: The median follow-up from sRT was 31.3 months (range, 0.2-205.5 months). Overall response rate was 84% (complete response: 36%; partial response: 48%). The median overall survival was 40.8 months (95% confidence interval, 34.2-56.3 months). The 5-year overall survival was 29% (95% confidence interval, 14%-44%). The 2-year progression-free survival (PFS) was 16%; the 2-year local PFS was 65%, whereas the 2-year systemic PFS was 17%. The 1-year PFS was higher in patients in whom all diseased sites were irradiated (49%) compared with those in whom only the symptomatic site was treated (22%, P=.07). Among 20 alive patients, 5 were disease free (at 6.4, 6.8, 7.4, 7.9, and 17.1 years). Conclusion: For patients with HL who fail ASCT, a selective use of RT provides a durable local control rate of 65% at 2 years and should be considered as part of the standard management plan for the palliation of incurable HL. Occasionally irradiation of truly localized disease can lead to long-term survival.« less

Effect of caffeine on radiation-induced mitotic delay: delayed expression of G/sub 2/ arrest

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rowley, R.; Zorch, M.; Leeper, D.B.

1984-01-01

In the presence of 5 mM caffeine, irradiated (1.5 Gy) S and G/sub 2/ cells progressed to mitosis in register and without arrest in G/sub 2/. Caffeine (5 mM) markedly reduced mitotic delay even after radiation doses up to 20 Gy. When caffeine was removed from irradiated (1.5 Gy) and caffeine-treated cells, a period of G/sub 2/ arrest followed, similar in length to that produced by radiation alone. The arrest expressed was independent of the duration of the caffeine treatment for exposures up to 3 hr. The similarity of the response to the cited effects of caffeine on S-phase delaymore » suggests a common basis for delay induction in S and G/sub 2/ phases.« less

Active Control of Sound Radiation due to Subsonic Wave Scattering from Discontinuities on Thin Elastic Beams.

NASA Astrophysics Data System (ADS)

Guigou, Catherine Renee J.

1992-01-01

Much progress has been made in recent years in active control of sound radiation from vibrating structures. Reduction of the far-field acoustic radiation can be obtained by directly modifying the response of the structure by applying structural inputs rather than by adding acoustic sources. Discontinuities, which are present in many structures are often important in terms of sound radiation due to wave scattering behavior at their location. In this thesis, an edge or boundary type discontinuity (clamped edge) and a point discontinuity (blocking mass) are analytically studied in terms of sound radiation. When subsonic vibrational waves impinge on these discontinuities, large scattered sound levels are radiated. Active control is then achieved by applying either control forces, which approximate shakers, or pairs of control moments, which approximate piezoelectric actuators, near the discontinuity. Active control of sound radiation from a simply-supported beam is also examined. For a single frequency, the flexural response of the beam subject to an incident wave or an input force (disturbance) and to control forces or control moments is expressed in terms of waves of both propagating and near-field types. The far-field radiated pressure is then evaluated in terms of the structural response, using Rayleigh's formula or a stationary phase approach, depending upon the application. The control force and control moment magnitudes are determined by optimizing a quadratic cost function, which is directly related to the control performance. On determining the optimal control complex amplitudes, these can be resubstituted in the constitutive equations for the system under study and the minimized radiated fields can be evaluated. High attenuation in radiated sound power and radiated acoustic pressure is found to be possible when one or two active control actuators are located near the discontinuity, as is shown to be mostly associated with local changes in beam response near the discontinuity. The effect of the control actuators on the far-field radiated pressure, the wavenumber spectrum, the flexural displacement and the near-field time averaged intensity and pressure distributions are studied in order to further understand the control mechanisms. The influence of the near-field structural waves is investigated as well. Some experimental results are presented for comparison.

Treatment of advanced canine anal sac adenocarcinoma with hypofractionated radiation therapy: 77 cases (1999-2013).

PubMed

McQuown, B; Keyerleber, M A; Rosen, K; McEntee, M C; Burgess, K E

2017-09-01

Currently no standard of care exists for advanced, inoperable or metastatic anal sac adenocarcinoma (ASAC). The objective of this retrospective study was to assess the role of hypofractionated radiation therapy (RT) in 77 dogs with measurable ASAC. A total of 38% of dogs experienced a partial response to RT. For dogs presenting with clinical signs related to the tumour, improvement or resolution of signs was noted in 63%. For dogs presenting with hypercalcemia of malignancy, resolution was noted in 31% with RT alone and an additional 46% with radiation, prednisone, and/or bisphosphonates. Median overall survival was 329 days (range: 252-448 days). Median progression free survival was 289 days (range: 224-469). There was no difference in survival based on radiation protocol, use of chemotherapy, previous surgery or advanced stage. Radiation toxicities were mild and infrequent. Hypofractionated RT is well tolerated and is applicable in the treatment of advanced primary, locoregional or metastatic ASAC. © 2016 John Wiley & Sons Ltd.

Hypofractionated stereotactic radiation therapy in three to five fractions for vestibular schwannoma.

PubMed

Morimoto, Masahiro; Yoshioka, Yasuo; Kotsuma, Tadayuki; Adachi, Kana; Shiomi, Hiroya; Suzuki, Osamu; Seo, Yuji; Koizumi, Masahiko; Kagawa, Naoki; Kinoshita, Manabu; Hashimoto, Naoya; Ogawa, Kazuhiko

2013-08-01

To retrospectively examine the outcomes of hypofractionated stereotactic radiation therapy in three to five fractions for vestibular schwannomas. Twenty-five patients with 26 vestibular schwannomas were treated with hypofractionated stereotactic radiation therapy using a CyberKnife. The vestibular schwannomas of 5 patients were associated with type II neurofibromatosis. The median follow-up time was 80 months (range: 6-167); the median planning target volume was 2.6 cm(3) (0.3-15.4); and the median prescribed dose (≥D90) was 21 Gy in three fractions (18-25 Gy in three to five fractions). Progression was defined as ≥2 mm 3-dimensional post-treatment tumor enlargement excluding transient expansion. Progression or any death was counted as an event in progression-free survival rates, whereas only progression was counted in progression-free rates. The 7-year progression-free survival and progression-free rates were 78 and 95%, respectively. Late adverse events (≥3 months) with grades based on Common Terminology Criteria for Adverse Events, v4.03 were observed in 6 patients: Grade 3 hydrocephalus in one patient, Grade 2 facial nerve disorders in two and Grade 1-2 tinnitus in three. In total, 12 out of 25 patients maintained pure tone averages ≤50 dB before hypofractionated stereotactic radiation therapy, and 6 of these 12 patients (50%) maintained pure tone averages at this level at the final audiometric follow-up after hypofractionated stereotactic radiation therapy. However, gradient deterioration of pure tone average was observed in 11 of these 12 patients. The mean pure tone averages before hypofractionated stereotactic radiation therapy and at the final follow-up for the aforementioned 12 patients were 29.8 and 57.1 dB, respectively. Treating vestibular schwannomas with hypofractionated stereotactic radiation therapy in three to five fractions may prevent tumor progression with tolerable toxicity. However, gradient deterioration of pure tone average was observed.

Quality of Life After Palliative Radiation Therapy for Patients With Painful Bone Metastases: Results of an International Study Validating the EORTC QLQ-BM22

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zeng Liang; Chow, Edward, E-mail: edward.chow@sunnybrook.ca; Bedard, Gillian

2012-11-01

Purpose: Radiation therapy (RT) is an effective method of palliating painful bone metastases and can improve function and reduce analgesic requirements. In advanced cancer patients, quality of life (QOL) is the primary outcome of interest over traditional endpoints such as survival. The purpose of our study was to compare bone metastasis-specific QOL scores among patients who responded differently to palliative RT. Methods and Materials: Patients receiving RT for bone metastases across 6 countries were prospectively enrolled from March 2010-January 2011 in a trial validating the QLQ-BM22 and completed the QLQ-BM22 and the core measure (QLQ-C30) at baseline and after 1more » month. Pain scores and analgesic intake were recorded, and response to RT was determined according to the latest published guidelines. The Kruskal-Wallis nonparametric and Wilcoxon rank sum tests compared changes in QOL among response groups. A Bonferroni-adjusted P<.003 indicated statistical significance. Results: Of 79 patients who received palliative RT, 59 were assessable. Partial response, pain progression, and indeterminate response were observed in 22, 8, and 29 patients, respectively; there were no patients with a complete response. Patients across all groups had similar baseline QOL scores apart from physical functioning (patients who progressed had better initial functioning). One month after RT, patients who responded had significant improvements in 3 of 4 QLQ-BM22 domains (painful site, P<.0001; painful characteristic, P<.0001; and functional interference, P<.0001) and 3 QLQ-C30 domains (physical functioning, P=.0006; role functioning, P=.0026; and pain, P<.0001). Patients with progression in pain had significantly worse functional interference (P=.0007) and pain (P=.0019). Conclusions: Patients who report pain relief after palliative RT also have better QOL with respect to bone metastasis-specific issues. The QLQ-BM22 and QLQ-C30 are able to discriminate among patients with varying responses and are recommended for use in future bone metastasis clinical trials.« less

Half brain irradiation in a murine model of breast cancer brain metastasis: magnetic resonance imaging and histological assessments of dose-response.

PubMed

Zarghami, Niloufar; Murrell, Donna H; Jensen, Michael D; Dick, Frederick A; Chambers, Ann F; Foster, Paula J; Wong, Eugene

2018-06-01

Brain metastasis is becoming increasingly prevalent in breast cancer due to improved extra-cranial disease control. With emerging availability of modern image-guided radiation platforms, mouse models of brain metastases and small animal magnetic resonance imaging (MRI), we examined brain metastases' responses from radiotherapy in the pre-clinical setting. In this study, we employed half brain irradiation to reduce inter-subject variability in metastases dose-response evaluations. Half brain irradiation was performed on a micro-CT/RT system in a human breast cancer (MDA-MB-231-BR) brain metastasis mouse model. Radiation induced DNA double stranded breaks in tumors and normal mouse brain tissue were quantified using γ-H2AX immunohistochemistry at 30 min (acute) and 11 days (longitudinal) after half-brain treatment for doses of 8, 16 and 24 Gy. In addition, tumor responses were assessed volumetrically with in-vivo longitudinal MRI and histologically for tumor cell density and nuclear size. In the acute setting, γ-H2AX staining in tumors saturated at higher doses while normal mouse brain tissue continued to increase linearly in the phosphorylation of H2AX. While γ-H2AX fluorescence intensities returned to the background level in the brain 11 days after treatment, the residual γ-H2AX phosphorylation in the radiated tumors remained elevated compared to un-irradiated contralateral tumors. With radiation, MRI-derived relative tumor growth was significantly reduced compared to the un-irradiated side. While there was no difference in MRI tumor volume growth between 16 and 24 Gy, there was a significant reduction in tumor cell density from histology with increasing dose. In the longitudinal study, nuclear size in the residual tumor cells increased significantly as the radiation dose was increased. Radiation damages to the DNAs in the normal brain parenchyma are resolved over time, but remain unrepaired in the treated tumors. Furthermore, there is a radiation dose response in nuclear size of surviving tumor cells. Increase in nuclear size together with unrepaired DNA damage indicated that the surviving tumor cells post radiation had continued to progress in the cell cycle with DNA replication, but failed cytokinesis. Half brain irradiation provides efficient evaluation of dose-response for cancer cell lines, a pre-requisite to perform experiments to understand radio-resistance in brain metastases.

Cell cycle control, checkpoint mechanisms, and genotoxic stress.

PubMed Central

Shackelford, R E; Kaufmann, W K; Paules, R S

1999-01-01

The ability of cells to maintain genomic integrity is vital for cell survival and proliferation. Lack of fidelity in DNA replication and maintenance can result in deleterious mutations leading to cell death or, in multicellular organisms, cancer. The purpose of this review is to discuss the known signal transduction pathways that regulate cell cycle progression and the mechanisms cells employ to insure DNA stability in the face of genotoxic stress. In particular, we focus on mammalian cell cycle checkpoint functions, their role in maintaining DNA stability during the cell cycle following exposure to genotoxic agents, and the gene products that act in checkpoint function signal transduction cascades. Key transitions in the cell cycle are regulated by the activities of various protein kinase complexes composed of cyclin and cyclin-dependent kinase (Cdk) molecules. Surveillance control mechanisms that check to ensure proper completion of early events and cellular integrity before initiation of subsequent events in cell cycle progression are referred to as cell cycle checkpoints and can generate a transient delay that provides the cell more time to repair damage before progressing to the next phase of the cycle. A variety of cellular responses are elicited that function in checkpoint signaling to inhibit cyclin/Cdk activities. These responses include the p53-dependent and p53-independent induction of Cdk inhibitors and the p53-independent inhibitory phosphorylation of Cdk molecules themselves. Eliciting proper G1, S, and G2 checkpoint responses to double-strand DNA breaks requires the function of the Ataxia telangiectasia mutated gene product. Several human heritable cancer-prone syndromes known to alter DNA stability have been found to have defects in checkpoint surveillance pathways. Exposures to several common sources of genotoxic stress, including oxidative stress, ionizing radiation, UV radiation, and the genotoxic compound benzo[a]pyrene, elicit cell cycle checkpoint responses that show both similarities and differences in their molecular signaling. Images Figure 3 PMID:10229703

Successful Retreatment of a Child with a Refractory Brainstem Ganglioglioma with Vemurafenib.

PubMed

Aguilera, Dolly; Janss, Anna; Mazewski, Claire; Castellino, Robert Craig; Schniederjan, Matthew; Hayes, Laura; Brahma, Barunashish; Fogelgren, Lauren; MacDonald, Tobey J

2016-03-01

A child with brainstem ganglioglioma underwent subtotal resection and focal radiation. Magnetic resonance imaging confirmed tumor progression 6 months later. Another partial resection revealed viable BRAF V600E-positive residual tumor. Vemurafenib (660 mg/m(2) /dose) was administered twice daily, resulting in >70% tumor reduction with sustained clinical improvement for 1 year. Vemurafenib was then terminated, but significant tumor progression occurred 3 months later. Vemurafenib was restarted, resulting in partial response. Toxicities included Grade I pruritus and Grade II rash. Vemurafenib was effectively crushed and administered in solution via nasogastric tube. We demonstrate benefit from restarting vemurafenib therapy. © 2015 Wiley Periodicals, Inc.

Progress in Studying Scintillator Proportionality: Phenomenological Model

NASA Astrophysics Data System (ADS)

Bizarri, G.; Cherepy, N. J.; Choong, W. S.; Hull, G.; Moses, W. W.; Payne, S. A.; Singh, J.; Valentine, J. D.; Vasilev, A. N.; Williams, R. T.

2009-08-01

We present a model to describe the origin of non-proportional dependence of scintillator light yield on the energy of an ionizing particle. The non-proportionality is discussed in terms of energy relaxation channels and their linear and non-linear dependences on the deposited energy. In this approach, the scintillation response is described as a function of the deposited energy deposition and the kinetic rates of each relaxation channel. This mathematical framework allows both a qualitative interpretation and a quantitative fitting representation of scintillation non-proportionality response as function of kinetic rates. This method was successfully applied to thallium doped sodium iodide measured with SLYNCI, a new facility using the Compton coincidence technique. Finally, attention is given to the physical meaning of the dominant relaxation channels, and to the potential causes responsible for the scintillation non-proportionality. We find that thallium doped sodium iodide behaves as if non-proportionality is due to competition between radiative recombinations and non-radiative Auger processes.

A Multiinstitutional Phase 2 Trial of Pazopanib Monotherapy in Advanced Anaplastic Thyroid Cancer

PubMed Central

Suman, Vera J.; Menefee, Michael E.; Smallridge, Robert C.; Molina, Julian R.; Maples, William J.; Karlin, Nina J.; Traynor, Anne M.; Kumar, Priya; Goh, Boon Cher; Lim, Wan-Teck; Bossou, Ayoko R.; Isham, Crescent R.; Webster, Kevin P.; Kukla, Andrea K.; Bieber, Carolyn; Burton, Jill K.; Harris, Pamela; Erlichman, Charles

2012-01-01

Context/Objectives: Pazopanib, an inhibitor of kinases including vascular endothelial growth factor receptor, demonstrated impressive activity in progressive metastatic differentiated thyroid cancer, prompting its evaluation in anaplastic thyroid cancer (ATC). Design/Setting/Patients/Interventions/Outcome Measures: Preclinical studies, followed by a multicenter single arm phase 2 trial of continuously administered 800 mg pazopanib daily by mouth (designed to provide 90% chance of detecting a response rate of >20% at the 0.10 significance level when the true response rate is >5%), were undertaken. The primary trial end point was Response Evaluation Criteria in Solid Tumors (RECIST) response. Results: Pazopanib displayed activity in the KTC2 ATC xenograft model, prompting clinical evaluation. Sixteen trial patients were enrolled; 15 were treated: 66.7% were female, median age was 66 yr (range 45–77 yr), and 11 of 15 had progressed through prior systemic therapy. Enrollment was halted, triggered by a stopping rule requiring more than one confirmed RECIST response among the first 14 of 33 potential patients. Four patients required one to two dose reductions; severe toxicities (National Cancer Institute Common Toxicity Criteria-Adverse Events version 3.0 grades >3) were hypertension (13%) and pharyngolaryngeal pain (13%). Treatment was discontinued because of the following: disease progression (12 patients), death due to a possibly treatment-related tumor hemorrhage (one patient), and intolerability (radiation recall tracheitis and uncontrolled hypertension, one patient each). Although transient disease regression was observed in several patients, there were no confirmed RECIST responses. Median time to progression was 62 d; median survival time was 111 d. Two patients are alive with disease 9.9 and 35 months after the registration; 13 died of disease. Conclusions: Despite preclinical in vivo activity in ATC, pazopanib has minimal single-agent clinical activity in advanced ATC. PMID:22774206

THE INDUCTION AND TESTING OF SOMATIC MUTATIONS IN APPLES, GRAPES AND OTHER ECONOMIC PLANTS. Progress Report for the Period February 1, 1956 to January 31, 1957

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pratt, C.; Einset, J.

1958-10-31

Preliminary data are presented from observations on the response of three varieties of apples and one variety of grapes subjected to a wide range of radiation damage at growth stages ramging from seed to matuee plants. Ultimate objectives of the study are the radioinduced production of mutations in apples and grapes. (C.H.)

3D-MR Spectroscopic Imaging at 3Tesla for Early Response Assessment of Glioblastoma Patients during External Beam Radiation Therapy

PubMed Central

Muruganandham, Manickam; Clerkin, Patrick P; Smith, Brian J; Anderson, Carryn M; Morris, Ann; Capizzano, Aristides A; Magnotta, Vincent; McGuire, Sarah M; Smith, Mark C; Bayouth, John E; Buatti, John M

2014-01-01

Purpose To evaluate the utility of 3D-MR proton spectroscopic imaging for treatment planning and its implications for early response assessment in glioblastoma multiforme. Methods and Materials Eighteen patients with newly diagnosed, histologically confirmed glioblastoma had 3D-MR proton spectroscopic imaging (MRSI) along with T2 and T1 gadolinium enhanced MR images at simulation and at boost treatment planning after 17-20 fractions of radiotherapy. All patients received standard radiotherapy with temozolomide and follow-up with every two month MR scans. Progression free survival was defined using MacDonald criteria. MRSI images obtained at initial simulation were analyzed for choline / N-acetylaspartate ratios (Cho/NAA) on a voxel by voxel basis with abnormal activity defined as Cho/NAA ≥ 2. These images were compared on anatomically matched MRSI data collected after 3 weeks of radiotherapy. Changes in Cho/NAA between pre-therapy and 3rd week RT scans were tested using Wilcoxon matched-pairs signed rank tests and correlated with progression free survival, radiation dose and location of recurrence using Cox proportional hazards regression. Results After 8.6 months (median follow-up), 50% of patients had progressed based on imaging. Patients with a decreased or stable mean or median Cho/NAA values had less risk of progression (p< 0.01). Patients with an increase in mean or median Cho/NAA values at the 3rd week RT scan had a significantly greater chance of early progression (p <0.01). An increased Cho/NAA at the 3rd week MRSI scan carried a hazard ratio of 2.72 (95% confidence interval 1.10-6.71, p= 0.03). Most patients received the prescription dose of RT to the Cho/NAA ≥ 2 volume, which was where recurrence most often occurred. Conclusion Change in mean and median Cho/NAA detected at 3 weeks was a significant predictor of early progression. The potential impact for risk-adaptive therapy based on early spectroscopic findings is suggested. PMID:24986746

Stereotactic body radiation therapy with concurrent full-dose gemcitabine for locally advanced pancreatic cancer: a pilot trial demonstrating safety

PubMed Central

2013-01-01

Background Concurrent chemoradiation is a standard option for locally advanced pancreatic cancer (LAPC). Concurrent conventional radiation with full-dose gemcitabine has significant toxicity. Stereotactic body radiation therapy (SBRT) may provide the opportunity to administer radiation in a shorter time frame with similar efficacy and reduced toxicity. This Pilot study assessed the safety of concurrent full-dose gemcitabine with SBRT for LAPC. Methods Patients received gemcitabine, 1000 mg/m2 for 6 cycles. During week 4 of cycle 1, patients received SBRT (25 Gy delivered in five consecutive daily fractions of 5 Gy prescribed to the 75-83% isodose line). Acute and late toxicities were assessed using NIH CTCAE v3. Tumor response was assessed by RECIST. Patients underwent an esophagogastroduodenoscopy at baseline, 2, and 6 months to assess the duodenal mucosa. Quality of life (QoL) data was collected before and after treatment using the QLQ-C30 and QLQ-PAN26 questionnaires. Results Between September 2009 and February 2011, 11 patients enrolled with one withdrawal during radiation therapy. Patients had grade 1 to 2 gastrointestinal toxicity from the start of SBRT to 2 weeks after treatment. There were no grade 3 or greater radiation-related toxicities or delays for cycle 2 of gemcitabine. On endoscopy, there were no grade 2 or higher mucosal toxicities. Two patients had a partial response. The median progression free and overall survival were 6.8 and 12.2 months, respectively. Global QoL did not change between baseline and immediately after radiation treatment. Conclusions SBRT with concurrent full dose gemcitabine is safe when administered to patients with LAPC. There is no delay in administration of radiation or chemotherapy, and radiation is completed with minimal toxicity. PMID:23452509

Death by polonium-210: lessons learned from the murder of former Soviet spy Alexander Litvinenko.

PubMed

McFee, Robin B; Leikin, Jerrold B

2009-02-01

The medical response to radiation--whether the result of radiological warfare, terrorist deployment of improvised radiation dispersal weapons, political assassination, occupational or industrial accidents or the medically radiated patient remains one of the least taught among all disciplines within medical education. In the aftermath of 9/11 among medical vulnerabilities to toxicant threats, of all the categories of weapons of mass destruction (WMD)--whether using the CBRNE (chemical, biological, radiological, nuclear, explosive) or NBC (nuclear, biological, chemical) acronym--radiation is the least taught in professional schools, responder cultures or civil preparedness organizations. To date, few health care professionals (HCP) possess the fundamental knowledge or skills to identify and diagnose, let alone treat a radiation victim; this vulnerability made even more obvious in the aftermath of the high profile assassination of former Russian agent Alexander Litvinenko. He was poisoned with Polonium210. Radioactive substances are ubiquitous with radiation sources being in or transported through virtually every region nationwide. It is essential to increase preparedness among community and rural health care facilities as well as urban and university hospitals. Managing radiation injuries effectively requires access to specialized equipment and expertise. Radiation sickness is progressive and may require acute, critical and long-term care throughout the course of illness. Regardless of the source, preparedness rests upon acknowledging a threat exists and dedicating the resources to address the risks including the enhancement of training and equipment. Mass or individual exposures to radiation present unique challenges to the entire response continuum from law enforcement, first responders and emergency medical care. Increased education about and practice in responding to radiological threats is essential to enhance preparedness.

Space, Atmospheric, and Terrestrial Radiation Environments

NASA Technical Reports Server (NTRS)

Barth, Janet L.; Dyer, C. S.; Stassinopoulos, E. G.

2003-01-01

The progress on developing models of the radiation environment since the 1960s is reviewed with emphasis on models that can be applied to predicting the performance of microelectronics used in spacecraft and instruments. Space, atmospheric, and ground environments are included. It is shown that models must be adapted continually to account for increased understanding of the dynamics of the radiation environment and the changes in microelectronics technology. The IEEE Nuclear and Space Radiation Effects Conference is a vital forum to report model progress to the radiation effects research community.

Dose-Response Relationship between Radiation Dose and Loco-regional Control in Patients with Stage II-III Esophageal Cancer Treated with Definitive Chemoradiotherapy.

PubMed

Kim, Hyun Ju; Suh, Yang-Gun; Lee, Yong Chan; Lee, Sang Kil; Shin, Sung Kwan; Cho, Byung Chul; Lee, Chang Geol

2017-07-01

The correlation between radiation dose and loco-regional control (LRC) was evaluated in patients with stage II-III esophageal cancer treated with definitive concurrent chemoradiotherapy (CRT). Medical records of 236 stage II-III esophageal cancer patients treated with definitive CRT at Yonsei Cancer Center between 1994 and 2013 were retrospectively reviewed. Among these, 120 received a radiation dose of < 60 Gy (standard-dose group), while 116 received ≥ 60 Gy (high-dose group). The median doses of radiation in the standard- and high-dose groups were 50.4 and 63 Gy, respectively. Concurrent 5-fluorouracil/cisplatin chemotherapy was administered to most patients. There were no differences in patient characteristics between the two groups except for high Karnofsky performance status and lower-thoracic lesions being more prevalent in the standard-dose group. The median progression-free survival (PFS) and overall survival (OS) times were 13.2 months and 26.2 months, respectively. Patients in the high-dose group had significantly better 2-year LRC (69.1% vs. 50.3%, p=0.002), median PFS (16.7 months vs. 11.7 months, p=0.029), and median OS (35.1 months vs. 22.3 months, p=0.043). Additionally, LRC exhibited a dose-response relationship and the complete response rate was significantly higher in the high-dose group (p=0.006). There were no significant differences in treatment-related toxicities between the groups. A higher radiation dose (> 60 Gy) is associated with increased LRC, PFS, and OS in patients with stage II-III esophageal cancer treated with definitive CRT.

A Prospective Phase 2 Multicenter Study for the Efficacy of Radiation Therapy Following Incomplete Transarterial Chemoembolization in Unresectable Hepatocellular Carcinoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Choi, Chihwan; Koom, Woong Sub; Kim, Tae Hyun

2014-12-01

Purpose: The purpose of this study was to investigate the efficacy and toxicity of radiation therapy (RT) following incomplete transarterial chemoembolization (TACE) in unresectable hepatocellular carcinoma (HCC). Methods and Materials: The study was designed as a prospective phase 2 multicenter trial. Patients with unresectable HCC, who had viable tumor after TACE of no more than 3 courses, were eligible. Three-dimensional conformal RT (3D-CRT) was added for HCC treatment with incomplete uptake of iodized oil, and the interval from TACE to RT was 4 to 6 weeks. The primary endpoint of this study was the tumor response after RT following incomplete TACEmore » in unresectable HCC. Secondary endpoints were patterns of failure, progression-free survival (PFS), time to tumor progression (TTP), overall survival (OS) rates at 2 years, and treatment-associated toxicity. Survival was calculated from the start of RT. Results: Between August 2008 and December 2010, 31 patients were enrolled. RT was delivered at a median dose of 54 Gy (range, 46-59.4 Gy) at 1.8 to 2 Gy per fraction. A best objective in-field response rate was achieved in 83.9% of patients, with complete response (CR) in 22.6% of patients and partial response in 61.3% of patients within 12 weeks post-RT. A best objective overall response rate was achieved in 64.5% of patients with CR in 19.4% of patients and PR in 45.1% of patients. The 2-year in-field PFS, PFS, TTP, and OS rates were 45.2%, 29.0%, 36.6%, and 61.3%, respectively. The Barcelona Clinic liver cancer stage was a significant independent prognostic factor for PFS (P=.023). Classic radiation-induced liver disease was not observed. There were no treatment-related deaths or hepatic failure. Conclusions: Early 3D-CRT following incomplete TACE is a safe and practical treatment option for patients with unresectable HCC.« less

Co-expression of CD147 and GLUT-1 indicates radiation resistance and poor prognosis in cervical squamous cell carcinoma.

PubMed

Huang, Xin-Qiong; Chen, Xiang; Xie, Xiao-Xue; Zhou, Qin; Li, Kai; Li, Shan; Shen, Liang-Fang; Su, Juan

2014-01-01

The aim of this study was to investigate the association of CD147 and GLUT-1, which play important roles in glycolysis in response to radiotherapy and clinical outcomes in patients with locally advanced cervical squamous cell carcinoma (LACSCC). The records of 132 female patients who received primary radiation therapy to treat LACSCC at FIGO stages IB-IVA were retrospectively reviewed. Forty-seven patients with PFS (progression-free survival) of less than 36 months were regarded as radiation-resistant. Eighty-five patients with PFS longer than 36 months were regarded as radiation-sensitive. Using pretreatment paraffin-embedded tissues, we evaluated CD147 and GLUT-1 expression by immunohistochemistry. Overexpression of CD147, GLUT-1, and CD147 and GLUT-1 combined were 44.7%, 52.9% and 36.5%, respectively, in the radiation-sensitive group, and 91.5%, 89.4% and 83.0%, respectively, in the radiation-resistant group. The 5-year progress free survival (PFS) rates in the CD147-low, CD147-high, GLUT-1-low, GLUT-1-high, CD147- and/or GLUT-1-low and CD147- and GLUT-1- dual high expression groups were 66.79%, 87.10%, 52.78%, 85.82%, 55.94%, 82.90% and 50.82%, respectively. CD147 and GLUT-1 co-expression, FIGO stage and tumor diameter were independent poor prognostic factors for patients with LACSCC in multivariate Cox regression analysis. Patients with high expression of CD147 alone, GLUT-1 alone or co-expression of CD147 and GLUT-1 showed greater resistance to radiotherapy and a shorter PFS than those with low expression. In particular, co-expression of CD147 and GLUT-1 can be considered as a negative independent prognostic factor.

Hypofractionation vs Conventional Radiation Therapy for Newly Diagnosed Diffuse Intrinsic Pontine Glioma: A Matched-Cohort Analysis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Janssens, Geert O., E-mail: g.janssens@rther.umcn.nl; Jansen, Marc H.; Lauwers, Selmer J.

2013-02-01

Purpose: Despite conventional radiation therapy, 54 Gy in single doses of 1.8 Gy (54/1.8 Gy) over 6 weeks, most children with diffuse intrinsic pontine glioma (DIPG) will die within 1 year after diagnosis. To reduce patient burden, we investigated the role of hypofractionation radiation therapy given over 3 to 4 weeks. A 1:1 matched-cohort analysis with conventional radiation therapy was performed to assess response and survival. Methods and Materials: Twenty-seven children, aged 3 to 14, were treated according to 1 of 2 hypofractionation regimens over 3 to 4 weeks (39/3 Gy, n=16 or 44.8/2.8 Gy, n=11). All patients had symptomsmore » for {<=}3 months, {>=}2 signs of the neurologic triad (cranial nerve deficit, ataxia, long tract signs), and characteristic features of DIPG on magnetic resonance imaging. Twenty-seven patients fulfilling the same diagnostic criteria and receiving at least 50/1.8 to 2.0 Gy were eligible for the matched-cohort analysis. Results: With hypofractionation radiation therapy, the overall survival at 6, 9, and 12 months was 74%, 44%, and 22%, respectively. Progression-free survival at 3, 6, and 9 months was 77%, 43%, and 12%, respectively. Temporary discontinuation of steroids was observed in 21 of 27 (78%) patients. No significant difference in median overall survival (9.0 vs 9.4 months; P=.84) and time to progression (5.0 vs 7.6 months; P=.24) was observed between hypofractionation vs conventional radiation therapy, respectively. Conclusions: For patients with newly diagnosed DIPG, a hypofractionation regimen, given over 3 to 4 weeks, offers equal overall survival with less treatment burden compared with a conventional regimen of 6 weeks.« less

Co-expression of CD147 and GLUT-1 indicates radiation resistance and poor prognosis in cervical squamous cell carcinoma

PubMed Central

Huang, Xin-Qiong; Chen, Xiang; Xie, Xiao-Xue; Zhou, Qin; Li, Kai; Li, Shan; Shen, Liang-Fang; Su, Juan

2014-01-01

The aim of this study was to investigate the association of CD147 and GLUT-1, which play important roles in glycolysis in response to radiotherapy and clinical outcomes in patients with locally advanced cervical squamous cell carcinoma (LACSCC). The records of 132 female patients who received primary radiation therapy to treat LACSCC at FIGO stages IB-IVA were retrospectively reviewed. Forty-seven patients with PFS (progression-free survival) of less than 36 months were regarded as radiation-resistant. Eighty-five patients with PFS longer than 36 months were regarded as radiation-sensitive. Using pretreatment paraffin-embedded tissues, we evaluated CD147 and GLUT-1 expression by immunohistochemistry. Overexpression of CD147, GLUT-1, and CD147 and GLUT-1 combined were 44.7%, 52.9% and 36.5%, respectively, in the radiation-sensitive group, and 91.5%, 89.4% and 83.0%, respectively, in the radiation-resistant group. The 5-year progress free survival (PFS) rates in the CD147-low, CD147-high, GLUT-1-low, GLUT-1-high, CD147- and/or GLUT-1-low and CD147- and GLUT-1- dual high expression groups were 66.79%, 87.10%, 52.78%, 85.82%, 55.94%, 82.90% and 50.82%, respectively. CD147 and GLUT-1 co-expression, FIGO stage and tumor diameter were independent poor prognostic factors for patients with LACSCC in multivariate Cox regression analysis. Patients with high expression of CD147 alone, GLUT-1 alone or co-expression of CD147 and GLUT-1 showed greater resistance to radiotherapy and a shorter PFS than those with low expression. In particular, co-expression of CD147 and GLUT-1 can be considered as a negative independent prognostic factor. PMID:24817962

Reirradiation on recurrent cervical cancer case: Treatment response and side effects

NASA Astrophysics Data System (ADS)

Siregar, M. F.; Supriana, N.; Nuranna, L.; Prihartono, J.

2017-08-01

Management of recurrent cervical cancer by reirradiation after radiation treatment remains controversial. In Indonesia, there is currently no data about reirradiation tumor response and side effects. This study aims to assess the tumor response to and side effects of reirradiation, the effect of time interval between first radiation treatment and cancer recurrence on the tumor response and side effects, and the effect of tumor size on tumor response. A cohort retrospective study with no comparison was done with the Radiotherapy Department at Cipto Mangunkusumo General Hospital, Jakarta. Participants were recurrent cervical cancer patients undergoing reirradiation. Data was collected from patients’ medical records and follow-up phone calls. Twenty-two patients participated in this study. Nine patients (40.9%) had complete responses, 10 patients (45.5%) had partial responses, 1 patient (4.5%) had a stable response, and 2 patients (9.1%) had tumor progressions. In general, 15 patients (68.2%) had no to light side effects (grade 0-2 RTOG) and 7 patients (31.8%) had severe side effects (grade 3-4 RTOG). Four patients (18.1%) had severe gastrointestinal acute side effects, 6 patients (27.3%) had severe gastrointestinal late side effects, 2 patients (9.1%) had severe urogenital side effects, and there were no patients had severe urogenital late side effects. There was no significant difference in tumor response between patients with time interval between first radiation treatment and recurrence of <12 months vs. ≥12 months. There was no significant difference in tumor response between patients with tumor size ≤4 cm vs. >4 cm. Reirradiation can be considered as a modality in recurrent cervical cancer management since good tumor response was achieved and the majority of patients had no to light side effects (grade 0-2 RTOG). This study found no correlation between tumor response, side effects, and time gap between first radiation treatment and recurrence of <12 months vs. ≥12 months. There was also no correlation between tumor response and tumor size of ≤4 cm vs. > 4 cm.

Identification of Differential Gene Expression Patterns after Acute Exposure to High and Low Doses of Low-LET Ionizing Radiation in a Reconstituted Human Skin Tissue

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tilton, Susan C.; Markillie, Lye Meng; Hays, Spencer

Our goal here was to identify dose and temporal dependent radiation responses in a complex tissue, reconstituted human skin. Direct sequencing of RNA (RNA-seq) was used to quantify altered transcripts following exposure to 0.1, 2 and 10 Gy of ionizing radiation at 3 and 8 hours. These doses include a low dose in the range of some medical diagnostic procedures (0.1 Gy), a dose typically received during radiotherapy (2.0 Gy) and a lethal dose (10 Gy). These doses could be received after an intentional or accidental radiation exposure and biomarkers are needed to rapidly and accurately triage exposed individuals. Amore » total of 1701 genes were deemed to be significantly affected by high dose radiation exposure with the majority of genes affected at 10 Gy. A group of 29 genes including GDF15, BBC3, PPM1D, FDXR, GADD45A, MDM2, CDKN1A, TP53INP1, CYCSP27, SESN1, SESN2, PCNA, and AEN were similarly altered at both 2 and 10 Gy, but not 0.1 Gy, at multiple time points. A much larger group of up regulated genes, including those involved in inflammatory responses, was significantly altered only after a 10 Gy exposure. At high doses, down regulated genes were associated with cell cycle regulation and exhibited an apparent linear response between 2 and 10 Gy. While only a handful of genes were significantly affected by 0.1 Gy exposure using stringent statistical filters, groups of related genes regulating cell cycle progression and inflammatory responses consistently exhibited opposite trends in their regulation compared to the high dose exposures. Differential regulation of PLK1 signaling at low and high doses was confirmed using qRT-PCR. These results indicate that some alterations in gene expression are qualitatively different at low and high doses of radiation in this model system.« less

Radiation Therapy for Pilocytic Astrocytomas of Childhood

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mansur, David B., E-mail: mansur@radonc.wustl.ed; Rubin, Joshua B.; Kidd, Elizabeth A.

Purpose: Though radiation therapy is generally considered the most effective treatment for unresectable pilocytic astrocytomas in children, there are few data to support this claim. To examine the efficacy of radiation therapy for pediatric pilocytic astrocytomas, we retrospectively reviewed the experience at our institution. Methods and Materials: Thirty-five patients 18 years old or younger with unresectable tumors and without evidence of neurofibromatosis have been treated since 1982. Patients were treated with local radiation fields to a median dose of 54 Gy. Six patients were treated with radiosurgery to a median dose of 15.5 Gy. Five patients were treated with initialmore » chemotherapy and irradiated after progression. Results: All patients were alive after a median follow-up of 5.0 years. However, progression-free survival was 68.7%. None of 11 infratentorial tumors progressed compared with 6 of 20 supratentorial tumors. A trend toward improved progression-free survival was seen with radiosurgery (80%) compared with external beam alone (66%), but this difference did not reach statistical significance. Eight of the 9 patients progressing after therapy did so within the irradiated volume. Conclusions: Although the survival of these children is excellent, almost one third of patients have progressive disease after definitive radiotherapy. Improvements in tumor control are needed in this patient population, and the optimal therapy has not been fully defined. Prospective trials comparing initial chemotherapy to radiation therapy are warranted.« less

Efficacy of Radiation Therapy for the Treatment of Sialocele in Dogs.

PubMed

Poirier, V J; Mayer-Stankeová, S; Buchholz, J; Vail, D M; Kaser Hotz, B

2018-01-01

Sialocele is a collection of saliva that has leaked from a damaged salivary gland or duct and is surrounded by granulation tissue. Surgery is the recognized first-line treatment. Recurrence rate after surgery is 5-14%. Salivary gland tissue is very sensitive to radiation therapy (RT). Radiation therapy will be useful for the treatment of sialocele. The aims were to characterize response rate and clinical course of dogs with sialocele treated with RT and to determine a starting dose for clinical use. Eleven dogs with sialocele. Retrospective study of response and outcome after RT. All dogs had cervical sialocele. Seven dogs (63.6%) were treated with 3 weekly fractions of 4 Gray (Gy); (total dose, 12 Gy). Three dogs (27.3%) received 4 fractions of 4 Gy (16 Gy) and 1 dog received 5 fractions of 4 Gy (20 Gy) on a Monday-Wednesday-Friday schedule. Six dogs (54%) achieved a complete response (CR), and 5 dogs (45%) achieved a partial response (PR). Three dogs had progression of their sialocele 2, 3, and 9 months after RT; all three had received 12 Gy initially and 2 received 2 additional fractions of 4 Gy (cumulative total dose, 20 Gy) and subsequently achieved remission for >2 years. Radiation therapy is useful for the treatment of recurrent sialocele refractory to surgical management and a minimum total dose of 16 or 20 Gy in 4 Gy fractions appears effective. Copyright © 2017 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.

Modern Radiobiology: Contention Of Concepts: Advanced Technology And Development Of Effective Prophylaxis, Prevention And Treatment Of Biological Consequences After Irradiation.

NASA Astrophysics Data System (ADS)

Popov, Dmitri; Maliev, Vecheslav; Jones, Jeffrey

"Alle Ding' sind Gift, und nichts ohn' Gift; allein die Dosis macht, daß ein Ding kein Gift ist." Paracelsus Philippus Aureolus Theophrastus Bombastus von Hohenheim. Key worlds: Apoptosis, Necrosis, Domains associated with Cell Death, Caspase (catalytic) Domains, Death Domains (DDs), Death Effector Domains (DEDs), Caspase-Associated Recruitment Domains (CARDs, BIR Domains (IAPs), Bcl-2 Homology (BH) Domains, death ligands - TRAIL (TNF-Related Apoptosis-Inducing Ligand), FasL (Fas Ligand), TNFalpha (Tumor Necrosis Factor alpha), Toll-like receptors (TLR), Systemic inflammatory response syndrome (SIRS), Toxic Multiple Organ Injury (TMOI), Toxic Multiple Organ Dysfunction Syndromes (TMODS), Toxic Multiple Organ Failure (TMOF), Anaphylatoxins, or complement peptides; membrane attack complex (MAC), ROS - Reactive Oxygen Species; ASMase, acid sphingomyelinase; Neurotoxins, Cytotoxins, Haemotoxins. Introduction: Radiation affects many cell structures, organelles and metabolic pathways. Different doses and types of radiation ( gamma-radiation, neutron, heavy ion radiation) progress to reversible and irreversible forms of cell injury. Consideration: Apoptosis and Necrosis, major forms of post-radiation cell death, can be initiated and modulated by programmed control and proceed by similar or different pathways.[Akadi et al.,1993, Dunlacht J., et al. 1999] Radiation induced cell death by triggering apoptosis pathways was described in many articles and supported by many scientists. [Rio et al. 2002, Rakesh et al. 1997.] However some authors present results that two distinct pathways can initiate or apoptotic or necrotic responses: the death receptors and mitochondrial pathways.

Stereotactic ablative body radiotherapy combined with immunotherapy: present status and future perspectives.

PubMed

Rekers, N H; Troost, E G C; Zegers, C M L; Germeraad, W T V; Dubois, L J; Lambin, P

2014-10-01

Radiotherapy is along with surgery and chemotherapy one of the prime treatment modalities in cancer. It is applied in the primary, neoadjuvant as well as the adjuvant setting. Radiation techniques have rapidly evolved during the past decade enabling the delivery of high radiation doses, reducing side-effects in tumour-adjacent normal tissues. While increasing local tumour control, current and future efforts ought to deal with microscopic disease at a distance of the primary tumour, ultimately responsible for disease-progression. This review explores the possibility of bimodal treatment combining radiotherapy with immunotherapy. Copyright © 2014 Société française de radiothérapie oncologique (SFRO). Published by Elsevier SAS. All rights reserved.

Interrogating the viscoelastic properties of tissue using viscoelastic response (VISR) ultrasound

NASA Astrophysics Data System (ADS)

Selzo, Mallory Renee

Affecting approximately 1 in 3,500 newborn males, Duchenne muscular dystrophy (DMD) is one of the most common lethal genetic disorders in humans. Boys with DMD suffer progressive loss of muscle strength and function, leading to wheelchair dependence, cardiac and respiratory compromise, and death during young adulthood. There are currently no treatments that can halt or reverse the disease progression, and translating prospective treatments into clinical trials has been delayed by inadequate outcome measures. Current outcome measures, such as functional and muscle strength assessments, lack sensitivity to individual muscles, require subjective effort of the child, and are impacted by normal childhood growth and development. The goal of this research is to develop Viscoelastic Response (VisR) ultrasound which can be used to delineate compositional changes in muscle associated with DMD. In VisR, acoustic radiation force (ARF) is used to produce small, localized displacements within the muscle. Using conventional ultrasound to track the motion, the displacement response of the tissue can be evaluated against a mechanical model. In order to develop signal processing techniques and assess mechanical models, finite element method simulations are used to model the response of a viscoelastic material to ARF excitations. Results are then presented demonstrating VisR differentiation of viscoelastic changes with progressive dystrophic degeneration in a dog model of DMD. Finally, clinical feasibility of VisR imaging is demonstrated in two boys with DMD.

Reverse-Contrast Imaging and Targeted Radiation Therapy of Advanced Pancreatic Cancer Models

DOE Office of Scientific and Technical Information (OSTI.GOV)

Thorek, Daniel L.J., E-mail: dthorek1@jhmi.edu; Kramer, Robin M.; Chen, Qing

2015-10-01

Purpose: To evaluate the feasibility of delivering experimental radiation therapy to tumors in the mouse pancreas. Imaging and treatment were performed using combined CT (computed tomography)/orthovoltage treatment with a rotating gantry. Methods and Materials: After intraperitoneal administration of radiopaque iodinated contrast, abdominal organ delineation was performed by x-ray CT. With this technique we delineated the pancreas and both orthotopic xenografts and genetically engineered disease. Computed tomographic imaging was validated by comparison with magnetic resonance imaging. Therapeutic radiation was delivered via a 1-cm diameter field. Selective x-ray radiation therapy of the noninvasively defined orthotopic mass was confirmed using γH2AX staining. Micemore » could tolerate a dose of 15 Gy when the field was centered on the pancreas tail, and treatment was delivered as a continuous 360° arc. This strategy was then used for radiation therapy planning for selective delivery of therapeutic x-ray radiation therapy to orthotopic tumors. Results: Tumor growth delay after 15 Gy was monitored, using CT and ultrasound to determine the tumor volume at various times after treatment. Our strategy enables the use of clinical radiation oncology approaches to treat experimental tumors in the pancreas of small animals for the first time. We demonstrate that delivery of 15 Gy from a rotating gantry minimizes background healthy tissue damage and significantly retards tumor growth. Conclusions: This advance permits evaluation of radiation planning and dosing parameters. Accurate noninvasive longitudinal imaging and monitoring of tumor progression and therapeutic response in preclinical models is now possible and can be expected to more effectively evaluate pancreatic cancer disease and therapeutic response.« less

Intercellular Communication of Tumor Cells and Immune Cells after Exposure to Different Ionizing Radiation Qualities.

PubMed

Diegeler, Sebastian; Hellweg, Christine E

2017-01-01

Ionizing radiation can affect the immune system in many ways. Depending on the situation, the whole body or parts of the body can be acutely or chronically exposed to different radiation qualities. In tumor radiotherapy, a fractionated exposure of the tumor (and surrounding tissues) is applied to kill the tumor cells. Currently, mostly photons, and also electrons, neutrons, protons, and heavier particles such as carbon ions, are used in radiotherapy. Tumor elimination can be supported by an effective immune response. In recent years, much progress has been achieved in the understanding of basic interactions between the irradiated tumor and the immune system. Here, direct and indirect effects of radiation on immune cells have to be considered. Lymphocytes for example are known to be highly radiosensitive. One important factor in indirect interactions is the radiation-induced bystander effect which can be initiated in unexposed cells by expression of cytokines of the irradiated cells and by direct exchange of molecules via gap junctions. In this review, we summarize the current knowledge about the indirect effects observed after exposure to different radiation qualities. The different immune cell populations important for the tumor immune response are natural killer cells, dendritic cells, and CD8+ cytotoxic T-cells. In vitro and in vivo studies have revealed the modulation of their functions due to ionizing radiation exposure of tumor cells. After radiation exposure, cytokines are produced by exposed tumor and immune cells and a modulated expression profile has also been observed in bystander immune cells. Release of damage-associated molecular patterns by irradiated tumor cells is another factor in immune activation. In conclusion, both immune-activating and -suppressing effects can occur. Enhancing or inhibiting these effects, respectively, could contribute to modified tumor cell killing after radiotherapy.

A phase II randomized trial of Observation versus stereotactic ablative RadiatIon for OLigometastatic prostate CancEr (ORIOLE).

PubMed

Radwan, Noura; Phillips, Ryan; Ross, Ashley; Rowe, Steven P; Gorin, Michael A; Antonarakis, Emmanuel S; Deville, Curtiland; Greco, Stephen; Denmeade, Samuel; Paller, Channing; Song, Daniel Y; Diehn, Maximilian; Wang, Hao; Carducci, Michael; Pienta, Kenneth J; Pomper, Martin G; DeWeese, Theodore L; Dicker, Adam; Eisenberger, Mario; Tran, Phuoc T

2017-06-29

We describe a randomized, non-blinded Phase II interventional study to assess the safety and efficacy of stereotactic ablative radiotherapy (SABR) for hormone-sensitive oligometastatic prostate adenocarcinoma, and to describe the biology of the oligometastatic state using immunologic, cellular, molecular, and functional imaging correlates. 54 men with oligometastatic prostate adenocarcinoma will be accrued. The primary clinical endpoint will be progression at 6 months from randomization with the hypothesis that SABR to all metastases will forestall progression by disrupting the metastatic process. Secondary clinical endpoints will include local control at 6 months post-SABR, toxicity and quality of life, and androgen deprivation therapy (ADT)-free survival (ADT-FS). Further fundamental analysis of the oligometastatic state with be achieved through correlation with investigational 18 F-DCFPyL PET/CT imaging and measurement of circulating tumor cells, circulating tumor DNA, and circulating T-cell receptor repertoires, facilitating an unprecedented opportunity to characterize, in isolation, the effects of SABR on the dynamics of and immunologic response to oligometastatic disease. Patients will be randomized 2:1 to SABR or observation with minimization to balance assignment by primary intervention, prior hormonal therapy, and PSA doubling time. Progression after 6 months will be compared using Fisher's exact test. Hazard ratios and Kaplan-Meier estimates of progression free survival (PFS), ADT free survival (ADT-FS), time to locoregional progression (TTLP) and time to distant progression (TTDP) will be calculated based on an intention-to-treat. Local control will be assessed using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Withdrawal from the study prior to 6 months will be counted as progression. Adverse events will be summarized by type and grade. Quality of life pre- and post- SABR will be measured by Brief Pain Inventory. The ORIOLE trial is the first randomized, non-blinded Phase II interventional study in the North America evaluating the safety and efficacy of SABR in oligometastatic hormone-sensitive prostate cancer. Leading-edge laboratory and imaging correlates will provide unique insight into the effects of SABR on the oligometastatic state. ClinicalTrials.gov Identifier: NCT02680587. URL of Registry: https://clinicaltrials.gov/show/NCT02680587 Date of Registration: 02/08/2016. Date of First Participant Enrollment: 05/23/2016.

11C-Choline-Pet Guided Stereotactic Body Radiation Therapy for Lymph Node Metastases in Oligometastatic Prostate Cancer.

PubMed

Franzese, Ciro; Lopci, Egesta; Di Brina, Lucia; D'Agostino, Giuseppe Roberto; Navarria, Pierina; Mancosu, Pietro; Tomatis, Stefano; Chiti, Arturo; Scorsetti, Marta

2017-10-21

aim is outcome of 11C-Choline-PET guided SBRT on lymph node metastases. patients with 1 - 4 lymph node metastases detected by 11C-choline-PET were treated with SBRT. Toxicity, treated metastases control and Progression Free Survival were computed. twenty-six patients, 38 lymph node metastases were irradiated. No grade ≥ 2 toxicity. Median PSA-nadir after RT was 1.02 ng/mL. Post-treatment 11C-Choline-PET showed metabolic complete response in 17 metastases (44,7%), partial response in 9 metastases (38%). SBRT is effective and safe for lymph node metastases. PET is important in identification of gross tumor and evaluation of the response.

Combined chemoradiation for the management of nasal natural killer (NK)/T-cell lymphoma: elucidating the significance of systemic chemotherapy.

PubMed

Guo, Ye; Lu, Jiade J; Ma, Xuejun; Wang, Biyun; Hong, Xiaonan; Li, Xiaoqiu; Li, Jin

2008-01-01

The objective of this analysis was to evaluate the efficacy and treatment outcome of CHOP and CHOP combined with nitrosourea chemotherapy in natural killer (NK)/T-cell lymphoma of the nasal cavity. Sixty-three patients with NK/T-cell lymphoma of the nasal cavity were treated with CHOP or CHOP combined with oral nitrosourea chemotherapy between January 1997 and June 2005. By the Ann Arbor Lymphoma Staging Classification, 57 patients (90%) had Stage IE or IIE disease and six patients (10%) had Stage III or IV disease. All patients with Stage IE or IIE disease were intended to be treated curatively with combined chemoradiation; and patients who had Stage III or IV disease were treated with chemotherapy alone with curative intention. Chemotherapy consisted of: (1) up to six cycles of the standard CHOP based regimen, or (2) up to six cycles of the standard CHOP based regimen with oral Semustine dosed at 120 mg (or Lomustine dosed at 100mg) on day 1 of each chemotherapy cycle. External beam radiation therapy was delivered by daily conventional fractionation by Co-60 or 6MVx linear accelerator for patients with Stage IE or IIE disease. The radiation dose to the tumor bed was between 36 and 50 Gy with a median dose of 45 Gy. Fifty-three patients received chemotherapy prior to radiation, and four patients were treated with involved field radiation before chemotherapy. The median follow up for all 44 surviving patients was 31 months (range: 6-104 months). The 2-year progression-free survival (PFS) and overall survival (OS) rates were 60% and 70%, respectively. The PFS and OS of patients who were treated with or without oral nitrosourea in addition to CHOP were 73% vs. 44% (P=0.035) and 75% vs. 64% (P=0.276), respectively. Nine patients with Stage IE or IIE diseases developed disease progression during their planned treatment and died within 10 months after the initiation of treatment; Six patients who achieved complete response (CR) after planned chemoradiation developed systemic recurrence and died at 13-48 months despite salvage treatment; one patient died of Hemophagocytic Syndrome during radiotherapy after achieving CR from chemotherapy. Three patients with Stage III or IV disease died during chemotherapy or during salvage treatment at 2, 4, and 19 months, respectively. Among the 59 patients who received chemotherapy as their initial treatment, 29, 6, 12, and 12 patients had complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) respectively after chemotherapy. The 2-year overall survival rates for these four groups of patients were 100%, 75%, 60%, and 17%, respectively (P<0.0001). Multivariate analysis revealed that International Prognostic Index (IPI) for Lymphoma, perforation of nasal septum as a presenting symptom, "B" symptoms, ECOG performance, as well as response after chemotherapy, were significant independent prognostic factors for this group of patients. The extent of response after induction chemotherapy is significantly related to the treatment outcome of patients with nasal NK/T-cell lymphoma. CHOP based chemotherapy combined with oral nitrosourea followed by involved field radiotherapy may provide improved treatment results compared to conventional CHOP chemotherapy and radiation. This strategy needs to be optimized and tested in a prospective trial for its efficacy.

Change in chemotherapy during concurrent radiation followed by surgery after a suboptimal positron emission tomography response to induction chemotherapy improves outcomes for locally advanced esophageal adenocarcinoma.

PubMed

Ku, Geoffrey Y; Kriplani, Anuja; Janjigian, Yelena Y; Kelsen, David P; Rusch, Valerie W; Bains, Manjit; Chou, Joanne; Capanu, Marinela; Wu, Abraham J; Goodman, Karyn A; Ilson, David H

2016-07-01

A positron emission tomography (PET) scan after induction chemotherapy before preoperative chemoradiation and surgery for esophageal adenocarcinoma predicts outcomes. Some patients with progression on PET after induction chemotherapy had long-term overall survival (OS) when they were changed to alternative chemotherapy during radiation. This study retrospectively reviewed esophageal adenocarcinoma patients who received induction chemotherapy and chemoradiation before planned surgery; all had undergone a PET scan before and after induction chemotherapy. There were 201 patients, and 113 (56%) were PET responders (≥35% decrease in the maximum standardized uptake value of the tumor). All PET responders received the same chemotherapy during radiation, whereas 38 of the 88 PET nonresponders (43%) changed chemotherapy. Among the 152 patients who underwent surgery, the pathologic complete response rate was 15% for PET responders and 3% for PET nonresponders who did not change chemotherapy (P = .046). The median progression-free survival (PFS; 18.9 vs 10.0 months, P < 0.01) and OS (37 vs 25.3 months, P = .02) were significantly better for PET responders versus PET nonresponders who did not change chemotherapy. The median PFS for PET nonresponders who changed chemotherapy was 17.9 months, and it was superior to the median PFS for PET nonresponders who did not change chemotherapy (P = .01). For PET nonresponders, the 5-year OS rates were 37% for those who changed chemotherapy and 25% for those who did not change chemotherapy (P = .18). A PET scan after induction chemotherapy predicts outcomes for locally advanced esophageal adenocarcinoma patients who undergo chemoradiation and surgery. The median PFS is improved, and trends toward improved OS appear possible in PET nonresponders who change chemotherapy during radiation. The fully accrued Cancer and Leukemia Group B 80803 study (NCT01333033) is evaluating this strategy. Cancer 2016;122:2083-90. © 2016 American Cancer Society. © 2016 American Cancer Society.

Treatment of isolated mediastinal and hilar recurrence of lung cancer with bronchoscopic endobronchial ultrasound guided intratumoral injection of chemotherapy with cisplatin.

PubMed

Mehta, Hiren J; Begnaud, Abbie; Penley, Andrea M; Wynne, John; Malhotra, Paras; Fernandez-Bussy, Sebastian; Cope, Jessica M; Shuster, Jonathan J; Jantz, Michael A

2015-12-01

A common pattern of recurrence in lung cancer after receiving full dose external beam radiation therapy (EBRT) to targeted sites is isolated mediastinal and hilar recurrence (IMHR). Treatment options for these patients are limited to palliative radiation, chemotherapy, and/or best supportive care. We describe our experience with treating IMHR with bronchoscopic endobronchial ultrasound (EBUS) guided intratumoral injection of cisplatin (ITC). Patients treated between Jan 2009-September 2014 with ITC for IMHR were included. Patient demographics, tumor histology, size, concurrent therapy, location, number of sites treated, treatment sessions, and encounters were abstracted. Responses were analyzed on follow-up scans 8-12 weeks after the last treatment session using RECIST 1.1 criteria. Locoregional recurrence, progression-free survival (PFS), and overall survival were measured. 50 sites were treated in 36 patients (19 males, 17 females) with mean age 61.9±8.5 years. Eight sites treated on subsequent encounters were excluded and one patient had an unevaluable response, leaving 35 patients and 41 sites for final analysis. 24/35 (69%) had complete or partial response (responders), whereas 11/35 (31%) had stable or progressive disease (non-responders). There were no significant differences in response based on histology, size, and concurrent therapy. Median survival for the group was 8 months (95% CI of 6-11 mo). Responders had significantly higher survival and PFS than non-responders. Two patients treated with concurrent EBRT, developed broncho-mediastinal fistula. EBUS guided intratumoral cisplatin for IMHR appears to be safe and effective, and may represent a new treatment paradigm for this patient population. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Current understanding of cancer stem cells: Review of their radiobiology and role in head and neck cancers.

PubMed

Reid, Paul Ambrose; Wilson, Puthenparampil; Li, Yanrui; Marcu, Loredana Gabriela; Bezak, Eva

2017-09-01

Evidence of cancer cells that bear attributes analogous to those of normal stem cells has developed a hierarchical model of cancer's architecture and progression. This subset of cancer stem cells (CSCs) drives the progression and therapy resistance of cancers. Research to identify the phenotypes of these CSCs presents evidence of a subpopulation that is more resistant to therapy and may proliferate in response. Literature shows that CSCs typically represent around 1%-10% of cell populations in head and neck cancer but this proportion may increase in response to a therapeutic radiation dose. This is shown to be not just as a result of preferential killing, but also their capacity to alter divisional dynamics and enlist the support of a complicit microenvironment in therapy resistance and proliferation. The CSCs represent the apex of a hierarchy in the heterogeneity of cancer cells and may be seen as the agents of treatment failure, metastasis, and tumor recurrence, the principal cause of mortality in head and neck cancers. Greater than 90% of head and neck cancers are squamous cell carcinomas (HNSCCs), and among these an increasing incidence of the involvement of the human papillomavirus (HPV) is reported. Chemoradiotherapy along with surgical resection are the interventions of choice for control and cure of HNSCC, but given CSCs therapy resistance and proliferative responses to radiation, the identification and understanding of the radiobiology of this subpopulation is critical to their targeted elimination. This article reviews the current evidence on CSC generally and in HNSCC specifically to identify their phenotype, evaluate their responses to radiotherapy, and evaluate the defensive mechanisms used to resist therapeutic control. © 2017 Wiley Periodicals, Inc.

Differential cellular responses to prolonged LDR-IR in MLH1-proficient and MLH1-deficient colorectal cancer HCT116 cells.

PubMed

Yan, Tao; Seo, Yuji; Kinsella, Timothy J

2009-11-15

MLH1 is a key DNA mismatch repair (MMR) protein involved in maintaining genomic stability by participating in the repair of endogenous and exogenous mispairs in the daughter strands during S phase. Exogenous mispairs can result following treatment with several classes of chemotherapeutic drugs, as well as with ionizing radiation. In this study, we investigated the role of the MLH1 protein in determining the cellular and molecular responses to prolonged low-dose rate ionizing radiation (LDR-IR), which is similar to the clinical use of cancer brachytherapy. An isogenic pair of MMR(+) (MLH1(+)) and MMR(-) (MLH1(-)) human colorectal cancer HCT116 cells was exposed to prolonged LDR-IR (1.3-17 cGy/h x 24-96 h). The clonogenic survival and gene mutation rates were examined. Cell cycle distribution was analyzed with flow cytometry. Changes in selected DNA damage repair proteins, DNA damage response proteins, and cell death marker proteins were examined with Western blotting. MLH1(+) HCT116 cells showed greater radiosensitivity with enhanced expression of apoptotic and autophagic markers, a reduced HPRT gene mutation rate, and more pronounced cell cycle alterations (increased late-S population and a G(2)/M arrest) following LDR-IR compared with MLH1(-) HCT116 cells. Importantly, a progressive increase in MLH1 protein levels was found in MLH1(+) cells during prolonged LDR-IR, which was temporally correlated with a progressive decrease in Rad51 protein (involved in homologous recombination) levels. MLH1 status significantly affects cellular responses to prolonged LDR-IR. MLH1 may enhance cell radiosensitivity to prolonged LDR-IR through inhibition of homologous recombination (through inhibition of Rad51).

The stimulation of auroral kilometric radiation by type III solar radio bursts

NASA Technical Reports Server (NTRS)

Calvert, W.

1981-01-01

It has been found that the onset of auroral kilometric radiation (AKR) frequently coincides with the arrival of type III solar radio bursts. Although the AKR onsets are usually abrupt and appear to be spontaneous, they sometimes develop from a discrete frequency near the leading edge of a type III burst or sometimes occur at progressively lower frequencies following that edge. From this, and the absence of the related solar electrons in specific cases, it was concluded that the incoming type III waves were sometimes responsible for stimulating auroral kilometric radiation. It was estimated that intense, isolated type III bursts were capable of stimulating AKR roughly one third of the time, and that at least ten percent of the observed AKR onsets could be attributed to these and weaker bursts, including some barely detectable by the ISEE plasma wave receivers.

Radiation physics, biophysics and radiation biology. Progress report for October 1, 1979-September 30, 1980. [Lead abstract

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rossi, H.H.; Hall, E.J.

1980-07-01

Separate abstracts were prepared for 31 of the 32 papers presented in this progress report. The other paper is represented by an abstract only and deals with field shaping and recalibration of x-ray facilities.

Excellent response to chemotherapy post immunotherapy

PubMed Central

Dwary, Ashish D.; Master, Samip; Patel, Abhishek; Cole, Constance; Mansour, Richard; Mills, Glenn; Koshy, Nebu; Peddi, Prakash; Burton, Gary; Hammoud, Dalia; Beedupalli, Kavitha

2017-01-01

Introduction Immunotherapy in the form of immune checkpoint inhibitors has changed the landscape of cancer treatment. Newer monoclonal antibodies are coming up and are being tested in various cancers during different stages of treatment. With the increasing use of immune checkpoint inhibitors in the management of various types of cancers, the question is raised as to what next can be offered to a patient who has progressed on this newer treatment. Does Sequence matter? There have been reports of improved responses to chemotherapy after immunotherapy in the form of vaccines. Here we present a case series of 6 patients who progressed on immunotherapy with immune checkpoint inhibitors after initial modality of treatment (chemotherapy/radiation), subsequently received chemotherapy with excellent response. Methods We have a cohort of six patients who had disease progression on second line Immunotherapy for solid or hematological malignancies and had ECOG < 2. All these patients received third line salvage chemotherapy. Three patients had metastatic head and neck cancer, 2 had non-small cell lung cancer (NSCLC), and one had T -cell rich B- cell lymphoma. Prior review and approval were obtained from our institutional review board. Results All patients had an excellent response to chemotherapy in third line setting, after immune checkpoint inhibitors and most of them achieved a complete response. Conclusion Targeting cancer with chemotherapy after failure of immunotherapy is a valid option and can lead to better response rates and PFS which may lead to OS. This effect may be secondary to immunotherapy removing the inhibition exerted by tumor cells or other immune cells initially followed by cytotoxic chemotherapy mediated killing of tumor cells. PMID:29207685

High order statistical signatures from source-driven measurements of subcritical fissile systems

NASA Astrophysics Data System (ADS)

Mattingly, John Kelly

1998-11-01

This research focuses on the development and application of high order statistical analyses applied to measurements performed with subcritical fissile systems driven by an introduced neutron source. The signatures presented are derived from counting statistics of the introduced source and radiation detectors that observe the response of the fissile system. It is demonstrated that successively higher order counting statistics possess progressively higher sensitivity to reactivity. Consequently, these signatures are more sensitive to changes in the composition, fissile mass, and configuration of the fissile assembly. Furthermore, it is shown that these techniques are capable of distinguishing the response of the fissile system to the introduced source from its response to any internal or inherent sources. This ability combined with the enhanced sensitivity of higher order signatures indicates that these techniques will be of significant utility in a variety of applications. Potential applications include enhanced radiation signature identification of weapons components for nuclear disarmament and safeguards applications and augmented nondestructive analysis of spent nuclear fuel. In general, these techniques expand present capabilities in the analysis of subcritical measurements.

Phase 2 prospective analysis of alectinib in ALK-positive, crizotinib-resistant non-small-cell lung cancer

PubMed Central

Shaw, Alice T.; Gandhi, Leena; Gadgeel, Shirish; Riely, Gregory J.; Cetnar, Jeremy; West, Howard; Camidge, D. Ross; Socinski, Mark A.; Chiappori, Alberto; Mekhail, Tarek; Chao, Bo H.; Borghaei, Hossein; Gold, Kathryn A.; Zeaiter, Ali; Bordogna, Walter; Balas, Bogdana; Puig, Oscar; Henschel, Volkmar; Ignatius Ou, Sai-Hong

2016-01-01

Summary Background Alectinib, a highly selective, central nervous system (CNS)-active anaplastic lymphoma kinase (ALK) inhibitor, demonstrated promising clinical activity in crizotinib-naïve and crizotinib-resistant ALK-positive non-small-cell lung cancer (NSCLC). This phase 2 study evaluated the safety and efficacy of alectinib in ALK-positive NSCLC patients who progressed on previous crizotinib. Methods This ongoing North American study (NCT01871805) enrolled patients with stage IIIB/IV ALK-positive NSCLC, who had progressed following crizotinib. Patients were treated with oral alectinib 600 mg twice daily until progression, death or withdrawal. Primary endpoint was overall response rate (ORR) by independent review committee (IRC) using RECIST v1.1. Secondary endpoints included progression-free survival (PFS), duration of response (DOR), intracranial ORR and DOR, safety, and patient-reported outcomes. The intent-to-treat population was used for efficacy and safety analyses, with the response evaluable population used for response endpoints. Findings A total of 87 patients were enrolled in the intent-to-treat population. All patients had received prior crizotinib therapy, and 64 patients (74%) had also received prior chemotherapy. Fifty-two patients (60%) had baseline CNS metastases, of whom 18 (35%) had received no prior brain radiation therapy. At the time of primary analysis (median follow-up 4.8 months), ORR by IRC was 48% (95% CI 36–60). Adverse events were predominantly grade 1 or 2, most commonly constipation, fatigue, myalgia and peripheral edema. The most common grade ≥3 AEs were changes in laboratory values, including increased blood creatine phosphokinase (in 8%, n=7), increased alanine aminotransferase (in 6% n=5), and increased aspartate aminotransferase (in 5% n=4). Interpretation Alectinib demonstrated clinical efficacy and was well tolerated in patients with ALK-positive NSCLC who had progressed on crizotinib. Alectinib was active in the CNS, as demonstrated by durable responses in the majority of crizotinib-resistant patients with CNS disease. Therefore, alectinib could be a suitable treatment for patients with ALK-positive disease who have progressed on crizotinib. PMID:26708155

Ultraviolet-radiation-induced inflammation promotes angiotropism and metastasis in melanoma

NASA Astrophysics Data System (ADS)

Bald, Tobias; Quast, Thomas; Landsberg, Jennifer; Rogava, Meri; Glodde, Nicole; Lopez-Ramos, Dorys; Kohlmeyer, Judith; Riesenberg, Stefanie; van den Boorn-Konijnenberg, Debby; Hömig-Hölzel, Cornelia; Reuten, Raphael; Schadow, Benjamin; Weighardt, Heike; Wenzel, Daniela; Helfrich, Iris; Schadendorf, Dirk; Bloch, Wilhelm; Bianchi, Marco E.; Lugassy, Claire; Barnhill, Raymond L.; Koch, Manuel; Fleischmann, Bernd K.; Förster, Irmgard; Kastenmüller, Wolfgang; Kolanus, Waldemar; Hölzel, Michael; Gaffal, Evelyn; Tüting, Thomas

2014-03-01

Intermittent intense ultraviolet (UV) exposure represents an important aetiological factor in the development of malignant melanoma. The ability of UV radiation to cause tumour-initiating DNA mutations in melanocytes is now firmly established, but how the microenvironmental effects of UV radiation influence melanoma pathogenesis is not fully understood. Here we report that repetitive UV exposure of primary cutaneous melanomas in a genetically engineered mouse model promotes metastatic progression, independent of its tumour-initiating effects. UV irradiation enhanced the expansion of tumour cells along abluminal blood vessel surfaces and increased the number of lung metastases. This effect depended on the recruitment and activation of neutrophils, initiated by the release of high mobility group box 1 (HMGB1) from UV-damaged epidermal keratinocytes and driven by Toll-like receptor 4 (TLR4). The UV-induced neutrophilic inflammatory response stimulated angiogenesis and promoted the ability of melanoma cells to migrate towards endothelial cells and use selective motility cues on their surfaces. Our results not only reveal how UV irradiation of epidermal keratinocytes is sensed by the innate immune system, but also show that the resulting inflammatory response catalyses reciprocal melanoma-endothelial cell interactions leading to perivascular invasion, a phenomenon originally described as angiotropism in human melanomas by histopathologists. Angiotropism represents a hitherto underappreciated mechanism of metastasis that also increases the likelihood of intravasation and haematogenous dissemination. Consistent with our findings, ulcerated primary human melanomas with abundant neutrophils and reactive angiogenesis frequently show angiotropism and a high risk for metastases. Our work indicates that targeting the inflammation-induced phenotypic plasticity of melanoma cells and their association with endothelial cells represent rational strategies to specifically interfere with metastatic progression.

Systemic Tolerance Mediated by Melanoma Brain Tumors is Reversible by Radiotherapy and Vaccination

PubMed Central

Jackson, Christopher M.; Kochel, Christina M.; Nirschl, Christopher J.; Durham, Nicholas M.; Ruzevick, Jacob; Alme, Angela; Francica, Brian J.; Elias, Jimmy; Daniels, Andrew; Dubensky, Thomas W.; Lauer, Peter; Brockstedt, Dirk G.; Baxi, Emily G.; Calabresi, Peter A.; Taube, Janis M.; Pardo, Carlos A.; Brem, Henry; Pardoll, Drew M.; Lim, Michael; Drake, Charles G.

2016-01-01

Purpose Immune responses to antigens originating in the CNS are generally attenuated, since collateral damage can have devastating consequences. The significance of this finding for the efficacy of tumor-targeted immunotherapies is largely unknown. Experimental Design The B16 murine melanoma model was used to compare cytotoxic responses against established tumors in the CNS and in the periphery. Cytokine analysis of tissues from brain tumor-bearing mice detected elevated TGF-β secretion from microglia and in the serum and TGF-β signaling blockade reversed tolerance of tumor antigen-directed CD8 T cells. Additionally, a treatment regimen using focal radiation therapy and recombinant Listeria monocytogenes was evaluated for immunologic activity and efficacy in this model. Results CNS melanomas were more tolerogenic than equivalently progressed tumors outside the CNS as antigen-specific CD8 T cells were deleted and exhibited impaired cytotoxicity. Tumor-bearing mice had elevated serum levels of TGF-β; however, blocking TGF-β signaling with a small molecule inhibitor or a monoclonal antibody did not improve survival. Conversely, tumor antigen-specific vaccination in combination with focal radiation therapy reversed tolerance and improved survival. This treatment regimen was associated with increased polyfunctionality of CD8 T cells, elevated T effector to T regulatory cell ratios and decreased TGF-β secretion from microglia. Conclusions These data suggest that CNS tumors may impair systemic antitumor immunity and consequently accelerate cancer progression locally as well as outside the CNS while antitumor immunity may be restored by combining vaccination with radiation therapy. These findings are hypothesis-generating and warrant further study in more contemporary melanoma models as well as human trials. PMID:26490306

Phenylbutyrate Attenuates the Expression of Bcl-XL, DNA-PK, Caveolin-1, and VEGF in Prostate Cancer Cells1

PubMed Central

Goh, Meidee; Chen, Feng; Paulsen, Michelle T; Yeager, Ann M; Dyer, Erica S; Ljungman, Mats

2001-01-01

Abstract Phenylbutyrate (PB) is a histone deacetylase inhibitor that has been shown to induce differentiation and apoptosis in various cancer cell lines. Although these effects are most likely due to modulation of gene expression, the specific genes and gene products responsible for the effects of PB are not well characterized. In this study, we used cDNA expression arrays and Western blot to assess the effect that PB has on the expression of various cancer and apoptosis-regulatory gene products. We show that PB attenuates the expression of the apoptosis antagonist Bcl-XL, the double-strand break repair protein DNA-dependent protein kinase, the prostate progression marker caveolin -1, and the pro-angiogenic vascular endothelial growth factor. Furthermore, PB was found to act in synergy with ionizing radiation to induce apoptosis in prostate cancer cells. Taken together, our results point to the possibility that PB may be an effective anti-prostate cancer agent when used in combination with radiation or chemotherapy and for the inhibition of cancer progression. PMID:11571633

Phase I Trial and Pharmacokinetic Study of Lexatumumab in Pediatric Patients With Solid Tumors

PubMed Central

Merchant, Melinda S.; Geller, James I.; Baird, Kristin; Chou, Alexander J.; Galli, Susana; Charles, Ava; Amaoko, Martha; Rhee, Eunice H.; Price, Anita; Wexler, Leonard H.; Meyers, Paul A.; Widemann, Brigitte C.; Tsokos, Maria; Mackall, Crystal L.

2012-01-01

Purpose Lexatumumab is an agonistic, fully human monoclonal antibody against tumor necrosis factor–related apoptosis-inducing ligand receptor 2 with preclinical evidence of activity in pediatric solid tumors. Patients and Methods This phase I dose-escalation study examined the safety, tolerability, pharmacokinetics, and immunogenicity of lexatumumab at doses up to, but not exceeding, the adult maximum-tolerated dose (3, 5, 8, and 10 mg/kg), administered once every 2 weeks to patients age ≤ 21 years with recurrent or progressive solid tumors. Results Twenty-four patients received a total of 56 cycles of lexatumumab over all four planned dose levels. One patient had grade 2 pericarditis consistent with radiation recall, and one patient developed grade 3 pneumonia with hypoxia during the second cycle. Five patients experienced stable disease for three to 24 cycles. No patients experienced complete or partial response, but several showed evidence of antitumor activity, including one patient with recurrent progressive osteosarcoma who experienced resolution of clinical symptoms and positron emission tomography activity, ongoing more than 1 year off therapy. One patient with hepatoblastoma showed a dramatic biomarker response. Conclusion Pediatric patients tolerate 10 mg/kg of lexatumumab administered once every 14 days, the maximum-tolerated dose identified in adults. The drug seems to mediate some clinical activity in pediatric solid tumors and may work with radiation to enhance antitumor effects. PMID:23071222

Hepatic radioembolization with yttrium-90 containing glass microspheres: Preliminary results and clinical follow-up

DOE Office of Scientific and Technical Information (OSTI.GOV)

Andrews, J.C.; Walker, S.C.; Ackermann, R.J.

1994-10-01

The treatment of hepatic tumors remains unsatisfactory. These lesions receive most of their blood supply from the hepatic artery, therefore the hepatic artery administration of beta-emitting particulate radiopharmaceuticals is an attractive approach to deliver therapeutic irradiation to the liver and differentially to tumors within the liver. A Phase 1 dose escalation study of the hepatic tolerance to radiation delivered by {sup 90}Y containing glass microspheres was carried out in 24 patients with hepatic malignancy. Doses of {sup 90}Y microspheres to achieve an estimated whole-liver nominal absorbed radiation dose of 5000 cGy (two patients), 7500cGy (six patients), 10,000 cGy (seven patients),more » 12,500 cGy (six patients), and 15,000 cGy (three patients) were administered via the hepatic artery. The administered nominal absorbed radiation dose (NARD) was estimated based on liver volume determined from CT scans and the assumption of uniform distribution of microspheres throughout the liver. No hematologic, hepatic or pulmonary toxicity was encountered in the dose range examined during a mean follow-up period of up to 53 mo. Reversible gastritis or duodenitis was encountered in four patients without imaging or biopsy evidence for extra-hepatic deposition of microspheres. Response data, based on CT scans obtained 16 wk after treatment, showed progressive disease in eight patients, stable disease in seven patients, minimal response in four patients and partial response in five patients. Subsequent follow-up revealed three long-term survivors at 204, 216 and 228 wk. These preliminary data demonstrates that in the examined dose range, radiation may be safely delivered to liver tumors by means of {sup 90}Y glass microspheres with encouraging response data. 39 refs., 3 figs., 1 tab.« less

Radiation arteriopathy in the transgenic arteriovenous fistula model.

PubMed

Lawton, Michael T; Arnold, Christine M; Kim, Yung J; Bogarin, Ernesto A; Stewart, Campbell L; Wulfstat, Amanda A; Derugin, Nikita; Deen, Dennis; Young, William L

2008-05-01

The transgenic arteriovenous fistula model, surgically constructed with transgenic mouse aorta interposed in common carotid artery-to-external jugular vein fistulae in nude rats, has a 4-month experimental window because patency and transgenic phenotype are lost over time. We adapted this model to investigate occlusive arteriopathy in brain arteriovenous malformations after radiosurgery by radiating grafted aorta before insertion in the fistula. We hypothesized that high-dose radiation would reproduce the arteriopathy observed clinically within the experimental time window and that deletions of endoglin (ENG) and endothelial nitric oxide synthase (eNOS) genes would modify the radiation response. Radiation arteriopathy in the common carotid arteries of 171 wild-type mice was examined with doses of 25, 80, 120, or 200 Gy (Experiment 1). Radiation arteriopathy in 68 wild-type arteriovenous fistulae was examined histologically and morphometrically with preoperative radiation doses of 0, 25, or 200 Gy (Experiment 2). Radiation arteriopathy in 51 transgenic arteriovenous fistulae (36 ENG and 15 eNOS knock-out fistulae) was examined using preoperative radiation doses of 0, 25, or 200 Gy (Experiment 3). High-dose radiation (200 Gy) of mouse common carotid arteries induced only mild arteriopathy (mean score, 0.66) without intimal hyperplasia and with high mortality (68%). Radiation arteriopathy in wild-type arteriovenous fistulae was severe (mean score, 3.5 at 200 Gy), with intimal hyperplasia and medial disruption at 3 months, decreasing luminal areas with increasing dose, and no mortality. Arteriopathy was robust in transgenic arteriovenous fistulae with ENG +/- and with eNOS +/-, with thick intimal hyperplasia in the former and distinct smooth muscle cell proliferation in the latter. The transgenic arteriovenous fistula model can be adapted to rapidly reproduce radiation arteriopathy observed in resected brain arteriovenous malformations after radiosurgery. High radiation doses accelerate the progression of arteriopathy to fit the 4-month time limitation of the model, allowing transgenic tissues to retain their phenotypes throughout the experimental window. Modified radiation responses in ENG and eNOS knock-out fistulae indicate that arteriopathy after arteriovenous malformation radiosurgery might potentially be enhanced by altered gene expression.

Progress in Space Weather Modeling and Observations Needed to Improve the Operational NAIRAS Model Aircraft Radiation Exposure Predictions

NASA Astrophysics Data System (ADS)

Mertens, C. J.; Kress, B. T.; Wiltberger, M. J.; Tobiska, W.; Xu, X.

2011-12-01

The Nowcast of Atmospheric Ionizing Radiation for Aviation Safety (NAIRAS) is a prototype operational model for predicting commercial aircraft radiation exposure from galactic and solar cosmic rays. NAIRAS predictions are currently streaming live from the project's public website, and the exposure rate nowcast is also available on the SpaceWx smartphone app for iPhone, IPad, and Android. Cosmic rays are the primary source of human exposure to high linear energy transfer radiation at aircraft altitudes, which increases the risk of cancer and other adverse health effects. Thus, the NAIRAS model addresses an important national need with broad societal, public health and economic benefits. The processes responsible for the variability in the solar wind, interplanetary magnetic field, solar energetic particle spectrum, and the dynamical response of the magnetosphere to these space environment inputs, strongly influence the composition and energy distribution of the atmospheric ionizing radiation field. During the development of the NAIRAS model, new science questions were identified that must be addressed in order to obtain a more reliable and robust operational model of atmospheric radiation exposure. Addressing these science questions require improvements in both space weather modeling and observations. The focus of this talk is to present these science questions, the proposed methodologies for addressing these science questions, and the anticipated improvements to the operational predictions of atmospheric radiation exposure. The overarching goal of this work is to provide a decision support tool for the aviation industry that will enable an optimal balance to be achieved between minimizing health risks to passengers and aircrew while simultaneously minimizing costs to the airline companies.

Modeling Acute Health Effects of Astronauts from Exposure to Large Solar Particle Events

NASA Technical Reports Server (NTRS)

Hu, Shaowen; Kim, Myung-Hee Y.; Cucinotta, Francis A.

2011-01-01

In space exploration outside the Earth s geomagnetic field, radiation exposure from solar particle events (SPE) presents a health concern for astronauts, that could impair their performance and result in possible failure of the mission. Acute risks are of special concern during extra-vehicular activities because of the rapid onset of SPE. However, most SPEs will not lead to acute risks but can lead to mission disruption if accurate projection methods are not available. Acute Radiation Sickness (ARS) is a group of clinical syndromes developing acutely (within several seconds to 3 days) after high dose whole-body or significant partial-body ionizing radiation exposures. The manifestation of these syndromes reflects the disturbance of physiological processes of various cellular groups damaged by radiation. Hematopoietic cells, skin, epithelium, intestine, and vascular endothelium are among the most sensitive tissues of human body to ionizing radiation. Most ARS symptoms are directly related to these tissues and other systems (nervous, endocrine, and cardiovascular, etc.) with coupled regulations. Here we report the progress in bio-mathematical models to describe the dose and time-dependent early human responses to ionizing radiation. The responses include lymphocyte depression, granulocyte modulation, fatigue and weakness syndrome, and upper gastrointestinal distress. The modest dose and dose-rates of SPEs are predicted to lead to large sparing of ARS, however detailed experimental data on a range of proton dose-rates for organ doses from 0.5 to 2 Gy is needed to validate the models. We also report on the ARRBOD code that integrates the BRYNTRN and SUMDOSE codes, which are used to estimate the SPE organ doses for astronauts under various space travel scenarios, with our models of ARS. The more recent effort is to provide easy web access to space radiation risk assessment using the ARRBOD code.

Biological indicators in response to radiofrequency/microwave exposure.

PubMed

Marjanović, Ana Marija; Pavičić, Ivan; Trošić, Ivančica

2012-09-01

Over the years, due to rapid technological progress, radiation from man-made sources exceeded that of natural origin. There is a general concern regarding a growing number of appliances that use radiofrequency/ microwave (RF/MW) radiation with particular emphasis on mobile communication systems. Since nonthermal biological effects and mechanisms of RF/MW radiation are still uncertain, laboratory studies on animal models, tissues, cells, and cell free system are of extraordinary importance in bioelectromagnetic research. We believe that such investigations play a supporting role in public risk assessment. Cellular systems with the potential for a clear response to RF/MW exposures should be used in those studies. It is known that organism is a complex electrochemical system where processes of oxidation and reduction regularly occur. One of the plausible mechanisms is connected with generation of reactive oxygen species (ROS). Depending on concentration, ROS can have both beneficial and deleterious effects. Positive effects are connected with cell signalling, defence against infectious agents, and proliferative cell ability. On the other hand, excessive production, which overloads antioxidant defence mechanism, leads to cellular damage with serious potential for disease development. ROS concentration increase within the cell caused by RF/MW radiation seems to be a biologically relevant hypothesis to give clear insight into the RF/MW action at non-thermal level of radiation. In order to better understand the exact mechanism of action and its consequences, further research is needed in the field. We would like to present current knowledge on possible biological mechanisms of RF/MW actions.

Stereotactic body radiation therapy for liver oligometastases: predictive factors of local response by 18F-FDG-PET/CT.

PubMed

Mazzola, Rosario; Fersino, Sergio; Alongi, Pierpaolo; Di Paola, Gioacchino; Gregucci, Fabiana; Aiello, Dario; Tebano, Umberto; Pasetto, Stefano; Ruggieri, Ruggero; Salgarello, Matteo; Alongi, Filippo

2018-05-23

To investigate metabolic parameters as predictive of local response after stereotactic body radiation therapy (SBRT) for liver-oligometastases. Inclusion criteria of the present retrospective study were: (a) liver oligometastases with controlled primary tumor; (b) absence of progressive disease ≥6 months; (c) metastases ≤ 3; (d) evaluation of SBRT-response by means of 18-fludeoxyglucose-PET/CT for at least two subsequent evaluations; (e) Karnofsky performance status >80; (f) life-expectancy >6 months. The following metabolic parameters were defined semi-quantitatively for each metastases: (1) standardized uptake value (SUVmax; (2) SUV-mean; (3) metabolic tumor volume (MTV), tumor volume with a SUV ≥3, threshold 40%; (4) total lesion glycolysis (TLG), i.e. the product of SUV-mean and MTV. Local control was defined as absence of recurrence in the field of irradiation. 41 liver metastases were analyzed. Pre-SBRT, median SUV-max was 8.7 (range, 4.5-23.59), median SUV-mean was 4.6 (range, 3-7.5), median MTV was 5.7 cc (range, 0.9-80.6) and median total lesion glycolysis was 24.1 (range, 3.6-601.5). At statistical analysis, metastases with SUV-mean >5 (p 0.04; odds ratio 4.75, sensitivity = 50%, specificity = 82.6%, area under the curve 0.66) and SUV-max >12 (p 0.02; odds ratio 5.03, sensitivity = 69%, specificity = 70%, area under the curve = 0.69) showed higher rates of infield-failure compared to the remaining lesions. According to current findings, pre-SBRT SUV-max and SUV-mean could be predictable of local response in liver oligometastases. Advances in knowledge: Present findings could support the hypothesis that fludeoxyglucose-PET/CT may be a powerful tool to predict tumor control. Specifically, current results might be helpful for clinicians in the decision-making process regarding liver oligometastatic patient selection as well as the individual therapy stratification distinguishing between slowly local progressing patients and rapidly progressing patients.

Phase II study of monthly pasireotide LAR (SOM230C) for recurrent or progressive meningioma

PubMed Central

Norden, Andrew D.; Ligon, Keith L.; Hammond, Samantha N.; Muzikansky, Alona; Reardon, David A.; Kaley, Thomas J.; Batchelor, Tracy T.; Plotkin, Scott R.; Raizer, Jeffrey J.; Wong, Eric T.; Drappatz, Jan; Lesser, Glenn J.; Haidar, Sam; Beroukhim, Rameen; Lee, Eudocia Q.; Doherty, Lisa; Lafrankie, Debra; Gaffey, Sarah C.; Gerard, Mary; Smith, Katrina H.; McCluskey, Christine; Phuphanich, Surasak

2015-01-01

Objective: A subset of meningiomas recur after surgery and radiation therapy, but no medical therapy for recurrent meningioma has proven effective. Methods: Pasireotide LAR is a long-acting somatostatin analog that may inhibit meningioma growth. This was a phase II trial in patients with histologically confirmed recurrent or progressive meningioma designed to evaluate whether pasireotide LAR prolongs progression-free survival at 6 months (PFS6). Patients were stratified by histology (atypical [World Health Organization grade 2] and malignant [grade 3] meningiomas in cohort A and benign [grade 3] in cohort B). Results: Eighteen patients were accrued in cohort A and 16 in cohort B. Cohort A had median age 59 years, median Karnofsky performance status 80, 17 (94%) had previous radiation therapy, and 11 (61%) showed high octreotide uptake. Cohort B had median age 52 years, median Karnofsky performance status 90, 11 (69%) had previous radiation therapy, and 12 (75%) showed high octreotide uptake. There were no radiographic responses to pasireotide LAR therapy in either cohort. Twelve patients (67%) in cohort A and 13 (81%) in cohort B achieved stable disease. In cohort A, PFS6 was 17% and median PFS 15 weeks (95% confidence interval: 8–20). In cohort B, PFS6 was 50% and median PFS 26 weeks (12–43). Treatment was well tolerated. Octreotide uptake and insulin-like growth factor–1 levels did not predict outcome. Expression of somatostatin receptor 3 predicted favorable PFS and overall survival. Conclusions: Pasireotide LAR has limited activity in recurrent meningiomas. The finding that somatostatin receptor 3 is associated with favorable outcomes warrants further investigation. Classification of evidence: This study provides Class IV evidence that in patients with recurrent or progressive meningioma, pasireotide LAR does not significantly increase the proportion of patients with PFS at 6 months. PMID:25527270

Radiation-induced inflammatory markers of brain injury are modulated by PPARdelta activation in vitro and in vivo

NASA Astrophysics Data System (ADS)

Schnegg, Caroline Isabel

As a result of improvements in cancer therapy and health care, the population of long-term cancer survivors is growing. For these approximately 12 million long-term cancer survivors, brain metastases are a significant risk. Fractionated partial or whole-brain irradiation (fWBI) is often required to treat both primary and metastatic brain cancer. Radiation-induced normal tissue injury, including progressive cognitive impairment, however, can significantly affect the well-being of the approximately 200,000 patients who receive these treatments each year. Recent reports indicate that radiation-induced brain injury is associated with chronic inflammatory and oxidative stress responses, as well as increased microglial activation in the brain. Anti-inflammatory drugs may, therefore, be a beneficial therapy to mitigate radiation-induced brain injury. We hypothesized that activation of peroxisomal proliferator activated receptor delta (PPARō) would prevent or ameliorate radiation-induced brain injury, including cognitive impairment, in part, by alleviating inflammatory responses in microglia. For our in vitro studies, we hypothesized that PPARō activation would prevent the radiation-induced inflammatory response in microglia following irradiation. Incubating BV-2 murine microglial cells with the (PPAR)ō agonist, L-165041, prevented the radiation-induced increase in: i) intracellular ROS generation, ii) Cox-2 and MCP-1 expression, and iii) IL-1β and TNF-α message levels. This occured, in part, through PPARō-mediated modulation of stress activated kinases and proinflammatory transcription factors. PPARō inhibited NF-κB via transrepression by physically interacting with the p65 subunit, and prevented activation of the PKCα/MEK1/2/ERK1/2/AP-1 pathway by inhibiting the radiation-induced increase in intracellular ROS generation. These data support the hypothesis that PPARō activation can modulate the radiation-induced oxidative stress and inflammatory responses in microglia in vitro. To extend our in vitro findings in vivo, we investigated whether administration of the peroxisomal proliferator-activated receptor (PPAR)ä agonist, GW0742, prevented radiation-induced brain injury in C57Bl/6 WT mice. Our data demonstrate that GW0742 prevented the radiation-induced increase in the number of activated microglia (CD68+ cells) in wild-type (WT) mice 1 week following 10 Gy WBI. Furthermore, GW0742 inhibited the WBI-induced increase in IL-1β message levels and ERK phosphorylation observed 3 h post-irradiation. In contrast, GW0742 administration failed to modulate the radiation-induced decrease in hippocampal neurogenesis (NeuN+/BrdU+ cells) determined 2 months after irradiation, or mitigate hippocampal-dependent spatial memory impairment observed 3 months post-irradiation using the Barnes Maze task. We used PPARō knockout (KO) mice to examine if the effects of GW0742 are PPARō-dependent. Unexpectedly, PPARō KO mice exhibited a differential response following WBI compared to WT mice; therefore, we were unable to make mechanistic conclusions about GW0742. KO mice do not exhibit a WBI-induced increase in activated microglia; however, they appeared to display a pronounced astrocytic response. In particular, PPARō KO but not WT mice displayed increased GFAP message levels 2 months after WBI. Additionally, the number of GFAP+ cells was reduced significantly in the WT mice 2 months after WBI, but it was not in the PPARō KO mice. These results demonstrate that: i) GW0742 prevents the radiation-induced increase in microglial activation and inflammatory markers, and ii) WT and PPARō KO mice have a differential response to WBI.

Efficacy and safety of retreatment with nivolumab in metastatic melanoma patients previously treated with nivolumab.

PubMed

Nomura, Motoo; Otsuka, Atsushi; Kondo, Tomohiro; Nagai, Hiroki; Nonomura, Yumi; Kaku, Yo; Matsumoto, Shigemi; Muto, Manabu

2017-11-01

Nivolumab is a monoclonal antibody directed against programmed death-1 that has been shown to improve survival in patients with metastatic melanoma. However, the efficacy of nivolumab and other agents in melanoma remains limited. The objective of this study was to evaluate the efficacy and safety of retreatment with nivolumab in metastatic melanoma patients who previously progressed on nivolumab. A retrospective review was performed on eight consecutive metastatic melanoma patients retreated with nivolumab who progressed on previous nivolumab. These patients received nivolumab 2 mg/kg every 3 weeks. Best responses to each treatment were assessed using RECIST 1.1. Of eight metastatic melanoma patients, three patients received chemotherapy before first nivolumab. The median first nivolumab treatment period was 4.1 months. During first nivolumab, 3 (37.5%) patients achieved a partial response and 3 (37.5%) patients achieved stable disease as their best response. First nivolumab was discontinued due to disease progression in seven patients and grade 3 colitis in 1 patient. Patients were subsequently treated with ipilimumab (n = 6), vemurafenib (n = 1), or no other medical treatment (n = 1). The median treatment period between first and second nivolumab was 3.0 months. Four patients received radiation therapy between first and second nivolumab. The median second nivolumab treatment period was 4.3 months. Among the eight patients who received second nivolumab, 2 (25%) patients achieved a partial response and 3 (37.5%) patients achieved stable disease as their best response. Second nivolumab was discontinued due to disease progression in seven patients. One patient continues to receive second nivolumab. Among the four patients treated with ipilimumab and radiotherapy between first and second nivolumab, the response rate was 50% and the disease control rate was 75%. This study showed that retreatment with nivolumab is an option for select metastatic melanoma patients after previous nivolumab treatment.

The Role of Lymphocytes in Radiotherapy-Induced Adverse Late Effects in the Lung

PubMed Central

Wirsdörfer, Florian; Jendrossek, Verena

2016-01-01

Radiation-induced pneumonitis and fibrosis are dose-limiting side effects of thoracic irradiation. Thoracic irradiation triggers acute and chronic environmental lung changes that are shaped by the damage response of resident cells, by the resulting reaction of the immune system, and by repair processes. Although considerable progress has been made during the last decade in defining involved effector cells and soluble mediators, the network of pathophysiological events and the cellular cross talk linking acute tissue damage to chronic inflammation and fibrosis still require further definition. Infiltration of cells from the innate and adaptive immune systems is a common response of normal tissues to ionizing radiation. Herein, lymphocytes represent a versatile and wide-ranged group of cells of the immune system that can react under specific conditions in various ways and participate in modulating the lung environment by adopting pro-inflammatory, anti-inflammatory, or even pro- or anti-fibrotic phenotypes. The present review provides an overview on published data about the role of lymphocytes in radiation-induced lung disease and related damage-associated pulmonary diseases with a focus on T lymphocytes and B lymphocytes. We also discuss the suspected dual role of specific lymphocyte subsets during the pneumonitic phase and fibrotic phase that is shaped by the environmental conditions as well as the interaction and the intercellular cross talk between cells from the innate and adaptive immune systems and (damaged) resident epithelial cells and stromal cells (e.g., endothelial cells, mesenchymal stem cells, and fibroblasts). Finally, we highlight potential therapeutic targets suited to counteract pathological lymphocyte responses to prevent or treat radiation-induced lung disease. PMID:28018357

VESsel GENeration Analysis (VESGEN): Innovative Vascular Mappings for Astronaut Exploration Health Risks and Human Terrestrial Medicine

NASA Technical Reports Server (NTRS)

Parsons-Wingerter, Patricia; Kao, David; Valizadegan, Hamed; Martin, Rodney; Murray, Matthew C.; Ramesh, Sneha; Sekaran, Srinivaas

2017-01-01

Currently, astronauts face significant health risks in future long-duration exploration missions such as colonizing the Moon and traveling to Mars. Numerous risks include greatly increased radiation exposures beyond the low earth orbit (LEO) of the ISS, and visual and ocular impairments in response to microgravity environments. The cardiovascular system is a key mediator in human physiological responses to radiation and microgravity. Moreover, blood vessels are necessarily involved in the progression and treatment of vascular-dependent terrestrial diseases such as cancer, coronary vessel disease, wound-healing, reproductive disorders, and diabetes. NASA developed an innovative, globally requested beta-level software, VESsel GENeration Analysis (VESGEN) to map and quantify vascular remodeling for application to astronaut and terrestrial health challenges. VESGEN mappings of branching vascular trees and networks are based on a weighted multi-parametric analysis derived from vascular physiological branching rules. Complex vascular branching patterns are determined by biological signaling mechanisms together with the fluid mechanics of multi-phase laminar blood flow.

Single nucleotide polymorphisms of DNA repair genes as predictors of radioresponse.

PubMed

Parliament, Matthew B; Murray, David

2010-10-01

Radiation therapy is a key modality in the treatment of cancer. Substantial progress has been made in unraveling the molecular events which underpin the responses of malignant and surrounding normal tissues to ionizing radiation. An understanding of the genes involved in processes such as DNA double-strand break repair, DNA damage response, cell-cycle control, apoptosis, cellular antioxidant defenses, and cytokine production, has evolved toward examination of how genetic variants, most often, single nucleotide polymorphisms (SNPs), may influence interindividual radioresponse. Experimental approaches, such as candidate SNP-association studies, genome-wide association studies, and massively parallel sequencing are being proposed to address these questions. We present a focused review of the evidence supporting an association between SNPs in DNA repair genes and radioresponse in normal tissues and tumors. Although preliminary results indicate possible associations, there are methodological weaknesses in many of the studies, and independent validation of SNPs as biomarkers of radioresponse in much larger cohorts will likely require research cooperation through international consortia. Copyright © 2010 Elsevier Inc. All rights reserved.

Differential Impact of Single-Dose Fe Ion and X-Ray Irradiation on Endothelial Cell Transcriptomic and Proteomic Responses

PubMed Central

Baselet, Bjorn; Azimzadeh, Omid; Erbeldinger, Nadine; Bakshi, Mayur V.; Dettmering, Till; Janssen, Ann; Ktitareva, Svetlana; Lowe, Donna J.; Michaux, Arlette; Quintens, Roel; Raj, Kenneth; Durante, Marco; Fournier, Claudia; Benotmane, Mohammed A.; Baatout, Sarah; Sonveaux, Pierre; Tapio, Soile; Aerts, An

2017-01-01

Background and Purpose: Radiotherapy is an essential tool for cancer treatment. In order to spare normal tissues and to reduce the risk of normal tissue complications, particle therapy is a method of choice. Although a large part of healthy tissues can be spared due to improved depth dose characteristics, little is known about the biological and molecular mechanisms altered after particle irradiation in healthy tissues. Elucidation of these effects is also required in the context of long term space flights, as particle radiation is the main contributor to the radiation effects observed in space. Endothelial cells (EC), forming the inner layer of all vascular structures, are especially sensitive to irradiation and, if damaged, contribute to radiation-induced cardiovascular disease. Materials and Methods: Transcriptomics, proteomics and cytokine analyses were used to compare the response of ECs irradiated or not with a single 2 Gy dose of X-rays or Fe ions measured one and 7 days post-irradiation. To support the observed inflammatory effects, monocyte adhesion on ECs was also assessed. Results: Experimental data indicate time- and radiation quality-dependent changes of the EC response to irradiation. The irradiation impact was more pronounced and longer lasting for Fe ions than for X-rays. Both radiation qualities decreased the expression of genes involved in cell-cell adhesion and enhanced the expression of proteins involved in caveolar mediated endocytosis signaling. Endothelial inflammation and adhesiveness were increased with X-rays, but decreased after Fe ion exposure. Conclusions: Fe ions induce pro-atherosclerotic processes in ECs that are different in nature and kinetics than those induced by X-rays, highlighting radiation quality-dependent differences which can be linked to the induction and progression of cardiovascular diseases (CVD). Our findings give a better understanding of the underlying processes triggered by particle irradiation in ECs, a crucial aspect for the development of protective measures for cancer patients undergoing particle therapy and for astronauts in space. PMID:28993729

Radioembolization for Unresectable Intrahepatic Cholangiocarcinoma: Review of Safety, Response Evaluation Criteria in Solid Tumors 1.1 Imaging Response and Survival.

PubMed

Swinburne, Nathaniel C; Biederman, Derek M; Besa, Cecilia; Tabori, Nora E; Fischman, Aaron M; Patel, Rahul S; Nowakowski, Francis Scott; Gunasekaran, Ganesh; Schwartz, Myron E; Lookstein, Robert A; Kim, Edward

2017-06-01

The optimal palliative treatment for unresectable intrahepatic cholangiocarcinoma (ICC) remains controversial. While selective internal radiation therapy (SIRT) using yttrium-90 microspheres is a well-accepted treatment for hepatocellular carcinoma, data related to its use for locally advanced ICC remain relatively scarce. Twenty-nine patients (mean age 66 ± 11 years; 15 female) with unresectable biopsy-proven ICC treated with SIRT between June 2008 and April 2015 were retrospectively evaluated for post-treatment toxicity, overall survival, and imaging response using response evaluation criteria in solid tumors (RECIST) 1.1 criteria. RECIST 1.1 response was evaluable following 26 treatments [complete response (CR):0, partial response (PR):3; stable disease (SD):16, progression of disease (PD):7]. Objective response rate (CR+PR) was 12%. Disease control rate (CR+PR+SD) was 73%. Median time to progression was 5.6 [95% confidence interval (CI): 0-12.0] months. Median survival following SIRT was 9.1 (95% CI: 1.7-16.4) months. Post-treatment survival was prolonged in patients with absence of extrahepatic disease (p = 0.03) and correlated with RECIST 1.1 response (p = 0.02). Toxicities were limited to grade I severity and occurred following 27% of treatments. These findings support the safe, effective use of SIRT for unresectable ICC. Post-treatment survival is prolonged in patients with absence of extrahepatic disease at baseline. RECIST 1.1 response following SIRT for ICC is predictive of survival.

Evaluation of radiation necrosis and malignant glioma in rat models using diffusion tensor MR imaging

PubMed Central

Wang, Silun; Chen, Yifei; Lal, Bachchu; Ford, Eric; Tryggestad, Erik; Armour, Michael; Yan, Kun; Laterra, John; Zhou, Jinyuan

2011-01-01

Standard MRI cannot distinguish between radiation necrosis and tumor progression; however, this distinction is critical in the assessment of tumor response to therapy. In this study, one delayed radiation necrosis model (dose, 40 Gy; radiation field, 10 × 10 mm2; n = 13) and two orthotopic glioma models in rats (9L gliosarcoma, n = 8; human glioma xenografts, n = 5) were compared using multiple DTI indices. A visible isotropic apparent diffusion coefficient (ADC) pattern was observed in the lesion due to radiation necrosis, which consisted of a hypointense central zone and a hyperintense peripheral zone. There were significantly lower ADC, parallel diffusivity, and perpendicular diffusivity in the necrotic central zone than in the peripheral zone (all p < 0.001). When radiation-induced necrosis was compared with viable tumor, radiation necrosis had significantly lower ADC than 9L gliosarcoma and human glioma xenografts (both p < 0.01) in the central zone, and significantly lower FA than 9L gliosarcoma (p = 0.005) and human glioma xenografts (p = 0.012) in the peripheral zone. Histological analysis revealed parenchymal coagulative necrosis in the central zone, and damaged vessels and reactive astrogliosis in the peripheral zone. These data suggest that qualitative and quantitative analysis of the DTI maps can provide useful information by which to distinguish between radiation necrosis and viable glioma. PMID:21948114

Radiosurgery for the treatment of spinal lung metastases.

PubMed

Gerszten, Peter C; Burton, Steven A; Belani, Chandra P; Ramalingam, Suresh; Friedland, David M; Ozhasoglu, Cihat; Quinn, Annette E; McCue, Kevin J; Welch, William C

2006-12-01

Spinal metastases are a common source of pain as well as neurologic deficit in patients with lung cancer. Metastases from lung cancer traditionally have been believed to be relatively responsive to radiation therapy. However, conventional external beam radiotherapy lacks the precision to allow delivery of large single-fraction doses of radiation and simultaneously limit the dose to radiosensitive structures such as the spinal cord. The current study evaluated the efficacy of single-fraction radiosurgery for the treatment of spinal lung cancer metastases. In the current prospective cohort evaluation, 87 lung cancer metastases to the spine in 77 patients were treated with a single-fraction radiosurgery technique with a follow-up period of 6 to 40 months (median, 12 months). The indication for radiosurgery treatment was pain in 73 cases, as a primary treatment modality in 7 cases, for radiographic tumor progression in 4 cases, and for progressive neurologic deficit in 3 cases. Tumor volume ranged from 0.2 to 264 cm(3) (mean, 25.7 cm(3)). The maximum tumor dose was maintained at 15 to 25 grays (Gy) (mean, 20 Gy; median, 20 Gy). No radiation-induced toxicity occurred during the follow-up period. Long-term axial and radicular pain improvement occurred in 65 of 73 patients (89%) who were treated primarily for pain. Long-term radiographic tumor control was observed in all patients who underwent radiosurgery as their primary treatment modality or for radiographic tumor progression. Spinal radiosurgery was found to be feasible, safe, and clinically effective for the treatment of spinal metastases from lung cancer. The results of the current study indicate the potential of radiosurgery in the treatment of patients with spinal lung metastases, especially those with solitary sites of spine involvement, to improve long-term palliation. (c) 2006 American Cancer Society.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Heyd, Reinhard, E-mail: reiniheyd@aol.com; Micke, Oliver; Surholt, Christine

Purpose: The German Cooperative Group on Radiotherapy for Benign Diseases conducted a national patterns-of-care study to investigate the value of radiation therapy (RT) in the management of Gorham-Stout syndrome. Methods and Materials: In 2009 a structured questionnaire was circulated to 230 German RT institutions to assess information about the number of patients, the RT indication and technique, and the target volume definition, as well as accompanying treatments, outcome data, and early or late radiation toxicity. Results: In November 2009 responses were available from 197 departments (85.6%): 29 university hospitals (14.7%), 89 community hospitals (45.2%), and 79 private RT offices (40.1%).more » Of these institutions, 8 (4.0%) had experience using RT, for a total of 10 cases in various anatomic sites. Four patients underwent irradiation postoperatively, and six patients received primary RT. The total doses applied after computed tomography-based treatment planning ranged from 30 to 45 Gy. After a median follow-up period of 42 months, local disease progression was avoided in 8 cases (80.0%). In 2 of these cases a progression occurred beyond the target volume. Acute and late toxicity was mild; in 4 patients RT was associated with Grade I side effects according to Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer criteria. The literature analysis of 38 previously published articles providing results after the use of RT in 44 patients showed stable or regressive disease in 77.3%. Conclusions: RT may prevent disease progression effectively in Gorham-Stout syndrome in 77% to 80% of cases. Total doses ranging from 30 to 45 Gy applied after computed tomography-based treatment planning are recommended.« less

Terrestrial ecosystems, increased solar ultraviolet radiation, and interactions with other climate change factors.

PubMed

Caldwell, M M; Bornman, J F; Ballaré, C L; Flint, S D; Kulandaivelu, G

2007-03-01

There have been significant advances in our understanding of the effects of UV-B radiation on terrestrial ecosystems, especially in the description of mechanisms of plant response. A further area of highly interesting research emphasizes the importance of indirect UV radiation effects on plants, pathogens, herbivores, soil microbes and ecosystem processes below the surface. Although photosynthesis of higher plants and mosses is seldom affected by enhanced or reduced UV-B radiation in most field studies, effects on growth and morphology (form) of higher plants and mosses are often manifested. This can lead to small reductions in shoot production and changes in the competitive balance of different species. Fungi and bacteria are generally more sensitive to damage by UV-B radiation than are higher plants. However, the species differ in their UV-B radiation sensitivity to damage, some being affected while others may be very tolerant. This can lead to changes in species composition of microbial communities with subsequent influences on processes such as litter decomposition. Changes in plant chemical composition are commonly reported due to UV-B manipulations (either enhancement or attenuation of UV-B in sunlight) and may lead to substantial reductions in consumption of plant tissues by insects. Although sunlight does not penetrate significantly into soils, the biomass and morphology of plant root systems of plants can be modified to a much greater degree than plant shoots. Root mass can exhibit sizeable declines with more UV-B. Also, UV-B-induced changes in soil microbial communities and biomass, as well as altered populations of small invertebrates have been reported and these changes have important implications for mineral nutrient cycling in the soil. Many new developments in understanding the underlying mechanisms mediating plant response to UV-B radiation have emerged. This new information is helpful in understanding common responses of plants to UV-B radiation, such as diminished growth, acclimation responses of plants to UV-B radiation and interactions of plants with consumer organisms such as insects and plant pathogens. The response to UV-B radiation involves both the initial stimulus by solar radiation and transmission of signals within the plants. Resulting changes in gene expression induced by these signals may have elements in common with those elicited by other environmental factors, and generate overlapping functional (including acclimation) responses. Concurrent responses of terrestrial systems to the combination of enhanced UV-B radiation and other global change factors (increased temperature, CO2, available nitrogen and altered precipitation) are less well understood. Studies of individual plant responses to combinations of factors indicate that plant growth can be augmented by higher CO2 levels, yet many of the effects of UV-B radiation are usually not ameliorated by the elevated CO2. UV-B radiation often increases both plant frost tolerance and survival under extreme high temperature conditions. Conversely, extreme temperatures sometimes influence the UV-B radiation sensitivity of plants directly. Plants that endure water deficit stress effectively are also likely to be tolerant of high UV-B flux. Biologically available nitrogen is exceeding historical levels in many regions due to human activities. Studies show that plants well supplied with nitrogen are generally more sensitive to UV-B radiation. Technical issues concerning the use of biological spectral weighting functions (BSWFs) have been further elucidated. The BSWFs, which are multiplication factors assigned to different wavelengths giving an indication of their relative biological effectiveness, are critical to the proper conduct and interpretation of experiments in which organisms are exposed to UV radiation, both in the field and in controlled environment facilities. The characteristics of BSWFs vary considerably among different plant processes, such as growth, DNA damage, oxidative damage and induction of changes in secondary chemicals. Thus, use of a single BSWF for plant or ecosystem response is not appropriate. This brief review emphasizes progress since the previous report toward the understanding of solar ultraviolet radiation effects on terrestrial systems as it relates to ozone column reduction and the interaction of climate change factors.

Molecular imaging biomarkers of resistance to radiation therapy for spontaneous nasal tumors in canines.

PubMed

Bradshaw, Tyler J; Bowen, Stephen R; Deveau, Michael A; Kubicek, Lyndsay; White, Pamela; Bentzen, Søren M; Chappell, Richard J; Forrest, Lisa J; Jeraj, Robert

2015-03-15

Imaging biomarkers of resistance to radiation therapy can inform and guide treatment management. Most studies have so far focused on assessing a single imaging biomarker. The goal of this study was to explore a number of different molecular imaging biomarkers as surrogates of resistance to radiation therapy. Twenty-two canine patients with spontaneous sinonasal tumors were treated with accelerated hypofractionated radiation therapy, receiving either 10 fractions of 4.2 Gy each or 10 fractions of 5.0 Gy each to the gross tumor volume. Patients underwent fluorodeoxyglucose (FDG)-, fluorothymidine (FLT)-, and Cu(II)-diacetyl-bis(N4-methylthiosemicarbazone) (Cu-ATSM)-labeled positron emission tomography/computed tomography (PET/CT) imaging before therapy and FLT and Cu-ATSM PET/CT imaging during therapy. In addition to conventional maximum and mean standardized uptake values (SUV(max); SUV(mean)) measurements, imaging metrics providing response and spatiotemporal information were extracted for each patient. Progression-free survival was assessed according to response evaluation criteria in solid tumor. The prognostic value of each imaging biomarker was evaluated using univariable Cox proportional hazards regression. Multivariable analysis was also performed but was restricted to 2 predictor variables due to the limited number of patients. The best bivariable model was selected according to pseudo-R(2). The following variables were significantly associated with poor clinical outcome following radiation therapy according to univariable analysis: tumor volume (P=.011), midtreatment FLT SUV(mean) (P=.018), and midtreatment FLT SUV(max) (P=.006). Large decreases in FLT SUV(mean) from pretreatment to midtreatment were associated with worse clinical outcome (P=.013). In the bivariable model, the best 2-variable combination for predicting poor outcome was high midtreatment FLT SUV(max) (P=.022) in combination with large FLT response from pretreatment to midtreatment (P=.041). In addition to tumor volume, pronounced tumor proliferative response quantified using FLT PET, especially when associated with high residual FLT PET at midtreatment, is a negative prognostic biomarker of outcome in canine tumors following radiation therapy. Neither FDG PET nor Cu-ATSM PET were predictive of outcome. Copyright © 2015 Elsevier Inc. All rights reserved.

Remote Sensor Application Studies Progress Report, July L, 1968 to June 30, 1969. Controlled Field Experiments

USGS Publications Warehouse

Rowan, L.C.; Offield, T.W.; Watson, R.D.; Cannon, P.J.; Grolier, H.J.; Pohn, H.A.; Watson, Kenneth

1970-01-01

Field Sites have been selected for controlled experiments to analyze physical and chemical parameters affecting the response of electromagnetic radiation to geological materials. Considerations in the selection of the sites are the availability of good exposures of nearly monomineralic rocks, level of geologic understanding, and ease of access. Seven sites, where work is underway or planned, contain extensive outcrops of the following rocks: stanstone, limestone, dolomite, and gypsum. Field measurement of quartz have been conducted at four sites.

Alectinib in Crizotinib-Refractory ALK-Rearranged Non-Small-Cell Lung Cancer: A Phase II Global Study.

PubMed

Ou, Sai-Hong Ignatius; Ahn, Jin Seok; De Petris, Luigi; Govindan, Ramaswamy; Yang, James Chih-Hsin; Hughes, Brett; Lena, Hervé; Moro-Sibilot, Denis; Bearz, Alessandra; Ramirez, Santiago Viteri; Mekhail, Tarek; Spira, Alexander; Bordogna, Walter; Balas, Bogdana; Morcos, Peter N; Monnet, Annabelle; Zeaiter, Ali; Kim, Dong-Wan

2016-03-01

Crizotinib confers improved progression-free survival compared with chemotherapy in anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC), but progression invariably occurs. We investigated the efficacy and safety of alectinib, a potent and selective ALK inhibitor with excellent CNS penetration, in patients with crizotinib-refractory ALK-positive NSCLC. Alectinib 600 mg was administered orally twice daily. The primary end point was objective response rate (ORR) by central independent review committee (IRC). Of the 138 patients treated, 84 patients (61%) had CNS metastases at baseline, and 122 were response evaluable (RE) by IRC. ORR by IRC was 50% (95% CI, 41% to 59%), and the median duration of response (DOR) was 11.2 months (95% CI, 9.6 months to not reached). In 96 patients (79%) previously treated with chemotherapy, the ORR was 45% (95% CI, 35% to 55%). Median IRC-assessed progression-free survival for all 138 patients was 8.9 months (95% CI, 5.6 to 11.3 months). CNS disease control rate was 83% (95% CI, 74% to 91%), and the median CNS DOR was 10.3 months (95% CI, 7.6 to 11.2 months). CNS ORR in 35 patients with baseline measurable CNS lesions was 57% (95% CI, 39% to 74%). Of the 23 patients with baseline CNS metastases (measurable or nonmeasurable) and no prior radiation, 10 (43%) had a complete CNS response. At 12 months, the cumulative CNS progression rate (24.8%) was lower than the cumulative non-CNS progression rate (33.2%) for all patients. Common adverse events were constipation (33%), fatigue (26%), and peripheral edema (25%); most were grade 1 to 2. Alectinib is highly active and well tolerated in patients with advanced, crizotinib-refractory ALK-positive NSCLC, including those with CNS metastases. © 2015 by American Society of Clinical Oncology.

Identification of biomarkers of radioresponse and subsequent progression towards lung cancer in normal human bronchial epithelial cells after HZE particle irradiation

NASA Astrophysics Data System (ADS)

Story, Michael; Ding, Liang-Hao; Park, Seongmi; Minna, John

Using variants of a non-oncogenically immortalized human bronchial epithelial cell line HBEC3-KT, we have examined global gene expression patterns after low and high LET irradiation up to 24h post-IR. Using supervised analyses we have identified 427 genes whoes expression can be used to discriminate the cellular response to γ-vs Si or Fe particles even when the biological outcome, cell death, is equivalent. Furthermore, genetic background also determines gene expression response. When HBEC3-KT is compared to the HBEC3-KT cells line where mutant k-RAS is over-expressed and p53 has been knocked down, HBEC-3KTr53, principal component analysis clearly shows that the response of each cell resides in a different 3-D space, that is, basal gene expression patterns as well as the gene expression response are unique to each cell type. Using regression analysis to examine these 427 genes show clusters of genes whose temporal expression patterns are the same and which are unique to a given radiation type. Ultimately, this approach will allow for the interrogation of gene promoters to identify response elements that drive how cells respond to different radiation types. We are extending our examination to O particles and are now examining gene expression as a function of beam quality. We have made substantial progress in the determination of cellular transformation by HZE particles for these cell lines. (Transformation as defined by the ability to grow in soft agar.) For HBEC-3KT, the spontaneous transformation frequency is about 10- 7.ExposuretoeitherF eorSiparticlesinc KT r53celllinedidnotshowanyincreaseintransf ormationf requencyaf terdosesof upto1Gy, however, thesp 3KT.W ehavenowisolatedover160individualf ocithatf ormedinsof tagarf romcellculturesthatwereirradia termcultureandthenre-introducedintosof tagartoassurethattheabilitytogrowinsof tagarisclonal.T odatew 30 With these cell isolates in hand we will begin to determine tumorigenicity by subcutaneous injections in nude mice. Tumors that develop will be examined for radiosensitivity and aggres-siveness and will be also be examined for genomic, epigenomic and proteomic changes. Com-parisons of unirradiated cells, transformed cells, and tumor cells will allow the development of biomarkers of radiation-induced lung cancer, in particular HZE-induced lung tumors, and help to generate risk factors for lung cancer as a result of travel through deep space environments.

[Treatment of keratitis superficialis chronica of the dog with strontium 90].

PubMed

Höcht, Stefan; Grüning, Georg; Allgoewer, Ingrid; Nausner, Martin; Brunnberg, Leo; Hinkelbein, Wolfgang

2002-02-01

Corneal pannus is a disease which, if untreated, nearly always is progressive and may lead to blindness of the affected dog. A therapeutic standard is yet to be defined. Beta-ray irradiation with Sr-90 is often recommended on a casuistic basis, but systematic studies are sparse. The aim of the present study was to evaluate efficacy and to document side effects of radiotherapy with Sr-90. 17 animals were treated. 13 of them received treatment of 15 Gy surface dose twice within 2 days with additional medical therapy with ciclosporin and prednisolon. Only the more affected eye was treated with radiation which was applied with an eye-applicator, the other eye served as control. Four animals with already advanced impairment of vision received keratectomy, afterwards radiation was applied on both sides. Medical treatment alone led to deterioration in vascularization and spread of pigmentation in eleven of 13 (85%) of the control-eyes, density of pigmentation increased in eight of 13 (62%). After radiation therapy, almost all animals showed a marked initial improvement. Even if progressive disease occurred later on, further worsening as it happened in the control-eyes could be stopped in nine resp. ten of 13 eyes (69% and 77%). All animals with keratectomy and radiotherapy regained and preserved adequate vision. Besides short-term blepharospasm, no side effects were recorded. Corneal pannus is responsive to radiation therapy with Sr-90 and long-term benefit can be achieved. Side effects are minimal. Optimal sequencing of therapy and dosage still have to be examined.

Clinical outcomes in extracranial tumor sites and unusual toxicities with concurrent whole brain radiation (WBRT) and Erlotinib treatment in patients with non-small cell lung cancer (NSCLC) with brain metastasis.

PubMed

Olmez, Inan; Donahue, Bernadine R; Butler, James S; Huang, Yiwu; Rubin, Philip; Xu, Yiqing

2010-11-01

Thirty percent of newly diagnosed NSCLC patients present with synchronous brain metastases, most of whom are treated with whole brain radiation. Systemic chemotherapy is usually avoided during WBRT due to concerns regarding toxicity. However, concurrent administration of targeted agents, such as Erlotinib, during WBRT may address systemic disease without causing toxicity. We report our institutional data on outcomes and toxicities with this treatment approach. Medical records of patients with newly diagnosed NSCLC and brain metastases receiving concurrent WBRT and Erlotinib treatment were reviewed. Radiographic response to therapy and toxicities were analyzed. Eight patients were identified and 7 were evaluable for response. All patients had intracranial disease control. In the extracranial sites, 3 (37.5%, intent-to-treat) showed partial response (PR), 2 (25%) had stable disease (SD), 1 (12.5%) had progression (PD) and 1 (12.5%) had new air space disease obscuring tumor response assessment. Among the three responders, two were female never smokers, while one was a female current smoker. Unanticipated grade 3 hepatotoxitity, hyponatremia, mental status changes, grade 3 and 4 thrombocytopenia, and grade 4 neutropenia with sepsis were observed. Three deaths occurred without clear signs of disease progression: one from neutropenic sepsis, one from wide spread air space disease, and one from neurologic deterioration. Our data demonstrates a high percentage of extracranial tumor response rates with first line Erlotinib in selected NSCLC patients. We observed unexpected serious complications and postulate possible mechanisms. We recommend caution to be exercised when considering Erlotinib treatment during WBRT, particularly in regard to drug-drug interactions and infection control. Data from prospective trials are needed to determine the benefits and toxicities of Erlotinib during WBRT. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

[A review of progress of real-time tumor tracking radiotherapy technology based on dynamic multi-leaf collimator].

PubMed

Liu, Fubo; Li, Guangjun; Shen, Jiuling; Li, Ligin; Bai, Sen

2017-02-01

While radiation treatment to patients with tumors in thorax and abdomen is being performed, further improvement of radiation accuracy is restricted by the tumor intra-fractional motion due to respiration. Real-time tumor tracking radiation is an optimal solution to tumor intra-fractional motion. A review of the progress of real-time dynamic multi-leaf collimator(DMLC) tracking is provided in the present review, including DMLC tracking method, time lag of DMLC tracking system, and dosimetric verification.

Stereotactic body radiotherapy reirradiation for recurrent epidural spinal metastases.

PubMed

Mahadevan, Anand; Floyd, Scott; Wong, Eric; Jeyapalan, Suriya; Groff, Michael; Kasper, Ekkehard

2011-12-01

When patients show progression after conventional fractionated radiation for spine metastasis, further radiation and surgery may not be options. Stereotactic body radiotherapy (SBRT) has been successfully used in treatment of the spine and may be applicable in these cases. We report the use of SBRT for 60 consecutive patients (81 lesions) who had radiological progressive spine metastasis with epidural involvement after previous radiation for spine metastasis. SBRT was used with fiducial and vertebral anatomy-based targeting. The radiation dose was prescribed based on the extent of spinal canal involvement; the dose was 8 Gy×3=24 Gy when the tumor did not touch the spinal cord and 5 to 6 Gyx5=25 to 30 Gy when the tumor abutted the cord. The cord surface received up to the prescription dose with no hot spots in the cord. The median overall survival was 11 months, and the median progression-free survival was 9 months. Overall, 93% of patients had stable or improved disease while 7% of patients showed disease progression; 65% of patients had pain relief. There was no significant toxicity other than fatigue. SBRT is feasible and appears to be an effective treatment modality for reirradiation after conventional palliative radiation fails for spine metastasis patients. Copyright © 2011 Elsevier Inc. All rights reserved.

Life science experiments performed in space in the ISS/Kibo facility and future research plans.

PubMed

Ohnishi, Takeo

2016-08-01

Over the past several years, current techniques in molecular biology have been used to perform experiments in space, focusing on the nature and effects of space radiation. In the Japanese 'Kibo' facility in the International Space Station (ISS), the Japan Aerospace Exploration Agency (JAXA) has performed five life science experiments since 2009, and two additional experiments are currently in progress. The first life science experiment in space was the 'Rad Gene' project, which utilized two human cultured lymphoblastoid cell lines containing a mutated P53 : gene (m P53 : ) and a parental wild-type P53 : gene (wt P53 : ) respectively. Four parameters were examined: (i) detecting space radiation-induced DSBs by observing γH2AX foci; (ii) observing P53 : -dependent gene expression during space flight; (iii) observing P53 : -dependent gene expression after space flight; and (iv) observing the adaptive response in the two cell lines containing the mutated and wild type P53 : genes after exposure to space radiation. These observations were completed and have been reported, and this paper is a review of these experiments. In addition, recent new information from space-based experiments involving radiation biology is presented here. These experiments involve human cultured cells, silkworm eggs, mouse embryonic stem cells and mouse eggs in various experiments designed by other principal investigators in the ISS/Kibo. The progress of Japanese science groups involved in these space experiments together with JAXA are also discussed here. The Japanese Society for Biological Sciences in Space (JSBSS), the Utilization Committee of Space Environment Science (UCSES) and the Science Council of Japan (ACJ) have supported these new projects and new experimental facilities in ISS/Kibo. Currently, these organizations are proposing new experiments for the ISS through 2024. © The Author 2016. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.

Phase I study of liposome-encapsulated c-raf antisense oligodeoxyribonucleotide infusion in combination with radiation therapy in patients with advanced malignancies.

PubMed

Dritschilo, Anatoly; Huang, Chao H; Rudin, Charles M; Marshall, John; Collins, Brian; Dul, Jeanne L; Zhang, Chuanbo; Kumar, Deepak; Gokhale, Prafulla C; Ahmad, Ateeq; Ahmad, Imran; Sherman, Jeffrey W; Kasid, Usha N

2006-02-15

Raf proteins are key elements of growth-related cellular signaling pathways and are a component of cancer cell resistance to radiation therapy. Antisense oligonucleotides to c-raf-1 permit highly selective inhibition of the gene product and offer a strategy for sensitizing cancer cells to radiation therapy. In this dose escalation study, we evaluated the safety of combined liposomal formulation of raf antisense oligonucleotide (LErafAON) and radiation therapy in patients with advanced malignancies. Patients with advanced solid tumors were treated with LErafAON in a phase I dose escalation study while receiving palliative radiation therapy. Drug-related and radiation-related toxicities were monitored. Pharmacokinetics and expression of c-raf-1 mRNA and Raf-1 protein were determined in peripheral blood mononuclear cells. Seventeen patients with palliative indications for radiation therapy were entered into this study. Thirteen patients received daily infusions of LErafAON and four received twice-weekly infusions. Radiation therapy was delivered in daily 300-cGy fractions over 2 weeks. Patients tolerated radiation, and no unexpected radiation-related side effects were observed. Drug-related reactions (grade > or =2), such as back pain, chills, dyspnea, fatigue, fever, flushing, and hypertension, were observed in most patients and were managed by premedication with corticosteroids and antihistamines. Serious adverse events occurred in five patients, including acute infusion-related symptoms, abnormal liver function tests, hypoxia, dehydration, diarrhea, esophagitis, fever, hypokalemia, pharyngitis, and tachypnea. Twelve of 17 patients were evaluable for tumor response at completion of treatment; four showed partial response, four showed stable disease, and four experienced progressive disease. The intact rafAON was detected in plasma for 30 minutes to several hours. Six patients with partial response or stable disease were evaluable for c-raf-1 mRNA and/or Raf-1 protein expression. Inhibition of c-raf-1 mRNA was observed in three of five patients. Raf-1 protein was inhibited in four of five patients. This is the first report of the combined modality treatment using antisense oligonucleotides with radiation therapy in patients with advanced cancer. A dose of 2.0 mg/kg of LErafAON administered twice weekly is tolerated with premedication and does not enhance radiation toxicity in patients. The observation of dose-dependent, infusion-related reactions has led to further modification of the liposomal composition for use in future clinical trials.

A synthetic superoxide dismutase/catalase mimetic EUK-207 mitigates radiation dermatitis and promotes wound healing in irradiated rat skin

PubMed Central

Doctrow, Susan R.; Lopez, Argelia; Schock, Ashley M.; Duncan, Nathan E.; Jourdan, Megan M.; Olasz, Edit B.; Moulder, John E.; Fish, Brian L.; Mäder, Marylou; Lazar, Jozef; Lazarova, Zelmira

2012-01-01

In the event of a radionuclear attack or nuclear accident, the skin would be the first barrier exposed to radiation, though skin injury can progress over days to years following exposure. Chronic oxidative stress has been implicated as being a potential contributor to the progression of delayed radiation-induced injury to skin and other organs. To examine the causative role of oxidative stress in delayed radiation-induced skin injury, including impaired wound healing, we tested a synthetic superoxide dismutase (SOD)/catalase mimetic, EUK-207, in a rat model of combined skin irradiation and wound injury. Administered systemically, beginning 48 h after irradiation, EUK-207 mitigated radiation dermatitis, suppressed indicators of tissue oxidative stress, and enhanced wound healing. Evaluation of gene expression in irradiated skin at 30 days after exposure revealed a significant upregulation of several key genes involved in detoxication of reactive oxygen and nitrogen species. This gene expression pattern was primarily reversed by EUK-207 therapy. These results demonstrate that oxidative stress plays a critical role in the progression of radiation-induced skin injury, and that the injury can be mitigated by appropriate antioxidant compounds administered 48 h after exposure. PMID:23190879

Radiation Segmentectomy versus TACE Combined with Microwave Ablation for Unresectable Solitary Hepatocellular Carcinoma Up to 3 cm: A Propensity Score Matching Study.

PubMed

Biederman, Derek M; Titano, Joseph J; Bishay, Vivian L; Durrani, Raisa J; Dayan, Etan; Tabori, Nora; Patel, Rahul S; Nowakowski, Francis S; Fischman, Aaron M; Kim, Edward

2017-06-01

Purpose To compare the outcomes of radiation segmentectomy (RS) and transarterial chemoembolization (TACE) combined with microwave ablation (MWA) in the treatment of unresectable solitary hepatocellular carcinoma (HCC) up to 3 cm. Materials and Methods This retrospective study was approved by the institutional review board, and the requirement to obtain informed consent was waived. From January 2010 to June 2015, a total of 417 and 235 consecutive patients with HCC underwent RS and TACE MWA, respectively. A cohort of 121 patients who had not previously undergone local-regional therapy (RS, 41; TACE MWA, 80; mean age, 65.4 years; 84 men [69.4%]) and who had solitary HCC up to 3 cm without vascular invasion or metastasis was retrospectively identified. Outcomes analyzed included procedure-related complications, laboratory toxicity levels, imaging response, time to progression (TTP), 90-day mortality, and survival. Propensity score matching was conducted by using a nearest-neighbor algorithm (1:1) to account for pretreatment clinical, laboratory, and imaging covariates. Postmatching statistical analysis was performed with conditional logistic regression for binary outcomes and the stratified log-rank test for time-dependent outcomes. Results Before matching, the complication rate was 8.9% and 4.9% in the TACE MWA and RS groups, respectively (P = .46). The overall complete response (CR) rate was 82.9% for RS and 82.5% for TACE MWA (odds ratio, 1.0; 95% confidence interval [CI]: 0.4, 2.8; P = .95). There were 41 (RS, 11; TACE MWA, 30) instances of progression occurring after an initial CR, of which 10 (24%) were classified as target progression (RS, one; TACE MWA, nine). Median overall TTP was 11.1 months (95% CI: 8.8 months, 25.6 months) in the RS group and 12.1 months (95% CI: 7.7 months, 19.1 months) in the TACE MWA group (P > .99). After matching, the overall CR rate (P = .94), TTP (P = .83), and overall survival (P > .99) were not significantly different between the two groups. The 90-day postoperative mortality rate was 0% in both groups. Conclusion Imaging response and progression outcomes of patients with solitary HCC up to 3 cm treated with RS were not significantly different when compared with those of patients treated with TACE MWA. © RSNA, 2016 Online supplemental material is available for this article.

Biosentinel: Developing a Space Radiation Biosensor

NASA Technical Reports Server (NTRS)

Santa Maria, Sergio R.; Marina, Diana B.; Parra, Macarena P.; Boone, Travis D.; Tan, Ming; Ricco, Antonio J.; Straume, Tore N.; Lusby, Terry C.; Harkness, T.; Reiss-Bubenheim, Debra;

An Experimental and Theoretical Study of Radiative Extinction of Diffusion Flames

NASA Technical Reports Server (NTRS)

Atreya, Arvind

1995-01-01

The objective of this research was to experimentally and theoretically investigate the radiation-induced extinction of gaseous diffusion flames in microgravity. The microgravity conditions were required because radiation-induced extinction is generally not possible in 1-g but is highly likely in microgravity. In 1-g, the flame-generated particulates (e.g. soot) and gaseous combustion products that are responsible for flame radiation, are swept away from the high temperature reaction zone by the buoyancy-induced flow and a steady state is developed. In microgravity, however, the absence of buoyancy-induced flow which transports the fuel and the oxidizer to the combustion zone and removes the hot combustion products from it enhances the flame radiation due to: (1) transient build-up of the combustion products in the flame zone which increases the gas radiation, and (2) longer residence time makes conditions appropriate for substantial amounts of soot to form which is usually responsible for most of the radiative heat loss. Numerical calculations conducted during the course of this work show that even non-radiative flames continue to become "weaker" (diminished burning rate per unit flame area) due to reduced rates of convective and diffusive transport. Thus, it was anticipated that radiative heat loss may eventually extinguish the already "weak" microgravity diffusion flame. While this hypothesis appears convincing and our numerical calculations support it, experiments for a long enough microgravity time could not be conducted during the course of this research to provide an experimental proof. Space shuttle experiments on candle flames show that in an infinite ambient atmosphere, the hemispherical candle flame in microgravity will burn indefinitely. It was hoped that radiative extinction can be experimentally shown by the aerodynamically stabilized gaseous diffusion flames where the fuel supply rate was externally controlled. While substantial progress toward this goal was made during this project, identifying the experimental conditions for which radiative extinction occurs for various fuels requires further study. Details concerning this research which are discussed in published articles are included in the appendices.

Pacific Northwest Laboratory annual report for 1993 to the DOE Office of Energy Research. Part 1: Biomedical Sciences

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lumetta, C.C.; Park, J.F.

1994-03-01

This report summarizes FY 1993 progress in biological and general life sciences research programs conducted for the Department of Energy`s Office of Health and Environmental REsearch (OHER) at Pacific Northwest Laboratory (PNL). This research provides knowledge of fundamental principles necessary to identify, understand, and anticipate the long-term health consequences of exposure to energy-related radiation and chemicals. The Biological Research section contains reports of studies using laboratory animals, in vitro cell systems, and molecular biological systems. This research includes studies of the impact of radiation, radionuclides, and chemicals on biological responses at all levels of biological organization. The General Life Sciencesmore » Research section reports research conducted for the OHER human genome program.« less

2015 Space Radiation Standing Review Panel

NASA Technical Reports Server (NTRS)

Steinberg, Susan

2015-01-01

The 2015 Space Radiation Standing Review Panel (from here on referred to as the SRP) met for a site visit in Houston, TX on December 8 - 9, 2015. The SRP met with representatives from the Space Radiation Element and members of the Human Research Program (HRP) to review the updated research plan for the Risk of Radiation Carcinogenesis Cancer Risk. The SRP also reviewed the newly revised Evidence Reports for the Risk of Acute Radiation Syndromes Due to Solar Particle Events (SPEs) (Acute Risk), the Risk of Acute (In-flight) and Late Central Nervous System Effects from Radiation Exposure (CNS Risk), and the Risk of Cardiovascular Disease and Other Degenerative Tissue Effects from Radiation (Degen Risk), as well as a status update on these Risks. The SRP would like to commend Dr. Simonsen, Dr. Huff, Dr. Nelson, and Dr. Patel for their detailed presentations. The Space Radiation Element did a great job presenting a very large volume of material. The SRP considers it to be a strong program that is well-organized, well-coordinated and generates valuable data. The SRP commended the tissue sharing protocols, working groups, systems biology analysis, and standardization of models. In several of the discussed areas the SRP suggested improvements of the research plans in the future. These include the following: It is important that the team has expanded efforts examining immunology and inflammation as important components of the space radiation biological response. This is an overarching and important focus that is likely to apply to all aspects of the program including acute, CVD, CNS, cancer and others. Given that the area of immunology/inflammation is highly complex (and especially so as it relates to radiation), it warrants the expansion of investigators expertise in immunology and inflammation to work with the individual research projects and also the NASA Specialized Center of Research (NSCORs). Historical data on radiation injury to be entered into the Watson “big data” study must be used with caution. The general scientific issues of reproducibility, details of experimental methods and data analysis from preclinical and basic research laboratories have been raised broadly over the last few years (not specific to this work) and indicate that caution must be applied in the ways these data are used. This pertains to preclinical data and also to phase 3 clinical trials in radiation oncology and medical oncology. Of course, appropriate use and analysis of these “big-data” sets also offer the potential of pinpointing limitations and extracting remaining useful information. Emphasis should be placed on the latter possibility. A key target is risk reduction from radiation exposure. Progress of the entire space program, now moving towards the Mars mission, requires timely answers to key components of human risk, which are known to be complex. Periodic review of progress should be conducted with additional resources directed into achieving critical milestones. Turning the long red bars to yellow and green (or for some risks such as CNS possibly to grey) must be high priority. That such progress will require new science and not engineering means that it should be viewed in a knowledge-based light. The technology-based aspects of engineering issues are certainly as important, however, science and knowledge-based problems are solved in a different way than engineering. Timelines for engineering are more predictable, while for science, progress can be methodical with occasional major incremental findings that can rapidly change the rate of progress. As opportunities for rapid incremental changes arise, periodic enhancement of investment is strongly recommended to enable such new knowledge to be quickly and efficiently exploited. Collaborations and linkages with National Institute of Allergy and Infectious Diseases (NIAID), the Biomedical Advanced Research and Development Authority (BARDA) and the Department of Defense (DoD) are in place and more are encouraged, where possible, with the radiation injury and medical countermeasure studies. This could include utilizing some of their animal model testing contracts to facilitate obtaining results using common platforms. Such approach will facilitate the comparison of results among laboratories, and will facilitate and accelerate the development of medical countermeasures. It is particularly noteworthy that the NASA Space Radiation Element is reaching out to the Multidisciplinary European Low Dose Initiative (MELODI) platform coordinating low dose radiation risk research, and to other international agencies that are studying low dose radiation effects in an effort to fill the void generated by the cancelation of the Department of Energy (DOE) low dose radiation program. While NASA is working actively with NIAID and BARDA to integrate their relevant findings of radiation mitigator investigations to NASA programs, the committee notes its disappointment that the United States currently lacks a dedicated low dose radiation program with clear mechanistic orientation and aimed at the quantification and mitigation of human radiation risk on Earth. This void gives to the NASA Space Radiation Program Element special societal value, but also makes its overall design more challenging.

Radiation injury to the temporal bone

DOE Office of Scientific and Technical Information (OSTI.GOV)

Guida, R.A.; Finn, D.G.; Buchalter, I.H.

1990-01-01

Osteoradionecrosis of the temporal bone is an unusual sequela of radiation therapy to the head and neck. Symptoms occur many years after the radiation is administered, and progression of the disease is insidious. Hearing loss (sensorineural, conductive, or mixed), otalgia, otorrhea, and even gross tissue extrusion herald this condition. Later, intracranial complications such as meningitis, temporal lobe or cerebellar abscess, and cranial neuropathies may occur. Reported here are five cases of this rare malady representing varying degrees of the disease process. They include a case of radiation-induced necrosis of the tympanic ring with persistent squamous debris in the external auditorymore » canal and middle ear. Another case demonstrates the progression of radiation otitis media to mastoiditis with bony sequestration. Further progression of the disease process is seen in a third case that evolved into multiple cranial neuropathies from skull base destruction. Treatment includes systemic antibiotics, local wound care, and debridement in cases of localized tissue involvement. More extensive debridement with removal of sequestrations, abscess drainage, reconstruction with vascularized tissue from regional flaps, and mastoid obliteration may be warranted for severe cases. Hyperbaric oxygen therapy has provided limited benefit.« less

Calculation of the acoustic radiation force on coated spherical shells in progressive and standing plane waves.

PubMed

Mitri, F G

2006-07-01

In this paper, analytical equations are derived for the time-averaged radiation force induced by progressive and standing acoustic waves incident on elastic spherical shells covered with a layer of viscoelastic and sound-absorbing material. The fluid surrounding the shells is considered compressible and nonviscous. The incident field is assumed to be moderate so that the scattered field from the shells is taken to linear approximation. The analytical results are illustrated by means of a numerical example in which the radiation force function curves are displayed, with particular emphasis on the coating thickness and the content of the hollow region of the shells. The fluid-loading on the radiation force function curves is analysed as well. This study attempts to generalize the various treatments of radiation force due to both progressive and standing waves on spherically-shaped structures immersed in ideal fluids. The results show that various ways can be effectively used for damping resonance peaks, such as by changing the fluid in the interior hollow region of the shells or by changing the coating thickness.

A ruthenium polypyridyl intercalator stalls DNA replication forks, radiosensitizes human cancer cells and is enhanced by Chk1 inhibition

NASA Astrophysics Data System (ADS)

Gill, Martin R.; Harun, Siti Norain; Halder, Swagata; Boghozian, Ramon A.; Ramadan, Kristijan; Ahmad, Haslina; Vallis, Katherine A.

2016-08-01

Ruthenium(II) polypyridyl complexes can intercalate DNA with high affinity and prevent cell proliferation; however, the direct impact of ruthenium-based intercalation on cellular DNA replication remains unknown. Here we show the multi-intercalator [Ru(dppz)2(PIP)]2+ (dppz = dipyridophenazine, PIP = 2-(phenyl)imidazo[4,5-f][1,10]phenanthroline) immediately stalls replication fork progression in HeLa human cervical cancer cells. In response to this replication blockade, the DNA damage response (DDR) cell signalling network is activated, with checkpoint kinase 1 (Chk1) activation indicating prolonged replication-associated DNA damage, and cell proliferation is inhibited by G1-S cell-cycle arrest. Co-incubation with a Chk1 inhibitor achieves synergistic apoptosis in cancer cells, with a significant increase in phospho(Ser139) histone H2AX (γ-H2AX) levels and foci indicating increased conversion of stalled replication forks to double-strand breaks (DSBs). Normal human epithelial cells remain unaffected by this concurrent treatment. Furthermore, pre-treatment of HeLa cells with [Ru(dppz)2(PIP)]2+ before external beam ionising radiation results in a supra-additive decrease in cell survival accompanied by increased γ-H2AX expression, indicating the compound functions as a radiosensitizer. Together, these results indicate ruthenium-based intercalation can block replication fork progression and demonstrate how these DNA-binding agents may be combined with DDR inhibitors or ionising radiation to achieve more efficient cancer cell killing.

A ruthenium polypyridyl intercalator stalls DNA replication forks, radiosensitizes human cancer cells and is enhanced by Chk1 inhibition.

PubMed

Gill, Martin R; Harun, Siti Norain; Halder, Swagata; Boghozian, Ramon A; Ramadan, Kristijan; Ahmad, Haslina; Vallis, Katherine A

2016-08-25

Ruthenium(II) polypyridyl complexes can intercalate DNA with high affinity and prevent cell proliferation; however, the direct impact of ruthenium-based intercalation on cellular DNA replication remains unknown. Here we show the multi-intercalator [Ru(dppz)2(PIP)](2+) (dppz = dipyridophenazine, PIP = 2-(phenyl)imidazo[4,5-f][1,10]phenanthroline) immediately stalls replication fork progression in HeLa human cervical cancer cells. In response to this replication blockade, the DNA damage response (DDR) cell signalling network is activated, with checkpoint kinase 1 (Chk1) activation indicating prolonged replication-associated DNA damage, and cell proliferation is inhibited by G1-S cell-cycle arrest. Co-incubation with a Chk1 inhibitor achieves synergistic apoptosis in cancer cells, with a significant increase in phospho(Ser139) histone H2AX (γ-H2AX) levels and foci indicating increased conversion of stalled replication forks to double-strand breaks (DSBs). Normal human epithelial cells remain unaffected by this concurrent treatment. Furthermore, pre-treatment of HeLa cells with [Ru(dppz)2(PIP)](2+) before external beam ionising radiation results in a supra-additive decrease in cell survival accompanied by increased γ-H2AX expression, indicating the compound functions as a radiosensitizer. Together, these results indicate ruthenium-based intercalation can block replication fork progression and demonstrate how these DNA-binding agents may be combined with DDR inhibitors or ionising radiation to achieve more efficient cancer cell killing.

Impact of tumor size on outcome after stereotactic body radiation therapy for inoperable hepatocellular carcinoma

PubMed Central

Kuo, Hsing-Tao; Que, Jenny; Lin, Li-Ching; Yang, Ching-Chieh; Koay, Lok-Beng; Lin, Chia-Hui

2017-01-01

Abstract Stereotactic body radiation therapy (SBRT) for inoperable hepatocellular carcinoma (HCC) offers excellent local control rates. This study retrospectively analyzed the influence of different tumor size on treatment outcomes after SBRT. Between December 2008 and February 2014, 141 HCC patients were treated with Cyberknife SBRT. Patients were divided into 3 groups namely small tumors (≤4 cm), intermediate-sized (>4–<10 cm), and large (≥10 cm) tumors. Treatment outcomes, prognoses, and safety at each tumor size were compared and analyzed. A total of 52 patients with small tumors, 55 with intermediate tumors, and 34 patients with large tumors were retrospectively analyzed with a median follow-up of 16 months. Objective responses were achieved at 96.15%, 90.90%, and 76.47% for small, intermediate, and large tumors, respectively (P ≤ .0001) and the 3-year local control rates were 97.85%, 71.99%, and 82.14%, respectively (P = .0035). The 3-year overall survival rates were 50.26%, 45.29%, and 33.38% for small, intermediate, and large tumors, respectively (P = .3757). No significant differences were found in overall-survival, intra-hepatic recurrence free survival, disease-progression free survival, or distant metastasis-free survival. SBRT offers the best effective local control rate and response rate for small HCCs. However, tumor size did not significantly affect the overall survival rate, intra-hepatic recurrence free rate, or disease-progression free rate. PMID:29390360

Intensity-modulated radiation therapy followed by GDP chemotherapy for newly diagnosed stage I/II extranodal natural killer/T cell lymphoma, nasal type.

PubMed

Huang, Yu; Yang, Jianliang; Liu, Peng; Zhou, Shengyu; Gui, Lin; He, Xiaohui; Qin, Yan; Zhang, Changgong; Yang, Sheng; Xing, Puyuan; Sun, Yan; Shi, Yuankai

2017-09-01

Extranodal natural killer (NK)/T cell lymphoma, nasal type (ENKTL) is an aggressive non-Hodgkin lymphoma and the majority of ENKTL cases are diagnosed at the localized stage. Radiotherapy in combination with chemotherapy has been used for localized ENKTL, but the optimal combination treatment modality and the best first-line chemotherapy regimen have not been defined. In this retrospective study, 44 patients with newly diagnosed, stages I/II ENKTL were enrolled and received intensity-modulated radiation therapy (IMRT, 50-56 Gy) followed by GDP (gemcitabine, dexamethasone, and cisplatin) chemotherapy. The median number of chemotherapy cycles per patient was 4 (range, 2-6 cycles). At the end of treatment, the overall response rate was 95% (42/44), including 39 patients (89%) who attained complete response. Two patients developed systemic progression after IMRT. With a median follow-up of 37.5 months, the 3-year overall survival (OS) rate and progression-free survival (PFS) rate were 85% (95% CI, 74 to 96%) and 77% (95% CI, 64 to 91%), respectively. Locoregional and systemic failure rates for this treatment were 9% (4/44) and 14% (6/44), respectively. The most common grades 3 to 4 adverse events included leukopenia (37%), neutropenia (34%), and mucositis (25%). No treatment-related deaths were observed. This study suggested high efficacy and low toxicity of IMRT followed by GDP regimen chemotherapy for newly diagnosed stage I/II ENKTL patients. These results require further investigation in prospective trials.

Radiative Cooling: Principles, Progress, and Potentials

PubMed Central

Hossain, Md. Muntasir

2016-01-01

The recent progress on radiative cooling reveals its potential for applications in highly efficient passive cooling. This approach utilizes the maximized emission of infrared thermal radiation through the atmospheric window for releasing heat and minimized absorption of incoming atmospheric radiation. These simultaneous processes can lead to a device temperature substantially below the ambient temperature. Although the application of radiative cooling for nighttime cooling was demonstrated a few decades ago, significant cooling under direct sunlight has been achieved only recently, indicating its potential as a practical passive cooler during the day. In this article, the basic principles of radiative cooling and its performance characteristics for nonradiative contributions, solar radiation, and atmospheric conditions are discussed. The recent advancements over the traditional approaches and their material and structural characteristics are outlined. The key characteristics of the thermal radiators and solar reflectors of the current state‐of‐the‐art radiative coolers are evaluated and their benchmarks are remarked for the peak cooling ability. The scopes for further improvements on radiative cooling efficiency for optimized device characteristics are also theoretically estimated. PMID:27812478

Photovoltaic cells and photodetectors made with semiconductor polymers: recent progress

NASA Astrophysics Data System (ADS)

Yu, Gang; Srdanov, Gordana; Wang, Hailiang; Cao, Yong; Heeger, Alan J.

2000-05-01

In this presentation, we discuss recent progress on polymer photovoltaic cells and polymer photodetectors. By improving the fill-factor of polymer photovoltaic cells, the energy conversion efficiency was improved significantly to over 4 percent. Such high efficiency polymer photovoltaic cells are promising for many applications including e-papers, e-books and smart-windows. Polymer photodetectors with similar device configuration show high photosensitivity, low dark current, large dynamic range, linear intensity dependence, low noise level and fast response time. These parameters are comparable to or even better than their inorganic counterparts. The advantages of low manufacturing cost, large detection area, and easy hybridization and integration with other electronic or optical components make them promising for a variety of applications including chemical/biomedical analysis, full-color digital image sensing and high energy radiation detection.

Neoadjuvant therapy for organ preservation in head and neck cancer.

PubMed

Urba, S G; Wolf, G T; Bradford, C R; Thornton, A F; Eisbruch, A; Terrell, J E; Carpenter, V; Miller, T; Tang, G; Strawderman, M

2000-12-01

We designed two sequential trials of induction chemotherapy followed by definitive radiation in patients with potentially resectable head and neck cancer to determine whether organ preservation is feasible without apparent compromise of survival Study Design Both trials were Phase II studies. Two clinical trials were conducted sequentially at the University of Michigan. Fifty-two patients enrolled in the first study and were treated with a planned three cycles of carboplatin and 5-fluorouracil. Patients who achieved at least 50% reduction in the size of the primary tumor received definitive radiation therapy, to a dose of 6600 to 7380 cGy. Patients with minimal response or progression had immediate salvage surgery. Thirty-seven patients enrolled in the second trial, in which the chemotherapy consisted of carboplatin, 5-fluororuracil, and leukovorin. Responders were treated with accelerated radiation therapy, to a total dose of 7120 cGy delivered in 41 fractions over 5.5 weeks. Toxicity and response were similar in both trials; therefore, the results are reported first separately and then combined for all 89 patients. Tumor sites included: oropharynx, 55 patients; hypopharynx, 34 patients. Eighty-three percent of patients tolerated all three cycles of chemotherapy and toxicity was mild. Response to chemotherapy was: 48% complete response at the primary tumor site, and 34% partial response at the primary tumor site. Initial organ preservation at individual tumor sites was: oropharynx, 58%; hypopharynx, 59%. Median survival was 28 months, and survival at 3 and 5 years was 40% and 24%, respectively. These two regimens were well tolerated, and survival did not appear to be compromised by organ preservation treatment compared with historical controls. This approach warrants further investigation, particularly in those patients for whom surgery could be functionally debilitating.

Protein Kinases and Transcription Factors Activation in Response to UV-Radiation of Skin: Implications for Carcinogenesis

PubMed Central

López-Camarillo, César; Ocampo, Elena Aréchaga; Casamichana, Mavil López; Pérez-Plasencia, Carlos; Álvarez-Sánchez, Elizbeth; Marchat, Laurence A.

2012-01-01

Solar ultraviolet (UV) radiation is an important environmental factor that leads to immune suppression, inflammation, photoaging, and skin carcinogenesis. Here, we reviewed the specific signal transduction pathways and transcription factors involved in the cellular response to UV-irradiation. Increasing experimental data supporting a role for p38, MAPK, JNK, ERK1/2, and ATM kinases in the response network to UV exposure is discussed. We also reviewed the participation of NF-κB, AP-1, and NRF2 transcription factors in the control of gene expression after UV-irradiation. In addition, we discussed the promising chemotherapeutic intervention of transcription factors signaling by natural compounds. Finally, we focused on the review of data emerging from the use of DNA microarray technology to determine changes in global gene expression in keratinocytes and melanocytes in response to UV treatment. Efforts to obtain a comprehensive portrait of the transcriptional events regulating photodamage of intact human epidermis after UV exposure reveals the existence of novel factors participating in UV-induced cell death. Progress in understanding the multitude of mechanisms induced by UV-irradiation could lead to the potential use of protein kinases and novel proteins as specific targets for the prevention and control of skin cancer. PMID:22312244

Recent advances in the management of radiation colitis

PubMed Central

Kountouras, Jannis; Zavos, Christos

2008-01-01

Radiation colitis, an insidious, progressive disease of increasing frequency, develops 6 mo to 5 years after regional radiotherapy for malignancy, owing to the deleterious effects of the latter on the colon and the small intestine. When dealing with radiation colitis and its complications, the most conservative modality should be employed because the areas of intestinal injury do not tend to heal. Acute radiation colitis is mostly self-limited, and usually, only supportive management is required. Chronic radiation colitis, a poorly predictable progressive disease, is considered as a precancerous lesion; radiation-associated malignancy has a tendency to be diagnosed at an advanced stage and to bear a dismal prognosis. Therefore, management of chronic radiation colitis remains a major challenge owing to the progressive evolution of the disease, including development of fibrosis, endarteritis, edema, fragility, perforation, partial obstruction, and cancer. Patients are commonly managed conservatively. Surgical intervention is difficult to perform because of the extension of fibrosis and alterations in the gut and mesentery, and should be reserved for intestinal obstruction, perforation, fistulas, and severe bleeding. Owing to the difficulty in managing the complications of acute and chronic radiation colitis, particular attention should be focused onto the prevention strategies. Uncovering the fibrosis mechanisms and the molecular events underlying radiation bowel disease could lead to the introduction of new therapeutic and/or preventive approaches. A variety of novel, mostly experimental, agents have been used mainly as a prophylaxis, and improvements have been made in radiotherapy delivery, including techniques to reduce the amount of exposed intestine in the radiation field, as a critical strategy for prevention. PMID:19109862

Radiation effects on Brassica seeds and seedlings

NASA Astrophysics Data System (ADS)

Deoli, Naresh; Hasenstein, Karl H.

2016-07-01

Space radiation consists of high energy charged particles and affects biological systems, but because of its stochastic, non-directional nature is difficult to replicate on Earth. Radiation damages biological systems acutely at high doses or cumulatively at low doses through progressive changes in DNA organization. These damages lead to death or cause of mutations. While radiation biology typically focuses on mammalian or human systems, little is known as to how radiation affects plants. In addition, energetic ion beams are widely used to generate new mutants in plants considering their high-LET (Linear Energy Transfer) as compared to gamma rays and X-rays. Understanding the effect of ionizing radiation on plant provides a basis for studying effects of radiation on biological systems and will help mitigate (space) radiation damage in plants. We exposed dry and imbibed Brassica rapa seeds and seedling roots to proton beams of varying qualities and compared the theoretical penetration range of different energy levels with observable growth response. We used 1, 2 and 3 MeV protons in air at the varying fluences to investigate the effect of direct irradiation on the seeds (1012 - 1015 ions/cm2) and seedlings (1013 ions/cm2). The range of protons in the tissue was calculated using Monte-Carlo based SRIM (Stopping and Range of Ions in Matter) software. The simulation and biological results indicate that ions did not penetrate the tissue of dry or hydrated seeds at all used ion energies. Therefore the entire energy was transferred to the treated tissue. Irradiated seeds were germinated vertically under dim light and roots growth was observed for two days after imbibition. The LD50 of the germination was about 2×1014 ions/cm2 and about 5×1014 ions/cm2 for imbibed and dry seeds, respectively. Since seedlings are most sensitive to gravity, the change in gravitropic behavior is a convenient means to assess radiation damage on physiological responses other than direct tissue damage. We compared curvature in untreated with irradiated roots and measured the inhibition of curvature at 2×1013 - 8×1013 ions/cm2. Despite greater mass of imbibed seeds, the dose-response curve showed greater sensitivity of imbibed than for dry seeds. In addition, germination rate was found to be strongly dependent on ion beam current, at least for 3 MeV protons. Our data show that weak ionizing particles (low MeV protons) are suitable to study radiation effects and seedlings are a useful biological systems to study space radiation. Supported by NASA grant NNX13AN05A.

The Influence of Radiation in Altering the Incidence of Mutations in Drosophila. Progress Report on the Past Twelve Months and Renewal Proposal for the Period September 15, 1960 to September 14, 1961

DOE R&D Accomplishments Database

Muller, H. J.

1960-05-31

Progress is reported in studies on the effects of radiation on the incidence of mutations in Drosophila. Results are summarized and the findings are interpreted. A list is included of papers published during the period. (C.H.)

In situ gene expression profiling of the thermoacidophilic alga Cyanidioschyzon in relation to visible and ultraviolet irradiance.

PubMed

Skorupa, Dana J; Castenholz, Richard W; Mazurie, Aurélien; Carey, Charles; Rosenzweig, Frank; McDermott, Timothy R

2014-06-01

Ultraviolet and high-intensity visible radiation generate reactive intermediates that damage phototrophic microorganisms. In Yellowstone National Park, the thermoacidophilic alga Cyanidioschyzon exhibits an annual seasonal biomass fluctuation referred to as 'mat decline', where algal viability decreases as ultraviolet and visible irradiances increase during summer. We examined the role irradiance might play in mat decline using irradiance filters that uncouple ultraviolet and visible effects along with custom microarrays to study gene expression in situ. Of the 6507 genes, 88% showed no response to ultraviolet or visible, implying that at the biomolecular level, these algae inhabit a chemostat-like environment and is consistent with the near constant aqueous chemistry measured. The remaining genes exhibited expression changes linked to ultraviolet exposure, to increased visible radiation, or to the apparent combined effects of ultraviolet and visible. Expression of DNA repetitive elements was synchronized, being repressed by visible but also influenced by ultraviolet. At highest irradiance levels, these algae reduced transcription of genes encoding functions involved with DNA replication, photosynthesis and cell cycle progression but exhibited an uptick in activities related to repairing DNA damage. This corroborates known physiological responses to ultraviolet and visible radiation, and leads us to provisionally conclude that mat decline is linked to photoinhibition. © 2013 Society for Applied Microbiology and John Wiley & Sons Ltd.

Neurodegeneration and adaptation in response to low-dose photon irradiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Limoli, Charles L.

2014-10-27

Neural stem and precursor cells (i.e. multipotent neural cells) are concentrated in the neurogenic regions of the brain (hippocampal dentate gyrus, subventricular zones), and considerable evidence suggests that these cells are important in mediating the stress response of the CNS after damage from ionizing radiation. The capability of these cells to proliferate, migrate and differentiate (i.e. to undergo neurogenesis) suggests they can participate in the repair and maintenance of CNS functions by replacing brain cells damaged or depleted due to irradiation. Importantly, we have shown that multipotent neural cells are markedly sensitive to irradiation and oxidative stress, insults that compromisemore » neurogenesis and hasten the onset and progression of degenerative processes that are likely to have an adverse impact on cognition. Our past and current work has demonstrated that relatively low doses of radiation cause a persistent (weeks-months) oxidative stress in multipotent neural cells that can elicit a range of degenerative sequelae in the CNS. Therefore, our project is focused on determining the extent that endogenous and redox sensitive multipotent neural cells represent important radioresponsive targets for low dose radiation effects. We hypothesize that the activation of redox sensitive signaling can trigger radioadaptive changes in these cells that can be either harmful or beneficial to overall cognitive health.« less

Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer.

PubMed

Antonia, Scott J; Villegas, Augusto; Daniel, Davey; Vicente, David; Murakami, Shuji; Hui, Rina; Yokoi, Takashi; Chiappori, Alberto; Lee, Ki H; de Wit, Maike; Cho, Byoung C; Bourhaba, Maryam; Quantin, Xavier; Tokito, Takaaki; Mekhail, Tarek; Planchard, David; Kim, Young-Chul; Karapetis, Christos S; Hiret, Sandrine; Ostoros, Gyula; Kubota, Kaoru; Gray, Jhanelle E; Paz-Ares, Luis; de Castro Carpeño, Javier; Wadsworth, Catherine; Melillo, Giovanni; Jiang, Haiyi; Huang, Yifan; Dennis, Phillip A; Özgüroğlu, Mustafa

2017-11-16

Most patients with locally advanced, unresectable, non-small-cell lung cancer (NSCLC) have disease progression despite definitive chemoradiotherapy (chemotherapy plus concurrent radiation therapy). This phase 3 study compared the anti-programmed death ligand 1 antibody durvalumab as consolidation therapy with placebo in patients with stage III NSCLC who did not have disease progression after two or more cycles of platinum-based chemoradiotherapy. We randomly assigned patients, in a 2:1 ratio, to receive durvalumab (at a dose of 10 mg per kilogram of body weight intravenously) or placebo every 2 weeks for up to 12 months. The study drug was administered 1 to 42 days after the patients had received chemoradiotherapy. The coprimary end points were progression-free survival (as assessed by means of blinded independent central review) and overall survival (unplanned for the interim analysis). Secondary end points included 12-month and 18-month progression-free survival rates, the objective response rate, the duration of response, the time to death or distant metastasis, and safety. Of 713 patients who underwent randomization, 709 received consolidation therapy (473 received durvalumab and 236 received placebo). The median progression-free survival from randomization was 16.8 months (95% confidence interval [CI], 13.0 to 18.1) with durvalumab versus 5.6 months (95% CI, 4.6 to 7.8) with placebo (stratified hazard ratio for disease progression or death, 0.52; 95% CI, 0.42 to 0.65; P<0.001); the 12-month progression-free survival rate was 55.9% versus 35.3%, and the 18-month progression-free survival rate was 44.2% versus 27.0%. The response rate was higher with durvalumab than with placebo (28.4% vs. 16.0%; P<0.001), and the median duration of response was longer (72.8% vs. 46.8% of the patients had an ongoing response at 18 months). The median time to death or distant metastasis was longer with durvalumab than with placebo (23.2 months vs. 14.6 months; P<0.001). Grade 3 or 4 adverse events occurred in 29.9% of the patients who received durvalumab and 26.1% of those who received placebo; the most common adverse event of grade 3 or 4 was pneumonia (4.4% and 3.8%, respectively). A total of 15.4% of patients in the durvalumab group and 9.8% of those in the placebo group discontinued the study drug because of adverse events. Progression-free survival was significantly longer with durvalumab than with placebo. The secondary end points also favored durvalumab, and safety was similar between the groups. (Funded by AstraZeneca; PACIFIC ClinicalTrials.gov number, NCT02125461 .).

The efficacy of concurrent cisplatin and 5-flurouracil chemotherapy and radiation therapy for locally advanced cancer of the uterine cervix

PubMed Central

Choi, Il Jung; Park, Eunku Seul; Han, Myung Seok; Choi, Youngmin; Je, Goo Hwa; Kim, Hyun Ho

2008-01-01

Objective To evaluate the efficacy of concurrent chemoradiation (CCRT) using 5-flurouracil (5-FU) and cisplatin for locally advanced cervical cancer. Methods We reviewed the medical records of 57 patients with locally advanced cervical cancer (stage IIB-IVA and bulky IB2-IIA tumor) who underwent the CCRT at Dong-A University Hospital from January 1997 to June 2007. The CCRT consisted of 5-FU, cisplatin and pelvic radiation. Every three weeks, 75 mg/m2 cisplatin was administered on the first day of each cycle and 5-FU was infused at the dose of 1,000 mg/m2/d from the second day to the fifth day of each cycle. Radiation was administered to the pelvis at a daily dose of 1.8 Gy for five days per week until a medium accumulated dose reached to 50.4 Gy. If necessary, the radiation field was extended to include paraaortic lymph nodes. Consolidation chemotherapy was performed using 5-FU and cisplatin. Results Fifty-seven patients were enrolled and the median follow-up duration was 53 months (range 7-120 months). The overall response rate was 91.5% (74% complete response and 17.5% partial response). The 5-year overall survival and 3-year progression free survival rates were 69.4% and 74.9%, respectively. During the follow-up period (median 23 months, range 7-60 months), fourteen patients were diagnosed as recurrent disease. Conclusion CCRT with 5-FU and cisplatin which is the primary treatment for patients with locally advanced cervical cancer was effective and well tolerated. PMID:19471554

Dabrafenib and Trametinib Treatment in Patients With Locally Advanced or Metastatic BRAF V600–Mutant Anaplastic Thyroid Cancer

PubMed Central

Subbiah, Vivek; Kreitman, Robert J.; Wainberg, Zev A.; Cho, Jae Yong; Schellens, Jan H.M.; Soria, Jean Charles; Wen, Patrick Y.; Zielinski, Christoph; Cabanillas, Maria E.; Urbanowitz, Gladys; Mookerjee, Bijoyesh; Wang, Dazhe; Rangwala, Fatima

2018-01-01

Purpose We report the efficacy and safety of dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) combination therapy in BRAF V600E–mutated anaplastic thyroid cancer, a rare, aggressive, and highly lethal malignancy with poor patient outcomes and no systemic therapies with clinical benefit. Methods In this phase II, open-label trial, patients with predefined BRAF V600E–mutated malignancies received dabrafenib 150 mg twice daily and trametinib 2 mg once daily until unacceptable toxicity, disease progression, or death. The primary end point was investigator-assessed overall response rate. Secondary end points included duration of response, progression-free survival, overall survival, and safety. Results Sixteen patients with BRAF V600E–mutated anaplastic thyroid cancer were evaluable (median follow-up, 47 weeks; range, 4 to 120 weeks). All patients had received prior radiation treatment and/or surgery, and six had received prior systemic therapy. The confirmed overall response rate was 69% (11 of 16; 95% CI, 41% to 89%), with seven ongoing responses. Median duration of response, progression-free survival, and overall survival were not reached as a result of a lack of events, with 12-month estimates of 90%, 79%, and 80%, respectively. The safety population was composed of 100 patients who were enrolled with seven rare tumor histologies. Common adverse events were fatigue (38%), pyrexia (37%), and nausea (35%). No new safety signals were detected. Conclusion Dabrafenib plus trametinib is the first regimen demonstrated to have robust clinical activity in BRAF V600E–mutated anaplastic thyroid cancer and was well tolerated. These findings represent a meaningful therapeutic advance for this orphan disease. PMID:29072975

Dabrafenib and Trametinib Treatment in Patients With Locally Advanced or Metastatic BRAF V600-Mutant Anaplastic Thyroid Cancer.

PubMed

Subbiah, Vivek; Kreitman, Robert J; Wainberg, Zev A; Cho, Jae Yong; Schellens, Jan H M; Soria, Jean Charles; Wen, Patrick Y; Zielinski, Christoph; Cabanillas, Maria E; Urbanowitz, Gladys; Mookerjee, Bijoyesh; Wang, Dazhe; Rangwala, Fatima; Keam, Bhumsuk

2018-01-01

Purpose We report the efficacy and safety of dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) combination therapy in BRAF V600E-mutated anaplastic thyroid cancer, a rare, aggressive, and highly lethal malignancy with poor patient outcomes and no systemic therapies with clinical benefit. Methods In this phase II, open-label trial, patients with predefined BRAF V600E-mutated malignancies received dabrafenib 150 mg twice daily and trametinib 2 mg once daily until unacceptable toxicity, disease progression, or death. The primary end point was investigator-assessed overall response rate. Secondary end points included duration of response, progression-free survival, overall survival, and safety. Results Sixteen patients with BRAF V600E-mutated anaplastic thyroid cancer were evaluable (median follow-up, 47 weeks; range, 4 to 120 weeks). All patients had received prior radiation treatment and/or surgery, and six had received prior systemic therapy. The confirmed overall response rate was 69% (11 of 16; 95% CI, 41% to 89%), with seven ongoing responses. Median duration of response, progression-free survival, and overall survival were not reached as a result of a lack of events, with 12-month estimates of 90%, 79%, and 80%, respectively. The safety population was composed of 100 patients who were enrolled with seven rare tumor histologies. Common adverse events were fatigue (38%), pyrexia (37%), and nausea (35%). No new safety signals were detected. Conclusion Dabrafenib plus trametinib is the first regimen demonstrated to have robust clinical activity in BRAF V600E-mutated anaplastic thyroid cancer and was well tolerated. These findings represent a meaningful therapeutic advance for this orphan disease.

Systems Biology Model of Interactions between Tissue Growth Factors and DNA Damage Pathways: Low Dose Response and Cross-Talk in TGFβ and ATM Signaling

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cucinotta, Francis A

The etiology of radiation carcinogenesis has been described in terms of aberrant changes that span several levels of biological organization. Growth factors regulate many important cellular and tissue functions including apoptosis, differentiation and proliferation. A variety of genetic and epigenetic changes of growth factors have been shown to contribute to cancer initiation and progression. It is known that cellular and tissue damage to ionizing radiation is in part initiated by the production of reactive oxygen species, which can activate cytokine signaling, and the DNA damage response pathways, most notably the ATM signaling pathway. Recently, the transforming growth factor β (TGFβ)more » pathway has been shown to regulate or directly interact with the ATM pathway in the response to radiation. The relevance of this interaction with the ATM pathway is not known although p53 becomes phosphorylated and DNA damage responses are involved. However, growth factor interactions with DNA damage responses have not been elucidated particularly at low doses, and further characterization of their relationship to cancer processes is warranted. Our goal will be to use a systems biology approach to mathematically and experimentally describe the low-dose responses and cross-talk between the ATM and TGFβ pathways initiated by low- and high-LET radiation. We will characterize ATM and TGFβ signaling in epithelial and fibroblast cells using 2D models and ultimately extending to 3D organotypic cell culture models to begin to elucidate possible differences that may occur for different cell types and/or inter-cellular communication. We will investigate the roles of the Smad and Activating transcription factor 2 (ATF2) proteins as the potential major contributors to crosstalk between the TGFβ and ATM pathways, and links to cell cycle control and/or the DNA damage response, and potential differences in their responses at low and high doses. We have developed various experimental approaches to apply to these problems using confocal microscopy and flow cytometry to detail changes at low dose/dose-rate in order to understand individual cell responses, and will establish our mathematical models based on the experimental findings resulting from changes in DNA repair, apoptosis and proliferation.« less

Systems Biology Model of Interactions Between Tissue Growth Factors and DNA Damage Pathways: Low Dose Response and Cross-Talk in TGFbeta and ATM Signaling

DOE Office of Scientific and Technical Information (OSTI.GOV)

O'Neill, Peter; Anderson, Jennifer

The etiology of radiation carcinogenesis has been described in terms of aberrant changes that span several levels of biological organization. Growth factors regulate many important cellular and tissue functions including apoptosis, differentiation and proliferation. A variety of genetic and epigenetic changes of growth factors have been shown to contribute to cancer initiation and progression. It is known that cellular and tissue damage to ionizing radiation is in part initiated by the production of reactive oxygen species, which can activate cytokine signaling, and the DNA damage response pathways, most notably the ATM signaling pathway. Recently the transforming growth factor β (TGFβ)more » pathway has been shown to regulate or directly interact with the ATM pathway in the response to radiation. The relevance of this interaction with the ATM pathway is not known although p53 becomes phosphorylated and DNA damage responses are involved. However, growth factor interactions with DNA damage responses have not been elucidated particularly at low doses and further characterization of their relationship to cancer processes is warranted. Our goal will be to use a systems biology approach to mathematically and experimentally describe the low dose responses and cross-talk between the ATM and TGFβ pathways initiated by low and high LET radiation. We will characterize ATM and TGFβ signaling in epithelial and fibroblast cells using 2D models and ultimately extending to 3D organotypic cell culture models to begin to elucidate possible differences that may occur for different cell types and/or inter-cellular communication. We will investigate the roles of the Smad and Activating transcription factor 2 (ATF2) proteins as the potential major contributors to cross- talk between the TGFβ and ATM pathways, and links to cell cycle control and/or the DNA damage response, and potential differences in their responses at low and high doses. We have developed various experimental approaches to apply to these problems using confocal microscopy and flow cytometry to detail changes at low dose/dose-rate in order to understand individual cell responses, and will establish our mathematical models based on the experimental findings resulting from changes in DNA repair, apoptosis and proliferation.« less

Radiation bronchitis and stenosis secondary to high dose rate endobronchial irradiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Speiser, B.L.; Spratling, L.

The purpose of the study was to describe a new clinical entity observed in follow-up bronchoscopies in patients who were treated with high dose rate and medium dose rate remote afterloading brachytherapy of the tracheobronchial tree. Patients were treated by protocol with medium dose rate, 47 patients receiving 1000 cGy at a 5 mm depth times three fractions, high dose rate 144 patients receiving 1000 cGy at a 10 mm depth for three fractions and high dose rate 151 patients receiving cGy at a 10 mm depth for three fractions followed by bronchoscopy. Incidence of this entity was 9% formore » the first group, 12% for the second, and 13% for the third group. Reactions were grade 1 consisting of mild inflammatory response with a partial whitish circumferential membrane in an asymptomatic patient; grade 2, thicker complete white circumferential membrane with cough and/or obstructive problems requiring intervention; grade 3, severe inflammatory response with marked membranous exudate and mild fibrotic reaction; and grade 4 a predominant fibrotic reaction with progressive stenosis. Variables associated with a slightly increased incidence of radiation bronchitis and stenosis included: large cell carcinoma histology, curative intent, prior laser photoresection, and/or concurrent external radiation. Survival was the strongest predictor of the reaction. Radiation bronchitis and stenosis is a new clinical entity that must be identified in bronchial brachytherapy patients and treated appropriately. 23 refs., 3 figs., 7 tabs.« less

microRNA-451a regulates colorectal cancer proliferation in response to radiation.

PubMed

Ruhl, Rebecca; Rana, Shushan; Kelley, Katherine; Espinosa-Diez, Cristina; Hudson, Clayton; Lanciault, Christian; Thomas, Charles R; Liana Tsikitis, V; Anand, Sudarshan

2018-05-03

Colorectal cancer (CRC) is a leading cause of cancer-related death. The biologic response of CRC to standard of care adjuvant therapies such as chemotherapy and radiation are poorly understood. MicroRNAs (miRs) have been shown to affect CRC progression and metastasis. Therefore, we hypothesized that specific miRs modulate CRC response to chemoradiation. In this study, we used miR expression profiling and discovered a set of microRNAs upregulated rapidly in response to either a single 2 Gy dose fraction or a 10 Gy dose of γ-radiation in mouse colorectal carcinoma models. We used gain and loss-of-function studies in 2D and 3Dcell proliferation assays and colony formation assays to understand the role of the top miR candidate from our profiling. We used Student's T-tests for simple comparisons and two-factor ANOVA for evaluating significance. The most upregulated candidate at early time points in our signature, miR-451a inhibited tumor cell proliferation and attenuated surviving fraction in longer-term cultures. Conversely, inhibition of miR-451a increased proliferation, tumorsphere formation, and surviving fraction of tumor cells. Using a bioinformatics approach, we identified four genes, CAB39, EMSY, MEX3C, and EREG, as targets of miR-451a. Transfection of miR-451a decreased both mRNA and protein levels of these targets. Importantly, we found miR-451a expression was high and CAB39, EMSY levels were low in a small subset of rectal cancer patients who had a partial response to chemoradiation when compared to patients that had no response. Finally, analysis of a TCGA colorectal cancer dataset revealed that CAB39 and EMSY are upregulated at the protein level in a significant number of CRC patients. Higher levels of CAB39 and EMSY correlated with poorer overall survival. Taken together, our data indicates miR-451a is induced by radiation and may influence colorectal carcinoma proliferation via CAB39 and EMSY pathways.

Radiation promotes colorectal cancer initiation and progression by inducing senescence-associated inflammatory responses.

PubMed

Kim, S B; Bozeman, R G; Kaisani, A; Kim, W; Zhang, L; Richardson, J A; Wright, W E; Shay, J W

2016-06-30

Proton radiotherapy is becoming more common as protons induce more precise DNA damage at the tumor site with reduced side effects to adjacent normal tissues. However, the long-term biological effects of proton irradiation in cancer initiation compared with conventional photon irradiation are poorly characterized. In this study, using a human familial adenomatous polyposis syndrome susceptible mouse model, we show that whole-body irradiation with protons are more effective in inducing senescence-associated inflammatory responses (SIRs), which are involved in colon cancer initiation and progression. After proton irradiation, a subset of SIR genes (Troy, Sox17, Opg, Faim2, Lpo, Tlr2 and Ptges) and a gene known to be involved in invasiveness (Plat), along with the senescence-associated gene (P19Arf), are markedly increased. Following these changes, loss of Casein kinase Iα and induction of chronic DNA damage and TP53 mutations are increased compared with X-ray irradiation. Proton irradiation also increases the number of colonic polyps, carcinomas and invasive adenocarcinomas. Pretreatment with the non-steroidal anti-inflammatory drug, 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid-ethyl amide (CDDO-EA), reduces proton irradiation-associated SIR and tumorigenesis. Thus exposure to proton irradiation elicits significant changes in colorectal cancer initiation and progression that can be mitigated using CDDO-EA.

University of California, Los Angeles Campus School of Medicine Atomic Energy Project quarterly progress report for period ending March 31, 1952

DOE Office of Scientific and Technical Information (OSTI.GOV)

Warren, S.L.

1952-04-10

The fifteenth quarterly report being submitted for Contract No. AT04-1-GEN-12 is issued in accordance with Service Request Number 1 except for the report of the Alamogordo Section, Code 91810, which is submitted in accordance with the provisions of Service Request Number 2. Work is in progress on continuing existing projects. In addition, new projects have been initiated including the Kinetics and Mechanism of Protein Denaturation (10018); The Effect of Irradiation on the Constituents of Embryonic Serum (30033); and The Use of Controlled Atmospheres for Spectrographic Excitation Sources (40053). Many of the Project units are either wholly or partially completed andmore » the following initial reports are available: Identification of Ferritin in Blood of Dogs Subjected to Radiation from an Atomic Detonation (UCLA-180); The Nutritional Value of Intravenous Tapioca Dextrin in Normal and Irradiated Rabbits (UCLA-181); The-Decarboxylation and Reconstitution of Linoleic Acid (UCLA-183); Preparation and Properties of Thymus Nucleic Acid (UCLA-184); The Radiation Chemistry of Cysteine Solutions Part II. (a) The Action of Sulfite on the Irradiated Solutions; (b) The Effect on Cystine (UCLA-185); A Revolving Specimen Stage for the Electron Microscope (UCLA-178); An Automatic Geiger-Mueller Tube Tester (UCLA-186); The Value of Gamma Radiation Dosimetry in Atomic Warfare Including a Discussion of Practical Dosage Ranges (UCLA-187); and A New Plastic Tape Film Badge Holder (UCLA-189). Two additional reports were issued; one by Dr. Wilbur Selle entitled Attempts to Alter the Response to Ionizing Radiations from the School of Medicine, UCLA (UCLA-176), and two, a restricted distribution report from the Alamogordo Section entitled Field Observations and Preliminary Field Data Obtained by the UCLA Survey Group on Operation Jangle, November 1951 (UCLA-182).« less

Hematopoietic tissue repair under chronic low daily dose irradiation

NASA Astrophysics Data System (ADS)

Seed, T. M.

The capacity of the hematopoietic system to repair constantly accruing cellular damage under chronic, low daily dose gamma irradiation is essential for the maintenance of a functional hematopoietic system, and, in turn, long term survival. In certain individuals, however, such continuous cycles of damage and repair provide an essential inductive environment for selected types of hematopathologies, e.g., myeloid leukemia (ML). In our laboratory we have been studying temporal and causal relationships between hematopoietic capacity, associated repair functions, and propensities for hematologic disease in canines under variable levels of chronic radiation stress (0.3-26.3 cGy d^-1). Results indicate that the maximum exposure rate tolerated by the hematopoietic system is highly individual-specific (three major responding subgroups identified) and is based largely on the degree to which repair capacity, and, in turn, hematopoietic restoration, is augmented under chronic exposure. In low-tolerance individuals (prone to aplastic anemia, subgroup 1), the failure to augment basic repair functions seemingly results in a progressive accumulation of genetic and cellular damage within vital progenitorial marrow compartments (particularly marked within erythroid compartments) that results in loss of reproductive capacity and ultimately in collapse of the hematopoietic system. The high-tolerance individuals (radioaccommodated and either prone- or not prone to ML, subgroup 2 & 3) appear to minimize the accumulating damage effect of daily exposures by extending repair functions, which preserves reproductive integrity and fosters regenerative hematopoietic responses. As the strength of the regenerative response manifests the extent of repair augmentation, the relatively strong response of high-tolerance individuals progressing to patent ML suggests an insufficiency of repair quality rather than repair quantity. The kinetics of these repair-mediated, regenerative hematopoietic responses within the major subgroups are under study and should provide useful insights into the nature of hematopoietic accommodation (or its failure) under greatly extended periods of chronic, low-daily-dose ionizing radiation exposure.

Profiling global kinome signatures of the radioresistant MCF-7/C6 breast cancer cells using MRM-based targeted proteomics.

PubMed

Guo, Lei; Xiao, Yongsheng; Fan, Ming; Li, Jian Jian; Wang, Yinsheng

2015-01-02

Ionizing radiation is widely used in cancer therapy; however, cancer cells often develop radioresistance, which compromises the efficacy of cancer radiation therapy. Quantitative assessment of the alteration of the entire kinome in radioresistant cancer cells relative to their radiosensitive counterparts may provide important knowledge to define the mechanism(s) underlying tumor adaptive radioresistance and uncover novel target(s) for effective prevention and treatment of tumor radioresistance. By employing a scheduled multiple-reaction monitoring analysis in conjunction with isotope-coded ATP affinity probes, we assessed the global kinome of radioresistant MCF-7/C6 cells and their parental MCF-7 human breast cancer cells. We rigorously quantified 120 kinases, of which (1)/3 exhibited significant differences in expression levels or ATP binding affinities. Several kinases involved in cell cycle progression and DNA damage response were found to be overexpressed or hyperactivated, including checkpoint kinase 1 (CHK1), cyclin-dependent kinases 1 and 2 (CDK1 and CDK2), and the catalytic subunit of DNA-dependent protein kinase. The elevated expression of CHK1, CDK1, and CDK2 in MCF-7/C6 cells was further validated by Western blot analysis. Thus, the altered kinome profile of radioresistant MCF-7/C6 cells suggests the involvement of kinases on cell cycle progression and DNA repair in tumor adaptive radioresistance. The unique kinome profiling results also afforded potential effective targets for resensitizing radioresistant cancer cells and counteracting deleterious effects of ionizing radiation exposure.

Systematic Review of Clinical Outcomes Following Various Treatment Options for Patients with Extraabdominal Desmoid Tumors.

PubMed

Smith, Kortnye; Desai, Jayesh; Lazarakis, Smaro; Gyorki, David

2018-06-01

Desmoid tumors (DT) are rare clonal proliferations that arise from mesenchymal cells. These tumors do not metastasize but are locally aggressive, and their growth may lead to significant morbidity. Their clinical course is both variable and unpredictable; tumors may rapidly progress but in other instances remain stable or regress without intervention. To examine current treatment of DT and assist with decision-making at time of presentation. A literature search was conducted of MEDLINE and Cochrane databases for published studies (1995-July 2015) using the search terms fibromatosis aggressive, desmoid with drug therapy, radiation therapy, prevention and control, radiotherapy, surgery, and therapy. Articles were categorized as surgery, radiation, surgery + radiation, systemic therapy, and front-line observation. Articles were included if they reported a retrospective or prospective comparative or observational study with an analyzed sample size of 10 patients or more with confirmed diagnosis of desmoid tumor and described one of the following clinical outcomes: relapse- or progression-free survival, local control rate, response rate. 258 articles were reviewed; following screening for eligibility, 54 were identified; following full-text screen, 31 were included in final evaluation. The control rate for patients treated with a "wait and see" observational approach compared favorably with management with surgery and resulted in disease control rates of between 60 and 92%. Decision-making in this rare tumor is complicated by the range of treatment options available. Our evidence supports use of an upfront observational approach.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bradshaw, Tyler J.; Bowen, Stephen R.; Deveau, Michael A.

Purpose: Imaging biomarkers of resistance to radiation therapy can inform and guide treatment management. Most studies have so far focused on assessing a single imaging biomarker. The goal of this study was to explore a number of different molecular imaging biomarkers as surrogates of resistance to radiation therapy. Methods and Materials: Twenty-two canine patients with spontaneous sinonasal tumors were treated with accelerated hypofractionated radiation therapy, receiving either 10 fractions of 4.2 Gy each or 10 fractions of 5.0 Gy each to the gross tumor volume. Patients underwent fluorodeoxyglucose (FDG)-, fluorothymidine (FLT)-, and Cu(II)-diacetyl-bis(N4-methylthiosemicarbazone) (Cu-ATSM)-labeled positron emission tomography/computed tomography (PET/CT) imaging before therapymore » and FLT and Cu-ATSM PET/CT imaging during therapy. In addition to conventional maximum and mean standardized uptake values (SUV{sub max}; SUV{sub mean}) measurements, imaging metrics providing response and spatiotemporal information were extracted for each patient. Progression-free survival was assessed according to response evaluation criteria in solid tumor. The prognostic value of each imaging biomarker was evaluated using univariable Cox proportional hazards regression. Multivariable analysis was also performed but was restricted to 2 predictor variables due to the limited number of patients. The best bivariable model was selected according to pseudo-R{sup 2}. Results: The following variables were significantly associated with poor clinical outcome following radiation therapy according to univariable analysis: tumor volume (P=.011), midtreatment FLT SUV{sub mean} (P=.018), and midtreatment FLT SUV{sub max} (P=.006). Large decreases in FLT SUV{sub mean} from pretreatment to midtreatment were associated with worse clinical outcome (P=.013). In the bivariable model, the best 2-variable combination for predicting poor outcome was high midtreatment FLT SUV{sub max} (P=.022) in combination with large FLT response from pretreatment to midtreatment (P=.041). Conclusions: In addition to tumor volume, pronounced tumor proliferative response quantified using FLT PET, especially when associated with high residual FLT PET at midtreatment, is a negative prognostic biomarker of outcome in canine tumors following radiation therapy. Neither FDG PET nor Cu-ATSM PET were predictive of outcome.« less

Forecasting of Radiation Belts: Results From the PROGRESS Project.

NASA Astrophysics Data System (ADS)

Balikhin, M. A.; Arber, T. D.; Ganushkina, N. Y.; Walker, S. N.

2017-12-01

Forecasting of Radiation Belts: Results from the PROGRESS Project. The overall goal of the PROGRESS project, funded in frame of EU Horizon2020 programme, is to combine first principles based models with the systems science methodologies to achieve reliable forecasts of the geo-space particle radiation environment.The PROGRESS incorporates three themes : The propagation of the solar wind to L1, Forecast of geomagnetic indices, and forecast of fluxes of energetic electrons within the magnetosphere. One of the important aspects of the PROGRESS project is the development of statistical wave models for magnetospheric waves that affect the dynamics of energetic electrons such as lower band chorus, hiss and equatorial noise. The error reduction ratio (ERR) concept has been used to optimise the set of solar wind and geomagnetic parameters for organisation of statistical wave models for these emissions. The resulting sets of parameters and statistical wave models will be presented and discussed. However the ERR analysis also indicates that the combination of solar wind and geomagnetic parameters accounts for only part of the variance of the emissions under investigation (lower band chorus, hiss and equatorial noise). In addition, advances in the forecast of fluxes of energetic electrons, exploiting empirical models and the first principles IMPTAM model achieved by the PROGRESS project is presented.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, Xi-Mei; Department of Radiation Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin; Li, Ye-Xiong, E-mail: yexiong@yahoo.com

Purpose: Early stage peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) is rare. The purpose of this study was to evaluate the outcome of treatment as well as the potential role of radiation therapy in PTCL-NOS. Methods and Materials: Thirty-five patients with early stage PTCL-NOS were included. There were 13 patients with stage I disease and 22 with stage II. All patients except 1 received doxorubicin-based chemotherapy alone (n=13) or a combination of chemotherapy and radiation therapy (CMT) (n=21). Results: The 3-year overall survival (OS) and progression-free survival (PFS) rates for the entire group were 41.3% and 25.7%, respectively. The additionmore » of radiation therapy to chemotherapy significantly improved OS and PFS in early stage PTCL-NOS. The 3-year OS and PFS rates were 49.7% and 33.3% for CMT, compared with 23.1% (P=.042) and 15.4% (P=.035) for chemotherapy alone, respectively. The prognosis for patients who achieved a complete response (CR) was significantly better than that observed in those who did not achieve a CR. Conclusions: Despite the aggressive clinical course of early stage PTCL-NOS, additional radiation therapy has a significant impact on outcome. The integration of local radiation therapy into more effective systemic therapies may further improve survival.« less

Randomized Clinical Trial Comparing Proton Beam Radiation Therapy with Transarterial Chemoembolization for Hepatocellular Carcinoma: Results of an Interim Analysis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bush, David A., E-mail: dbush@llu.edu; Smith, Jason C.; Slater, Jerry D.

2016-05-01

Purpose: To describe results of a planned interim analysis of a prospective, randomized clinical trial developed to compare treatment outcomes among patients with newly diagnosed hepatocellular carcinoma (HCC). Methods and Materials: Eligible subjects had either clinical or pathologic diagnosis of HCC and met either Milan or San Francisco transplant criteria. Patients were randomly assigned to transarterial chemoembolization (TACE) or to proton beam radiation therapy. Patients randomized to TACE received at least 1 TACE with additional TACE for persistent disease. Proton beam radiation therapy was delivered to all areas of gross disease to a total dose of 70.2 Gy in 15 daily fractionsmore » over 3 weeks. The primary endpoint was progression-free survival, with secondary endpoints of overall survival, local tumor control, and treatment-related toxicities as represented by posttreatment days of hospitalization. Results: At the time of this analysis 69 subjects were available for analysis. Of these, 36 were randomized to TACE and 33 to proton. Total days of hospitalization within 30 days of TACE/proton was 166 and 24 days, respectively (P<.001). Ten TACE and 12 proton patients underwent liver transplantation after treatment. Viable tumor identified in the explanted livers after TACE/proton averaged 2.4 and 0.9 cm, respectively. Pathologic complete response after TACE/proton was 10%/25% (P=.38). The 2-year overall survival for all patients was 59%, with no difference between treatment groups. Median survival time was 30 months (95% confidence interval 20.7-39.3 months). There was a trend toward improved 2-year local tumor control (88% vs 45%, P=.06) and progression-free survival (48% vs 31%, P=.06) favoring the proton beam treatment group. Conclusions: This interim analysis indicates similar overall survival rates for proton beam radiation therapy and TACE. There is a trend toward improved local tumor control and progression-free survival with proton beam. There are significantly fewer hospitalization days after proton treatment, which may indicate reduced toxicity with proton beam therapy.« less

Status of LDEF ionizing radiation measurements and analysis

NASA Technical Reports Server (NTRS)

Parnell, T. A.

1992-01-01

The LDEF-1 results from the particle astrophysics, radiation environments, and dosimetry measurements on LDEF-1 are summarized, including highlights from presentations at the 2nd symposium. Progress in using LDEF data to improve radiation environment models and calculation methods is reviewed. Radiation effects, or the lack thereof are discussed. Future plans of the LDEF Ionizing Radiation Special Investigation Group are presented.

Survivable pulse power space radiator

DOEpatents

Mims, James; Buden, David; Williams, Kenneth

1989-01-01

A thermal radiator system is described for use on an outer space vehicle, which must survive a long period of nonuse and then radiate large amounts of heat for a limited period of time. The radiator includes groups of radiator panels that are pivotally connected in tandem, so that they can be moved to deployed configuration wherein the panels lie largely coplanar, and to a stowed configuration wherein the panels lie in a stack to resist micrometeorite damage. The panels are mounted on a boom which separates a hot power source from a payload. While the panels are stowed, warm fluid passes through their arteries to keep them warm enough to maintain the coolant in a liquid state and avoid embrittlement of material. The panels can be stored in a largely cylindrical shell, with panels progressively further from the boom being of progressively shorter length.

Immunotherapy and stereotactic ablative radiotherapy (ISABR): a curative approach?

PubMed

Bernstein, Michael B; Krishnan, Sunil; Hodge, James W; Chang, Joe Y

2016-08-01

Conventional radiotherapy, in addition to its well-established tumoricidal effects, can also activate the host immune system. Radiation therapy modulates tumour phenotypes, enhances antigen presentation and tumour immunogenicity, increases production of cytokines and alters the tumour microenvironment, enabling destruction of the tumour by the immune system. Investigating the combination of radiotherapy with immunotherapeutic agents, which also promote the host antitumour immune response is, therefore, a logical progression. As the spectrum of clinical use of stereotactic radiotherapy continues to broaden, the question arose as to whether the ablative radiation doses used can also stimulate immune responses and, if so, whether we can amplify these effects by combining immunotherapy and stereotactic ablative radiotherapy (SABR). In this Perspectives article, we explore the preclinical and clinical evidence supporting activation of the immune system following SABR. We then examine studies that provide data on the effectiveness of combining these two techniques - immunotherapy and SABR - in an approach that we have termed 'ISABR'. Lastly, we provide general guiding principles for the development of future clinical trials to investigate the efficacy of ISABR in the hope of generating further interest in these exciting developments.

Recent Progress in Using Advanced Characterization and Modeling Approaches to Study Radiation Effects in Oxide Ceramics

DOE PAGES

Bai, Xian-Ming

2014-10-23

I serve as a Guest Editor for the Nuclear Materials Committee of the TMS Structural Materials Division, and coordinated the topic ‘‘Radiation Effects in Oxide Ceramics and Novel LWR Fuels" for JOM in the December 2014 issue. I selected five articles related this topic. These articles talk about some recent progress of using advanced experimental and modeling tools to study radiation effects in oxide ceramics at atomistic scale and mesoscale. In this guest editor commentary article, I summarize the novel aspects of these papers and also provide some suggestions for future research directions.

Organotypic culture in three dimensions prevents radiation-induced transformation in human lung epithelial cells

NASA Astrophysics Data System (ADS)

El-Ashmawy, Mariam; Coquelin, Melissa; Luitel, Krishna; Batten, Kimberly; Shay, Jerry W.

2016-08-01

The effects of radiation in two-dimensional (2D) cell culture conditions may not recapitulate tissue responses as modeled in three-dimensional (3D) organotypic culture. In this study, we determined if the frequency of radiation-induced transformation and cancer progression differed in 3D compared to 2D culture. Telomerase immortalized human bronchial epithelial cells (HBECs) with shTP53 and mutant KRas expression were exposed to various types of radiation (gamma, +H, 56Fe) in either 2D or 3D culture. After irradiation, 3D structures were dissociated and passaged as a monolayer followed by measurement of transformation, cell growth and expression analysis. Cells irradiated in 3D produced significantly fewer and smaller colonies in soft agar than their 2D-irradiated counterparts (gamma P = 0.0004 +H P = 0.049 56Fe P < 0.0001). The cell culture conditions did not affect cell killing, the ability of cells to survive in a colony formation assay, and proliferation rates after radiation—implying there was no selection against cells in or dissociated from 3D conditions. However, DNA damage repair and apoptosis markers were increased in 2D cells compared to 3D cells after radiation. Ideally, expanding the utility of 3D culture will allow for a better understanding of the biological consequences of radiation exposure.

Phase 2 Study of Accelerated Hypofractionated Thoracic Radiation Therapy and Concurrent Chemotherapy in Patients With Limited-Stage Small-Cell Lung Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Xia, Bing; Department of Radiation Oncology, Hangzhou Cancer Hospital, Hangzhou; Hong, Ling-Zhi

Purpose: To prospectively investigate the efficacy and toxicity of accelerated hypofractionated thoracic radiation therapy (HypoTRT) combined with concurrent chemotherapy in the treatment of limited-stage small-cell lung cancer (LS-SCLC), with the hypothesis that both high radiation dose and short radiation time are important in this setting. Methods and Materials: Patients with previously untreated LS-SCLC, Eastern Cooperative Oncology Group performance status of 0 to 2, and adequate organ function were eligible. HypoTRT of 55 Gy at 2.5 Gy per fraction over 30 days was given on the first day of the second or third cycle of chemotherapy. An etoposide/cisplatin regimen was given to 4 tomore » 6 cycles. Patients who had a good response to initial treatment were offered prophylactic cranial irradiation. The primary endpoint was the 2-year progression-free survival rate. Results: Fifty-nine patients were enrolled from July 2007 through February 2012 (median age, 58 years; 86% male). The 2-year progression-free survival rate was 49.0% (95% confidence interval [CI] 35.3%-62.7%). Median survival time was 28.5 months (95% CI 9.0-48.0 months); the 2-year overall survival rate was 58.2% (95% CI 44.5%-71.9%). The 2-year local control rate was 76.4% (95% CI 63.7%-89.1%). The severe hematologic toxicities (grade 3 or 4) were leukopenia (32%), neutropenia (25%), and thrombocytopenia (15%). Acute esophagitis and pneumonitis of grade ≥3 occurred in 25% and 10% of the patients, respectively. Thirty-eight patients (64%) received prophylactic cranial irradiation. Conclusion: Our study showed that HypoTRT of 55 Gy at 2.5 Gy per fraction daily concurrently with etoposide/cisplatin chemotherapy has favorable survival and acceptable toxicity. This radiation schedule deserves further investigation in LS-SCLC.« less

Intensity Modulated Radiation Therapy for Early-Stage Primary Gastric Diffuse Large B-Cell Lymphoma: Dosimetric Analysis, Clinical Outcome, and Quality of Life

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu, Xin; Fang, Hui; Tian, Yuan

Purpose: To evaluate the dosimetric superiority, efficacy, toxicity, and quality of life (QOL) data of intensity modulated radiation therapy (IMRT) in patients with primary gastric diffuse large B-cell lymphoma (PG-DLBCL). Methods and Materials: Forty-six consecutive patients with early-stage PG-DLBCL underwent IMRT after chemotherapy. The majority of patients (61.5%) were subclassified as the non-germinal center B cell–like subtype. Dosimetric parameters of the planning target volume (PTV) and organs at risk were assessed. Survival rates were depicted with the Kaplan-Meier method and compared with the log-rank test. Quality of life was evaluated using the QLQ-C30-STO22 questionnaires at the last follow-up contact. Results: Themore » median PTV mean dose was 41.6 Gy. Only 0.73% of the PTV received <95% of the prescribed dose, indicating excellent target coverage. The median kidney V20 and liver V30 were 14.1% and 16.1%, respectively. The 5-year overall survival (OS), progression-free survival, and locoregional control rates for all patients were 80.4%, 75.0%, and 93.2%, respectively. Stage, lactate dehydrogenase level, and immunophenotype were significant prognostic factors for OS, and only stage was a significant factor for locoregional control. Consolidation IMRT in patients with complete response after chemotherapy resulted in significantly better OS and progression-free survival than salvage IMRT in patients with non-complete response. Two of 8 patients who had chronic liver disease experienced grade 4 or grade 5 acute hepatic failure after 4 to 5 cycles of rituximab-based chemotherapy and IMRT (40 Gy). No other serious acute or late toxicity was observed. The long-term global and functional QOL scales were excellent, with negligible symptom scales. Conclusions: Intensity modulated radiation therapy yielded excellent target coverage and critical tissue sparing and achieved favorable outcomes with acceptable toxicity and good long-term QOL in early-stage PG-DLBCL.« less

Examining Relativistic Electron Loss in the Outer Radiation Belt

NASA Astrophysics Data System (ADS)

Green, J. C.; Onsager, T. G.; O'Brien, P.

2003-12-01

Since the discovery of earth's radiation belts researchers have sought to identify the mechanisms that dictate the seemingly erratic relativistic electron flux levels in the outer belt. Contrary to intuition, relativistic electron flux levels do not always increase during geomagnetic storms even though these storms signify enhanced energy input from the solar wind to the magnetosphere [Reeves et al., 2003; O'Brien et al., 2001]. The fickle response of the radiation belt electrons to geomagnetic activity suggests that flux levels are determined by the outcome of a continuous competition between acceleration and loss. Some progress has been made developing and testing acceleration mechanisms but little is known about how relativistic electrons are lost. We examine relativistic electron losses in the outer belt focusing our attention on flux decrease events of the type first described by Onsager et al. [2002]. The study showed a sudden decrease of geosynchronous >2MeV electron flux occurring simultaneously with local stretching of the magnetic field. The decrease was first observed near 15:00 MLT and progressed to all local times after a period of ˜10 hours. Expanding on the work of Onsager et al. [2002], we have identified ˜ 51 such flux decrease events in the GOES and LANL data and present the results of a superposed epoch analysis of solar wind data, geomagnetic activity indicators, and locally measured magnetic field and plasma data. The analysis shows that flux decreases occur after 1-2 days of quiet condition. They begin when either the solar wind dynamic pressure increases or Bz turns southward pushing hot dense plasma earthward to form a partial ring current and stretched magnetic field at dusk. Adiabatic electron motion in response to the stretched magnetic field may explain the initial flux reduction; however, often the flux does not recover with the magnetic field recovery, indicating that true loss from the magnetosphere is occurring. Using Polar and SAMPEX data, we examine whether precipitation to the atmosphere or magnetopause encounters can account for the additional loss.

Effect of Exposure to 900 MHz GSM Mobile Phone Radiofrequency Radiation on Estrogen Receptor Methylation Status in Colon Cells of Male Sprague Dawley Rats.

PubMed

Mokarram, P; Sheikhi, M; Mortazavi, S M J; Saeb, S; Shokrpour, N

2017-03-01

Over the past several years, the rapidly increasing use of mobile phones has raised global concerns about the biological effects of exposure to radiofrequency (RF) radiation. Numerous studies have shown that exposure to electromagnetic fields (EMFs) can be associated with effects on the nervous, endocrine, immune, cardiovascular, hematopoietic and ocular systems. In spite of genetic diversity, the onset and progression of cancer can be controlled by epigenetic mechanisms such as gene promoter methylation. There are extensive studies on the epigenetic changes of the tumor suppressor genes as well as the identification of methylation biomarkers in colorectal cancer. Some studies have revealed that genetic changes can be induced by exposure to RF radiation. However, whether or not RF radiation is capable of inducing epigenetic alteration has not been clarified yet. To date, no study has been conducted on the effect of radiation on epigenetic alterations in colorectal cancer (CRC). Several studies have also shown that methylation of estrogen receptor α (ERα), MYOD, MGMT, SFRP2 and P16 play an important role in CRC. It can be hypothesized that RF exposure can be a reason for the high incidence of CRC in Iran. This study aimed to investigate whether epigenetic pattern of ERα is susceptible to RF radiation and if RF radiation can induce radioadaptive response as epigenetic changes after receiving the challenge dose (γ-ray). 40 male Sprague-Dawley rats were divided into 4 equal groups (Group I: exposure to RF radiation of a GSM cell phone for 4 hours and sacrificed after 24 hours; Group II: RF exposure for 4 hours, exposure to Co-60 gamma radiation (3 Gy) after 24 hours and sacrificed after 72 hrs; Group III: only 3Gy gamma radiation; Group 4: control group). DNA from colon tissues was extracted to evaluate the methylation status by methylation specific PCR. Our finding showed that exposure to GSM cell phone RF radiation was capable of altering the pattern of ERα gene methylation compared to that of non-exposed controls. Furthermore, no adaptive response phenomenon was induced in the pattern of ERα gene methylation after exposure to the challenging dose of Co-60 γ-rays. It can be concluded that exposure to RF radiation emitted by GSM mobile phones can lead to epigenetic detrimental changes in ERα promoter methylation pattern.

(11)C-Choline PET/CT as a guide to radiation treatment planning of lymph-node relapses in prostate cancer patients.

PubMed

Picchio, M; Berardi, G; Fodor, A; Busnardo, E; Crivellaro, C; Giovacchini, G; Fiorino, C; Kirienko, M; Incerti, E; Messa, C; Gianolli, L; Di Muzio, N

2014-07-01

To evaluate, in prostate cancer (PCa) patients the potential of (11)C-choline PET/CT as a guide to helical tomotherapy (HTT) of lymph-node (LN) relapses with simultaneous integrated boost (SIB). The efficacy and feasibility of HTT in terms of acute toxicity were assessed. We enrolled 83 PCa patients (mean age 68 years, range 51 - 82 years) with biochemical recurrence after radical primary treatment (mean serum PSA 7.61 ng/ml, range 0.37 - 187.00 ng/ml; PSA0) who showed pathological findings on (11)C-choline PET/CT only at the LN site. (11)C-Choline PET/CT was performed for restaging and then for radiation treatment planning (PET/CT0). Of the 83 patients, 8 experienced further LN relapse, of whom 5 were retreated once and 3 were retreated twice (total 94 radiotherapy treatments). All pelvic and/or abdominal LNs positive on PET/CT0 were treated with high doses using SIB. Doses were in the range 36 - 74 Gy administered in 28 fractions. After the end of HTT (mean 83 days, range 16 - 365 days), serum PSA was measured in all patients (PSA1) and compared with PSA0 to evaluate early biochemical response. In 47 patients PET/CT was repeated (PET/CT1) to assess metabolic responses at the treated areas. Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) were used to assess acute toxicity. PET/CT0 revealed pathological LNs in the pelvis in 49 patients, pathological LNs in the abdomen in 15 patients pathological LNs in both the pelvis and abdomen in 18 patients, and pathological LNs in the pelvis or abdomen and other sites in 12 patients. All these sites were treated with HTT. With respect to PSA0, PSA1 (mean 6.28 ng/ml, range 0.00 - 220.46 ng/ml) showed a complete biochemical response after 66 of the 94 HTT treatments, a partial response after 12 treatments, stable disease after 1 treatment and progression of disease after 15 treatments. Of the 47 patients receiving PET/CT1, 20 showed a complete metabolic response at the treated area, 22 a partial metabolic response, 3 progression of disease and 2 stable disease. HTT with SIB was well tolerated in all patients. Grade 3 acute toxicity in the genitourinary tract was observed in two patients. (11)C-Choline PET/CT is a valuable tool for planning and monitoring HTT in LN relapse after primary treatment. High-dose hypofractionated (11)C-choline PET/CT-guided HTT with SIB is well tolerated and is associated with a high early biochemical response rate.

A phase 1b trial of the combination of the antiangiogenic agent sunitinib and radiation therapy for patients with primary and metastatic central nervous system malignancies.

PubMed

Wuthrick, Evan J; Kamrava, Mitchell; Curran, Walter J; Werner-Wasik, Maria; Camphausen, Kevin A; Hyslop, Terry; Axelrod, Rita; Andrews, David W; Glass, Jon; Machtay, Mitchell; Dicker, Adam P

2011-12-15

In this phase 1 trial, the authors evaluated sunitinib combined with radiation therapy (RT) for the treatment of primary or metastatic central nervous system (CNS) malignancies. Eligible patients had CNS malignancies that required a (minimum) 2-week course of RT. Sunitinib (37.5 mg) was administered daily for the duration of RT with optional treatment extension of 1 month. Urine was collected at 3 time points for correlative biomarker studies. The primary endpoint was acute toxicity defined according to Common Toxicity Criteria version 3. Fifteen patients were enrolled (12 with CNS metastasis and 3 with primary tumors). RT doses ranged from 14 Gray (Gy) to 70 Gy (1.8-3.5 Gy per fraction). Acute toxicities included hematologic, nausea, hyperglycemia, fatigue, hypocalcemia, and diarrhea. Six patients (40%) developed grade ≤ 2 toxicities. Grade 3 toxicities occurred in 7 patients (47%) and included hematologic toxicity, fatigue, deep vein thrombosis, dysphasia, hyperglycemia, and hyponatremia. No grade 3 through 5 hypertensive events or intracerebral hemorrhages occurred. Two grade 5 adverse events attributed to disease progression occurred. The median follow-up was 34.2 months. Two patients (13%) achieved a partial response, 9 patients (60%) had stable disease, and 2 patients (13%) patients had progressive disease. The 6-month progression-free survival rate for patients who had brain metastasis was 58%. Grade 3 hematologic toxicity was correlated with greater changes in vascular endothelial growth factor levels changes between baseline and the completion of RT. Continuous 37.5-mg sunitinib combined with RT in patients who had CNS malignancies yielded acceptable toxicities and adverse events. The current results indicated that changes in urine vascular endothelial growth factor levels are associated with hematologic toxicity, and this association should be analyzed in a larger cohort. The feasibility, safety, and early response results warrant a phase 2 trial. Copyright © 2011 American Cancer Society.

Combined spectrophotometry and tensile measurements of human connective tissues: potentials and limitations.

PubMed

Ernstberger, Markus; Sichting, Freddy; Baselt, Tobias; Hartmann, Peter; Aust, Gabriela; Hammer, Niels

2013-06-01

Strain-dependent transmission data of nine iliotibial tract specimens are determined using a custom-built optical setup with a halogen light source and an industrial norm material testing machine. Polarized light microscopy and hematoxylin-eosin staining indicated that lateral contraction of collagen structures is responsible for total intensity variations during a 20-cycle preconditioning and a 5-cycle tensile test. Tensile force progress is opposite to total transmission progress. Due to dehydration, wavelength-specific radiation intensity shifting is determined during the test, primarily noticeable in a water absorption band between 1400 and 1500 nm. The results show the capability of integrating spectrophotometry technology into biomechanics for determining structural alterations of human collagen due to applied strain. Being more sensitive to drying, spectrophotometry may likely serve as a quality control in stress-strain testing of biological structures.

A novel 3D human glioblastoma cell culture system for modeling drug and radiation responses

PubMed Central

Stevenson, Katrina; Gilmour, Lesley; Hamilton, Graham; Chalmers, Anthony J

2017-01-01

Abstract Background. Glioblastoma (GBM) is the most common primary brain tumor, with dismal prognosis. The failure of drug–radiation combinations with promising preclinical data to translate into effective clinical treatments may relate to the use of simplified 2-dimensional in vitro GBM cultures. Methods. We developed a customized 3D GBM culture system based on a polystyrene scaffold (Alvetex) that recapitulates key histological features of GBM and compared it with conventional 2D cultures with respect to their response to radiation and to molecular targeted agents for which clinical data are available. Results. In 3 patient-derived GBM lines, no difference in radiation sensitivity was observed between 2D and 3D cultures, as measured by clonogenic survival. Three different molecular targeted agents, for which robust clinical data are available were evaluated in 2D and 3D conditions: (i) temozolomide, which improves overall survival and is standard of care for GBM, exhibited statistically significant effects on clonogenic survival in both patient-derived cell lines when evaluated in the 3D model compared with only one cell line in 2D cells; (ii) bevacizumab, which has been shown to increase progression-free survival when added to standard chemoradiation in phase III clinical trials, exhibited marked radiosensitizing activity in our 3D model but had no effect on 2D cells; and (iii) erlotinib, which had no efficacy in clinical trials, displayed no activity in our 3D GBM model, but radiosensitized 2D cells. Conclusions. Our 3D model reliably predicted clinical efficacy, strongly supporting its clinical relevance and potential value in preclinical evaluation of drug–radiation combinations for GBM. PMID:27576873

Determining significant endpoints for ecological risk analyses. 1997 annual progress report

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hinton, T.G.; Congdon, J.; Rowe, C.

1997-11-01

'This report summarizes the first year''s progress of research funded under the Department of Energy''s Environmental Management Science Program. The research was initiated to better determine ecological risks from toxic and radioactive contaminants. More precisely, the research is designed to determine the relevancy of sublethal cellular damage to the performance of individuals and to identify characteristics of non-human populations exposed to chronic, low-level radiation, as is typically found on many DOE sites. The authors propose to establish a protocol to assess risks to non-human species at higher levels of biological organization by relating molecular damage to more relevant responses thatmore » reflect population health. They think that they can achieve this by coupling changes in metabolic rates and energy allocation patterns to meaningful population response variables, and by using novel biological dosimeters in controlled, manipulative dose/effects experiments. They believe that a scientifically defensible endpoint for measuring ecological risks can only be determined once its understood the extent to which molecular damage from contaminant exposure is detrimental at the individual and population levels of biological organization.'« less

Pharmacological doses of daily ascorbate protect tumors from radiation damage after a single dose of radiation in an intracranial mouse glioma model.

PubMed

Grasso, Carole; Fabre, Marie-Sophie; Collis, Sarah V; Castro, M Leticia; Field, Cameron S; Schleich, Nanette; McConnell, Melanie J; Herst, Patries M

2014-01-01

Pharmacological ascorbate is currently used as an anti-cancer treatment, potentially in combination with radiation therapy, by integrative medicine practitioners. In the acidic, metal-rich tumor environment, ascorbate acts as a pro-oxidant, with a mode of action similar to that of ionizing radiation; both treatments kill cells predominantly by free radical-mediated DNA damage. The brain tumor, glioblastoma multiforme (GBM), is very resistant to radiation; radiosensitizing GBM cells will improve survival of GBM patients. Here, we demonstrate that a single fraction (6 Gy) of radiation combined with a 1 h exposure to ascorbate (5 mM) sensitized murine glioma GL261 cells to radiation in survival and colony-forming assays in vitro. In addition, we report the effect of a single fraction (4.5 Gy) of whole brain radiation combined with daily intraperitoneal injections of ascorbate (1 mg/kg) in an intracranial GL261 glioma mouse model. Tumor-bearing C57BL/6 mice were divided into four groups: one group received a single dose of 4.5 Gy to the brain 8 days after tumor implantation, a second group received daily intraperitoneal injections of ascorbate (day 8-45) after implantation, a third group received both treatments and a fourth control group received no treatment. While radiation delayed tumor progression, intraperitoneal ascorbate alone had no effect on tumor progression. Tumor progression was faster in tumor-bearing mice treated with radiation and daily ascorbate than in those treated with radiation alone. Histological analysis showed less necrosis in tumors treated with both radiation and ascorbate, consistent with a radio-protective effect of ascorbate in vivo. Discrepancies between our in vitro and in vivo results may be explained by differences in the tumor microenvironment, which determines whether ascorbate remains outside the cell, acting as a pro-oxidant, or whether it enters the cells and acts as an anti-oxidant.

Molecular investigation of genetic assimilation during the rapid adaptive radiations of East African cichlid fishes.

PubMed

Gunter, Helen M; Schneider, Ralf F; Karner, Immanuel; Sturmbauer, Christian; Meyer, Axel

2017-12-01

Adaptive radiations are characterized by adaptive diversification intertwined with rapid speciation within a lineage resulting in many ecologically specialized, phenotypically diverse species. It has been proposed that adaptive radiations can originate from ancestral lineages with pronounced phenotypic plasticity in adaptive traits, facilitating ecologically driven phenotypic diversification that is ultimately fixed through genetic assimilation of gene regulatory regions. This study aimed to investigate how phenotypic plasticity is reflected in gene expression patterns in the trophic apparatus of several lineages of East African cichlid fishes, and whether the observed patterns support genetic assimilation. This investigation used a split brood experimental design to compare adaptive plasticity in species from within and outside of adaptive radiations. The plastic response was induced in the crushing pharyngeal jaws through feeding individuals either a hard or soft diet. We find that nonradiating, basal lineages show higher levels of adaptive morphological plasticity than the derived, radiated lineages, suggesting that these differences have become partially genetically fixed during the formation of the adaptive radiations. Two candidate genes that may have undergone genetic assimilation, gif and alas1, were identified, in addition to alterations in the wiring of LPJ patterning networks. Taken together, our results suggest that genetic assimilation may have dampened the inducibility of plasticity related genes during the adaptive radiations of East African cichlids, flattening the reaction norms and canalizing their feeding phenotypes, driving adaptation to progressively more narrow ecological niches. © 2017 John Wiley & Sons Ltd.

¹⁸F-choline positron emission tomography/computed tomography-driven high-dose salvage radiation therapy in patients with biochemical progression after radical prostatectomy: feasibility study in 60 patients.

PubMed

D'Angelillo, Rolando M; Sciuto, Rosa; Ramella, Sara; Papalia, Rocco; Jereczek-Fossa, Barbara A; Trodella, Luca E; Fiore, Michele; Gallucci, Michele; Maini, Carlo L; Trodella, Lucio

2014-10-01

To retrospectively review data of a cohort of patients with biochemical progression after radical prostatectomy, treated according to a uniform institutional treatment policy, to evaluate toxicity and feasibility of high-dose salvage radiation therapy (80 Gy). Data on 60 patients with biochemical progression after radical prostatectomy between January 2009 and September 2011 were reviewed. The median value of prostate-specific antigen before radiation therapy was 0.9 ng/mL. All patients at time of diagnosis of biochemical recurrence underwent dynamic (18)F-choline positron emission tomography/computed tomography (PET/CT), which revealed in all cases a local recurrence. High-dose salvage radiation therapy was delivered up to total dose of 80 Gy to 18F-choline PET/CT-positive area. Toxicity was recorded according to the Common Terminology Criteria for Adverse Events, version 3.0, scale. Treatment was generally well tolerated: 54 patients (90%) completed salvage radiation therapy without any interruption. Gastrointestinal grade ≥2 acute toxicity was recorded in 6 patients (10%), whereas no patient experienced a grade ≥2 genitourinary toxicity. No grade 4 acute toxicity events were recorded. Only 1 patient (1.7%) experienced a grade 2 gastrointestinal late toxicity. With a mean follow-up of 31.2 months, 46 of 60 patients (76.6%) were free of recurrence. The 3-year biochemical progression-free survival rate was 72.5%. At early follow-up, (18)F-choline PET/CT-driven high-dose salvage radiation therapy seems to be feasible and well tolerated, with a low rate of toxicity. Copyright © 2014 Elsevier Inc. All rights reserved.

The impact of the new biology on radiation risks in space

NASA Technical Reports Server (NTRS)

Dicello, John F.

2003-01-01

Radiation is considered to be one of three or four major hazards for personnel in space and has emerged as the most critical issue to be resolved for long-term missions, both orbital and interplanetary. Space habitats are stressful and dangerous environments. Health and medical consequences arising from microgravity, stress, and trauma include weakened immune systems, increased viral activity, and loss of bone mass. The greatest risks from radiation are generally assumed to be cancers and possibly damage to the central nervous system. Synergistic effects arising from the other environmental hazards along with abscopal and exogenic factors are likely. Space programs represent an exceptional opportunity for examining the biological consequences of low-dose exposures of humans to radiation at every level of progression. Although astronauts are a relatively small population, they are healthy, physically active volunteers who undergo extensive testing and medical examinations before, during, and after protracted exposures with periodic follow-up examinations. The radiation environments along with other hazards are likewise monitored and documented. Extensive international research programs are in progress. Seven years ago the U.S. National Aeronautics and Space Administration established the National Space Biomedical Research Institute through a cooperative agreement with a consortium of research and academic institutions in order to address radiation issues through a concerted, programmatic effort. Advanced technologies are rapidly being incorporated into these programs to determine the significance of new biological data and to evaluate the interplay among the different medical hazards. Programmatic in vivo and in vitro studies of the processes leading to carcinogenesis are in progress. Drugs and dietary supplements are being examined at the cellular and in vivo levels to assess their potential as dose-modifying agents. The infrastructure of this new approach, recent results, and research in progress are reviewed and discussed.

{sup 18}F-Choline Positron Emission Tomography/Computed Tomography–Driven High-Dose Salvage Radiation Therapy in Patients With Biochemical Progression After Radical Prostatectomy: Feasibility Study in 60 Patients

DOE Office of Scientific and Technical Information (OSTI.GOV)

D'Angelillo, Rolando M., E-mail: r.dangelillo@unicampus.it; Sciuto, Rosa; Ramella, Sara

Purpose: To retrospectively review data of a cohort of patients with biochemical progression after radical prostatectomy, treated according to a uniform institutional treatment policy, to evaluate toxicity and feasibility of high-dose salvage radiation therapy (80 Gy). Methods and Materials: Data on 60 patients with biochemical progression after radical prostatectomy between January 2009 and September 2011 were reviewed. The median value of prostate-specific antigen before radiation therapy was 0.9 ng/mL. All patients at time of diagnosis of biochemical recurrence underwent dynamic {sup 18}F-choline positron emission tomography/computed tomography (PET/CT), which revealed in all cases a local recurrence. High-dose salvage radiation therapy was delivered up tomore » total dose of 80 Gy to 18F-choline PET/CT-positive area. Toxicity was recorded according to the Common Terminology Criteria for Adverse Events, version 3.0, scale. Results: Treatment was generally well tolerated: 54 patients (90%) completed salvage radiation therapy without any interruption. Gastrointestinal grade ≥2 acute toxicity was recorded in 6 patients (10%), whereas no patient experienced a grade ≥2 genitourinary toxicity. No grade 4 acute toxicity events were recorded. Only 1 patient (1.7%) experienced a grade 2 gastrointestinal late toxicity. With a mean follow-up of 31.2 months, 46 of 60 patients (76.6%) were free of recurrence. The 3-year biochemical progression-free survival rate was 72.5%. Conclusions: At early follow-up, {sup 18}F-choline PET/CT-driven high-dose salvage radiation therapy seems to be feasible and well tolerated, with a low rate of toxicity.« less

Implementation of nanoparticles in therapeutic radiation oncology

NASA Astrophysics Data System (ADS)

Beeler, Erik; Gabani, Prashant; Singh, Om V.

2017-05-01

Development and progress of cancer is a very complex disease process to comprehend because of the multiple changes in cellular physiology, pathology, and pathophysiology resulting from the numerous genetic changes from which cancer originates. As a result, most common treatments are not directed at the molecular level but rather at the tissue level. While personalized care is becoming an increasingly aim, the most common cancer treatments are restricted to chemotherapy, radiation, and surgery, each of which has a high likelihood of resulting in rather severe adverse side effects. For example, currently used radiation therapy does not discriminate between normal and cancerous cells and greatly relies on the external targeting of the radiation beams to specific cells and organs. Because of this, there is an immediate need for the development of new and innovative technologies that help to differentiate tumor cells and micrometastases from normal cells and facilitate the complete destruction of those cells. Recent advancements in nanoscience and nanotechnology have paved a way for the development of nanoparticles (NPs) as multifunctional carriers to deliver therapeutic radioisotopes for tumor targeted radiation therapy, to monitor their delivery, and improve the therapeutic index of radiation and tumor response to the treatment. The application of NPs in radiation therapy has aimed to improve outcomes in radiation therapy by increasing therapeutic effect in tumors and reducing toxicity on normal tissues. Because NPs possess unique properties, such as preferential accumulation in tumors and minimal uptake in normal tissues, it makes them ideal for the delivery of radiotherapy. This review provides an overview of the recent development of NPs for carrying and delivering therapeutic radioisotopes for systemic radiation treatment for a variety of cancers in radiation oncology.

Photodamage: all signs lead to actinic keratosis and early squamous cell carcinoma.

PubMed

Wei, Jerry; Kok, Lai Fong; Byrne, Scott N; Halliday, Gary M

2015-01-01

Ultraviolet (UV) radiation is likely to drive the initiation and progression of skin cancer from actinic keratosis to squamous cell carcinoma. Signs of photodamage occur at multiple steps. UV radiation damages many cellular constituents, including lipids, proteins and DNA, all of which are likely to contribute to UV-induced skin cancer. Two biological events culminating from photodamage are mutations in the genes critical to the control of cell division, differentiation and invasion and immunosuppression. DNA photodamage, if unrepaired prior to cell division, can result in the incorporation of an incorrect nucleotide into newly synthesised DNA. Mutations in critical genes contribute to carcinogenesis. Photodamage to proteins such as those involved in DNA repair or proteins or lipids involved in cellular signalling can interfere with this repair process and contribute to mutagenesis. Mutations in key genes, including TP53, BRM, PTCH1, and HRAS, contribute to skin carcinogenesis. UV also damages immunity. Photodamage to DNA and signalling lipids as well as other molecular changes are detrimental to the key cells that regulate immunity. Photodamaged dendritic cells and altered responses by mast cells lead to the activation of T and B regulatory cells that suppress immunity to the protein products of UV-mutated genes. This stops the immune response from its protective function of destroying mutated cells, enabling the transformed cells to progress to skin cancer. UV appears to play a pivotal role at each of these steps, and therefore, signs of photodamage point to the development of skin cancer. © 2015 S. Karger AG, Basel.

Radiation Therapy to the Primary and Postinduction Chemotherapy MIBG-Avid Sites in High-Risk Neuroblastoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mazloom, Ali; Louis, Chrystal U.; Nuchtern, Jed

2014-11-15

Purpose: Although it is generally accepted that consolidation therapy for neuroblastoma includes irradiation of the primary site and any remaining metaiodobenzylguanidine (MIBG)-avid metastatic sites, limited information has been published regarding the efficacy of this approach. Methods and Materials: Thirty patients with high-risk neuroblastoma were treated at 1 radiation therapy (RT) department after receiving 5 cycles of induction chemotherapy and resection. All patients had at least a partial response after induction therapy, based upon international neuroblastoma response criteria. The primary sites were treated with 24 to 30 Gy whereas the MIBG-avid metastatic sites were treated with 24 Gy. RT was followed by high-dosemore » chemotherapy with autologous stem cell rescue and 6 months of cis-retinoic acid. Results: The 5-year progression-free survival (PFS) and overall survival (OS) rates were 48% and 59%, respectively. The 5-year locoregional control at the primary site was 84%. There were no differences in locoregional control according to degree of primary surgical resection. The 5-year local control rate for metastatic sites was 74%. The 5-year PFS rates for patients with 0, 1, 2, and >3 postinduction MIBG sites were 66%, 57%, 20%, and 0% (P<.0001), respectively, whereas 5-year OS rates were 80%, 57%, 50%, and 0%, respectively (P<.0001). Conclusions: RT to the primary site and postinduction MIBG-positive metastatic sites was associated with 84% and 74% local control, respectively. The number of MIBG-avid sites present after induction chemotherapy and surgery was predictive of progression-free and overall survival.« less

The role of ultraviolet radiation in the pathogenesis of pterygia (Review).

PubMed

Zhou, Wei-Ping; Zhu, Yuan-Fang; Zhang, Bei; Qiu, Wen-Ya; Yao, Yu-Feng

2016-07-01

Pterygium is a common ophthalmic disease affecting humans only. Extensive epidemiological data have demonstrated a causative effect of chronic ultraviolet (UV) radiation on pterygia. Progress has been made in determining the origin of pterygia, their nasal predilection and wing‑shaped appearance, and the roles of UV radiation in the initiation and the development of pterygia. In the present review, the current understanding of the involvement of UV radiation in the pathogenesis of pterygia is summarized. This involvement includes the alteration of limbal stem cells and fibroblasts that contribute to the initiation of pterygia and the induction of various pro‑inflammatory cytokines, growth factors and matrix metalloproteinases that promote the progression of pterygia. Further elucidation of the roles of UV radiation in the pathogenesis of pterygia may help to encourage individuals at risk of developing pterygia to take preventive measures and aid researchers in the development of novel targeted therapeutic agents to treat pterygia.

Basics of particle therapy I: physics

PubMed Central

Park, Seo Hyun

2011-01-01

With the advance of modern radiation therapy technique, radiation dose conformation and dose distribution have improved dramatically. However, the progress does not completely fulfill the goal of cancer treatment such as improved local control or survival. The discordances with the clinical results are from the biophysical nature of photon, which is the main source of radiation therapy in current field, with the lower linear energy transfer to the target. As part of a natural progression, there recently has been a resurgence of interest in particle therapy, specifically using heavy charged particles, because these kinds of radiations serve theoretical advantages in both biological and physical aspects. The Korean government is to set up a heavy charged particle facility in Korea Institute of Radiological & Medical Sciences. This review introduces some of the elementary physics of the various particles for the sake of Korean radiation oncologists' interest. PMID:22984664

Survivable pulse power space radiator

DOEpatents

Mims, J.; Buden, D.; Williams, K.

1988-03-11

A thermal radiator system is described for use on an outer space vehicle, which must survive a long period of nonuse and then radiate large amounts of heat for a limited period of time. The radiator includes groups of radiator panels that are pivotally connected in tandem, so that they can be moved to deployed configuration wherein the panels lie largely coplanar, and to a stowed configuration wherein the panels lie in a stack to resist micrometerorite damage. The panels are mounted on a boom which separates a hot power source from a payload. While the panels are stowed, warm fluid passes through their arteries to keep them warm enough to maintain the coolant in a liquid state and avoid embrittlement of material. The panels can be stored in a largely cylindrical shell, with panels progressively further from the boom being of progressively shorter length. 5 figs.

The oncogenic action of ionizing radiation on rat skin. Final progress report, May 1, 1990--April 30, 1992

DOE Office of Scientific and Technical Information (OSTI.GOV)

Burns, F.J.; Garte, S.J.

1992-12-31

The multistage theory of carcinogenesis specifies that cells progress to cancer through a series of discrete, irreversible genetic alterations, but data on radiation-induced cancer incidence in rat skin suggests that an intermediate repairable alteration may occur. Data are presented on cancer induction in rat skin exposed to an electron beam (LET=0.34 keV/{mu}), a neon ion beam (LET=45) or an argon ion beam (LET=125). The rats were observed for tumors at least 78 weeks with squamous and basal cell carcinomas observed. The total cancer yield was fitted by the quadratic equation, and the equation parameters were estimated by linear regression formore » each type of radiation. Analysis of the DNA from the electron-induced carcinomas indicated that K-ras and/or c-myc oncogenes were activated. In situ hybridization indicated that the cancers contain subpopulations of cells with differing amounts of c-myc and H-ras amplification. The results are consistent with the idea that ionizing radiation produces stable, carcinogenically relevant lesions via 2 repairable events at low LET and via a non-repairable linked event pathway at high LET; either pathway may advance the cell by 1 stage. The proliferative response of rat epidermis following exposure to ionizing radiation was quantified by injection of {sup 14}C-thymidine. The return of these cells to S-phase a second time was detected by a second label ({sup 3}H). When the labeled cells were in G1-phase, the dorsal skin was irradiated with X-rays. All labeling indices were determined. The {sup 14}C labeling index was constant and unaffected by the radiation. The proportion of all cells entering S-phase averaged 3.5% at 18 hr and increased after 44, 52 and 75 hr to average levels of 11.8%, 5. 3%, and 6.6% at 0, 10 and 25 Gy respectively. The proportion of S-phase cells labeled with {sup 14}C increased after 42 hr and remained relatively constant thereafter.« less

Cranial Radiation Therapy and Damage to Hippocampal Neurogenesis

ERIC Educational Resources Information Center

Monje, Michelle

2008-01-01

Cranial radiation therapy is associated with a progressive decline in cognitive function, prominently memory function. Impairment of hippocampal neurogenesis is thought to be an important mechanism underlying this cognitive decline. Recent work has elucidated the mechanisms of radiation-induced failure of neurogenesis. Potential therapeutic…

Ribosome Synthesis and MAPK Activity Modulate Ionizing Radiation-Induced Germ Cell Apoptosis in Caenorhabditis elegans

PubMed Central

Eberhard, Ralf; Stergiou, Lilli; Hofmann, E. Randal; Hofmann, Jen; Haenni, Simon; Teo, Youjin; Furger, André; Hengartner, Michael O.

2013-01-01

Synthesis of ribosomal RNA by RNA polymerase I (RNA pol I) is an elemental biological process and is key for cellular homeostasis. In a forward genetic screen in C. elegans designed to identify DNA damage-response factors, we isolated a point mutation of RNA pol I, rpoa-2(op259), that leads to altered rRNA synthesis and a concomitant resistance to ionizing radiation (IR)-induced germ cell apoptosis. This weak apoptotic IR response could be phenocopied when interfering with other factors of ribosome synthesis. Surprisingly, despite their resistance to DNA damage, rpoa-2(op259) mutants present a normal CEP-1/p53 response to IR and increased basal CEP-1 activity under normal growth conditions. In parallel, rpoa-2(op259) leads to reduced Ras/MAPK pathway activity, which is required for germ cell progression and physiological germ cell death. Ras/MAPK gain-of-function conditions could rescue the IR response defect in rpoa-2(op259), pointing to a function for Ras/MAPK in modulating DNA damage-induced apoptosis downstream of CEP-1. Our data demonstrate that a single point mutation in an RNA pol I subunit can interfere with multiple key signalling pathways. Ribosome synthesis and growth-factor signalling are perturbed in many cancer cells; such an interplay between basic cellular processes and signalling might be critical for how tumours evolve or respond to treatment. PMID:24278030

Progress and future tasks in food irradiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

None

1973-09-01

Progress in the use of atomic energy for preserving food was reviewed at recent meetings of the Second International Symposium on Food Irradiation in India. The technical feasibility of radiation control was discussed with regard to the inhibition of sprouting in yams by gamma radiation; combined radiation and chemical treatment of potatoes and onions to prevent sprouting; effects of radiation on starch preparations and seasonings; radiation preservation of fish; radiation effects on bacteria; and control of insect pests. The importance of assessing the economic feasibility on the basis of practical, large-scale tests is emphasized. With regard to wholesomeness reports weremore » given of acute and chronic toxicity tests with irradiated wheat, shrimp, whole diets, beef, strawberries, mushrooms, and chicken. No harmful effects were observed following large-scale animal testing of irradiated complete diets. A summary of tasks ahead includes an assessment of economic benefits of food irradiation; criteria of public health acceptance; education of the public; and internationsl collaboration with the FAO and IAEA. (HLW)« less

Diagnostic and therapeutic challenges of EBV-positive mucocutaneous ulcer: a case report and systematic review of the literature.

PubMed

Roberts, Toni K; Chen, Xueyan; Liao, Jay Justin

2015-01-01

Epstein-Barr virus-positive mucocutaneous ulcer (EBVMCU) is a recently recognized B cell lymphoproliferative disorder that is driven by latent EBV infection and causes discrete ulcerations in the oropharynx, gastrointestinal tract, and skin. Local attenuation of immunosurveillance associated with iatrogenic immunosuppressant use, primary immunodeficiency, or age-associated immunosenescence has been implicated as a predisposing factor. This disorder is likely under reported, as it was only first defined in 2010 and shares histological features with other B-cell proliferative neoplasms. The first case series that described EBVMCU suggested that EBVMCU is generally self-limited and is likely to resolve without treatment. Since that publication, additional cases have been reported that describe a more heterogeneous clinical course, often requiring aggressive therapy. We now systematically review all published cases of EBVMCU and detail a case of aggressive and progressive EBVMCU, including diagnostic and management challenges, as well as successful treatment with radiation therapy. A forty-nine year old woman presented with painful and debilitating multifocal oral EBVMCU that initially responded to four weekly doses of rituximab. Her disease relapsed within 3 months and continued to progress and cause significant morbidity. She was successfully treated with local external beam radiation therapy of 30 Gy in 15 fractions, with duration of response of at least 6 months. We suggest that although many patients with EBVMCU experience a self-limited course, for others EBVMCU can be a debilitating, persistent disorder that requires aggressive therapy to prevent disease progression. CD20- and CD30-directed antibody therapy, local radiation therapy, local surgical excision, systemic chemotherapy, and a combination of these therapies have all been successfully used to treat EBVMCU with high rates of durable clinical remission. As EBVMCU is not currently included in the 2008 WHO classification of lymphoproliferative disorders and no evidence-based guidelines or expert opinions have been proposed to guide therapy, this case report and systematic review provides a foundation on which to guide therapeutic decisions.

Beneficial uses program. Progress report for period ending March 31, 1977

DOE Office of Scientific and Technical Information (OSTI.GOV)

None

1977-07-01

Progress is reported in a program aimed at recovering radiation sources from radioactive wastes and using these sources, mainly /sup 137/Cs, for irradiating sewage sludge. Information is included on: development and cost of dried sludge irradiator; heat and radiation inactivation of sludge-contained viruses and bacteria; virucidal agents in sludge; use of thermoradiated sludge as animal feed; and a comparison of the efficiency of various source materials. (LCL)

An Introduction to Atmospheric Radiation: Review for the Bulletin of AMS

NASA Technical Reports Server (NTRS)

Marshak, Alexander

2003-01-01

Whether you like a certain geophysical book or not, largely depends on your background. The field of radiative transfer and atmospheric radiation, in particular, combines people with a wide range of mathematical skills: from theoretical astrophysicists and nuclear physicists to meteorologists and ecologists. There is always a delicate balance between physical explanations and their mathematical interpretations. This balance is very personal and is based on your background. I came to the field of atmospheric radiative transfer as a mathematician with little knowledge of atmospheric physics. After being in the field for more than a decade, I still have gaps in my atmospheric science education. Thus I assess a radiative transfer book fi-om two main criteria: how well does it describe the material that is familiar to me (the radiative transfer equation and its numerical solutions) and how well does it help me to fill the gaps in my personal knowledge. So I present this review fi-om the perspective of a former mathematician working in the field of atmospheric radiation. . After being asked to review the book, my first intention was to compare the new edition with the previous one (Liou, 1980). In doing so, you can clearly follow the progress made in the field of atmospheric radiation over the past two decades. If there are few changes (as in Fundamental Radiative Transfer) or no changes at all (as in the Maxwell s equations), then the field has not seen much development. To the contrary, many differences between the two editions illustrate areas of major progress in the field, such as evidenced in Thermal Ineared Radiative Transfer and even in the creations of completely new fields like Three-Dimensional Radiative Transfer or Light Scattering by Nonspherical Particles. Obviously, the major changes happened not in the theory, which is at least half a century old, but in data quality and completely new measurements (mostly due to new satellite data) with higher accuracy and more reliability. The new edition illustrates this progress well.

Impact of 18F-fluorodeoxyglucose positron emission tomography before and after definitive radiation therapy in patients with apparently solitary plasmacytoma.

PubMed

Kim, Paul J; Hicks, Rodney J; Wirth, Andrew; Ryan, Gail; Seymour, John F; Prince, H Miles; Mac Manus, Michael P

2009-07-01

To evaluate the impact of (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) on management of patients with apparently isolated plasmacytoma. Twenty-one patients with apparently solitary plasmacytoma who underwent FDG-PET for staging or restaging were identified from a central PET database. They were either candidates for or had received definitive radiation therapy (RT). Seventeen patients had initial staging scans for bone (n = 11) or soft tissue (n = 6) plasmacytomas, and 11 had PET scans after RT. Only 1 of 14 known untreated sites of plasmacytoma was not identified on staging PET (lesion sensitivity = 93%). Three plasmacytomas were excised before PET. Staging PET influenced management in 6 of 17 patients (35%) by showing multiple myeloma (n = 1), discouraging RT after complete resection (n = 1), excluding plasmacytoma at a second site (n = 1), by increasing RT fields (n = 2), or by suggesting sarcoidosis (n = 1). Fifteen of 17 patients with initial staging PET scans received definitive RT. Restaging PET scans after RT showed complete metabolic response in 8 of 11 cases and progressive disease in 2. Two patients with either no response or partial metabolic response had late responses. Staging sestamibi and PET scans were concordant in five of six occasions (one sestamibi scan was false negative). FDG-PET has value for staging and RT planning in plasmacytoma and potentially could have a role in response-assessment after RT. Slow resolution of FDG uptake posttreatment does not necessarily imply an adverse prognosis.

Determining significant endpoints for ecological risk analyses. 1998 annual progress report

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hinton, T.G.; Congdon, J.; Scott, D.

1998-06-01

'The goal of this report is to establish a protocol for assessing risks to non-human populations exposed to environmental stresses typically found on many DOE sites. The authors think that they can achieve this by using novel biological dosimeters in controlled, manipulative dose/effects experiments, and by coupling changes in metabolic rates and energy allocation patterns to meaningful population response variables (such as age-specific survivorship, reproductive output, age at maturity and longevity). This research is needed to determine the relevancy of sublethal cellular damage to the performance of individuals and populations exposed to chronic, low-level radiation, and radiation with concomitant exposuremore » to chemicals. They believe that a scientifically defensible endpoint for measuring ecological risks can only be determined once its understood the extent to which molecular damage from contaminant exposure is detrimental at the individual and population levels of biological organization. The experimental facility will allow them to develop a credible assessment tool for appraising ecological risks, and to evaluate the effects of radionuclide/chemical synergisms on non-human species. This report summarizes work completed midway of a 3-year project that began in November 1996. Emphasis to date has centered on three areas: (1) developing a molecular probe to measure stable chromosomal aberrations known as reciprocal translocations, (2) constructing an irradiation facility where the statistical power inherent in replicated mesocosms can be used to address the response of non-human organisms to exposures from low levels of radiation and metal contaminants, and (3) quantifying responses of organisms living in contaminated mesocosms and field sites.'« less

Performance limiting processes in room temperature thallium bromide radiation detectors

NASA Astrophysics Data System (ADS)

Datta, Amlan; Becla, Piotr; Moed, Demi; Motakef, Shariar

2015-09-01

Thallium Bromide (TlBr) is a promising room-temperature radiation detector candidate with excellent charge transport properties. However, several critical issues are needed to be addressed before deployment of this material for long-term field applications. In this paper, the relevance and, scientific and technological progress made towards solving these challenges for TlBr have been discussed. The possible research pathways to mitigate the concerns related to this material have been analyzed and clearly established. Findings from novel experiments performed at CapeSym have revealed that the most significant factors for achieving long-term performance stability for TlBr devices involve physical and chemical conditions of the surface, residual stress, and choice of metal contacts. Palladium electrodes on TlBr devices resulted in a 20-fold improvement in the device lifetime when compared to its Br-etched Pt counterpart. Electron and hole contributions towards the spectroscopic response of the TlBr detector significantly depend on the interaction position of the incoming radiation and was clearly observed in this study. TlBr device fabrication techniques need significant improvement in order to attain reliable, repeatable, and stable, long-term performance.

The future impacts of non-targeted effects.

PubMed

Bright, Scott; Kadhim, Munira

2018-04-11

Ionizing radiation was traditionally thought to exert its detrimental effects through interaction with sensitive cellular targets, nuclear DNA being of most importance. This theory has since merged with a more recently described radiation response called non-targeted effects (NTE). This review will briefly look at the various types of NTE and the potential implications they may have for radiobiology research and its applications. The most well-known NTE are genomic instability (GI) and bystander effects (BE). Other NTE include abscopal effects, which are similar to bystander effects but are generally based in a clinical environment with immune involvement as the defining feature. Currently, our understanding of NTE is limited to certain signaling pathways/molecules, and as yet there is no theory that describes or can accurately predict the occurrence or outcome of these NTE. There are numerous groups investigating these processes in vitro and in vivo, and thus steady progress is being made. Developing a deeper understanding of NTE has potential impacts for therapy and diagnosis, safer occupational exposures, space flight and our general understanding of radiation biology.

Radiation countermeasure agents: an update (2011 – 2014)

PubMed Central

Newman, Victoria L; Romaine, Patricia LP; Wise, Stephen Y; Seed, Thomas M

2014-01-01

Introduction Despite significant scientific advances over the past 60 years towards the development of a safe, nontoxic and effective radiation countermeasure for the acute radiation syndrome (ARS), no drug has been approved by the US FDA. A radiation countermeasure to protect the population at large from the effects of lethal radiation exposure remains a significant unmet medical need of the US citizenry and, thus, has been recognized as a high priority area by the government. Area covered This article reviews relevant publications and patents for recent developments and progress for potential ARS treatments in the area of radiation countermeasures. Emphasis is placed on the advanced development of existing agents since 2011 and new agents identified as radiation countermeasure for ARS during this period. Expert opinion A number of promising radiation countermeasures are currently under development, seven of which have received US FDA investigational new drug status for clinical investigation. Four of these agents, CBLB502, Ex-RAD, HemaMax and OrbeShield, are progressing with large animal studies and clinical trials. G-CSF has high potential and well-documented therapeutic effects in countering myelosuppression and may receive full licensing approval by the US FDA in the future. PMID:25315070

Real-space analysis of radiation-induced specific changes with independent component analysis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Borek, Dominika; Bromberg, Raquel; Hattne, Johan

A method of analysis is presented that allows for the separation of specific radiation-induced changes into distinct components in real space. The method relies on independent component analysis (ICA) and can be effectively applied to electron density maps and other types of maps, provided that they can be represented as sets of numbers on a grid. Here, for glucose isomerase crystals, ICA was used in a proof-of-concept analysis to separate temperature-dependent and temperature-independent components of specific radiation-induced changes for data sets acquired from multiple crystals across multiple temperatures. ICA identified two components, with the temperature-independent component being responsible for themore » majority of specific radiation-induced changes at temperatures below 130 K. The patterns of specific temperature-independent radiation-induced changes suggest a contribution from the tunnelling of electron holes as a possible explanation. In the second case, where a group of 22 data sets was collected on a single thaumatin crystal, ICA was used in another type of analysis to separate specific radiation-induced effects happening on different exposure-level scales. Here, ICA identified two components of specific radiation-induced changes that likely result from radiation-induced chemical reactions progressing with different rates at different locations in the structure. In addition, ICA unexpectedly identified the radiation-damage state corresponding to reduced disulfide bridges rather than the zero-dose extrapolated state as the highest contrast structure. The application of ICA to the analysis of specific radiation-induced changes in real space and the data pre-processing for ICA that relies on singular value decomposition, which was used previously in data space to validate a two-component physical model of X-ray radiation-induced changes, are discussed in detail. This work lays a foundation for a better understanding of protein-specific radiation chemistries and provides a framework for analysing effects of specific radiation damage in crystallographic and cryo-EM experiments.« less

DCE-MRI defined subvolumes of a brain metastatic lesion by principle component analysis and fuzzy-c-means clustering for response assessment of radiation therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Farjam, Reza; Tsien, Christina I.; Lawrence, Theodore S.

Purpose: To develop a pharmacokinetic modelfree framework to analyze the dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) data for assessment of response of brain metastases to radiation therapy. Methods: Twenty patients with 45 analyzable brain metastases had MRI scans prior to whole brain radiation therapy (WBRT) and at the end of the 2-week therapy. The volumetric DCE images covering the whole brain were acquired on a 3T scanner with approximately 5 s temporal resolution and a total scan time of about 3 min. DCE curves from all voxels of the 45 brain metastases were normalized and then temporally aligned. Amore » DCE matrix that is constructed from the aligned DCE curves of all voxels of the 45 lesions obtained prior to WBRT is processed by principal component analysis to generate the principal components (PCs). Then, the projection coefficient maps prior to and at the end of WBRT are created for each lesion. Next, a pattern recognition technique, based upon fuzzy-c-means clustering, is used to delineate the tumor subvolumes relating to the value of the significant projection coefficients. The relationship between changes in different tumor subvolumes and treatment response was evaluated to differentiate responsive from stable and progressive tumors. Performance of the PC-defined tumor subvolume was also evaluated by receiver operating characteristic (ROC) analysis in prediction of nonresponsive lesions and compared with physiological-defined tumor subvolumes. Results: The projection coefficient maps of the first three PCs contain almost all response-related information in DCE curves of brain metastases. The first projection coefficient, related to the area under DCE curves, is the major component to determine response while the third one has a complimentary role. In ROC analysis, the area under curve of 0.88 ± 0.05 and 0.86 ± 0.06 were achieved for the PC-defined and physiological-defined tumor subvolume in response assessment. Conclusions: The PC-defined subvolume of a brain metastasis could predict tumor response to therapy similar to the physiological-defined one, while the former is determined more rapidly for clinical decision-making support.« less

DCE-MRI defined subvolumes of a brain metastatic lesion by principle component analysis and fuzzy-c-means clustering for response assessment of radiation therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Farjam, Reza; Tsien, Christina I.; Lawrence, Theodore S.

2014-01-15

Purpose: To develop a pharmacokinetic modelfree framework to analyze the dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) data for assessment of response of brain metastases to radiation therapy. Methods: Twenty patients with 45 analyzable brain metastases had MRI scans prior to whole brain radiation therapy (WBRT) and at the end of the 2-week therapy. The volumetric DCE images covering the whole brain were acquired on a 3T scanner with approximately 5 s temporal resolution and a total scan time of about 3 min. DCE curves from all voxels of the 45 brain metastases were normalized and then temporally aligned. Amore » DCE matrix that is constructed from the aligned DCE curves of all voxels of the 45 lesions obtained prior to WBRT is processed by principal component analysis to generate the principal components (PCs). Then, the projection coefficient maps prior to and at the end of WBRT are created for each lesion. Next, a pattern recognition technique, based upon fuzzy-c-means clustering, is used to delineate the tumor subvolumes relating to the value of the significant projection coefficients. The relationship between changes in different tumor subvolumes and treatment response was evaluated to differentiate responsive from stable and progressive tumors. Performance of the PC-defined tumor subvolume was also evaluated by receiver operating characteristic (ROC) analysis in prediction of nonresponsive lesions and compared with physiological-defined tumor subvolumes. Results: The projection coefficient maps of the first three PCs contain almost all response-related information in DCE curves of brain metastases. The first projection coefficient, related to the area under DCE curves, is the major component to determine response while the third one has a complimentary role. In ROC analysis, the area under curve of 0.88 ± 0.05 and 0.86 ± 0.06 were achieved for the PC-defined and physiological-defined tumor subvolume in response assessment. Conclusions: The PC-defined subvolume of a brain metastasis could predict tumor response to therapy similar to the physiological-defined one, while the former is determined more rapidly for clinical decision-making support.« less

Excitation of XUV radiation in solar flares

NASA Technical Reports Server (NTRS)

Emslie, A. Gordon

1992-01-01

The goal of the proposed research was to understand the means by which XUV radiation in solar flares is excited, and to use this radiation as diagnostics of the energy release and transport processes occurring in the flare. Significant progress in both of these areas, as described, was made.

Dried Plum Protects From Radiation-Induced Bone Loss by Attenuating Pro-Osteoclastic and Oxidative Stress Responses

NASA Technical Reports Server (NTRS)

Globus, Ruth

2015-01-01

Future space explorations beyond the earths magnetosphere will increase human exposure to space radiation and associated risks to skeletal health. We hypothesize that oxidative stress resulting from radiation exposure plays a major role in progressive bone loss and dysfunction in associated tissue. In animal studies, increased free radical formation is associated with pathological changes in bone structure, enhanced bone resorption, reduced bone formation and decreased bone mineral density, which can lead to skeletal fragility. Our long-term goals are to define the mechanisms and risk of bone loss in the spaceflight environment and to facilitate the development of effective countermeasures. We had previously reported that exposure to low or high-LET radiation correlates with an acute increase in the expression of pro-osteoclastic and oxidative stress genes in bone during the early response to radiation followed by pathological changes in skeletal structure. We then conducted systematic screening for potential countermeasures against bone loss where we tested the ability of various antioxidants to mitigate the radiation-induced increase in expression of these markers. For the screen, 16-week old C57Bl6J mice were treated with a dietary antioxidant cocktail, injectable DHLA or a dried plum-enriched diet (DP). Mice were then exposed to 2Gy 137Cs radiation and one day later, marrow cells were collected and the relevant genes analyzed for expression levels. Among the candidate countermeasures tested, DP was most effective in reducing the expression of genes associated with bone loss. Furthermore, analysis of skeletal structure by microcomputed tomography (microCT) revealed that DP also prevents the radiation-induced deterioration in skeletal microarchitecture as indicated by parameters such as percent bone volume (BVTV), trabecular spacing and trabecular number. We also found that DP has similar protective effects on skeletal structure in a follow-up study using 1 Gy of sequential proton and iron, radiation species relevant to spaceflight. When cultured ex vivo under osteogenic conditions, bone marrow-derived cells from DP-fed animals exhibited increased colony numbers compared to control diet-fed animals. These findings suggest that DP exerts pro-osteogenic effects apart from its previously demonstrated anti-resorptive action, which may be one of the mechanisms underlying its radioprotective effect on bone. In conclusion, a diet enriched in certain types of antioxidants may be useful as an intervention for radiation-induced bone loss.

Simulated Space Radiation: Murine Skeletal Responses During Recovery and with Mechanical Stimulation

NASA Technical Reports Server (NTRS)

Shirazi-Fard, Yasaman; Zaragoza, Josergio; Schreurs, Ann-Sofie; Truong, Tiffany; Tahimic, Candice; Alwood, Joshua S.; Castillo, Alesha B.; Globus, R. K.

2016-01-01

Simulated space radiation at doses similar to those of solar particle events or a round-trip sojourn to Mars (1-2Gy) may cause skeletal tissue degradation and deplete stem/progenitor cell pools throughout the body. We hypothesized that simulated space radiation (SSR) causes late, time-dependent deficits in bone structure and bone cell function reflected by changes in gene expression in response to anabolic stimuli. We used a unique sequential dual ion exposure (proton and iron) for SSR to investigate time-dependence of responses in gene expression, cell function, and microarchitecture with respect to radiation and an anabolic stimulus of axial loading (AL). Male 16-wk C57BL6/J mice (n=120 total) were exposed to 0Gy (Sham, n=10), 56Fe (2Gy, positive control dose, n=10), or sequential ions for SSR (1Gy 1H/56Fe/1H, n=10) by total body irradiation (IR), and the tissues were harvested 2 or 6 mo. later. Further, to assess the response to anabolic stimuli, we subjected additional Sham-AL (n=15) and SSR-AL (n=15) groups to rest-inserted tibial axial loading (AL) starting at 1 and 5 months post-IR (-9N, 60 cycles/day, 3 days/wk, 4 wks). Exposure to 56Fe caused a significant reduction in cancellous bone volume fraction (BV/TV) compared to Sham (-34%) and SSR (-20%) in the proximal tibia metaphysis at 2-months post-IR; however BV/TV for SSR group was not different than Sham. Both 56Fe and SSR caused significant reduction in trabecular number (Tb.N) compared to Sham (-33% and -16%, respectively). Further, Tb.N for 56Fe (2Gy) was significantly lower than SSR (-21%). Ex vivo culture of marrow cells to assess growth and differentiation of osteoblast lineage cells 6 months post-IR showed that both 56Fe and SSR exposures significantly impaired colony formation compared to Sham (-66% and -54%, respectively), as well as nodule mineralization (-90% and -51%, respectively). Two-way analysis of variance showed that both mechanical loading and radiation reduced BV/TV, mechanical loading reduced trabecular thickness (Tb.Th), and radiation reduced Tb.N, at both time points. To assess acute response to mechanical stimuli, samples were harvested from a subset of Sham-AL (n=5) and SSR-AL (n=5) to measure changes in gene expression levels. Preliminary results indicate that axial loading increased expression of the antioxidant response gene Nfe2l2 and the osteoprogenitor-associated marker Runx2 in the bone marrow cells, and there was an interaction effect between axial loading and radiation at 2-months post-IR. Additional analyses of gene expression levels in the mineralized tissue are in progress. Results indicate that SSR caused persistent impairment of osteoblast colony formation and nodule mineralization 6-mo post-IR. Contrary to our hypothesis, simulated space radiation did not impair the ability of cancellous bone to respond to a mechanical anabolic stimulus, consistent with our previous findings [1]. Hence, compressive loading may be a potential countermeasure against spaceflight-induced bone loss.

Simulated Space Radiation: Murine Skeletal Responses During Recovery and with Mechanical Stimulation

NASA Technical Reports Server (NTRS)

Shirazi-Fard, Yasaman; Zaragoza, Josergio; Schreurs, Ann-Sofie; Truong, Tiffany; Tahimic, Candice; Alwood, Joshua S.; Globus, R. K.

2016-01-01

Simulated space radiation at doses similar to those of solar particle events or a round-trip sojourn to Mars (1-2Gy) may cause skeletal tissue degradation and deplete stem/progenitor cell pools throughout the body. We hypothesized that simulated space radiation (SSR) causes late, time-dependent deficits in bone structure and bone cell function reflected by changes in gene expression in response to anabolic stimuli. We used a unique sequential dual ion exposure (proton and iron) for SSR to investigate time-dependence of responses in gene expression, cell function, and microarchitecture with respect to radiation and an anabolic stimulus of axial loading (AL). Male 16-wk C57BL6/J mice (n=120 total) were exposed to 0Gy (Sham, n=10), 56Fe (2Gy, positive control dose, n=10), or sequential ions for SSR (1Gy 1H/56Fe/1H, n=10) by total body irradiation (IR), and the tissues were harvested 2 or 6 mo. later. Further, to assess the response to anabolic stimuli, we subjected additional Sham-AL (n=15) and SSR-AL (n=15) groups to rest-inserted tibial axial loading (AL) starting at 1 and 5 months post-IR (-9N, 60 cycles/day, 3 days/wk, 4 wks). Exposure to 56Fe caused a significant reduction in cancellous bone volume fraction (BV/TV) compared to Sham (-34%) and SSR (-20%) in the proximal tibia metaphysis at 2-months post-IR; however BV/TV for SSR group was not different than Sham. Both 56Fe and SSR caused significant reduction in trabecular number (Tb.N) compared to Sham (-33% and -16%, respectively). Further, Tb.N for 56Fe (2Gy) was significantly lower than SSR (-21%). Ex vivo culture of marrow cells to assess growth and differentiation of osteoblast lineage cells 6 months post-IR showed that both 56Fe and SSR exposures significantly impaired colony formation compared to Sham (-66% and -54%, respectively), as well as nodule mineralization (-90% and -51%, respectively). Two-way analysis of variance showed that both mechanical loading and radiation reduced BV/TV, mechanical loading reduced trabecular thickness (Tb.Th), and radiation reduced Tb.N, at both time points. To assess acute response to mechanical stimuli, samples were harvested from a subset of Sham-AL (n=5) and SSR-AL (n=5) to measure changes in gene expression levels. Preliminary results indicate that axial loading increased expression of the antioxidant response gene Nfe2l2 and the osteoprogenitor-associated marker Runx2 in the bone marrow cells, and there was an interaction effect between axial loading and radiation at 2-months post-IR. Additional analyses of gene expression levels in the mineralized tissue are in progress. Results indicate that SSR caused persistent impairment of osteoblast colony formation and nodule mineralization 6-mo post-IR. Contrary to our hypothesis, simulated space radiation did not impair the ability of cancellous bone to respond to a mechanical anabolic stimulus, consistent with our previous findings. Hence, compressive loading may be a potential countermeasure against spaceflight-induced bone loss.

Radiotherapy With or Without Surgery for Patients With Idiopathic Sclerosing Orbital Inflammation Refractory or Intolerant to Steroid Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lee, Jong Hoon; Kim, Yeon-Sil, E-mail: yeonkim7@catholic.ac.kr; Yang, Suk Woo

Purpose: To evaluate the outcomes of patients with idiopathic sclerosing orbital inflammation (ISOI) treated with radiotherapy with or without surgery. Methods and Materials: We retrospectively reviewed 22 patients with histopathologically confirmed ISOI who had been refractory or intolerant to steroid therapy and treated with radiation with or without surgery. The radiation dose ranged from 20 to 40 Gy (median, 20 Gy) at 2 Gy per fraction. Presenting signs and treatment outcomes were assessed. Results: Proptosis was the most common sign at presentation, seen in 19 (86.3%) patients, followed by restriction of extraocular movements in 10 (45.4%) patients. Response to radiotherapymore » was complete in 15 (68.1%) patients, partial in 3 (13.6%) patients, and none in 4 (18.2%) patients. At the median follow-up of 34 months, 14 (63.6%) patients had progression-free state of symptoms and signs, with the progression-free duration ranging from 3 to 75 months (median, 41.5 months), whereas 8 (36.4%) patients had recurrent or persistent disease although they had received radiotherapy. Of the 14 progression-free patients, 6 underwent a bimodality treatment of debulking surgery of ocular disease and radiotherapy. They had had no recurrent disease. Cataract was the most common late complications, and 2 patients experienced a Grade 3 cataract. Conclusion: Our study suggests that for patients with ISOI who are refractory or intolerant to steroid therapy, 20 Gy of radiotherapy appears to be effective for the control of disease with acceptable complications, especially when it is combined with surgery.« less

Rationale and Design of a Phase 1 Clinical Trial to Evaluate HSV G207 Alone or with a Single Radiation Dose in Children with Progressive or Recurrent Malignant Supratentorial Brain Tumors.

PubMed

Waters, Alicia M; Johnston, James M; Reddy, Alyssa T; Fiveash, John; Madan-Swain, Avi; Kachurak, Kara; Bag, Asim K; Gillespie, G Yancey; Markert, James M; Friedman, Gregory K

2017-03-01

Primary central nervous system tumors are the most common solid neoplasm of childhood and the leading cause of cancer-related death in pediatric patients. Survival rates for children with malignant supratentorial brain tumors are poor despite aggressive treatment with combinations of surgery, radiation, and chemotherapy, and survivors often suffer from damaging lifelong sequelae from current therapies. Novel innovative treatments are greatly needed. One promising new approach is the use of a genetically engineered, conditionally replicating herpes simplex virus (HSV) that has shown tumor-specific tropism and potential efficacy in the treatment of malignant brain tumors. G207 is a genetically engineered HSV-1 lacking genes essential for replication in normal brain cells. Safety has been established in preclinical investigations involving intracranial inoculation in the highly HSV-sensitive owl monkey (Aotus nancymai), and in three adult phase 1 trials in recurrent/progressive high-grade gliomas. No dose-limiting toxicities were seen in the adult studies and a maximum tolerated dose was not reached. Approximately half of the 35 treated adults had radiographic or neuropathologic evidence of response at a minimum of one time point. Preclinical studies in pediatric brain tumor models indicate that a variety of pediatric tumor types are highly sensitive to killing by G207. This clinical protocol outlines a first in human children study of intratumoral inoculation of an oncolytic virus via catheters placed directly into recurrent or progressive supratentorial malignant tumors.

Acute and Chronic Kidney Injury in a Non-Human Primate Model of Partial-Body Irradiation with Bone Marrow Sparing.

PubMed

Cohen, Eric P; Hankey, Kim G; Bennett, Alexander W; Farese, Ann M; Parker, George A; MacVittie, Thomas J

2017-12-01

The development of medical countermeasures against acute and delayed multi-organ injury requires animal models predictive of the human response to radiation and its treatment. Late chronic injury is a well-known feature of radiation nephropathy, but acute kidney injury has not been reported in an appropriate animal model. We have established a single-fraction partial-body irradiation model with minimal marrow sparing in non-human primates. Subject-based medical management was used including parenteral fluids according to prospective morbidity criteria. We show herein that 10 or 11 Gy exposures caused both acute and chronic kidney injury. Acute and chronic kidney injury appear to be dose-independent between 10 and 11 Gy. Acute kidney injury was identified during the first 50 days postirradiation and appeared to resolve before the occurrence of chronic kidney injury, which was progressively more severe up to 180 days postirradiation, which was the end of the study. These findings show that mitigation of the acute radiation syndrome by medical management will unmask delayed late effects that occur months after partial-body irradiation. They further emphasize that both acute and chronic changes in kidney function must be taken into account in the use and timing of mitigators and medical management for acute radiation syndrome and delayed effects of acute radiation exposure (DEARE).

Comparative phylogeography of oceanic archipelagos: Hotspots for inferences of evolutionary process

PubMed Central

Shaw, Kerry L.; Gillespie, Rosemary G.

2016-01-01

Remote island archipelagos offer superb opportunities to study the evolution of community assembly because of their relatively young and simple communities where speciation contributes to the origin and evolution of community structure. There is great potential for common phylogeographic patterns among remote archipelagos that originate through hotspot volcanism, particularly when the islands formed are spatially isolated and linearly arranged. The progression rule is characterized by a phylogeographic concordance between island age and lineage age in a species radiation. Progression is most likely to arise when a species radiation begins on an older island before the emergence of younger islands of a hotspot archipelago. In the simplest form of progression, colonization of younger islands as they emerge and offer appropriate habitat, is coincident with cladogenesis. In this paper, we review recent discoveries of the progression rule on seven hotspot archipelagos. We then discuss advantages that progression offers to the study of community assembly, and insights that community dynamics may offer toward understanding the evolution of progression. We describe results from two compelling cases of progression where the mosaic genome may offer insights into contrasting demographic histories that shed light on mechanisms of speciation and progression on remote archipelagos. PMID:27432948

The Role of Diffusion-Weighted Magnetic Resonance Imaging in the Treatment Response Evaluation of Hepatocellular Carcinoma Patients Treated With Radiation Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yu, Jeong Il; Park, Hee Chul, E-mail: hee.ro.park@skku.edu; Lim, Do Hoon

2014-07-15

Purpose: We investigated the role of diffusion-weighted magnetic resonance imaging (DW MRI) as a response evaluation indicator for hepatocellular carcinoma (HCC) treated with radiation therapy (RT). Methods and Materials: Inclusion criteria of this retrospective study were DW MRI acquisition within 1 month before and 3 to 5 months after RT. In total, 48 patients were enrolled. Two radiation oncologists measured the apparent diffusion coefficient (ADC). Possible predictive factors, including alteration of the ADC value before and 3 to 5 month after RT, in relation to local progression-free survival (LPFS) were analyzed and compared. Results: Three months after RT, 6 patients (12.5%) showed amore » complete response, and 27 patients (56.3%) showed a partial response when evaluated using the modified response evaluation criteria in solid tumors (mRECIST). The average ADC ± SD values were 1.21 ± 0.27 ( × 10{sup −3} mm{sup 2}/s) before and 1.41 ± 0.36 ( × 10{sup −3} mm{sup 2}/s) after RT (P<.001). The most significant prognostic factor related to LPFS was mRECIST (P<.001). The increment of ADC value (≥20%) was also a significant factor (P=.02), but RECIST (version 1.1; P=.11) was not. When RECIST was combined with the increment of ADC value (≥20%), the LPFS rates were significantly different between the groups (P=.004), and the area under the curve value (0.745) was comparable with that of mRECIST (0.765). Conclusions: ADC value change before and after RT in HCC was closely related to LPFS. ADC value and RECIST may substitute for mRECIST in patients who cannot receive contrast agents.« less

Proton Therapy for Reirradiation of Progressive or Recurrent Chordoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

McDonald, Mark W., E-mail: mmcdona2@iuhealth.org; Indiana University Health Proton Therapy Center, Bloomington, Indiana; Linton, Okechuckwu R.

2013-12-01

Purpose: To report the results in patients reirradiated with proton therapy for recurrent or progressive chordoma, with or without salvage surgery. Methods and Materials: A retrospective review of 16 consecutive patients treated from 2005 to 2012 was performed. All patients had received at least 1 prior course of radiation therapy to the same area, and all but 1 patient had at least 1 surgical resection for disease before receiving reirradiation. At the time of recurrence or progression, half of the patients underwent additional salvage surgery before receiving reirradiation. The median prior dose of radiation was 75.2 Gy (range, 40-79.2 Gy).more » Six patients had received prior proton therapy, and the remainder had received photon radiation. The median gross tumor volume at the time of reirradiation was 71 cm{sup 3} (range, 0-701 cm{sup 3}). Reirradiation occurred at a median interval of 37 months after prior radiation (range, 12-129 months), and the median dose of reirradiation was 75.6 Gy (relative biological effectiveness [RBE]) (range. 71.2-79.2 Gy [RBE]), given in standard daily fractionation (n=14) or hyperfractionation (n=2). Results: The median follow-up time was 23 months (range, 6-63 months); it was 26 months in patients alive at the last follow-up visit (range, 12-63 months). The 2-year estimate for local control was 85%, overall survival 80%, chordoma-specific survival 88%, and development of distant metastases 20%. Four patients have had local progression: 3 in-field and 1 marginal. Late toxicity included grade 3 bitemporal lobe radionecrosis in 1 patient that improved with hyperbaric oxygen, a grade 4 cerebrospinal fluid leak with meningitis in 1 patient, and a grade 4 ischemic brainstem stroke (out of radiation field) in 1 patient, with subsequent neurologic recovery. Conclusions: Full-dose proton reirradiation provided encouraging initial disease control and overall survival for patients with recurrent or progressive chordoma, although additional toxicities may develop with longer follow-up times.« less

PubMed Central

BENSON, R.; BHASKER, S.; MOHANTI, B.K.

2015-01-01

SUMMARY Juvenile nasopharyngeal angiofibroma (JNA) is a disease of adolescent males characterised by high vascularity with local aggressiveness. This analysis was intended to see the effectiveness of radiation in locally advanced JNA. We included patients treated from 1990-2012. A total of 31 patients met study criteria. Median age was 16 years (range: 12-33 years). Radiation was used for refractory, residual or unresectable locally advanced disease. The median radiation dose was 30 Gy (range: 30-45 Gy). Median follow-up was 36 months (Range: 1-271 months). The median progression-free survival [PFS] was not reached. PFS at 3, 5 and 10 years was 91.7, 70.7 and 70.7% respectively. Three patients progressed at 38, 43 and 58 months after completion of treatment and opted for alternative therapy. One patient developed squamous cell carcinoma of the nasal ale 15 years after radiation. PMID:26019389

Nanoparticle radio-enhancement: principles, progress and application to cancer treatment

NASA Astrophysics Data System (ADS)

Kuncic, Zdenka; Lacombe, Sandrine

2018-01-01

Enhancement of radiation effects by high-atomic number nanoparticles (NPs) has been increasingly studied for its potential to improve radiotherapeutic efficacy. The underlying principle of NP radio-enhancement is the potential to release copious electrons into a nanoscale volume, thereby amplifying radiation-induced biological damage. While the vast majority of studies to date have focused on gold nanoparticles with photon radiation, an increasing number of experimental, theoretical and simulation studies have explored opportunities offered by other NPs (e.g. gadolinium, platinum, iron oxide, hafnium) and other therapeutic radiation sources such as ion beams. It is thus of interest to the research community to consolidate findings from the different studies and summarise progress to date, as well as to identify strategies that offer promising opportunities for clinical translation. This is the purpose of this Topical Review.

Radiation of a resonant medium excited by few-cycle optical pulses at superluminal velocity

NASA Astrophysics Data System (ADS)

Arkhipov, R. M.; Pakhomov, A. V.; Arkhipov, M. V.; Babushkin, I.; Tolmachev, Yu A.; Rosanov, N. N.

2017-05-01

Recent progress in generation of optical pulses of durations comparable to one optical cycle has presented great opportunities for studies of the fundamental processes in matter as well as time-resolved spectroscopy of ultrafast processes in nonlinear media. It opened up a new area of research in modern ultrafast nonlinear optics and led to appearance of the attosecond science. In parallel, a new research area related to emission from resonant media excited by superluminally propagating ultrashort bursts of electromagnetic radiation has been actively developed over the last few years. In this paper, we review our recent results on theoretical analysis of the Cherenkov-type radiation of a resonant medium excited by few-cycle optical pulses propagating at superluminal velocity. This situation can be realized when an electromagnetic pulse with a plane wavefront incidents on a straight string of resonant atoms or a spot of light rotates at very large angular frequency and excites a distant circular string of resonant dipoles. Theoretical analysis revealed some unusual and remarkable features of the Cherenkov radiation generated in this case. This radiation arises in a transient regime which leads to the occurrence of new frequencies in the radiation spectrum. Analysis of the characteristics of this radiation can be used for the study of the resonant structure properties. In addition, a nonlinear resonant medium excited at superluminal velocity can emit unipolar optical pulses, which can be important in ultrafast control of wave-packet dynamics of matter. Specifics of the few-cycle pulse-driven optical response of a resonant medium composed of linear and nonlinear oscillators is discussed.

Medical Implications of Space Radiation Exposure Due to Low-Altitude Polar Orbits.

PubMed

Chancellor, Jeffery C; Auñon-Chancellor, Serena M; Charles, John

2018-01-01

Space radiation research has progressed rapidly in recent years, but there remain large uncertainties in predicting and extrapolating biological responses to humans. Exposure to cosmic radiation and solar particle events (SPEs) may pose a critical health risk to future spaceflight crews and can have a serious impact on all biomedical aspects of space exploration. The relatively minimal shielding of the cancelled 1960s Manned Orbiting Laboratory (MOL) program's space vehicle and the high inclination polar orbits would have left the crew susceptible to high exposures of cosmic radiation and high dose-rate SPEs that are mostly unpredictable in frequency and intensity. In this study, we have modeled the nominal and off-nominal radiation environment that a MOL-like spacecraft vehicle would be exposed to during a 30-d mission using high performance, multicore computers. Projected doses from a historically large SPE (e.g., the August 1972 solar event) have been analyzed in the context of the MOL orbit profile, providing an opportunity to study its impact to crew health and subsequent contingencies. It is reasonable to presume that future commercial, government, and military spaceflight missions in low-Earth orbit (LEO) will have vehicles with similar shielding and orbital profiles. Studying the impact of cosmic radiation to the mission's operational integrity and the health of MOL crewmembers provides an excellent surrogate and case-study for future commercial and military spaceflight missions.Chancellor JC, Auñon-Chancellor SM, Charles J. Medical implications of space radiation exposure due to low-altitude polar orbits. Aerosp Med Hum Perform. 2018; 89(1):3-8.

Boron Neutron Capture Therapy in the Treatment of Recurrent Laryngeal Cancer.

PubMed

Haapaniemi, Aaro; Kankaanranta, Leena; Saat, Riste; Koivunoro, Hanna; Saarilahti, Kauko; Mäkitie, Antti; Atula, Timo; Joensuu, Heikki

2016-05-01

To investigate the safety and efficacy of boron neutron capture therapy (BNCT) as a larynx-preserving treatment option for patients with recurrent laryngeal cancer. Six patients with locally recurrent squamous cell laryngeal carcinoma and 3 patients with persistent laryngeal cancer after prior treatment were treated with BNCT at the FiR1 facility (Espoo, Finland) in 2006 to 2012. The patients had received prior radiation therapy with or without concomitant chemotherapy to a cumulative median dose of 66 Gy. The median tumor diameter was 2.9 cm (range, 1.4-10.9 cm) before BNCT. Boron neutron capture therapy was offered on a compassionate basis to patients who either refused laryngectomy (n=7) or had an inoperable tumor (n=2). Boronophenylalanine-fructose (400 mg/kg) was used as the boron carrier and was infused over 2 hours intravenously before neutron irradiation. Six patients received BNCT once and 3 twice. The estimated average gross tumor volume dose ranged from 22 to 38 Gy (W) (mean; 29 Gy [W]). Six of the 8 evaluable patients responded to BNCT; 2 achieved complete and 4 partial response. One patient died early and was not evaluable for response. Most common side effects were stomatitis, fatigue, and oral pain. No life-threatening or grade 4 toxicity was observed. The median time to progression within the target volume was 6.6 months, and the median overall survival time 13.3 months after BNCT. One patient with complete response is alive and disease-free with a functioning larynx 60 months after BNCT. Boron neutron capture therapy given after prior external beam radiation therapy is well tolerated. Most patients responded to BNCT, but long-term survival with larynx preservation was infrequent owing to cancer progression. Selected patients with recurrent laryngeal cancer may benefit from BNCT. Copyright © 2016 Elsevier Inc. All rights reserved.

Boron Neutron Capture Therapy in the Treatment of Recurrent Laryngeal Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Haapaniemi, Aaro, E-mail: aaro.haapaniemi@hus.fi; Kankaanranta, Leena; Saat, Riste

2016-05-01

Purpose: To investigate the safety and efficacy of boron neutron capture therapy (BNCT) as a larynx-preserving treatment option for patients with recurrent laryngeal cancer. Methods and Materials: Six patients with locally recurrent squamous cell laryngeal carcinoma and 3 patients with persistent laryngeal cancer after prior treatment were treated with BNCT at the FiR1 facility (Espoo, Finland) in 2006 to 2012. The patients had received prior radiation therapy with or without concomitant chemotherapy to a cumulative median dose of 66 Gy. The median tumor diameter was 2.9 cm (range, 1.4-10.9 cm) before BNCT. Boron neutron capture therapy was offered on a compassionate basis to patientsmore » who either refused laryngectomy (n=7) or had an inoperable tumor (n=2). Boronophenylalanine-fructose (400 mg/kg) was used as the boron carrier and was infused over 2 hours intravenously before neutron irradiation. Results: Six patients received BNCT once and 3 twice. The estimated average gross tumor volume dose ranged from 22 to 38 Gy (W) (mean; 29 Gy [W]). Six of the 8 evaluable patients responded to BNCT; 2 achieved complete and 4 partial response. One patient died early and was not evaluable for response. Most common side effects were stomatitis, fatigue, and oral pain. No life-threatening or grade 4 toxicity was observed. The median time to progression within the target volume was 6.6 months, and the median overall survival time 13.3 months after BNCT. One patient with complete response is alive and disease-free with a functioning larynx 60 months after BNCT. Conclusions: Boron neutron capture therapy given after prior external beam radiation therapy is well tolerated. Most patients responded to BNCT, but long-term survival with larynx preservation was infrequent owing to cancer progression. Selected patients with recurrent laryngeal cancer may benefit from BNCT.« less

Prospective, open, multicentre Phase I/II trial to assess safety and efficacy of neoadjuvant radiochemotherapy with docetaxel and cisplatin for esophageal carcinoma.

PubMed

Ma, Hong-Bing; Di, Zheng-Li; Wen, Jiao; Ke, Yue; Sun, Xiaodong; Ren, Juan

2015-02-01

Esophageal squamous cell carcinoma is increasingly treated with trimodality therapy. The objective of this Phase I/II clinical study is to assess the efficacy and safety of neoadjuvant radiochemotherapy with docetaxel and cisplatin and radiotherapy in patients with esophagectomy for locally advanced squamous cell carcinoma of the esophagus with neoadjuvant chemoradiotherapy. Patients with esophageal squamous cell carcinoma received radiochemotherapy (50 Gy/25 fractions during Weeks 1-5) using a three-dimensional conformal radiation therapy or intensity-modulated radiation therapy technique together with weekly docetaxel (20 mg/m(2) at dose levels 1 and 2, 25 mg/m(2) at dose level 3 on Weeks 1-5) and cisplatin (30 mg/m(2) at dose level 1, 40 mg/m(2) at dose levels 2 and 3 on Weeks 1-5) from January 2009 to December 2011. The dose-limiting toxicities and maximum tolerated dose were the primary endpoints and overall response rate and progression-free survival were the secondary endpoints. Over this timeframe, a total of 49 patients completed trimodality therapy. Thirteen patients were treated at dose level 1, 21 patients at dose level 2 and 15 patients at dose level 3.The maximum tolerated dose for docetaxel was 20 mg/m(2) and cisplatin 40 mg/m(2). The complete response or partial response was observed in 26.5% (13/49) of patients. Thirty-four patients (69.4%) were treated with neoadjuvant radiochemotherapy followed by surgical resection. The median progression-free survival and median overall survival for all patients (n = 49) were 8 and 17.2 months, respectively. The median overall survival was 27.5 months for patients treated at dose level 2. Neoadjuvant radiochemotherapy with docetaxel 20 mg/m(2) and cisplatin 40 mg/m(2) was effective and tolerable induction regimen in patients with esophageal tumors. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Parameterization of GCM subgrid nonprecipitating cumulus and stratocumulus clouds using stochastic/phenomenological methods. Annual technical progress report, 1 December 1992--30 November 1993

DOE Office of Scientific and Technical Information (OSTI.GOV)

Stull, R.B.

1993-08-27

This document is a progress report to the USDOE Atmospheric Radiation and Measurement Program (ARM). The overall project goal is to relate subgrid-cumulus-cloud formation, coverage, and population characteristics to statistical properties of surface-layer air, which in turn are modulated by heterogeneous land-usage within GCM-grid-box-size regions. The motivation is to improve the understanding and prediction of climate change by more accurately describing radiative and cloud processes.

Effect of Exposure to 900 MHz GSM Mobile Phone Radiofrequency Radiation on Estrogen Receptor Methylation Status in Colon Cells of Male Sprague Dawley Rats

PubMed Central

Mokarram, P.; Sheikhi, M.; Mortazavi, S.M.J.; Saeb, S.; Shokrpour, N.

2017-01-01

Background: Over the past several years, the rapidly increasing use of mobile phones has raised global concerns about the biological effects of exposure to radiofrequency (RF) radiation. Numerous studies have shown that exposure to electromagnetic fields (EMFs) can be associated with effects on the nervous, endocrine, immune, cardiovascular, hematopoietic and ocular systems. In spite of genetic diversity, the onset and progression of cancer can be controlled by epigenetic mechanisms such as gene promoter methylation. There are extensive studies on the epigenetic changes of the tumor suppressor genes as well as the identification of methylation biomarkers in colorectal cancer. Some studies have revealed that genetic changes can be induced by exposure to RF radiation. However, whether or not RF radiation is capable of inducing epigenetic alteration has not been clarified yet. To date, no study has been conducted on the effect of radiation on epigenetic alterations in colorectal cancer (CRC). Several studies have also shown that methylation of estrogen receptor α (ERα), MYOD, MGMT, SFRP2 and P16 play an important role in CRC. It can be hypothesized that RF exposure can be a reason for the high incidence of CRC in Iran. This study aimed to investigate whether epigenetic pattern of ERα is susceptible to RF radiation and if RF radiation can induce radioadaptive response as epigenetic changes after receiving the challenge dose (γ-ray). Material and Method: 40 male Sprague-Dawley rats were divided into 4 equal groups (Group I: exposure to RF radiation of a GSM cell phone for 4 hours and sacrificed after 24 hours; Group II: RF exposure for 4 hours, exposure to Co-60 gamma radiation (3 Gy) after 24 hours and sacrificed after 72 hrs; Group III: only 3Gy gamma radiation; Group 4: control group). DNA from colon tissues was extracted to evaluate the methylation status by methylation specific PCR. Results: Our finding showed that exposure to GSM cell phone RF radiation was capable of altering the pattern of ERα gene methylation compared to that of non-exposed controls. Furthermore, no adaptive response phenomenon was induced in the pattern of ERα gene methylation after exposure to the challenging dose of Co-60 γ-rays. Conclusion: It can be concluded that exposure to RF radiation emitted by GSM mobile phones can lead to epigenetic detrimental changes in ERα promoter methylation pattern. PMID:28451581

Late effects from particulate radiations in primate and rabbit tissues

NASA Astrophysics Data System (ADS)

Lett, J. T.; Cox, A. B.; Bergtold, D. S.; Lee, A. C.; Pickering, J. E.

Optic tissues in groups of New Zealand white rabbits were irradiated locally at different stages throughout the median life span of the species with a single dose (9 Gy) of 425 MeV/amu Ne ions (LET∞~30 keV/μm) and then inspected routinely for the progression of radiation cataracts. The level of early cataracts was found to be highest in the youngest group of animals irradiated (8 weeks old) but both the onset of late cataracts and loss of vision occurred earlier when animals were irradiated during the second half of the median life span. This age response can have serious implications in terms of space radiation hazards to man. Rhesus monkeys that had been subjected to whole-body skin irradiation (2.8 and 5.6 Gy) by 32 MeV protons (range in tissue ~ 1 cm) some twenty years previously were analysed for radiation damage by the propagation of skin fibroblasts in primary cultures. Such propagation from skin biopsies in MEM-α medium (serial cultivation) or in supplemented Ham's F-10 medium (cultivation without dilution) revealed late damage in the stem (precursor) cells of the skins of the animals. The proton fluxes employed in this experiment are representative of those occurring in major solar flares.

Enhancing radiotherapy with cyclooxygenase-2 enzyme inhibitors: a rational advance?

PubMed

Choy, Hak; Milas, Luka

2003-10-01

Results of preclinical studies suggesting that the efficacy of molecular therapies is enhanced when they are combined with radiation have generated a surge of clinical trials combining these modalities. We reviewed the literature to identify the rationale and experimental foundation supporting the use of cyclooxygenase-2 (COX-2) inhibitors with standard radiotherapy regimens in current clinical trials. Radiation affects the ability of cells to divide and proliferate and induces the expression of genes involved in signaling pathways that promote cell survival or trigger cell death. Future advances in radiotherapy will hinge on understanding mechanisms by which radiation-induced transcription of genes governs cell death and survival, the selective control of this process, and the optimal approaches to combining this knowledge with existing therapeutic modalities. COX-2 is expressed in all stages of cancer, and in several cancers its overexpression is associated with poor prognosis. Evidence from clinical and preclinical studies indicates that COX-2-derived prostaglandins participate in carcinogenesis, inflammation, immune response suppression, apoptosis inhibition, angiogenesis, and tumor cell invasion and metastasis. Clinical trial results have demonstrated that selective inhibition of COX-2 can alter the development and the progression of cancer. In animal models, selective inhibition of COX-2 activity is associated with the enhanced radiation sensitivity of tumors without appreciably increasing the effects of radiation on normal tissue, and preclinical evidence suggests that the principal mechanism of radiation potentiation through selective COX-2 inhibition is the direct increase in cellular radiation sensitivity and the direct inhibition of tumor neovascularization. Results of current early-phase studies of non-small-cell lung, esophageal, cervical, and brain cancers will determine whether therapies that combine COX-2 inhibitors and radiation will enter randomized clinical trials.

Hypofractionated whole breast radiation and partial breast radiation for early-stage breast cancers: an update on progress.

PubMed

McCormick, Beryl

2012-09-01

This article provides an update of recent progress using partial breast irradiation (PBI) for the treatment of early-stage breast cancer, rather than whole breast radiotherapy (WBRT), which is the standard of care. Several large, prospective, randomized trials are nearing target accrual or have been completed, including the NSABP/RTOG trial, the Milan-based intraoperative radiation trial, and the international TARGIT trial, and the status of each is discussed. The American Society for Radiation Oncology has also published a consensus statement to guide the use of PBI until some of the phase III trials are more mature. Finally, several articles have appeared recently, reporting unexpected adverse effects of PBI in small series, and this information is reviewed. Several recent prospective trials of WBRT are also discussed, with the theme of comparing the standard 25 fractions to a shortened, hypofractionated trial arm delivering equivalent doses of WBRT in approximately 15 treatments, another radiation strategy for a shortened course of treatment after breast-conserving surgery.

SEMIANNUAL REPORT TO THE ATOMIC ENERGY COMMISSION

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jacobson, L.O. ed.

Progress in radiobiology and caneer research is reported. Topics covered include: comparison of the effects of isologous, homologous, and heterologous hematopoietic tissues on post-irradiation survival; survival of transfused blood in rats; erythropoietic response to erythropoietin; inhibition of erythropoiesis by estrogens; tryptophan metabolism; effect of daily exposure to l5-r gamma radiation on susceptibility of mice to experinrental infection; restorailon of serum bactericidal activity and prevention of its loss in x- irradiated mice; immunohistochemical study of Ehrlich ascites tumor; comparison of effects of I/sup 131/-induced hypothyroidism and L-triiodothyronine on irradiated hair roots in mice; modification of radiation responses of tissue by colchicine;more » production and use of I/sup 131/; localization of ocl evaluation of brain scanning system; thick target yield and excitation function for the reaction Rh/sup 103/(p,n)Pb/sup 103/; incorporation of C/sup 14/ and tritium precursors into brain; net synthesis of RNA with a microleial enzyme requiring DNA and four ribonueleoside triphosphates; snythesis of (P/sup 37/) uridine 5'- phosphate; and of 17- alpha -hydroxyprogesterone-4-C/sup 14/-l7 alpha -caproate by homogenates of rat liver and human placenta. (M.C.G.)« less

Inter- and intra-cellular mechanism of NF-kB-dependent survival advantage and clonal expansion of radio-resistant cancer cells.

PubMed

Yu, Hui; Aravindan, Natarajan; Xu, Ji; Natarajan, Mohan

2017-02-01

Understanding the underlying mechanism by which cancer cells acquire resistance to radiation and favorably selected for its clonal expansion will provide molecular insight into tumor recurrence at the treatment site. In the present study, we investigated the molecular mechanisms prompted in MCF-7 breast cancer cells in response to clinical radiation and the associated coordination of intra- and inter-cellular signaling that orchestrate radio-resistance and tumor relapse/recurrence. Our findings showed that 2 or 10Gy of 137 Cs γ-rays at a dose rate of 1.03Gy/min trigger the activation of nuclear factor kappa B (NF-κB), its DNA-binding activity and recycles its own transcription. NF-κB DNA-binding kinetic analysis demonstrated both sustained and dual phase NF-κB activation with radiation. Gene manipulation approach revealed that radiation triggered NF-κB-mediated TNF-α transcriptional activity. TNF-α blocking approach confirmed that the de novo synthesis and secretion of TNF-α serves as a pre-requisite for the second phase of NF-κB activation and sustained maintenance. Radiation-associated NF-κB-dependent secretion of TNF-α from irradiated cells, in parallel, activates NF-κB in the non-targeted un-irradiated bystander cells. Together, these findings demonstrated that radiation-triggered NF-κB-dependent TNFα secretion is critical for self-sustenance of NF-κB (through autocrine positive feedback signaling) and for coordinating bystander response (through inter-cellular paracrine mechanism) after radiation exposure. Further, the data suggest that this self-sustained NF-κB in the irradiated cells determines radio-resistance, survival advantage and clonal expansion of the tumor cells at the treatment site. Parallel maintenance of NF-ΚB-TNF-α-NF-κB feedback-cycle in the un-irradiated non-targeted bystander cells initiates supportive mechanism for the promotion and progression of surviving tumor cells. Intervening this molecular pathway would help us to achieve disease-free cancer survivors. Copyright © 2017 Elsevier Inc. All rights reserved.

PROSPECTIVE EVALUATION OF AN IN VITRO RADIATION RESISTANCE ASSAY IN LOCALLY ADVANCED CANCER OF THE UTERINE CERVIX: A SOUTHWEST ONCOLOGY GROUP STUDY

PubMed Central

Randall, Leslie M; Monk, Bradley J; Moon, James; Parker, Ricardo; Al-Ghazi, Muthana; Wilczynski, Sharon; Fruehauf, John P; Markman, Maurie; Burger, Robert A

2010-01-01

Objectives To investigate the feasibility of performing a fresh-tissue, in vitro radiation resistance assay (IVRRA) in a cooperative group setting and to assess the association of IVRRA results with clinical outcomes. Methods Women with Stages IIB-IVA carcinoma of the uterine cervix without obvious para-aortic lymphadenopathy on imaging were eligible. Primary tumor biopsies were shipped to a central testing facility where agar-based cell suspensions were exposed to 300 cGy of RT ± cisplatin and cultured for 5 days. 3H-thymidine incorporation was used to determine percent cell inhibition (PCI) of test specimen compared to that of the untreated control. Tumors were considered to exhibit extreme radiation resistance (ERR), intermediate radiation resistance (IRR) or low radiation resistance (LRR) based on a standard data set from 39 previously studied specimens. Standardized doses of external beam radiation and intracavitary brachytherapy, when feasible, in addition to platinum-based chemotherapy were mandated. Progression-free survival (PFS) was the primary endpoint. Clinical response and overall survival (OS) were secondary endpoints. Clinical investigators were blinded to assay data and vice versa. Results Thirty-six patients were enrolled, but analysis was limited to 17 patients whose specimens were adequate for IVRRA. The median follow-up time was 40 months. There was no association between IVRRA and response. In the Cox model, IRR/ERR tumors showed worse PFS [HR=11.2 (95% CI 1.3–96, p=0.03)] and worse OS [HR=11.7 (95% CI 1.4–99.6, p=0.03)] compared to LRR tumors when IVRRA was performed with RT alone, but there were no associations between IVRRA and PFS or OS when cisplatin was added to the IVRRA. Conclusions IVRRA (RT alone) results correlated with PFS and OS in this prospective trial, but follow-up trials are indicated to address feasibility and to confirm results in an expanded cohort. If confirmed, IVRRA could potentially direct molecular identification of novel targeted therapeutic approaches which might counteract radiation resistance. PMID:20846714

Superior Treatment Response and In-field Tumor Control in Epidermal Growth Factor Receptor-mutant Genotype of Stage III Nonsquamous Non-Small cell Lung Cancer Undergoing Definitive Concurrent Chemoradiotherapy.

PubMed

Lim, Yu Jin; Chang, Ji Hyun; Kim, Hak-Jae; Keam, Bhumsuk; Kim, Tae Min; Kim, Dong-Wan; Paeng, Jin Chul; Kang, Keon Wook; Chung, June-Key; Jeon, Yoon Kyung; Chung, Doo Hyun; Wu, Hong-Gyun

2017-05-01

Although previous in vitro data have suggested a more radio-sensitive nature of epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) cell lines, the clinical behavior according to the EGFR mutational status has not been well-established. In this study, we performed a comparative outcome analysis of EGFR-mutant and wild-type locally advanced NSCLC with chemoradiotherapy (CRT). A total of 102 patients with stage III nonsquamous NSCLC undergoing primary CRT were identified. Clinicopathologic characteristics, including the degree of glucose uptake, were evaluated. Failure patterns considering the radiation field and survival outcomes were compared according to the EGFR mutational status. Pre- and post-CRT maximum standardized uptake values were significantly lower in EGFR-mutant tumors (P = .010 and .018, respectively). The overall response rate was higher in the EGFR-mutant group compared with the wild-type (89% vs. 64%, respectively; P = .023). The 3-year overall survival rate was better with the genetic alteration (68.0% vs. 47.4%, P = .046), but the statistical significance did not remain in multivariate analysis (hazard ratio, 0.68; 95% confidence interval, 0.30-1.55). Considering the tumor progression inside or outside the radiation field, the EGFR-mutant group showed longer in-field time to progression (P = .002), even after adjusting for other related baseline variables (hazard ratio, 0.27; 95% confidence interval, 0.11-0.71). The differential metabolic activity, failure patterns, and prognosis suggest the distinct nature of the EGFR-mutant tumors. EGFR mutational status needs to be considered for more precise curative-intent treatment strategies of locally advanced nonsquamous NSCLC. Copyright © 2017 Elsevier Inc. All rights reserved.

Defining local-regional control and its importance in locally advanced non-small cell lung carcinoma.

PubMed

Machtay, Mitchell; Paulus, Rebecca; Moughan, Jennifer; Komaki, Ritsuko; Bradley, J Effrey; Choy, Hak; Albain, Kathy; Movsas, Benjamin; Sause, William T; Curran, Walter J

2012-04-01

Local-regional control (LRC) rates for non-small cell lung cancer after chemoradiotherapy were studied (using two different definitions of LRC) for the association between LRC and survival. Seven legacy Radiation Therapy Ooncology Group trials of chemoradiotherapy for locally advanced non-small cell lung cancer were analyzed. Two different definitions of LRC were studied: (1) freedom from local progression (FFLP-LRC), the traditional Radiation Therapy Oncology Group methodology, in which a failure is intrathoracic tumor progression by World Health Oorganization criteria; and (2) response-mandatory (strict-LRC), in which any patient not achieving at least partial response was considered to have failure at day 0. Testing for associations between LRC and survival was performed using a Cox multivariate model that included other potential predictive factors. A total of 1390 patients were analyzed. The LRC rate at 3 years was 38% based on the FFLP-LRC definition and 14% based on the strict-LRC definition. Performance status, concurrent chemotherapy, and radiotherapy dose intensity (biologically equivalent dose) were associated with better LRC (using either definition). With the strict-LRC definition (but not FFLP-LRC), age was also important. There was a powerful association between LRC and overall survival (p, 0.0001) on univariate and multivariate analyses. Age, performance status, chemotherapy sequencing, and biologically equivalent dose were also significantly associated with survival. Histology and gender were also significant if the strict-LRC model was used. LRC is associated with survival. The definition of LRC affects the results of these analyses. A consensus definition of LRC, incorporating functional imaging and/or central review, is needed, with the possibility of using LRC as a surrogate end point in future trials.

NEW ULTRA-WIDE-FIELD ANGIOGRAPHIC GRADING SCHEME FOR RADIATION RETINOPATHY AFTER IODINE-125 BRACHYTHERAPY FOR UVEAL MELANOMA.

PubMed

McCannel, Tara A; Kim, EunAh; Kamrava, Mitchell; Lamb, James; Caprioli, Joseph; Yang, Dong; McCannel, Colin A

2017-10-06

Radiation retinopathy remains incompletely characterized and may cause severe vision loss. Ultra-wide-field fluorescein angiography provides a pan-fundus view of vascular alterations caused by radiation treatment and may predict visual and ocular outcomes. We have developed a grading scheme to describe pan-fundus severity and to predict the progression of radiation retinopathy in patients treated for uveal melanoma with iodine-125 brachytherapy. A retrospective review of patients treated with standard iodine-125 brachytherapy for uveal melanoma at the Ophthalmic Oncology Center at the University of California, Los Angeles, who had undergone both baseline and postbrachytherapy ultra-wide-field fluorescein angiography. A grading scheme was devised based on observations of vascular leakage, retinal perfusion status, and retinal proliferation. The correlation of grade severity with patient characteristics, tumor features, visual acuity, optical coherence tomography findings, and neovascular glaucoma was measured with chi-square and one-way analysis of variance analyses. Sixty-seven patients were identified for review. Consistent wide-field angiographic patterns after brachytherapy were observed and graded as follows: Grade 0: normal; Grade 1: late foveal leakage; Grade 2: late peripheral leakage; Grade 3: presence of nonperfusion; and Grade 4: retinal neovascularization. Six eyes (8.9%) were Grade 0; 16 (23.8%) were Grade 1; 25 (37.3%) were Grade 2; 16 (23.4%) were Grade 3; and 4 (6.0%) were Grade 4. Higher grade radiation severity correlated significantly with duration of follow-up (P < 0.02); younger age (P = 0.035); worse visual acuity (P = 0.001); cystoid macular edema or atrophy on optical coherence tomography (P < 0.0001); and neovascular glaucoma (P = 0.003). Wide-field fluorescein angiography revealed distinct fundus-wide patterns of vascular damage, which were progressive in nature in eyes treated with iodine-125 brachytherapy for uveal melanoma and correlated with signs of progressive vascular injury. This grading scheme may have prognostic value to predict the progression of radiation retinopathy and to prognosticate visual outcomes in patients undergoing brachytherapy.

Effects of estrogen and gender on cataractogenesis induced by high-LET radiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Henderson, M.A.; Rusek, A.; Valluri, S.

2010-02-01

Planning for long-duration manned lunar and interplanetary missions requires an understanding of radiation-induced cataractogenesis. Previously, it was demonstrated that low-linear energy transfer (LET) irradiation with 10 Gy of {sup 60}Co {gamma} rays resulted in an increased incidence of cataracts in male rats compared to female rats. This gender difference was not due to differences in estrogen, since male rats treated with the major secreted estrogen 17-{beta}-estradiol (E2) showed an identical increase compared to untreated males. We now compare the incidence and rate of progression of cataracts induced by high-LET radiation in male and female Sprague-Dawley rats. Rats received a singlemore » dose of 1 Gy of 600 MeV {sup 56}Fe ions. Lens opacification was measured at 2-4 week intervals with a slit lamp. The incidence and rate of progression of radiation-induced cataracts was significantly increased in the animals in which estrogen was available from endogenous or exogenous sources. Male rats with E2 capsules implanted had significantly higher rates of progression compared to male rats with empty capsules implanted (P = 0.025) but not compared to the intact female rats. These results contrast with data obtained after low-LET irradiation and suggest the possibility that the different types of damage caused by high- and low-LET radiation may be influenced differentially by steroid sex hormones.« less

Long-Term Follow-Up of a Phase II Trial of High-Dose Radiation With Concurrent 5-Fluorouracil and Cisplatin in Patients With Anal Cancer (ECOG E4292)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chakravarthy, A. Bapsi, E-mail: bapsi.chak@vanderbilt.edu; Catalano, Paul J.; Martenson, James A.

Purpose: Although chemoradiation using 5-fluorouracil (5-FU) and mitomycin-C (MMC) is the standard of care in the treatment of anal cancer, many patients are unable to tolerate MMC. This Phase II clinical trial was performed to determine whether cisplatin could replace MMC in the treatment of anal cancer. Methods and Materials: Thirty-three patients with localized anal cancer were enrolled. One patient registered but never received any assigned therapy and was excluded from all analyses. Between February 1, 1993, and July 21, 1993, 19 patients were accrued to Cohort 1. Radiation consisted of 45 Gy to the primary tumor and pelvic nodes,more » followed by a boost to the primary and involved nodes to 59.4 Gy. A planned 2-week treatment break was used after 36 Gy. Concurrent chemotherapy consisted of 5-FU 1,000 mg/m{sup 2}/day on Days 1 to 4 and cisplatin 75 mg/m{sup 2} on Day 1. A second course of 5-FU and cisplatin was given after 36 Gy, when the patient resumed radiation therapy. Between April 4, 1996, and September 23, 1996, an additional 13 patients (Cohort 2) were accrued to the study and received the same treatment except without the planned treatment break. Results: Complete response was seen in 78% (90% CI, 63-89) of patients and was higher in patients who did not get a planned treatment break (92% vs. 68%). The overall Grade 4 toxicity rate was 31%. One treatment-related death (Grade 5) occurred in a patient who developed sepsis. The 5-year overall survival was 69%. Conclusions: Radiation therapy, cisplatin, and 5-FU resulted in an overall objective response (complete response + partial response) of 97%. Although the 5-year progression-free survival was only 55%, the overall 5-year survival was 69%. Given the excellent salvage provided by surgery, this study affirms that cisplatin-based regimens may be an alternative for patients who cannot tolerate the severe hematologic toxicities associated with mitomycin-based chemoradiation regimens.« less

Long-term follow-up of a Phase II trial of high-dose radiation with concurrent 5-fluorouracil and cisplatin in patients with anal cancer (ECOG E4292).

PubMed

Chakravarthy, A Bapsi; Catalano, Paul J; Martenson, James A; Mondschein, Joshua K; Wagner, Henry; Mansour, Edward G; Talamonti, Mark S; Benson, Al Bowen

2011-11-15

Although chemoradiation using 5-fluorouracil (5-FU) and mitomycin-C (MMC) is the standard of care in the treatment of anal cancer, many patients are unable to tolerate MMC. This Phase II clinical trial was performed to determine whether cisplatin could replace MMC in the treatment of anal cancer. Thirty-three patients with localized anal cancer were enrolled. One patient registered but never received any assigned therapy and was excluded from all analyses. Between February 1, 1993, and July 21, 1993, 19 patients were accrued to Cohort 1. Radiation consisted of 45 Gy to the primary tumor and pelvic nodes, followed by a boost to the primary and involved nodes to 59.4 Gy. A planned 2-week treatment break was used after 36 Gy. Concurrent chemotherapy consisted of 5-FU 1,000 mg/m(2)/day on Days 1 to 4 and cisplatin 75 mg/m(2) on Day 1. A second course of 5-FU and cisplatin was given after 36 Gy, when the patient resumed radiation therapy. Between April 4, 1996, and September 23, 1996, an additional 13 patients (Cohort 2) were accrued to the study and received the same treatment except without the planned treatment break. Complete response was seen in 78% (90% CI, 63-89) of patients and was higher in patients who did not get a planned treatment break (92% vs. 68%). The overall Grade 4 toxicity rate was 31%. One treatment-related death (Grade 5) occurred in a patient who developed sepsis. The 5-year overall survival was 69%. Radiation therapy, cisplatin, and 5-FU resulted in an overall objective response (complete response + partial response) of 97%. Although the 5-year progression-free survival was only 55%, the overall 5-year survival was 69%. Given the excellent salvage provided by surgery, this study affirms that cisplatin-based regimens may be an alternative for patients who cannot tolerate the severe hematologic toxicities associated with mitomycin-based chemoradiation regimens. Copyright © 2011 Elsevier Inc. All rights reserved.

Sensitivity of human glioma U-373MG cells to radiation and the protein kinase C inhibitor, calphostin C.

PubMed

Acevedo-Duncan, M; Pearlman, J; Zachariah, B

2001-02-01

We assessed the radiosensitivity of the grade III human glioma cell line U-373MG by investigating the effects of radiation and the specific protein kinase C inhibitor, calphostin C on the cell cycle and cell proliferation. Irradiated glioma U-373MG cells progressed through G1-S and underwent an arrest in G2-M phase. The radiosensitivity of U-373MG cells to graded doses of either photons or electrons was determine by microculture tetrazolium assay. The data was fitted to the linear-quadratic model. The proliferation curves demonstrated that U-373MG cells appear to be highly radiation resistant since 8 Gy was required to achieve 50% cell mortality. Compared to radiation alone, exposure to calphostin C (250 nM) 1 h prior to radiation decreased the proliferation of U-373MG by 76% and calphostin C provoked a weakly synergistic effect in concert with radiation. Depending on the time of application following radiation, calphostin C produced an additive or less than additive effect on cell proliferation. We postulate that the enhanced radiosensitivity observed when cells are exposed to calphostin C prior to radiation may be due to direct or indirect inhibition of protein kinase C isozymes required for cell cycle progression.

The American Society for Therapeutic Radiology and Oncology (ASTRO) evidence-based review of the role of radiosurgery for malignant glioma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tsao, May N.; Mehta, Minesh P.; Whelan, Timothy J.

2005-09-01

Purpose: To systematically review the evidence for the use of stereotactic radiosurgery or stereotactic fractionated radiation therapy in adult patients with malignant glioma. Methods: Key clinical questions to be addressed in this evidence-based review were identified. Outcomes considered were overall survival, quality of life or symptom control, brain tumor control or response and toxicity. MEDLINE (1990-2004 June Week 2), CANCERLIT (1990-2003), CINAHL (1990-2004 June Week 2), EMBASE (1990-2004 Week 25), and the Cochrane library (2004 issue 2) databases were searched using OVID. In addition, the Physician Data Query clinical trials database, the proceedings of the American Society of Clinical Oncologymore » (1997-2004), ASTRO (1997-2004), and the European Society of Therapeutic Radiology and Oncology (ESTRO) (1997-2003) were searched. Data from the literature search were reviewed and tabulated. This process included an assessment of the level of evidence. Results: For patients with newly diagnosed malignant glioma, radiosurgery as boost therapy with conventional external beam radiation was examined in one randomized trial, five prospective cohort studies, and seven retrospective series. There is Level I evidence that the use of radiosurgery boost followed by external beam radiotherapy and carmustine (BCNU) does not confer benefit with respect to overall survival, quality of life, or patterns of failure as compared with external beam radiotherapy and BCNU. There is Level I-III evidence of toxicity associated with radiosurgery boost as compared with external beam radiotherapy alone. The results of the prospective and retrospective studies may be influenced by selection bias. Radiosurgery used as salvage for recurrent or progressive malignant glioma after conventional external beam radiotherapy failure was reported in zero randomized trials, three prospective cohort studies, and five retrospective series. The available data are sparse and insufficient to make absolute recommendations. Stereotactic fractionated radiation therapy has been reported as boost therapy with external beam radiotherapy for patients with newly diagnosed malignant glioma in only three prospective studies. As primary therapy alone without conventional external beam radiotherapy for newly diagnosed malignant glioma patients, stereotactic fractionated radiation therapy has been reported in only one prospective study. There were only three prospective series and two retrospective studies reported for patients with recurrent or progressive malignant glioma. Conclusions: For patients with malignant glioma, there is Level I-III evidence that the use of radiosurgery boost followed by external beam radiotherapy and BCNU does not confer benefit in terms of overall survival, local brain control, or quality of life as compared with external beam radiotherapy and BCNU. The use of radiosurgery boost is associated with increased toxicity. For patients with malignant glioma, there is insufficient evidence regarding the benefits/harms of using radiosurgery at the time progression or recurrence. There is also insufficient evidence regarding the benefits/harms in the use of stereotactic fractionated radiation therapy for patients with newly diagnosed or progressive/recurrent malignant glioma.« less

Hypoxia induced EMT: A review on the mechanism of tumor progression and metastasis in OSCC.

PubMed

Joseph, Joel P; Harishankar, M K; Pillai, Aruthra Arumugam; Devi, Arikketh

2018-05-01

Hypoxia, a condition of low oxygen tension in tissues, has emerged as a crucial factor in tumor pathophysiology. Hypoxic microenvironment gives rise to altered cellular metabolism and triggers varied molecular responses. These responses promote tumor progression and confer radiation resistance and chemo resistance to tumors. The predominant molecules that are associated with hypoxia research are the hypoxia inducible factors (HIFs). HIFs are known to regulate a large group of genes that are involved in cell survival, proliferation, motility, metabolism, pH regulation, extracellular matrix function, inflammatory cell recruitment and angiogenesis by inducing the expression of their downstream target genes. The process of epithelial to mesenchymal transition (EMT) has been associated with metastasis in cancer. Reports also suggest that hypoxia triggers EMT in several types of cancer including breast cancer, prostate cancer and oral cancer. Oral cancer is a predominant cancer in Central and South East Asia. However, in the recent times, the incidence rates of oral cancer have been increasing in Northern and Eastern Europe as well. This review articulates the role of hypoxia and the associated factors like HIFs in inducing EMT in oral cancer (OSCC). Copyright © 2018 Elsevier Ltd. All rights reserved.

Influence of Ionizing Radiation on Stromal-Epithelial Communication in Esophageal Carcinogenesis

NASA Astrophysics Data System (ADS)

Huff, Janice; Patel, Zarana; Grugan, Katharine; Rustgi, Anil; Cucinotta, Francis A.

Esophageal cancer is the 6th leading cause of cancer death worldwide and is associated with a variety of risk factors including tobacco use, heavy alcohol consumption, human papilloma virus infection, and certain dietary factors such as trace mineral and vitamin deficiencies. A connection with ionizing radiation exposure is revealed by the high excess relative risk for esophageal squamous cell carcinoma observed in the survivors of the atomic bomb detonations in Japan. Esophageal carcinomas are also seen as secondary malignancies in patients who received radiotherapy for breast and thoracic cancers; additionally, patients with head/neck and oral squamous cell cancers are at increased risk for metachronous esophageal squamous cell cancers. This malignancy is rapidly fatal, mainly because it remains asymptomatic until late, advanced stages when the disease is rarely responsive to treatment. In normal epithelium, the stromal microenvironment is essential for the maintenance and modulation of cell growth and differentiation. Cross talk between the epithelial and stromal compartments can influence many aspects of malignant progression, including tumor cell proliferation, migration, invasion and recruitment of new blood vessels. To test the hypothesis that radiation exposure plays a role in esophageal carcinogenesis via non-targeted mechanisms involving stromal-epithelial cell communication, we are studying radiation effects on hTERT-immortalized human esophageal epithelial cells and genetic variants grown in co-culture with human esophageal stromal fibrob-lasts (Okawa et al., Genes Dev. 2007. 21: 2788-2803). We examined how irradiation of stromal fibroblasts affected epithelial migration and invasion, behaviors associated with cancer promotion and progression. These assays were conducted in modified Boyden chambers using conditioned media from irradiated fibroblasts. Our results using low LET gamma radiation showed a dose-dependent increase in migration of epithelial cells when exposed to conditioned media from irradiated vs. non-irradiated fibroblasts. We also observed enhanced invasion through a basement membrane matrix in similarly treated cells. Candidate factors that me-diate these effects were identified using antibody capture arrays, and their increased secretion in irradiated fibroblasts was confirmed using ELISAs. We are currently analyzing the effect of these individual factors on epithelial migration and invasion, as well as their influence on cell survival and DNA repair. Our current studies using high-LET radiation will elucidate radiation quality effects on these processes. These results should further our understanding of the mechanisms by which radiation impacts the tissue microenvironment and how it influences cancer development processes.

Location of subventricular zone recurrence and its radiation dose predicts survival in patients with glioblastoma.

PubMed

Weinberg, Brent D; Boreta, Lauren; Braunstein, Steve; Cha, Soonmee

2018-07-01

Glioblastomas are aggressive brain tumors that frequently recur in the subventricular zone (SVZ) despite maximal treatment. The purpose of this study was to evaluate imaging patterns of subventricular progression and impact of recurrent subventricular tumor involvement and radiation dose to patient outcome. Retrospective review of 50 patients diagnosed with glioblastoma and treated with surgery, radiation, and concurrent temozolomide from January 2012 to June 2013 was performed. Tumors were classified based on location, size, and cortical and subventricular zone involvement. Survival was compared based on recurrence type, distance from the initial enhancing tumor (local ≤ 2 cm, distant > 2 cm), and the radiation dose at the recurrence site. Progression of enhancing subventricular tumor was common at both local (58%) and distant (42%) sites. Median survival was better after local SVZ recurrence than distant SVZ recurrence (8.7 vs. 4.3 months, p = 0.04). Radiation doses at local SVZ recurrence sites recurrence averaged 57.0 ± 4.0 Gy compared to 44.7 ± 6.7 Gy at distant SVZ recurrence sites (p = 0.008). Distant subventricular progression at a site receiving ≤ 45 Gy predicted worse subsequent survival (p = 0.05). Glioblastomas frequently recurred in the subventricular zone, and patient survival was worse when enhancing tumor occurred at sites that received lower radiation doses. This recurrent disease may represent disease undertreated at the time of diagnosis, and further study is needed to determine if improved treatment strategies, such as including the subventricular zone in radiation fields, could improve clinical outcomes.

Future directions for LDEF ionizing radiation modeling and assessments

NASA Technical Reports Server (NTRS)

Armstrong, T. W.; Colborn, B. L.

1993-01-01

A calculational program utilizing data from radiation dosimetry measurements aboard the Long Duration Exposure Facility (LDEF) satellite to reduce the uncertainties in current models defining the ionizing radiation environment is in progress. Most of the effort to date has been on using LDEF radiation dose measurements to evaluate models defining the geomagnetically trapped radiation, which has provided results applicable to radiation design assessments being performed for Space Station Freedom. Plans for future data comparisons, model evaluations, and assessments using additional LDEF data sets (LET spectra, induced radioactivity, and particle spectra) are discussed.

Assessing cell cycle progression of neural stem and progenitor cells in the mouse developing brain after genotoxic stress.

PubMed

Etienne, Olivier; Bery, Amandine; Roque, Telma; Desmaze, Chantal; Boussin, François D

2014-05-07

Neurons of the cerebral cortex are generated during brain development from different types of neural stem and progenitor cells (NSPC), which form a pseudostratified epithelium lining the lateral ventricles of the embryonic brain. Genotoxic stresses, such as ionizing radiation, have highly deleterious effects on the developing brain related to the high sensitivity of NSPC. Elucidation of the cellular and molecular mechanisms involved depends on the characterization of the DNA damage response of these particular types of cells, which requires an accurate method to determine NSPC progression through the cell cycle in the damaged tissue. Here is shown a method based on successive intraperitoneal injections of EdU and BrdU in pregnant mice and further detection of these two thymidine analogues in coronal sections of the embryonic brain. EdU and BrdU are both incorporated in DNA of replicating cells during S phase and are detected by two different techniques (azide or a specific antibody, respectively), which facilitate their simultaneous detection. EdU and BrdU staining are then determined for each NSPC nucleus in function of its distance from the ventricular margin in a standard region of the dorsal telencephalon. Thus this dual labeling technique allows distinguishing cells that progressed through the cell cycle from those that have activated a cell cycle checkpoint leading to cell cycle arrest in response to DNA damage. An example of experiment is presented, in which EdU was injected before irradiation and BrdU immediately after and analyzes performed within the 4 hr following irradiation. This protocol provides an accurate analysis of the acute DNA damage response of NSPC in function of the phase of the cell cycle at which they have been irradiated. This method is easily transposable to many other systems in order to determine the impact of a particular treatment on cell cycle progression in living tissues.

Systemic irradiation for selected stage IV and recurrent pediatric solid tumors: method, toxicity, and preliminary results

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wharam, M.D.; Kaizer, H.; Leventhal, B.G.

1980-02-01

Eight patients with advanced pediatric solid tumors received either sequential upper and lower half-body irradiation (HBI) (7.5 rad/min to 500 rad total) or total body irradiation (TBI) (7.5 rad/min to 800 rad total) as part of two multimodality treatment regimens. All patients received combination chemotherapy; drugs were determined by the tumor type. The TBI regimen was selected for two patients who had progression of disease with conventional chemotherapy and for two patients with stage IV neuroblastoma. This intensive regimen consisted of bone marrow harvesting, followed by local radiation to gross disease, marrow-ablative chemotherapy, TBI, and re-infusion of the cryopreserved autologousmore » marrow. Significant acute toxicity was followed by hematologic reconstitution in each patient within seven weeks. At this writing, two patients survived, one of whom is disease free two and one half years without maintenance chemotherapy. A less intensive, outpatient regimen was selected for four patients; three had a complete or good partial response to chemotherapy. The fourth patient had tumor-involved bone marrow not responsive to chemotherapy and was therefore ineligible for marrow cryopreservation and TBI. Each of these four patients received HBI after chemotherapy and local radiation to the primary and/or metastatic sites. Acute toxicity was limited to nausea and vomiting. Significant leukopenia and thrombocytopenia occurred in three patients. All four patients were alive 10 to 26 months post HBI. This pilot study demonstrates that chemotherapy can be integrated with local fractionated radiation, and systemic radiation given as HBI or TBI with acceptable toxicity; sufficient bone marrow stem cells can be harvested after conventional chemotherapy and then cryopreserved to permit hematologic reconstitution of the patient who receives marrow ablative therapy.« less

Impact of {sup 18}F-Fluorodeoxyglucose Positron Emission Tomography Before and After Definitive Radiation Therapy in Patients With Apparently Solitary Plasmacytoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kim, Paul J.; Hicks, Rodney J.; Wirth, Andrew

2009-07-01

Purpose: To evaluate the impact of {sup 18}F-fluorodeoxyglucose positron emission tomography (FDG-PET) on management of patients with apparently isolated plasmacytoma. Methods and Materials: Twenty-one patients with apparently solitary plasmacytoma who underwent FDG-PET for staging or restaging were identified from a central PET database. They were either candidates for or had received definitive radiation therapy (RT). Results: Seventeen patients had initial staging scans for bone (n = 11) or soft tissue (n = 6) plasmacytomas, and 11 had PET scans after RT. Only 1 of 14 known untreated sites of plasmacytoma was not identified on staging PET (lesion sensitivity = 93%).more » Three plasmacytomas were excised before PET. Staging PET influenced management in 6 of 17 patients (35%) by showing multiple myeloma (n = 1), discouraging RT after complete resection (n = 1), excluding plasmacytoma at a second site (n = 1), by increasing RT fields (n = 2), or by suggesting sarcoidosis (n = 1). Fifteen of 17 patients with initial staging PET scans received definitive RT. Restaging PET scans after RT showed complete metabolic response in 8 of 11 cases and progressive disease in 2. Two patients with either no response or partial metabolic response had late responses. Staging sestamibi and PET scans were concordant in five of six occasions (one sestamibi scan was false negative). Conclusions: FDG-PET has value for staging and RT planning in plasmacytoma and potentially could have a role in response-assessment after RT. Slow resolution of FDG uptake posttreatment does not necessarily imply an adverse prognosis.« less

Salvage radiotherapy in prostate cancer patients. Planning, treatment response and prognosis using (11)C-choline PET/CT.

PubMed

García, J R; Cozar, M; Soler, M; Bassa, P; Riera, E; Ferrer, J

2016-01-01

To assess the prognostic value of the therapeutic response by (11)C-choline PET/CT in prostate cancer patients with biochemical recurrence in which (11)C-choline PET/CT indicated radio-guided radiotherapy. The study included 37 patients initially treated with prostatectomy, who were treated due to biochemical recurrence. (11)C-choline PE/CT detected infra-diaphragmatic lymph-node involvement. All were selected for intensity modulated radiation therapy, escalating the dose according to the PET findings. One year after treatment patients underwent PSA and (11)C-choline PET/CT categorizing response (complete/partial/progression). Clinical/biochemical/image monitoring was performed until appearance of second relapse or 36 months in disease-free patients. (11)C-choline PET/CT could detect lymph nodes in all 37 patients. They were 18 (48.6%) of more than a centimetre in size and 19 (51.3%) with no pathological CT morphology: 9 (24.3%) with positive lymph nodes of around one centimetre and 10 (27.0%) only less than a centimetre in size. The response by (11)C-choline PET/CT was categorised one year after radiotherapy: 16 patients (43.2%) complete response; 15 (40.5%) partial response, and 6 (16.2%) progression. The response was concordant between the PSA result and (11)C-choline PET/CT in 32 patients (86.5%), and discordant in five (13.5%). New recurrence was detected in 12 patients (80%) with partial response, and 5 (31.2%) with complete response. The mean time to recurrence was 9 months after partial response, and 18 months after complete response (significant difference, p<.0001). (11)C-choline PET/CT allows the selection of patients with recurrent prostate cancer candidates for radiotherapy and to plan the technique. The evaluation of therapeutic response by (11)C-choline PET/CT has prognostic significance. Copyright © 2015 Elsevier España, S.L.U. and SEMNIM. All rights reserved.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Doss, Mohan

Oxidative damage has been implicated in the pathogenesis of most aging-related diseases including neurodegenerative diseases. Antioxidant supplementation has been found to be ineffective in reducing such diseases, but increased endogenous production of antioxidants from the adaptive response due to physical and cognitive exercises (which increase oxidative metabolism and oxidative stress) has been effective in reducing some of the diseases. Low dose radiation (LDR), which increases oxidative stress and results in adaptive response of increased antioxidants, may provide an alternative method of controlling the aging-related diseases. We have studied the effect of LDR on the induction of adaptive response in ratmore » brains and the effectiveness of the LDR in reducing the oxidative damage caused by subsequent high dose radiation. We have also investigated the effect of LDR on apomorphine-induced rotations in the 6-hydroxydopamine (6-OHDA) unilaterally-lesioned rat model of Parkinson?s disease (PD). LDR was observed to initiate an adaptive response in the brain, and reduce the oxidative damage from subsequent high dose radiation exposure, confirming the effectiveness of LDR adaptive response in reducing the oxidative damage from the free radicals due to high dose radiation. LDR resulted in a slight improvement in Tyrosine hydroxylase expression on the lesioned side of substantia nigra (indicative of its protective effect on the dopaminergic neurons), and reduced the behavioral symptoms in the 6-OHDA rat model of PD. Translation of this concept to humans, if found to be applicable, may be a possible approach for controlling the progression of PD and other neurodegenerative diseases. Since any translation of the concept to humans would be hindered by the currently prevalent carcinogenic concerns regarding LDR based on the linear no-threshold (LNT) model, we have also studied the justifications for the use of the LNT model. One of the shortcomings of the LNT model is that it ignores the effects of any adaptive response of the body to the LDR. The importance of considering adaptive response becomes obvious when one considers the sharp contrast between (i) the failure of well-designed anti-angiogenesis therapies which resulted in aggressive tumors because of ignoring adaptive response and (ii) the occasional cure of untreated metastatic lesions likely due to the incidental adaptive response from the LDR exposure to parts of the body during radiation therapy of a primary tumor, known as the abscopal effect. Another shortcoming of the LNT model is that it pays exclusive attention to increase in mutations, which is not a decisive factor in the occurrence of clinical cancers, as the cause of excess cancers. On the other hand, LNT model ignores the immune system response, which plays a very important role in preventing occult cancers from becoming clinical cancers, as demonstrated by the large increase in cancers in organ transplant patients whose immune system is suppressed. There is also recent epidemiological evidence against the LNT model. A re-analysis of the latest update to the atomic bomb survivor data has shown that the data no longer support the LNT model but are consistent with the radiation hormesis hypothesis. A re-analysis of cancer incidence data of Taiwanese apartment dwellers that were exposed to LDR from contaminated building materials has also shown a reduction in cancers from the LDR. The present LDR carcinogenic concerns would preclude any human study of cancer prevention using LDR, since the study would require subjecting a large asymptomatic population to LDR. However, pilot studies of radiation hormesis in cancer patients may be more acceptable since these would require irradiation of limited numbers of patients in order to assess the effectiveness of the LDR treatments. Some of the LDR applications that may be considered for cancer patients are: LDR treatment of early stage cancers without the adverse side effects of current treatments such as radiation therapy or chemotherapy, adjuvant LDR treatment of cancer patients undergoing radiation therapy for better tumor control and reduced metastasis, and the use of LDR treatment following radiation therapy to reduce the risk of second cancers from the radiation therapy. Studies of LDR for the control of early-stage neurodegenerative diseases may also be more acceptable since currently there are no effective treatments available for controlling these diseases, and since such studies would require LDR exposure to limited parts of the brain, and the carcinogenic risk from such treatments would be very small due to the low radiation tissue-weighting factor for the brain. Success in these studies can lead to the study of LDR for preventing and controlling other aging-related diseases.« less

Induction Chemotherapy With Gemcitabine, Oxaliplatin, and 5-Fluorouracil/Leucovorin Followed by Concomitant Chemoradiotherapy in Patients With Locally Advanced Pancreatic Cancer: A Taiwan Cooperative Oncology Group Phase II Study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ch'ang, Hui-Ju; Department of Radiation Oncology, National Cheng Kung University Hospital, Tainan, Taiwan; Lin, Yu-Lin

Purpose: To evaluate the therapeutic efficacy of 3-month triplet induction chemotherapy (ICT) followed by concomitant chemoradiotherapy (CCRT) in patients with locally advanced pancreatic cancer (LAPC). Patients and Methods: Chemonaieve patients with measurable, histologically confirmed LAPC were eligible. The ICT consisted of biweekly gemcitabine (800 mg/m{sup 2}) infusion at a fixed dose rate (10 mg/m{sup 2}/min), followed by 85 mg/m{sup 2} oxaliplatin and 48-h infusion of 5-fluorouracil/leucovorin (3000/150 mg/m{sup 2}) for 6 cycles. Patients without disease progression 4 weeks after ICT would receive weekly 400 mg/m{sup 2} gemcitabine and 5040 cGy radiation in 28 fractions. After CCRT, patients were subjected formore » surgical intervention and/or maintenance chemotherapy until progression or intolerable toxicity. Results: Between December 2004 and August 2008, 50 patients were enrolled. The best responses after ICT were partial response (PR) in 9, stable disease in 26, and progressive disease or not evaluable in 15. Among the former 35 patients, 2 had disease progression before CCRT, and 3 declined to have CCRT. Of the 30 patients receiving CCRT, an additional 4 and 1 patient(s) achieved PR at the end of CCRT and during maintenance chemotherapy, respectively. On intent-to-treat analysis, the overall best response was PR in 14 patients and stable disease in 21. The overall response rate and disease control rate were 28% (95% confidence interval [CI], 16.2-42.5%) and 70% (95% CI, 44.4-99.2%), respectively. The median time to progression and overall survival of the intent-to-treat population was 9.3 (95% CI, 5.8-12.8) months and 14.5 (95% CI, 11.9-17.1) months, respectively. One- and two-year survival rates were 68% (95% CI, 55.1-80.9%) and 20.6% (95% CI, 8.7-32.5%), respectively. Neutropenia was the most common Grade 3-4 toxicity of both ICT and CCRT, with a frequency of 28% and 26.7%, respectively. Significant sensory neuropathy occurred in 9 patients (18%). Conclusion: Three months of triplet ICT followed by gemcitabine-based CCRT is feasible, moderately active, and associated with encouraging survival in patients with LAPC.« less

The Impact of Chemotherapy, Radiation and Epigenetic Modifiers in Cancer Cell Expression of Immune Inhibitory and Stimulatory Molecules and Anti-Tumor Efficacy.

PubMed

Chacon, Jessica Ann; Schutsky, Keith; Powell, Daniel J

2016-11-14

Genomic destabilizers, such as radiation and chemotherapy, and epigenetic modifiers are used for the treatment of cancer due to their apoptotic effects on the aberrant cells. However, these therapies may also induce widespread changes within the immune system and cancer cells, which may enable tumors to avoid immune surveillance and escape from host anti-tumor immunity. Genomic destabilizers can induce immunogenic death of tumor cells, but also induce upregulation of immune inhibitory ligands on drug-resistant cells, resulting in tumor progression. While administration of immunomodulatory antibodies that block the interactions between inhibitory receptors on immune cells and their ligands on tumor cells can mediate cancer regression in a subset of treated patients, it is crucial to understand how genomic destabilizers alter the immune system and malignant cells, including which inhibitory molecules, receptors and/or ligands are upregulated in response to genotoxic stress. Knowledge gained in this area will aid in the rational design of trials that combine genomic destabilizers, epigenetic modifiers and immunotherapeutic agents that may be synergized to improve clinical responses and prevent tumor escape from the immune system. Our review article describes the impact genomic destabilizers, such as radiation and chemotherapy, and epigenetic modifiers have on anti-tumor immunity and the tumor microenvironment. Although genomic destabilizers cause DNA damage on cancer cells, these therapies can also have diverse effects on the immune system, promote immunogenic cell death or survival and alter the cancer cell expression of immune inhibitor molecules.

The influence of direct mobile phone radiation on sperm quality.

PubMed

Gorpinchenko, Igor; Nikitin, Oleg; Banyra, Oleg; Shulyak, Alexander

2014-01-01

It is impossible to imagine a modern socially-active man who does not use mobile devices and/or computers with Wi-Fi function. The effect of mobile phone radiation on male fertility is the subject of recent interest and investigations. The aim of this study was to investigate the direct in vitro influence of mobile phone radiation on sperm DNA fragmentation and motility parameters in healthy subjects with normozoospermia. 32 healthy men with normal semen parameters were selected for the study. Each sperm sample was divided into two equal portions (A and B). Portions A of all involved men were placed for 5 hours in a thermostat, and portions B were placed into a second thermostat for the same period of time, where a mobile phone in standby/talk mode was placed. After 5 hours of incubation the sperm samples from both thermostats were re-evaluated regarding basic motility parameters. The presence of DNA fragmentation in both A and B portions of each sample was determined each hour using a standard sperm chromatin dispersion test. The number of spermatozoa with progressive movement in the group, influenced by electromagnetic radiation, is statistically lower than the number of spermatozoa with progressive movement in the group under no effect of the mobile phone. The number of non-progressive movement spermatozoa was significantly higher in the group, which was influenced by cell phone radiation. The DNA fragmentation was also significantly higher in this group. A correlation exists between mobile phone radiation exposure, DNA-fragmentation level and decreased sperm motility.

The influence of direct mobile phone radiation on sperm quality

PubMed Central

Gorpinchenko, Igor; Nikitin, Oleg; Shulyak, Alexander

2014-01-01

Introduction It is impossible to imagine a modern socially–active man who does not use mobile devices and/or computers with Wi–Fi function. The effect of mobile phone radiation on male fertility is the subject of recent interest and investigations. The aim of this study was to investigate the direct in vitro influence of mobile phone radiation on sperm DNA fragmentation and motility parameters in healthy subjects with normozoospermia. Material and methods 32 healthy men with normal semen parameters were selected for the study. Each sperm sample was divided into two equal portions (A and B). Portions A of all involved men were placed for 5 hours in a thermostat, and portions B were placed into a second thermostat for the same period of time, where a mobile phone in standby/talk mode was placed. After 5 hours of incubation the sperm samples from both thermostats were re–evaluated regarding basic motility parameters. The presence of DNA fragmentation in both A and B portions of each sample was determined each hour using a standard sperm chromatin dispersion test. Results The number of spermatozoa with progressive movement in the group, influenced by electromagnetic radiation, is statistically lower than the number of spermatozoa with progressive movement in the group under no effect of the mobile phone. The number of non–progressive movement spermatozoa was significantly higher in the group, which was influenced by cell phone radiation. The DNA fragmentation was also significantly higher in this group. Conclusions A correlation exists between mobile phone radiation exposure, DNA–fragmentation level and decreased sperm motility. PMID:24982785

Identification of radiation responsive genes and transcriptome profiling via complete RNA sequencing in a stable radioresistant U87 glioblastoma model.

PubMed

Doan, Ninh B; Nguyen, Ha S; Alhajala, Hisham S; Jaber, Basem; Al-Gizawiy, Mona M; Ahn, Eun-Young Erin; Mueller, Wade M; Chitambar, Christopher R; Mirza, Shama P; Schmainda, Kathleen M

2018-05-04

The absence of major progress in the treatment of glioblastoma (GBM) is partly attributable to our poor understanding of both GBM tumor biology and the acquirement of treatment resistance in recurrent GBMs. Recurrent GBMs are characterized by their resistance to radiation. In this study, we used an established stable U87 radioresistant GBM model and total RNA sequencing to shed light on global mRNA expression changes following irradiation. We identified many genes, the expressions of which were altered in our radioresistant GBM model, that have never before been reported to be associated with the development of radioresistant GBM and should be concertedly further investigated to understand their roles in radioresistance. These genes were enriched in various biological processes such as inflammatory response, cell migration, positive regulation of epithelial to mesenchymal transition, angiogenesis, apoptosis, positive regulation of T-cell migration, positive regulation of macrophage chemotaxis, T-cell antigen processing and presentation, and microglial cell activation involved in immune response genes. These findings furnish crucial information for elucidating the molecular mechanisms associated with radioresistance in GBM. Therapeutically, with the global alterations of multiple biological pathways observed in irradiated GBM cells, an effective GBM therapy may require a cocktail carrying multiple agents targeting multiple implicated pathways in order to have a chance at making a substantial impact on improving the overall GBM survival.

Review of advanced radiator technologies for spacecraft power systems and space thermal control

NASA Technical Reports Server (NTRS)

Juhasz, Albert J.; Peterson, George P.

1994-01-01

A two-part overview of progress in space radiator technologies is presented. The first part reviews and compares the innovative heat-rejection system concepts proposed during the past decade, some of which have been developed to the breadboard demonstration stage. Included are space-constructable radiators with heat pipes, variable-surface-area radiators, rotating solid radiators, moving-belt radiators, rotating film radiators, liquid droplet radiators, Curie point radiators, and rotating bubble-membrane radiators. The second part summarizes a multielement project including focused hardware development under the Civil Space Technology Initiative (CSTI) High Capacity Power program carried out by the NASA Lewis Research Center and its contractors to develop lightweight space radiators in support of Space Exploration Initiative (SEI) power systems technology.

Adaptation of the Black Yeast Wangiella dermatitidis to Ionizing Radiation: Molecular and Cellular Mechanisms

PubMed Central

Robertson, Kelly L.; Mostaghim, Anahita; Cuomo, Christina A.; Soto, Carissa M.; Lebedev, Nikolai; Bailey, Robert F.; Wang, Zheng

2012-01-01

Observations of enhanced growth of melanized fungi under low-dose ionizing radiation in the laboratory and in the damaged Chernobyl nuclear reactor suggest they have adapted the ability to survive or even benefit from exposure to ionizing radiation. However, the cellular and molecular mechanism of fungal responses to such radiation remains poorly understood. Using the black yeast Wangiella dermatitidis as a model, we confirmed that ionizing radiation enhanced cell growth by increasing cell division and cell size. Using RNA-seq technology, we compared the transcriptomic profiles of the wild type and the melanin-deficient wdpks1 mutant under irradiation and non-irradiation conditions. It was found that more than 3000 genes were differentially expressed when these two strains were constantly exposed to a low dose of ionizing radiation and that half were regulated at least two fold in either direction. Functional analysis indicated that many genes for amino acid and carbohydrate metabolism and cell cycle progression were down-regulated and that a number of antioxidant genes and genes affecting membrane fluidity were up-regulated in both irradiated strains. However, the expression of ribosomal biogenesis genes was significantly up-regulated in the irradiated wild-type strain but not in the irradiated wdpks1 mutant, implying that melanin might help to contribute radiation energy for protein translation. Furthermore, we demonstrated that long-term exposure to low doses of radiation significantly increased survivability of both the wild-type and the wdpks1 mutant, which was correlated with reduced levels of reactive oxygen species (ROS), increased production of carotenoid and induced expression of genes encoding translesion DNA synthesis. Our results represent the first functional genomic study of how melanized fungal cells respond to low dose ionizing radiation and provide clues for the identification of biological processes, molecular pathways and individual genes regulated by radiation. PMID:23139812

TU-C-12A-02: Development of a Multiparametric Statistical Response Map for Quantitative Imaging

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bosca, R; The University of Texas MD Anderson Cancer Center, Houston, TX; Mahajan, A

2014-06-15

Purpose: Quantitative imaging biomarkers (QIB) are becoming increasingly utilized in early phase clinical trials as a means of non-invasively assessing treatment response and associated response heterogeneity. The aim of this study was to develop a flexible multiparametric statistical framework to predict voxel-by-voxel response of several potential MRI QIBs. Methods: Patients with histologically proven glioblastomas (n=11) were treated with chemoradiation (with/without bevacizumab) and underwent one baseline and two mid-treatment (3–4wks) MRIs. Dynamic contrast-enhanced (3D FSPGR, 6.3sec/phase, 0.1 mmol/kg Gd-DTPA), dynamic susceptibility contrast (2D GRE-EPI, 1.5sec/phase, 0.2mmol/kg Gd-DTPA), and diffusion tensor (2D DW-EPI, b=0, 1200 s/mm{sup 2}, 27 directions) imaging acquisitions weremore » obtained during each study. Mid-treatment and pre-treatment images were rigidly aligned, and regions of partial response (PR), stable disease (SD), and progressive disease (PD) were contoured in consensus by two experienced radiation oncologists. Voxels in these categories were used to train ordinal (PR« less

Life science experiments performed in space in the ISS/Kibo facility and future research plans

PubMed Central

Ohnishi, Takeo

2016-01-01

Over the past several years, current techniques in molecular biology have been used to perform experiments in space, focusing on the nature and effects of space radiation. In the Japanese ‘Kibo’ facility in the International Space Station (ISS), the Japan Aerospace Exploration Agency (JAXA) has performed five life science experiments since 2009, and two additional experiments are currently in progress. The first life science experiment in space was the ‘Rad Gene’ project, which utilized two human cultured lymphoblastoid cell lines containing a mutated p53 gene (mp53) and a parental wild-type p53 gene (wtp53) respectively. Four parameters were examined: (i) detecting space radiation–induced DSBs by observing γH2AX foci; (ii) observing p53-dependent gene expression during space flight; (iii) observing p53-dependent gene expression after space flight; and (iv) observing the adaptive response in the two cell lines containing the mutated and wild type p53 genes after exposure to space radiation. These observations were completed and have been reported, and this paper is a review of these experiments. In addition, recent new information from space-based experiments involving radiation biology is presented here. These experiments involve human cultured cells, silkworm eggs, mouse embryonic stem cells and mouse eggs in various experiments designed by other principal investigators in the ISS/Kibo. The progress of Japanese science groups involved in these space experiments together with JAXA are also discussed here. The Japanese Society for Biological Sciences in Space (JSBSS), the Utilization Committee of Space Environment Science (UCSES) and the Science Council of Japan (ACJ) have supported these new projects and new experimental facilities in ISS/Kibo. Currently, these organizations are proposing new experiments for the ISS through 2024. PMID:27130692

A Phase I trial using local regional treatment, nonlethal irradiation, intratumoral and systemic polyinosinic-polycytidylic acid polylysine carboxymethylcellulose to treat liver cancer: in search of the abscopal effect

PubMed Central

de la Torre, Andrew N; Contractor, Sohail; Castaneda, Ismael; Cathcart, Charles S; Razdan, Dolly; Klyde, David; Kisza, Piotr; Gonzales, Sharon F; Salazar, Andres M

2017-01-01

Purpose To determine the safety of an approach to immunologically enhance local treatment of hepatocellular cancer (HCC) by combining nonlethal radiation, local regional therapy with intratumoral injection, and systemic administration of a potent Toll-like receptor (TLR) immune adjuvant. Methods Patients with HCC not eligible for liver transplant or surgery were subject to: 1) 3 fractions of 2-Gy focal nonlethal radiation to increase tumor antigen expression, 2) intra-/peri-tumoral (IT) injection of the TLR3 agonist, polyinosinic-polycytidylic acid polylysine carboxymethylcellulose (poly-ICLC), to induce an immunologic “danger” response in the tumor microenvironment with local regional therapy, and 3) systemic boosting of immunity with intramuscular poly-ICLC. Primary end points were safety and tolerability; secondary end points were progression-free survival (PFS) and overall survival (OS) at 6 months, 1 year, and 2 years. Results Eighteen patients with HCC not eligible for surgery or liver transplant were treated. Aside from 1 embolization-related severe adverse event, all events were ≤grade II. PFS was 66% at 6 months, 39% at 12 months, and 28% at 24 months. Overall 1-year survival was 69%, and 2-year survival 38%. In patients <60 years old, 2-year survival was 62.5% vs. 11.1% in patients aged >60 years (P<0.05). Several patients had prolonged PFS and OS. Conclusion Intra-tumoral injection of the TLR3 agonist poly-ICLC in patients with HCC is safe and tolerable when combined with local nonlethal radiation and local regional treatment. Further work is in progress to evaluate if this approach improves survival compared to local regional treatment alone and characterize changes in anticancer immunity. PMID:28848723

RADIATION AND OTHER FACTORS INFLUENCING THE DISTRIBUTION OF ANIMALS. Progress Report and Renewal Proposal

DOE Office of Scientific and Technical Information (OSTI.GOV)

Breckenridge, W.J.; Tester, J.R.

1962-01-01

Progress is reported for studies of environmental and radiation effects on three species of toads, Bufo americanus, B. cognatus and B. hemiophrys. Controlled surival tests in which tadpoles of B. americanus and B. hemiophrys were subjected to physical and chemical extremes indicated that B. hemiophrys is more resistant than B. americanus. The status of the subprojects on factors influencing toad survival during hibernatlon and irradistion of dormant toads is outlined. A soil simulator was built for studying the burrowing behavior of toads. (D.L.C.)

Recent advances in spacecraft thermal-control materials research.

NASA Technical Reports Server (NTRS)

Zerlaut, G. A.; Gilligan, J. E.; Gates, D. W.

1972-01-01

The state-of-the-art of spacecraft thermal-control materials technology has been significantly advanced during the past 4 years. Selective black coatings are discussed together with black paints, dielectric films on metal surfaces, and white radiator coatings. Criteria for the selection of thermal-control surfaces are considered, giving attention to prelaunch protection, the capability of being measured, reproducibility, simulator response, and aspects of a nonindigenous space environment. Progress in space simulation is related to vacuum technology, ultraviolet sources, solar wind simulation, and the production of protons. Advances have been made in the protection against space environmental effects, and in the development of thermal-control surfaces and pigments.

What we have learned: the impact of quality from a clinical trials perspective

PubMed Central

FitzGerald, T. J.

2011-01-01

In this review article we address the radiation oncology process improvements in clinical trials and review how these changes improve the quality for the next generation of trials. In recent years we have progressed from a time of limited data acquisition to the present in which we have real time influence of clinical trials quality. This enables immediate availability of the important elements including staging, eligibility, response and outcome for all trial investigators. Modern informatics platforms are well designed for future adaptive clinical trials. We review what will be needed in the informatics architecture of current and future clinical trials. PMID:22177875

Electrodynamic response of the middle atmosphere to auroral pulsations

NASA Technical Reports Server (NTRS)

Goldberg, R. A.; Croskey, C. L.; Hale, L. C.; Mitchell, J. D.; Barcus, J. R.

1990-01-01

The MAC/EPSILON observational campaign encompassed the use of two Nike Orion rocket payloads which studied the effects of auroral energetics on the middle atmosphere. While one payload was launched during the recovery phase of a moderate magnetic substorm, during fairly stable auroral conditions, the other was launched during highly active postbreakup conditions during which Pc5 pulsations were in progress. The energetic radiation of the first event was composed almost entirely of relativistic electrons below 200 keV, while that of the second was dominated by much softer electrons whose high X-ray fluxes exceeded the cosmic ray background as an ionizing source down to below 30 km.

Plant water use responses along secondary forest succession during the 2015-2016 El Niño drought in Panama.

PubMed

Bretfeld, Mario; Ewers, Brent E; Hall, Jefferson S

2018-03-05

Tropical forests are increasingly being subjected to hotter, drier conditions as a result of global climate change. The effects of drought on forests along successional gradients remain poorly understood. We took advantage of the 2015-2016 El Niño event to test for differences in drought response along a successional gradient by measuring the sap flow in 76 trees, representing 42 different species, in 8-, 25- and 80-yr-old secondary forests in the 15-km 2 'Agua Salud Project' study area, located in central Panama. Average sap velocities and sapwood-specific hydraulic conductivities were highest in the youngest forest. During the dry season drought, sap velocities increased significantly in the 80-yr-old forest as a result of higher evaporative demand, but not in younger forests. The main drivers of transpiration shifted from radiation to vapor pressure deficit with progressing forest succession. Soil volumetric water content was a limiting factor only in the youngest forest during the dry season, probably as a result of less root exploration in the soil. Trees in early-successional forests displayed stronger signs of regulatory responses to the 2015-2016 El Niño drought, and the limiting physiological processes for transpiration shifted from operating at the plant-soil interface to the plant-atmosphere interface with progressing forest succession. © 2018 The Authors. New Phytologist © 2018 New Phytologist Trust.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ogo, Etsuyo; Komaki, Ritsuko; Fujimoto, Kiminori

Purpose: We observed a rare and unique occurrence of radiation-induced pulmonary injury outside the tangential field for early breast cancer treatment. The findings appeared to be idiopathic and were called radiation-induced bronchiolitis obliterans organizing pneumonia (BOOP) syndrome. We surveyed major hospitals in Japan to review their findings of radiation-induced BOOP, in particular the clinical and pictorial characteristics of the entity. Methods and Materials: We reviewed surveys completed and returned by 20 institutions. The survey responses were based on a total of 37 cases of BOOP syndrome. We also reviewed X-ray and computed tomography scans provided by these institutions. We discussedmore » the information derived from the questionnaire and analyzed patients' characteristics, methods used in the treatment of BOOP syndrome, and prognosis. Results: The incidence of the radiation-induced BOOP syndrome was about 1.8% (37 of 2,056). We did not find a relationship between the characteristics of patients and the occurrence of radiation-induced BOOP syndrome. The pulmonary findings were classified into four patterns on chest computed tomography scans. Progression of the pulmonary lesions observed on chest X-ray was classified into three patterns. Pneumonitis appeared within 6 months after radiotherapy was completed and disappeared within 6-12 months after its onset. At 5-year follow-up, 2 patients had died, 1 of breast cancer and the other of interstitial pneumonitis, which seemed to be idiopathic and unrelated to the radiation-induced BOOP syndrome. Conclusions: Although the incidence of BOOP syndrome and its associated prognosis are not significant, the patients' clinical condition must be carefully followed.« less

Whole-brain hippocampal sparing radiation therapy: Volume-modulated arc therapy vs intensity-modulated radiation therapy case study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lee, Katrina, E-mail: Trinabena23@gmail.com; Lenards, Nishele; Holson, Janice

The hippocampus is responsible for memory and cognitive function. An ongoing phase II clinical trial suggests that sparing dose to the hippocampus during whole-brain radiation therapy can help preserve a patient's neurocognitive function. Progressive research and advancements in treatment techniques have made treatment planning more sophisticated but beneficial for patients undergoing treatment. The aim of this study is to evaluate and compare hippocampal sparing whole-brain (HS-WB) radiation therapy treatment planning techniques using volume-modulated arc therapy (VMAT) and intensity-modulated radiation therapy (IMRT). We randomly selected 3 patients to compare different treatment techniques that could be used for reducing dose to themore » hippocampal region. We created 2 treatment plans, a VMAT and an IMRT, from each patient's data set and planned on the Eclipse 11.0 treatment planning system (TPS). A total of 6 plans (3 IMRT and 3 VMAT) were created and evaluated for this case study. The physician contoured the hippocampus as per the Radiation Therapy Oncology Group (RTOG) 0933 protocol atlas. The organs at risk (OR) were contoured and evaluated for the plan comparison, which included the spinal cord, optic chiasm, the right and left eyes, lenses, and optic nerves. Both treatment plans produced adequate coverage on the planning target volume (PTV) while significantly reducing dose to the hippocampal region. The VMAT treatment plans produced a more homogenous dose distribution throughout the PTV while decreasing the maximum point dose to the target. However, both treatment techniques demonstrated hippocampal sparing when irradiating the whole brain.« less

Health and Safety Research Division progress report, July 1, 1984-September 30, 1985

DOE Office of Scientific and Technical Information (OSTI.GOV)

Not Available

1986-01-01

This report summarizes progress made for the period July 1984 through September 1985. Sections describe research in health studies, dosimetry and biophysical transport, biological and radiation physics, chemical physics, and risk analysis. (ACR)

Increased expression of cyclin B1 mRNA coincides with diminished G{sub 2}-phase arrest in irradiated HeLa cells treated with staurosporine or caffeine

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bernhard, E.J.; Maity, A.; McKenna, W.G.

1994-12-01

The irradiation of cells results in delayed progression through the G{sub 2} phase of the cell cycle. Treatment of irradiated HeLa cells with caffeine greatly reduces the G{sub 2}-phase delay, while caffeine does not alter progression of cells through the cell cycle in unirradiated cells. In this report we demonstrate that treatment of HeLa cells with the kinase inhibitor staurosporine, but not with the inhibitor H7, also results in a reduction of the G{sub 2}-phase arrest after irradiation. Cell cycle progression in unirradiated cells is unaffected by 4.4 nM (2ng/ml) staurosporine, which releases the radiation-induced G{sub 2}-phase arrest. In HeLamore » cells, the G{sub 2}-phase delay after irradiation in S phase is accompanied by decreased expression of cyclin B1 mRNA. Coincident with the reduction in G{sub 2}-phase delay, we observed an increase in cyclin B1 mRNA accumulation in irradiated, staurosporine-treated cells compared to cells treated with irradiation alone. Caffeine treatment of irradiated HeLa cells also resulted in an elevation in the levels of cyclin B1 message. These results support the hypothesis that diminished cyclin B1 mRNA levels influence G{sub 2}-phase arrest to some degree. The findings that both staurosporine and caffeine treatments reverse the depression in cyclin B1 expression suggest that these two compounds may act on a common pathway of cell cycle control in response to radiation injury. 33 refs., 6 figs.« less

Liver metastases from colorectal cancer: propensity score-based comparison of stereotactic body radiation therapy vs. microwave ablation.

PubMed

Franzese, Ciro; Comito, Tiziana; Clerici, Elena; Di Brina, Lucia; Tomatis, Stefano; Navarria, Pierina; Reggiori, Giacomo; Viganò, Luca; Poretti, Dario; Pedicini, Vittorio; Torzilli, Guido; Solbiati, Luigi; Scorsetti, Marta

2018-06-22

The study aim was to compare the disease control in two groups of patients affected by liver metastases from CRC treated with microwave ablation (MWA) or stereotactic body radiation therapy (SBRT). We extracted data of patients treated between 2009 and 2016. Inclusion criteria were: (1) maximum diameter of the liver lesions less than 4 cm; (2) no more than three liver lesions; (3) no evidence of progressive or untreated gross disease outside the liver; (4) adequate liver function; (5) no concurrent chemotherapy; (6) minimum age of 18. Tumour response was classified according to EORTC-RECIST criteria. Aim of the present study was to evaluate freedom from local progression (FFLP). To reduce indication bias, an inverse probability of treatment weighting was used to estimate treatment effect. A total of 135 patients with 214 lesions were included in the analysis. Median follow-up time was 24.5 months (range 2.4-95.8). The 1-year freedom from local progression (FFLP) was 88% (95%CI 80-92). In the SBRT group, FFLP was statistically longer than MWA group (p = 0.0214); the 1-year FFLP was 91% (95% CI 81-95) in SBRT group and 84% (95% CI 0.72-0.91) in MWA group. Patients treated with SBRT showed a reduce risk of local relapse compared to MWA (adjusted HR 0.31; 95%CI 0.13-0.70, p = 0.005). As expected, analogous result obtained in the inverse probability weighting analysis (HR 0.38; 95%CI 0.18-0.80; p = 0.011). In conclusion, there seems to be an advantage of SBRT compared to MWA in treating CRC liver metastases, particularly for lesions bigger than 30 mm.

Radiation track, DNA damage and response—a review

NASA Astrophysics Data System (ADS)

Nikjoo, H.; Emfietzoglou, D.; Liamsuwan, T.; Taleei, R.; Liljequist, D.; Uehara, S.

2016-11-01

The purpose of this paper has been to review the current status and progress of the field of radiation biophysics, and draw attention to the fact that physics, in general, and radiation physics in particular, with the aid of mathematical modeling, can help elucidate biological mechanisms and cancer therapies. We hypothesize that concepts of condensed-matter physics along with the new genomic knowledge and technologies and mechanistic mathematical modeling in conjunction with advances in experimental DNA (Deoxyrinonucleic acid molecule) repair and cell signaling have now provided us with unprecedented opportunities in radiation biophysics to address problems in targeted cancer therapy, and genetic risk estimation in humans. Obviously, one is not dealing with ‘low-hanging fruit’, but it will be a major scientific achievement if it becomes possible to state, in another decade or so, that we can link mechanistically the stages between the initial radiation-induced DNA damage; in particular, at doses of radiation less than 2 Gy and with structural changes in genomic DNA as a precursor to cell inactivation and/or mutations leading to genetic diseases. The paper presents recent development in the physics of radiation track structure contained in the computer code system KURBUC, in particular for low-energy electrons in the condensed phase of water for which we provide a comprehensive discussion of the dielectric response function approach. The state-of-the-art in the simulation of proton and carbon ion tracks in the Bragg peak region is also presented. The paper presents a critical discussion of the models used for elastic scattering, and the validity of the trajectory approach in low-electron transport. Brief discussions of mechanistic and quantitative aspects of microdosimetry, DNA damage and DNA repair are also included as developed by the authors’ work.

Ablative Hypofractionated Radiation Therapy Enhances Non-Small Cell Lung Cancer Cell Killing via Preferential Stimulation of Necroptosis In Vitro and In Vivo.

PubMed

Wang, Huan-Huan; Wu, Zhi-Qiang; Qian, Dong; Zaorsky, Nicholas G; Qiu, Ming-Han; Cheng, Jing-Jing; Jiang, Chao; Wang, Juan; Zeng, Xian-Liang; Liu, Chun-Lei; Tian, Li-Jun; Ying, Guo-Guang; Meng, Mao-Bin; Hao, Xi-Shan; Yuan, Zhi-Yong

2018-05-01

To investigate how necroptosis (ie, programmed necrosis) is involved in killing of non-small cell lung cancer (NSCLC) after ablative hypofractionated radiation therapy (HFRT). Deoxyribonucleic acid damage, DNA repair, and the death form of NSCLC cells were assessed after radiation therapy. The overexpression and silencing of receptor-interacting protein kinases 3 (RIP3, a key protein involved activation of necroptosis)-stable NSCLC cell lines were successfully constructed. The form of cell death, the number and area of colonies, and the regulatory proteins of necroptosis were characterized after radiation therapy in vitro. Finally, NSCLC xenografts and patient specimens were used to examine involvement of necroptosis after ablative HFRT in vivo. Radiation therapy induced expected DNA damage and repair of NSCLC cell lines, but ablative HFRT at ≥10 Gy per fraction preferentially stimulated necroptosis in NSCLC cells and xenografts with high RIP3 expression, as characterized by induction and activation of RIP3 and mixed-lineage kinase domain-like protein and release of immune-activating chemokine high-mobility group box 1. In contrast, RNA interference of RIP3 attenuated ablative HFRT-induced necroptosis and activation of its regulatory proteins. Among central early-stage NSCLC patients receiving stereotactic body radiation therapy, high expression of RIP3 was associated with improved local control and progression-free survival (all P < .05). Ablative HFRT at ≥10 Gy per fraction enhances killing of NSCLC with high RIP3 expression via preferential stimulation of necroptosis. RIP3 may serve as a useful biomarker to predict favorable response to stereotactic body radiation therapy. Copyright © 2018 Elsevier Inc. All rights reserved.

American Society for Radiation Oncology (ASTRO) Survey of Radiation Biology Educators in U.S. and Canadian Radiation Oncology Residency Programs

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rosenstein, Barry S., E-mail: barry.rosenstein@mssm.ed; Department of Radiation Oncology, New York University School of Medicine, New York, NY; Held, Kathryn D.

2009-11-01

Purpose: To obtain, in a survey-based study, detailed information on the faculty currently responsible for teaching radiation biology courses to radiation oncology residents in the United States and Canada. Methods and Materials: In March-December 2007 a survey questionnaire was sent to faculty having primary responsibility for teaching radiation biology to residents in 93 radiation oncology residency programs in the United States and Canada. Results: The responses to this survey document the aging of the faculty who have primary responsibility for teaching radiation biology to radiation oncology residents. The survey found a dramatic decline with time in the percentage of educatorsmore » whose graduate training was in radiation biology. A significant number of the educators responsible for teaching radiation biology were not fully acquainted with the radiation sciences, either through training or practical application. In addition, many were unfamiliar with some of the organizations setting policies and requirements for resident education. Freely available tools, such as the American Society for Radiation Oncology (ASTRO) Radiation and Cancer Biology Practice Examination and Study Guides, were widely used by residents and educators. Consolidation of resident courses or use of a national radiation biology review course was viewed as unlikely by most programs. Conclusions: A high priority should be given to the development of comprehensive teaching tools to assist those individuals who have responsibility for teaching radiation biology courses but who do not have an extensive background in critical areas of radiobiology related to radiation oncology. These findings also suggest a need for new graduate programs in radiobiology.« less

Radiation damage of biomolecules (RADAM) database development: current status

NASA Astrophysics Data System (ADS)

Denifl, S.; Garcia, G.; Huber, B. A.; Marinković, B. P.; Mason, N.; Postler, J.; Rabus, H.; Rixon, G.; Solov'yov, A. V.; Suraud, E.; Yakubovich, A. V.

2013-06-01

Ion beam therapy offers the possibility of excellent dose localization for treatment of malignant tumours, minimizing radiation damage in normal tissue, while maximizing cell killing within the tumour. However, as the underlying dependent physical, chemical and biological processes are too complex to treat them on a purely analytical level, most of our current and future understanding will rely on computer simulations, based on mathematical equations, algorithms and last, but not least, on the available atomic and molecular data. The viability of the simulated output and the success of any computer simulation will be determined by these data, which are treated as the input variables in each computer simulation performed. The radiation research community lacks a complete database for the cross sections of all the different processes involved in ion beam induced damage: ionization and excitation cross sections for ions with liquid water and biological molecules, all the possible electron - medium interactions, dielectric response data, electron attachment to biomolecules etc. In this paper we discuss current progress in the creation of such a database, outline the roadmap of the project and review plans for the exploitation of such a database in future simulations.

[Effective combination therapy using radiation and a daily low dose of cis-platinum for advanced oropharyngeal carcinoma in an elderly patient--report of a case].

PubMed

Tamura, M; Miyashita, T; Ogiso, A; Kotani, A; Oguchi, M; Izuno, I

1994-01-01

An 83-year-old male with advanced oropharyngeal carcinoma was treated with combined radiotherapy and a daily low dose of cis-platinum with excellent results. In the early part of the treatment, radiotherapy was delivered in fractions of 1.8 Gy/day (5 days/week) to a cumulative dose of 20 Gy, concomitantly with UFT (400 mg/day po), but the response was not adequate. Then, instead of UFT, a single intravenous injection of cis-platinum (5 mg) was administered within 30 min after each radiation session without intravenous hydration. The total dose of cis-platinum was 140 mg and that of radiation was 70 Gy. Moderate leukocytopenia and moderate mucositis/dermatitis were observed as side effects, but despite the lack of intravenous hydration no signs of renal toxicity were observed. Partial remission was attained by the end of the therapy, remnant lesions progressively diminished in size, and 4 months later all of them had completely disappeared on the computed tomogram. The prognosis is favorable, and neither recurrence nor metastasis has been found in the 14-month follow-up period since the lesions disappeared.

Diallyl disulfide attenuated carbon ion irradiation-induced apoptosis in mouse testis through changing the ratio of Tap73/ΔNp73 via mitochondrial pathway

PubMed Central

Di, Cui-xia; Han, Lu; Zhang, Hong; Xu, Shuai; Mao, Ai-hong; Sun, Chao; Liu, Yang; Si, Jing; Li, Hong-yan; Zhou, Xin; Liu, Bing; Miao, Guo-ying

2015-01-01

Diallyl disulfide (DADS), a major organosulfur compound derived from garlic, has various biological properties, including anti-cancer effects. However, the protective mechanism of DADS against radiation-induced mouse testis cell apoptosis has not been elucidated. In this study, the magnitude of radiation effects evoked by carbon ion irradiation was marked by morphology changes, significant rise in apoptotic cells, activation expression of p53, up regulation the ratio of pro-apoptotic Tap73/anti-apoptotic ΔNp73, as well as alterations of crucial mediator of the mitochondrial pathway. Interestingly, pretreatment with DADS attenuated carbon ion irradiation-induced morphology damages and apoptotic cells. Additionally, DADS elevated radiation-induced p53 and p21 expression, suggesting that p53 might be involved in the inhibition of cell cycle progression through up regulation of p21. Furthermore, administration with DADS prevented radiation-induced Tap73/ΔNp73 expression and consequently down regulated Bax/Bcl-2 ratio, cytochrome c release and caspase-3 expression, indicating that the balance between Tap73 and ΔNp73 had potential to activate p53 responsive genes. Thus, our results showed that radio protection effect of DADS on mouse testis is mediated by blocking apoptosis through changing the ratio of Tap73/ΔNp73 via mitochondrial pathway, suggesting that DADS could be used as a potential radio protection agent for the testis against heavy-ion radiation. PMID:26526304

Radiation processing: adapting to a changing world.

PubMed

Woolston, J

2009-01-01

The 15th International Meeting on Radiation Processing was held in London, UK, on 21-25 September 2008. It provided a forum for researchers, academics, the radiation processing industry and its users and regulators to review progress. This report focuses on the developments relevant to medical device sterilisation in products, processes, technology and the regulatory environment that were examined at the event.

DOE Office of Scientific and Technical Information (OSTI.GOV)

None

Progress is reported in studies on the metabolism, radiation dose, radiation effects, and toxic effects of prolonged expesure of dogs following injection of various doses 8/, Th/sup 228, and Sr/sup 90/ An imporved live dog gamma counter is described. (For preceding period see AECU 3522.) (C.H.)

Changes in biologically active ultraviolet radiation reaching the Earth's surface.

PubMed

McKenzie, Richard L; Björn, Lars Olof; Bais, Alkiviadis; Ilyasad, Mohammad

2003-01-01

Since publication of the 1998 UNEP Assessment, there has been continued rapid expansion of the literature on UV-B radiation. Many measurements have demonstrated the inverse relationship between column ozone amount and UV radiation, and in a few cases long-term increases due to ozone decreases have been identified. The quantity, quality and availability of ground-based UV measurements relevant to assessing the environmental impacts of ozone changes continue to improve. Recent studies have contributed to delineating regional and temporal differences due to aerosols, clouds, and ozone. Improvements in radiative transfer modelling capability now enable more accurate characterization of clouds, snow-cover, and topographical effects. A standardized scale for reporting UV to the public has gained wide acceptance. There has been increased use of satellite data to estimate geographic variability and trends in UV. Progress has been made in assessing the utility of satellite retrievals of UV radiation by comparison with measurements at the Earth's surface. Global climatologies of UV radiation are now available on the Internet. Anthropogenic aerosols play a more important role in attenuating UV irradiances than has been assumed previously, and this will have implications for the accuracy of UV retrievals from satellite data. Progress has been made inferring historical levels of UV radiation using measurements of ozone (from satellites or from ground-based networks) in conjunction with measurements of total solar radiation obtained from extensive meteorological networks. We cannot yet be sure whether global ozone has reached a minimum. Atmospheric chlorine concentrations are beginning to decrease. However, bromine concentrations are still increasing. While these halogen concentrations remain high, the ozone layer remains vulnerable to further depletion from events such as volcanic eruptions that inject material into the stratosphere. Interactions between global warming and ozone depletion could delay ozone recovery by several years, and this topic remains an area of intense research interest. Future changes in greenhouse gases will affect the future evolution of ozone through chemical, radiative, and dynamic processes In this highly coupled system, an evaluation of the relative importance of these processes is difficult: studies are ongoing. A reliable assessment of these effects on total column ozone is limited by uncertainties in lower stratospheric response to these changes. At several sites, changes in UV differ from those expected from ozone changes alone, possibly as a result of long-term changes in aerosols, snow cover, or clouds. This indicates a possible interaction between climate change and UV radiation. Cloud reflectance measured by satellite has shown a long-term increase at some locations, especially in the Antarctic region, but also in Central Europe, which would tend to reduce the UV radiation. Even with the expected decreases in atmospheric chlorine, it will be several years before the beginning of an ozone recovery can be unambiguously identified at individual locations. Because UV-B is more variable than ozone, any identification of its recovery would be further delayed.

The molecular and cellular response of normal and progressed human bronchial epithelial cells to HZE particles

NASA Astrophysics Data System (ADS)

Story, Michael; Ding, Liang-Hao; Minna, John; Park, Seong-mi; Larsen, Jill

We have used a model of non-oncogenically immortalized normal human bronchial epithelial cells to determine the response of such cells to particles found outside the protection of the earth’s electromagnetic field. We have identified an enhanced frequency of cellular transformation, as measured by growth in soft agar, for both 56Fe and 28Si (1 GeV/n) that is maximal (4-6 fold) at 0.25 Gy and 0.40 Gy, respectively. At 4 months post-irradiation 38 individual soft agar clones were isolated. These clones were characterized extensively for cellular and molecular changes. Gene expression analysis suggested that these clones had down-regulated several genes associated with anti-oxidant pathways including GLS2, GPX1 and 4, SOD2, PIG3, and NQO1 amongst others. As a result, many of these transformed clones were exposed to high levels of intracellular radical oxygen species (ROS), although there appeared not to be any enhanced mitochondrial ROS. DNA repair pathways associated with ATM/ATR signaling were also upregulated. However, these transformants do not develop into tumors when injected into immune-compromised mice, suggesting that they have not progressed sufficiently to become oncogenic. Therefore we chose 6 soft agar clones for continuous culture for an additional 14 months. Amongst the 6 clones, only one clone showed any significant change in phenotype. Clone 3kt-ff.2a, propagated for 18 months, were 2-fold more radioresistant, had a shortened doubling time and the background rate of transformation more than doubled. Furthermore, the morphology of transformed clones changed. Clones from this culture are being compared to the original clone as well as the parental HBEC3KT and will be injected into immune-compromised mice for oncogenic potential. Oncogenically progressed HBECs, HBEC3KT cells that overexpress a mutant RAS gene and where p53 has been knocked down, designated HBEC3KTR53, responded quite differently to HZE particle exposure. First, these cells are more radioresistant to all radiations used when compared to the parental cell line HBEC3KT. Furthermore, within days of their exposure to low and high LET radiations they exhibit enhanced cellular transformation over the parental cells. Moreover, HZE radiations are many fold more effective at initiating cellular transformation. Gene expression analysis identified several pathways that support oncogenic growth as overrepresented in the progressed cells. With continual culture some clones undergo epithelial to mesenchymal transition, change morphology and express markers associated with EMT. And, at least one clone is oncogenic forming highly aggressive tumors in an immune compromised mouse strain. It is important to note that HBEC3KTR53 cells will not form tumors in mice, however, this irradiated clone has moved through the multi-step process of carcinogenesis. We are now examining the molecular alterations that led to oncogenesis in this clone.

Stereotactic Body Radiation Therapy for Oligometastatic Prostate Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Muldermans, Jonathan L.; Romak, Lindsay B.; Kwon, Eugene D.

Purpose: To review outcomes of patients with oligometastatic prostate cancer (PCa) treated with stereotactic body radiation therapy (SBRT) and to identify variables associated with local failure. Methods and Materials: We retrospectively reviewed records of patients treated with SBRT for oligometastatic PCa. Metastasis control (ie, control of the treated lesion, MC), biochemical progression-free survival, distant progression-free survival, and overall survival were estimated with the Kaplan-Meier method. Results: Sixty-six men with 81 metastatic PCa lesions, 50 of which were castrate-resistant, were included in the analysis. Lesions were in bone (n=74), lymph nodes (n=6), or liver (n=1). Stereotactic body radiation therapy was deliveredmore » in 1 fraction to 71 lesions (88%), at a median dose of 16 Gy (range, 16-24 Gy). The remaining lesions received 30 Gy in 3 fractions (n=6) or 50 Gy in 5 fractions (n=4). Median follow-up was 16 months (range, 3-49 months). Estimated MC at 2 years was 82%. Biochemical progression-free survival, distant progression-free survival, and overall survival were 54%, 45%, and 83%, respectively. On multivariate analysis, only the dose of SBRT was significantly associated with MC; lesions treated with 16 Gy had 58% MC, and those treated with ≥18 Gy had 95% MC at 2 years (P≤.001). At 2 years, MC for lesions treated with 18 Gy (n=21) was 88%. No patient treated with ≥18 Gy in a single fraction or with any multifraction regimen had local failure. Six patients (9%) had grade 1 pain flare, and 2 (3%) had grade 2 pain flare. No grade 2 or greater late toxicities were reported. Conclusions: Stereotactic body radiation therapy for patients with oligometastatic prostate cancer provided optimal metastasis control and acceptable toxicity with doses ≥18 Gy. Biochemical progression-free survival was 54% at 16 months with the inclusion of SBRT in the treatment regimen. Stereotactic body radiation therapy should be considered in patients with castration-refractory, oligometastatic prostate cancer who have limited options for systemic therapy.« less

Axial acoustic radiation force on rigid oblate and prolate spheroids in Bessel vortex beams of progressive, standing and quasi-standing waves.

PubMed

Mitri, F G

2017-02-01

The analysis using the partial-wave series expansion (PWSE) method in spherical coordinates is extended to evaluate the acoustic radiation force experienced by rigid oblate and prolate spheroids centered on the axis of wave propagation of high-order Bessel vortex beams composed of progressive, standing and quasi-standing waves, respectively. A coupled system of linear equations is derived after applying the Neumann boundary condition for an immovable surface in a non-viscous fluid, and solved numerically by matrix inversion after performing a single numerical integration procedure. The system of linear equations depends on the partial-wave index n and the order of the Bessel vortex beam m using truncated but converging PWSEs in the least-squares sense. Numerical results for the radiation force function, which is the radiation force per unit energy density and unit cross-sectional surface, are computed with particular emphasis on the amplitude ratio describing the transition from the progressive to the pure standing waves cases, the aspect ratio (i.e., the ratio of the major axis over the minor axis of the spheroid), the half-cone angle and order of the Bessel vortex beam, as well as the dimensionless size parameter. A generalized expression for the radiation force function is derived for cases encompassing the progressive, standing and quasi-standing waves of Bessel vortex beams. This expression can be reduced to other types of beams/waves such as the zeroth-order Bessel non-vortex beam or the infinite plane wave case by appropriate selection of the beam parameters. The results for progressive waves reveal a tractor beam behavior, characterized by the emergence of an attractive pulling force acting in opposite direction of wave propagation. Moreover, the transition to the quasi-standing and pure standing wave cases shows the acoustical tweezers behavior in dual-beam Bessel vortex beams. Applications in acoustic levitation, particle manipulation and acousto-fluidics would benefit from the results of the present investigation. Copyright © 2016 Elsevier B.V. All rights reserved.

Disease Control After Reduced Volume Conformal and Intensity Modulated Radiation Therapy for Childhood Craniopharyngioma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Merchant, Thomas E., E-mail: thomas.merchant@stjude.org; Kun, Larry E.; Hua, Chia-Ho

2013-03-15

Purpose: To estimate the rate of disease control after conformal radiation therapy using reduced clinical target volume (CTV) margins and to determine factors that predict for tumor progression. Methods and Materials: Eighty-eight children (median age, 8.5 years; range, 3.2-17.6 years) received conformal or intensity modulated radiation therapy between 1998 and 2009. The study group included those prospectively treated from 1998 to 2003, using a 10-mm CTV, defined as the margin surrounding the solid and cystic tumor targeted to receive the prescription dose of 54 Gy. The CTV margin was subsequently reduced after 2003, yielding 2 groups of patients: those treatedmore » with a CTV margin greater than 5 mm (n=26) and those treated with a CTV margin less than or equal to 5 mm (n=62). Disease progression was estimated on the basis of additional variables including sex, race, extent of resection, tumor interventions, target volume margins, and frequency of weekly surveillance magnetic resonance (MR) imaging during radiation therapy. Median follow-up was 5 years. Results: There was no difference between progression-free survival rates based on CTV margins (>5 mm vs ≤5 mm) at 5 years (88.1% ± 6.3% vs 96.2% ± 4.4% [P=.6386]). There were no differences based on planning target volume (PTV) margins (or combined CTV plus PTV margins). The PTV was systematically reduced from 5 to 3 mm during the time period of the study. Factors predictive of superior progression-free survival included Caucasian race (P=.0175), no requirement for cerebrospinal fluid shunting (P=.0066), and number of surveillance imaging studies during treatment (P=.0216). Patients whose treatment protocol included a higher number of weekly surveillance MR imaging evaluations had a lower rate of tumor progression. Conclusions: These results suggest that targeted volume reductions for radiation therapy using smaller margins are feasible and safe but require careful monitoring. We are currently investigating the differences in outcome based on host factors to explain the results.« less

Dynamic acoustic radiation force acting on cylindrical shells: theory and simulations.

PubMed

Mitri, F G; Fatemi, M

2005-05-01

An object placed in an acoustic field is known to experience a force due to the transfer of momentum from the wave to the object itself. This force is known to be steady when the incident field is considered to be continuous with constant amplitude. One may define the dynamic (oscillatory) radiation force for a continuous wave-field whose intensity varies slowly with time. This paper extends the theory of the dynamic acoustic radiation force resulting from an amplitude-modulated progressive plane wave-field incident on solid cylinders to the case of solid cylindrical shells with particular emphasis on their thickness and contents of their hollow regions. A new factor corresponding to the dynamic radiation force is defined as Y(d) and stands for the dynamic radiation force per unit energy density and unit cross sectional surface. The results of numerical calculations are presented, indicating the ways in which the form of the dynamic radiation force function curves are affected by variations in the material mechanical parameters and by changes in the interior fluid inside the shell's hollow region. It was shown that the dynamic radiation force function Y(d) deviates from the static radiation force function for progressive waves Y(p) when the modulation frequency increases. These results indicate that the theory presented here is broader than the existing theory on cylinders.

Paclitaxel poliglumex, temozolomide, and radiation for newly diagnosed high-grade glioma: a Brown University Oncology Group Study.

PubMed

Jeyapalan, Suriya; Boxerman, Jerrold; Donahue, John; Goldman, Marc; Kinsella, Timothy; Dipetrillo, Thomas; Evans, Devon; Elinzano, Heinrich; Constantinou, Maria; Stopa, Edward; Puthawala, Yakub; Cielo, Deus; Santaniello, Alyson; Oyelese, Adetokunbo; Mantripragada, Kalyan; Rosati, Kayla; Isdale, Debora; Safran, Howard

2014-10-01

Paclitaxel poliglumex (PPX), a drug conjugate that links paclitaxel to poly-L-glutamic acid, is a potent radiation sensitizer. Prior studies in esophageal cancer have demonstrated that PPX (50 mg/m/wk) can be administered with concurrent radiation with acceptable toxicity. The primary objective of this study was to determine the safety of the combination of PPX with temozolomide and concurrent radiation for high-grade gliomas. Eligible patients were required to have WHO grade 3 or 4 gliomas. Patients received weekly PPX (50 mg/m/wk) combined with standard daily temozolomide (75 mg/m) for 6 weeks with concomitant radiation (2.0 Gy, 5 d/wk for a total dose of 60 Gy). Twenty-five patients were enrolled, 17 with glioblastoma and 8 with grade 3 gliomas. Seven of 25 patients had grade 4 myelosuppression. Hematologic toxicity lasted up to 5 months suggesting a drug interaction between PPX and temozolomide. For patients with glioblastoma, the median progression-free survival was 11.5 months and the median overall survival was 18 months. PPX could not be safely combined with temozolomide due to grade 4 hematologic toxicity. However, the favorable progression-free and overall survival suggest that PPX may enhance radiation for glioblastoma. A randomized study of single agent PPX/radiation versus temozolomide/radiation for glioblastoma without MGMT methylation is underway.

[Radiation protection in interventional cardiology].

PubMed

Durán, Ariel

2015-01-01

INTERVENTIONAL: cardiology progress makes each year a greater number of procedures and increasing complexity with a very good success rate. The problem is that this progress brings greater dose of radiation not only for the patient but to occupationally exposed workers as well. Simple methods for reducing or minimizing occupational radiation dose include: minimizing fluoroscopy time and the number of acquired images; using available patient dose reduction technologies; using good imaging-chain geometry; collimating; avoiding high-scatter areas; using protective shielding; using imaging equipment whose performance is controlled through a quality assurance programme; and wearing personal dosimeters so that you know your dose. Effective use of these methods requires both appropriate education and training in radiation protection for all interventional cardiology personnel, and the availability and use of appropriate protective tools and equipment. Regular review and investigation of personnel monitoring results, accompanied as appropriate by changes in how procedures are performed and equipment used, will ensure continual improvement in the practice of radiation protection in the interventional suite. Copyright © 2014 Instituto Nacional de Cardiología Ignacio Chávez. Published by Masson Doyma México S.A. All rights reserved.

Beneficial uses program. Progress report ending December 31, 1979

DOE Office of Scientific and Technical Information (OSTI.GOV)

None

1980-06-01

Progress is reported in research on uses of irradiated sewage sludge, particularly as a cattle feed supplement and commercial fertilizer additive, on potential sites for irradiator demonstration plants, and on the inactivation of enteric bacteria by radiation treatment. (LCL)

Effect of Gamma Knife Radiosurgery and Programmed Cell Death 1 Receptor Antagonists on Metastatic Melanoma

PubMed Central

Hubbard, Molly; Nordmann, Tyler; Sperduto, Paul W; Clark, H. Brent; Hunt, Matthew A

2017-01-01

Learning objectives To evaluate radiation-induced changes in patients with brain metastasis secondary to malignant melanoma who received treatment with Gamma Knife radiosurgery (GKRS) and programmed cell death 1 (PD-1) receptor antagonists. Introduction  Stereotactic radiosurgery and chemotherapeutics are used together for treatment of metastatic melanoma and have been linked to delayed radiation-induced vasculitic leukoencephalopathy (DRIVL). There have been reports of more intense interactions with new immunotherapeutics targeting PD-1 receptors, but their interactions have not been well described and may result in an accelerated response to GKRS. Here we present data on subjects treated with this combination from a single institution. Methods Records from patients who underwent treatment for metastatic melanoma to the brain with GKRS from 2011 to 2016 were reviewed. Demographics, date of brain metastasis diagnosis, cause of death when applicable, immunotherapeutics, and imaging findings were recorded. The timing of radiation therapy and medications were also documented.  Results A total of 79 subjects were treated with GKRS, and 66 underwent treatment with both GKRS and immunotherapy. Regarding the 30 patients treated with anti-PD-1 immunotherapy, 21 patients received pembrolizumab, seven patients received nivolumab, and two patients received pembrolizumab and nivolumab. Serial imaging was available for interpretation in 25 patients, with 13 subjects who received GKRS and anti-PD-1 immunotherapy less than six weeks of each other. While four subjects had indeterminate/mixed findings on subsequent magnetic resonance imaging (MRI), nine subjects were noted to have progression. Two of these patients showed progression but subsequent imaging revealed a decrease in progression or improvement on MRI to previously targeted lesions by GKRS. None of the 13 subjects had surgery following their combined therapies. Conclusions This data suggests that there is need for further investigation of the role for concurrent treatment with PD-1 inhibitors and GKRS to enhance the treatment of metastatic melanoma. We present data on 13 patients who appear to have some radiologic benefit to this treatment combination, two of whom had radiographic pseudoprogression. PMID:29468099

Commercial Sensory Survey Radiation Testing Progress Report

NASA Technical Reports Server (NTRS)

Becker, Heidi N.; Dolphic, Michael D.; Thorbourn, Dennis O.; Alexander, James W.; Salomon, Phil M.

2008-01-01

The NASA Electronic Parts and Packaging (NEPP) Program Sensor Technology Commercial Sensor Survey task is geared toward benefiting future NASA space missions with low-cost, short-duty-cycle, visible imaging needs. Such applications could include imaging for educational outreach purposes or short surveys of spacecraft, planetary, or lunar surfaces. Under the task, inexpensive commercial grade CMOS sensors were surveyed in fiscal year 2007 (FY07) and three sensors were selected for total ionizing dose (TID) and displacement damage dose (DDD) tolerance testing. The selected sensors had to meet selection criteria chosen to support small, low-mass cameras that produce good resolution color images. These criteria are discussed in detail in [1]. This document discusses the progress of radiation testing on the Micron and OmniVision sensors selected in FY07 for radiation tolerance testing.

A Prospective Clinical Trial Combining Radiation Therapy With Systemic Immunotherapy in Metastatic Melanoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hiniker, Susan M., E-mail: shiniker@stanford.edu; Reddy, Sunil A.; Maecker, Holden T.

Purpose: Local radiation therapy (RT) combined with systemic anti-cytotoxic T-lymphocyte–associated protein-4 immunotherapy may enhance induction of systemic antimelanoma immune responses. The primary objective of the present trial was to assess the safety and efficacy of combining ipilimumab with RT in patients with stage IV melanoma. The secondary objectives included laboratory assessment of induction of antimelanoma immune responses. Methods and Materials: In our prospective clinical trial, 22 patients with stage IV melanoma were treated with palliative RT and ipilimumab for 4 cycles. RT to 1 to 2 disease sites was initiated within 5 days after starting ipilimumab. Patients had ≥1 nonirradiated metastasismore » measuring ≥1.5 cm available for response assessment. Tumor imaging studies were obtained at baseline, 2 to 4 weeks after cycle 4 of ipilimumab, and every 3 months until progression. Laboratory immune response parameters were measured before and during treatment. Results: Combination therapy was well-tolerated without unexpected toxicities. Eleven patients (50.0%) experienced clinical benefit from therapy, including complete and partial responses and stable disease at median follow-up of 55 weeks. Three patients (27.3%) achieved an ongoing systemic complete response at a median follow-up of 55 weeks (range 32-65), and 3 (27.3%) had an initial partial response for a median of 40 weeks. Analysis of immune response data suggested a relationship between elevated CD8-activated T-cells and response. Conclusion: This is the second prospective clinical trial of treatment of metastatic melanoma using the combination of RT and systemic immunotherapy and the first using this sequence of therapy. The results from the present trial demonstrate that a subset of patients may benefit from combination therapy, arguing for continued clinical investigation of the use of RT combined with immunotherapy, including programmed cell death 1 inhibitors, which might have the potential to be even more effective in combination with RT.« less

Subtype-Specific Radiation Response and Therapeutic Effect of FAS Death Receptor Modulation in Human Breast Cancer.

PubMed

Lee, Chen-Ting; Zhou, Yingchun; Roy-Choudhury, Kingshuk; Siamakpour-Reihani, Sharareh; Young, Kenneth; Hoang, Peter; Kirkpatrick, John P; Chi, Jen-Tsan A; Dewhirst, Mark W; Horton, Janet K

2017-08-01

Breast cancer is the most common malignancy diagnosed among women and represents a heterogeneous group of subtypes. Radiation therapy is a critical component of treatment for breast cancer patients. However, little is known about radiation response among these intrinsic subtypes. In previous studies, we identified a significant induction of FAS after irradiation in biologically favorable breast cancer patients and breast cancer cell lines. Here, we expanded our study and investigated radiation response in a mouse model of breast cancer. MCF7 (luminal), HCC1954 (HER2 + ) or SUM159 (basal) cells were implanted orthotopically into the dorsal mammary fat pad of nude mice. These mice were then treated with different doses of radiation to assess tumor growth control. We further investigated the therapeutic effect of FAS modulation by silencing FAS in radiation-responsive tumors and injecting FAS agonist antibody into radiation-resistant tumors. Exposure to radiation inhibited MCF7, and to a lesser extent HCC1954 tumor growth in a dose-dependent manner. In contrast, SUM159 tumors were resistant to radiation. The estimated TCD 50 values were 19.3 Gy for MCF7 and 44.9 Gy for SUM159. Radiation induced FAS expression in MCF7 tumors, but not SUM159 tumors. We found that silencing of FAS did not negatively impact radiation response in MCF7 tumors, possibly due to compensation by other apoptotic pathways. On the other hand, FAS activating antibody in combination with radiation treatment delayed SUM159 and HCC1954 tumor growth. However, it did not reach statistical significance compared to radiation treatment alone. Our results suggest that there is intrinsic variation in radiation response among breast cancer subtypes. FAS activation concurrent with radiation slows tumor growth in the radiation-resistant subtypes, but the effect was not significant. Alternative subtype-specific modulators of radiation response are under investigation.

No adaptive response is induced by chronic low-dose radiation from Ra-226 in the CHSE/F fish embryonic cell line and the HaCaT human epithelial cell line

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shi, Xiaopei, E-mail: shix22@mcmaster.ca; Mothersi

Purpose: To determine whether chronic low-dose α-particle radiation from Ra-226 over multiple cell generations can lead to an adaptive response in CHSE/F fish embryonic cells or HaCaT human epithelial cells receiving subsequent acute high-dose γ-ray radiation. Methods: CHSE/F and HaCaT cells were exposed to very low doses of Ra-226 in medium for multiple generations prior to being challenged by a higher dose γ-ray radiation. The clonogenic assay was used to test the clonogenic survival of cells with or without being pretreated by radiation from Ra-226. Results: In general, pretreatment with chronic radiation has no significant influence on the reaction ofmore » cells to the subsequent challenge radiation. Compared to unprimed cells, the change in clonogenic survival of primed cells after receiving challenge radiation is mainly due to the influence of the chronic exposure, and there's little adaptive response induced. However at several dose points, pretreatment of CHSE/F fish cells with chronic radiation resulted in a radiosensitive response to a challenge dose of γ-ray radiation, and pretreatment of HaCaT cells resulted in no effect except for a slightly radioresistant response to the challenge radiation which was not significant. Conclusion: The results suggest that chronic low-dose radiation is not effective enough to induce adaptive response. There was a difference between human and fish cells and it may be important to consider results from multiple species before making conclusions about effects of chronic or low doses of radiation in the environment. The term “radiosensitive” or “adaptive” make no judgment about whether such responses are ultimately beneficial or harmful. - Highlights: • No obvious adaptive response is induced by chronic low-dose radiation from Ra-226. • Priming radiation from Ra-226 sensitized CHSE/F cells to the challenge radiation. • Linear model is inconsistent with current work using chronic low-dose radiation.« less

Effects of tempol and redox-cycling nitroxides in models of oxidative stress

PubMed Central

Wilcox, Christopher S.

2010-01-01

Tempol is a redox cycling nitroxide that promotes the metabolism of many reactive oxygen species (ROS) and improves nitric oxide bioavailability. It has been studied extensively in animal models of oxidative stress. Tempol has been shown to preserve mitochondria against oxidative damage and improve tissue oxygenation. Tempol improved insulin responsiveness in models of diabetes mellitus and improved the dyslipidemia, reduced the weight gain and prevented diastolic dysfunction and heart failure in fat-fed models of the metabolic syndrome. Tempol protected many organs, including the heart and brain, from ischemia/reperfusion damage. Tempol prevented podocyte damage, glomerulosclerosis, proteinuria and progressive loss of renal function in models of salt and mineralocorticosteroid excess. It reduced brain or spinal cord damage after ischemia or trauma and exerted a spinal analgesic action. Tempol improved survival in several models of shock. It protected normal cells from radiation while maintaining radiation sensitivity of tumor cells. Its paradoxical pro-oxidant action in tumor cells accounted for a reduction in spontaneous tumor formation. Tempol was effective in some models of neurodegeneration. Thus, tempol has been effective in preventing several of the adverse consequences of oxidative stress and inflammation that underlie radiation damage and many of the diseases associated with aging. Indeed, tempol given from birth prolonged the life span of normal mice. However, presently tempol has been used only in human subjects as a topical agent to prevent radiation-induced alopecia. PMID:20153367

Biophysical modelling of early and delayed radiation damage at chromosome level

NASA Astrophysics Data System (ADS)

Andreev, S.; Eidelman, Y.

Exposure by ionising radiation increases cancer risk in human population Cancer is thought to originate from an altered expression of certain number of specific genes It is now widely recognised that chromosome aberrations CA are involved in stable change in expression of genes by gain or loss of their functions Thus CA can contribute to initiation or progression of cancer Therefore understanding mechanisms of CA formation in the course of cancer development might be valuable tool for quantification and prognosis of different stages of radiation carcinogenesis Early CA are defined as aberrations induced in first post-irradiation mitotic cycle The present work describes the original biophysical technique for early CA modelling It includes the following simulation steps the ionising particle track structure the structural organisation of all chromosomes in G 0 G 1 cell nucleus spatial distribution of radiation induced DNA double-strand breaks dsb within chromosomes dsb rejoining and misrejoining modelling cell cycle taking into account mitotic delay which results in complex time dependence of aberrant cells in first mitosis The results on prediction of dose-response curves for simple and complex CA measured in cells undergoing first division cycle are presented in comparison with recent experimental data There is increasing evidence that CA are also observed in descendents of irradiated cells many generations after direct DNA damage These delayed CA or chromosome instability CI are thought to be a manifestation of genome

Progress Toward Electrostatic Radiation Shielding of Interplanetary Spacecraft: Strategies, Concepts and Technical Challenges of Human Exploration Beyond Low Earth Orbit

NASA Technical Reports Server (NTRS)

Metzger, Philip T.; Lane, John E.; Youngquist, Robert C.

2004-01-01

The radiation problem is a serious obstacle to solar system exploration. Electrostatic shielding was previously dismissed as unworkable. This was based on the false assumption that radial symmetry is needed to provide isotropic protection. KSC recently demonstrated the feasibility of asymmetric, multipole electrostatic shielding. Combined with passive shielding it might solve the radiation problem

Simple Benchmark Specifications for Space Radiation Protection

NASA Technical Reports Server (NTRS)

Singleterry, Robert C. Jr.; Aghara, Sukesh K.

2013-01-01

This report defines space radiation benchmark specifications. This specification starts with simple, monoenergetic, mono-directional particles on slabs and progresses to human models in spacecraft. This report specifies the models and sources needed to what the team performing the benchmark needs to produce in a report. Also included are brief descriptions of how OLTARIS, the NASA Langley website for space radiation analysis, performs its analysis.

Clinical Outcomes of Image Guided Adaptive Hypofractionated Weekly Radiation Therapy for Bladder Cancer in Patients Unsuitable for Radical Treatment

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hafeez, Shaista, E-mail: shaista.hafeez@icr.ac.uk; The Royal Marsden NHS Foundation Trust, Sutton, Surrey; McDonald, Fiona

Purpose and Objectives: We report on the clinical outcomes of a phase 2 study assessing image guided hypofractionated weekly radiation therapy in bladder cancer patients unsuitable for radical treatment. Methods and Materials: Fifty-five patients with T2-T4aNx-2M0-1 bladder cancer not suitable for cystectomy or daily radiation therapy treatment were recruited. A “plan of the day” radiation therapy approach was used, treating the whole (empty) bladder to 36 Gy in 6 weekly fractions. Acute toxicity was assessed weekly during radiation therapy, at 6 and 12 weeks using the Common Terminology Criteria for Adverse Events version 3.0. Late toxicity was assessed at 6 months and 12 monthsmore » using Radiation Therapy Oncology Group grading. Cystoscopy was used to assess local control at 3 months. Cumulative incidence function was used to determine local progression at 1 at 2 years. Death without local progression was treated as a competing risk. Overall survival was estimated using the Kaplan-Meier method. Results: Median age was 86 years (range, 68-97 years). Eighty-seven percent of patients completed their prescribed course of radiation therapy. Genitourinary and gastrointestinal grade 3 acute toxicity was seen in 18% (10/55) and 4% (2/55) of patients, respectively. No grade 4 genitourinary or gastrointestinal toxicity was seen. Grade ≥3 late toxicity (any) at 6 and 12 months was seen in 6.5% (2/31) and 4.3% (1/23) of patients, respectively. Local control after radiation therapy was 92% of assessed patients (60% total population). Cumulative incidence of local progression at 1 year and 2 years for all patients was 7% (95% confidence interval [CI] 2%-17%) and 17% (95% CI 8%-29%), respectively. Overall survival at 1 year was 63% (95% CI 48%-74%). Conclusion: Hypofractionated radiation therapy delivered weekly with a plan of the day approach offers good local control with acceptable toxicity in a patient population not suitable for radical bladder treatment.« less

Three-dimensional power doppler ultrasound is useful to monitor the response to treatment in a patient with primary papillary serous carcinoma of the peritoneum.

PubMed

Su, Jen-Min; Huang, Yu-Fang; Chen, Helen H W; Cheng, Ya-Min; Chou, Cheng-Yang

2006-05-01

To date, this is the first report to monitor changes of intratumor vascularization and the response to radiation and Cyberknife therapy in a patient with recurrent primary papillary serous carcinoma of the peritoneum by three dimensional (3D) power Doppler ultrasonography (PDUS). Transvaginal 3D PDUS detected a recurrent presacral tumor with abundant intratumor vascularity. Serial examinations of the tumor volume and serum CA-125 level were studied before, during, and 6 mo after therapy. Meanwhile, the intratumor blood flow was measured and expressed as vascularity indices. All of the tumor volume, intratumor vascularity indices and serum CA-125 level decreased progressively following therapy. A remaining lesion with nearly absent intratumor power Doppler signals suggested a scarring lesion posttreatment. Indeed, CT-guided tissue biopsy confirmed fibrotic change. 3D PDUS is useful to monitor the response to treatments and to differentiate residual tumors from lesions of scarring change posttreatment. It provides more accurate posttreatment information than pelvic computed tomography.

SP-100 - The national space reactor power system program in response to future needs

NASA Astrophysics Data System (ADS)

Armijo, J. S.; Josloff, A. T.; Bailey, H. S.; Matteo, D. N.

The SP-100 system has been designed to meet comprehensive and demanding NASA/DOD/DOE requirements. The key requirements include: nuclear safety for all mission phases, scalability from 10's to 100's of kWe, reliable performance at full power for seven years of partial power for ten years, survivability in civil or military threat environments, capability to operate autonomously for up to six months, capability to protect payloads from excessive radiation, and compatibility with shuttle and expendable launch vehicles. The authors address of major progress in terms of design, flexibility/scalability, survivability, and development. These areas, with the exception of survivability, are discussed in detail. There has been significant improvement in the generic flight system design with substantial mass savings and simplification that enhance performance and reliability. Design activity has confirmed the scalability and flexibility of the system and the ability to efficiently meet NASA, AF, and SDIO needs. SP-100 development continues to make significant progress in all key technology areas.

The Role of NFIB in Prostate Cancer Progression

DTIC Science & Technology

2015-09-01

Class:____Y____N____DNA Salvage Case after Radiation: ____Y ____N Hormones: Lupron/Casodex: ____Y ____N 5-ARI: Avodart/Proscar/ Propecia : ____Y ____N...Y____N____DNA Salvage Case after Radiation: ____Y ____N Hormones: Lupron/Casodex: ____Y ____N 5-ARI: Avodart/Proscar/ Propecia : ____Y ____N Additional

The Effects of Low Dose Irradiation on Inflammatory Response Proteins in a 3D Reconstituted Human Skin Tissue Model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Varnum, Susan M.; Springer, David L.; Chaffee, Mary E.

Skin responses to moderate and high doses of ionizing radiation include the induction of DNA repair, apoptosis, and stress response pathways. Additionally, numerous studies indicate that radiation exposure leads to inflammatory responses in skin cells and tissue. However, the inflammatory response of skin tissue to low dose radiation (<10 cGy) is poorly understood. In order to address this, we have utilized a reconstituted human skin tissue model (MatTek EpiDerm FT) and assessed changes in 23 cytokines twenty-four and forty eight hours following treatment of skin with either 3 or 10 cGy low-dose of radiation. Three cytokines, IFN-γ, IL-2, MIP-1α, weremore » significantly altered in response to low dose radiation. In contrast, seven cytokines were significantly altered in response to a high radiation dose of 200 cGy (IL-2, IL-10, IL-13, IFN-γ, MIP-1α, TNF α, and VEGF) or the tumor promoter 12-O-tetradecanoylphorbol 13-acetate (G-CSF, GM-CSF, IL-1α, IL-8, MIP-1α, MIP-1β, RANTES). Additionally, radiation induced inflammation appears to have a distinct cytokine response relative to the non-radiation induced stressor, TPA. Overall, these results indicate that there are subtle changes in the inflammatory protein levels following exposure to low dose radiation and this response is a sub-set of what is seen following a high dose in a human skin tissue model.« less

The role of radiotherapy in the management of patients with diffuse low grade glioma: A systematic review and evidence-based clinical practice guideline.

PubMed

Ryken, Timothy C; Parney, Ian; Buatti, John; Kalkanis, Steven N; Olson, Jeffrey J

2015-12-01

(1) What is the optimal role of external beam radiotherapy in the management of adult patients with newly diagnosed low-grade glioma (LGG) in terms of improving outcome (i.e., survival, complications, seizure control or other reported outcomes of interest)? (2) Which radiation strategies (dose, timing, fractionation, stereotactic radiation, brachytherapy, chemotherapy) improve outcomes compared to standard external beam radiation therapy in the initial management of low grade gliomas in adults? (3) Do specific factors (e.g., age, volume, extent of resection, genetic subtype) identify subgroups with better outcomes following radiation therapy than the general population of adults with newly diagnosed low-grade gliomas? These recommendations apply to adults with newly diagnosed diffuse LGG. OUTCOMES IN ADULT PATIENTS WITH NEWLY DIAGNOSED LOW GRADE GLIOMA TREATED WITH RADIOTHERAPY: Level I Radiotherapy is recommended in the management of newly diagnosed low-grade glioma in adults to prolong progression free survival, irrespective of extent of resection. Level II Radiotherapy is recommended in the management of newly diagnosed low grade glioma in adults as an equivalent alternative to observation in preserving cognitive function, irrespective of extent of resection. Level III Radiotherapy is recommended in the management of newly diagnosed low grade glioma in adults to improve seizure control in patients with epilepsy and subtotal resection. Level III Radiotherapy is recommended in the management of newly diagnosed low-grade glioma in adults to prolong overall survival in patients with subtotal resection. Level III Consideration of the risk of radiation induced morbidity, including cognitive decline, imaging abnormalities, metabolic dysfunction and malignant transformation, is recommended when the delivery of radiotherapy is selected in the management of newly diagnosed low-grade glioma in adults. STRATEGIES OF RADIOTHERAPY IN ADULT PATIENTS WITH NEWLY DIAGNOSED LOW GRADE GLIOMA: Level I Lower dose radiotherapy is recommended as an equivalent alternative to higher dose immediate postoperative radiotherapy (45-50.4 vs. 59.4-64.8 Gy) in the management of newly diagnosed low-grade glioma in adults with reduced toxicity. Level III Delaying radiotherapy until recurrence or progression is recommended as an equivalent alternative to immediate postoperative radiotherapy in the management of newly diagnosed low-grade glioma in adults but may result in shorter time to progression. Level III The addition of chemotherapy to radiotherapy is not recommended over whole brain radiotherapy alone in the management of low-grade glioma, as it provides no additional survival benefit. Level III Limited-field radiotherapy is recommended over whole brain radiotherapy in the management of low-grade glioma. Level III Either stereotactic radiosurgery or brachytherapy are recommended as acceptable alternatives to external radiotherapy in selected patients. PROGNOSTIC FACTORS IN ADULT PATIENTS WITH NEWLY DIAGNOSED LOW GRADE GLIOMA TREATED WITH RADIOTHERAPY: Level II It is recommended that age greater than 40 years, astrocytic pathology, diameter greater than 6 cm, tumor crossing the midline and preoperative neurological deficit be considered as negative prognostic indicators when predicting overall survival in adult low grade glioma patients treated with radiotherapy. Level II It is recommended that smaller tumor size, extent of surgical resection and higher mini-mental status exam be considered as positive prognostic indicators when predicting overall survival and progression free survival in patients in adult low grade glioma patients treated with radiotherapy. Level III It is recommended that seizures at presentation, presence of oligodendroglial histological component and 1p19q deletion (along with additional relevant factors-see Table 1) be considered as positive prognostic indicators when predicting response to radiotherapy in adults with low grade gliomas. Level III It is recommended that increasing age, decreasing performance status, decreasing cognition, presence of astrocytic histological component (along with additional relevant factors (see Tables 1, 2) be considered as negative prognostic indicators when predicting response to radiotherapy.

Cytological study of radiation induced alterations in cytoplasmic factors controlling male sterility in corn. Progress report, February 28, 1975--December 1, 1975

DOE Office of Scientific and Technical Information (OSTI.GOV)

Edwardson, J.R.

1975-01-01

Progress is reported on the following research projects: cytoplasmic constituents of the embryo of various gymnosperms and angiosperms; cytoplasmic male sterility in corn; modification of cytoplasmic sterility factors using gamma radiation, EMS, and ethidium bromide; selection for sterile, blight-resistant corn plants; electron microscopy study of abnormal mitochondria in cytoplasm of corn; cytoplasmic male sterility in Petunia; non-Mendelian variegation in Petunia and Nicotiana; graft transmission of cytoplasmic male sterility; cytoplasmic male sterility in Vicia faba; and studies on Blakeslee's I virus in Datura. (HLW)

The development of diamond tracking detectors for the LHC

NASA Astrophysics Data System (ADS)

Adam, W.; Berdermann, E.; Bergonzo, P.; de Boer, W.; Bogani, F.; Borchi, E.; Brambilla, A.; Bruzzi, M.; Colledani, C.; Conway, J.; D'Angelo, P.; Dabrowski, W.; Delpierre, P.; Doroshenko, J.; Dulinski, W.; van Eijk, B.; Fallou, A.; Fischer, P.; Fizzotti, F.; Furetta, C.; Gan, K. K.; Ghodbane, N.; Grigoriev, E.; Hallewell, G.; Han, S.; Hartjes, F.; Hrubec, J.; Husson, D.; Kagan, H.; Kaplon, J.; Karl, C.; Kass, R.; Keil, M.; Knöpfle, K. T.; Koeth, T.; Krammer, M.; Logiudice, A.; Lu, R.; mac Lynne, L.; Manfredotti, C.; Marshall, R. D.; Meier, D.; Menichelli, D.; Meuser, S.; Mishina, M.; Moroni, L.; Noomen, J.; Oh, A.; Perera, L.; Pernegger, H.; Pernicka, M.; Polesello, P.; Potenza, R.; Riester, J. L.; Roe, S.; Rudge, A.; Sala, S.; Sampietro, M.; Schnetzer, S.; Sciortino, S.; Stelzer, H.; Stone, R.; Sutera, C.; Trischuk, W.; Tromson, D.; Tuve, C.; Vincenzo, B.; Weilhammer, P.; Wermes, N.; Wetstein, M.; Zeuner, W.; Zoeller, M.; RD42 Collaboration

2003-11-01

Chemical vapor deposition diamond has been discussed extensively as an alternate sensor material for use very close to the interaction region of the LHC where extreme radiation conditions exist. During the last few years diamond devices have been manufactured and tested with LHC electronics with the goal of creating a detector usable by all LHC experiment. Extensive progress on diamond quality, on the development of diamond trackers and on radiation hardness studies has been made. Transforming the technology to the LHC specific requirements is now underway. In this paper we present the recent progress achieved.

Multimodality Management of "Borderline Resectable" Pancreatic Neuroendocrine Tumors: Report of a Single-Institution Experience.

PubMed

Ambe, Chenwi M; Nguyen, Phuong; Centeno, Barbara A; Choi, Junsung; Strosberg, Jonathan; Kvols, Larry; Hodul, Pamela; Hoffe, Sarah; Malafa, Mokenge P

2017-01-01

Pancreatic neuroendocrine tumors (PanNETs) constitute approximately 3% of pancreatic neoplasms. Like patients with pancreatic ductal adenocarcinoma (PDAC), some of these patients present with "borderline resectable disease." For these patients, an optimal treatment approach is lacking. We report our institution's experience with borderline resectable PanNETs using multimodality treatment. We identified patients with borderline resectable PanNETs who had received neoadjuvant therapy at our institution between 2000 and 2013. The definition of borderline resectability was based on National Comprehensive Cancer Network criteria for PDAC. Neoadjuvant regimen, radiographic response, pathologic response, surgical margins, nodal retrieval, number of positive nodes, and recurrence were documented. Statistics were descriptive. Of 112 patients who underwent surgical resection for PanNETs during the study period, 23 received neoadjuvant therapy, 6 of whom met all inclusion criteria and had borderline resectable disease. These 6 patients received at least 1 cycle of temozolomide and capecitabine, with 3 also receiving radiation. All had radiographic evidence of treatment response. Four (67%) had negative-margin resections. Four patients had histologic evidence of a moderate response. Follow-up (3.0-4.3 years) indicated that all patients were alive, with 5/6 free of disease (1 patient with metastatic disease still on treatment without progression). A multimodality treatment strategy (neoadjuvant temozolomide and capecitabine ± radiation) can be successfully applied to patients with PanNETs who meet NCCN borderline resectable criteria for PDAC. To our knowledge, this is the first report of the use of a multimodality protocol in the treatment of patients with borderline resectable PanNETs.

Ultrasonic transient bounded-beam propagation in a solid cylinder waveguide embedded in a solid medium.

PubMed

Laguerre, Laurent; Grimault, Anne; Deschamps, Marc

2007-04-01

A semianalytical solution alternative and complementary to modal technique is presented to predict and interpret the ultrasonic pulsed-bounded-beam propagation in a solid cylinder embedded in a solid matrix. The spectral response to an inside axisymmetric velocity source of longitudinal and transversal cylindrical waves is derived from Debye series expansion of the embedded cylinder generalized cylindrical reflection/transmission coefficients. So, the transient guided wave response, synthesized by inverse double Fourier-Bessel transform, is expressed as a combination of the infinite medium contribution, longitudinal, transversal, and coupled longitudinal and transversal waveguide sidewall interactions. Simulated (f, 1/lambdaz) diagrams show the influence of the number of waveguide sidewall interactions to progressively recover dispersion curves. Besides, they show the embedding material filters specific signal portions by concentrating the propagating signal in regions where phase velocity is closer to phase velocity in steel. Then, simulated time waveforms using broadband high-frequency excitation show that signal leading portions exhibit a similar periodical pattern, for both free and embedded waveguides. Debye series-based interpretation shows that double longitudinal/transversal and transversal/longitudinal conversions govern the time waveform leading portion as well as the radiation attenuation in the surrounding cement grout. Finally, a methodology is deduced to minimize the radiation attenuation for the long-range inspection of embedded cylinders.

Multimodal nonlinear nanophotonics (Conference Presentation)

NASA Astrophysics Data System (ADS)

Kivshar, Yuri S.

2017-05-01

Nonlinear nanophotonics is a rapidly developing field of research with many potential applications for the design of nonlinear nanoantennas, light sources, nanolasers, and ultrafast miniature metadevices. A tight confinement of the local electromagnetic fields in resonant photonic nanostructures can boost nonlinear optical effects, thus offering versatile opportunities for the subwavelength control of light. To achieve the desired functionalities, it is essential to gain flexible control over the near- and far-field properties of nanostructures. To engineer nonlinear scattering from resonant nanoscale elements, both modal and multipolar control of the nonlinear response are widely exploited for enhancing the near-field interaction and optimizing the radiation directionality. Motivated by the recent progress of all-dielectric nanophotonics, where the electric and magnetic multipolar contributions may become comparable, here we review the advances in the recently emerged field of multipolar nonlinear nanophotonics, starting from earlier relevant studies of metallic and metal-dielectric structures supporting localized plasmonic resonances to then discussing the latest results for all-dielectric nanostructures driven by Mie-type multipolar resonances and optically induced magnetic response. These recent developments suggest intriguing opportunities for a design of nonlinear subwavelength light sources with reconfigurable radiation characteristics and engineering large effective optical nonlinearities at the nanoscale, which could have important implications for novel nonlinear photonic devices operating beyond the diffraction limit.

Meningioma Causing Visual Impairment: Outcomes and Toxicity After Intensity Modulated Radiation Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Maclean, Jillian, E-mail: jillian.maclean@uclh.nhs.uk; Fersht, Naomi; Bremner, Fion

2013-03-15

Purpose: To evaluate ophthalmologic outcomes and toxicity of intensity modulated radiation therapy (IMRT) in patients with meningiomas causing visual deficits. Methods and Materials: A prospective observational study with formal ophthalmologic and clinical assessment of 30 consecutive cases of meningioma affecting vision treated with IMRT from 2007 to 2011. Prescriptions were 50.4 Gy to mean target dose in 28 daily fractions. The median follow-up time was 28 months. Twenty-six meningiomas affected the anterior visual pathway (including 3 optic nerve sheath meningiomas); 4 were posterior to the chiasm. Results: Vision improved objectively in 12 patients (40%). Improvements were in visual field (5/16more » patients), color vision (4/9 patients), acuity (1/15 patients), extraocular movements (3/11 patients), ptosis (1/5 patients), and proptosis (2/6 patients). No predictors of clinical response were found. Two patients had minor reductions in tumor dimensions on magnetic resonance imaging, 1 patient had radiological progression, and the other patients were stable. One patient experienced grade 2 keratitis, 1 patient had a minor visual field loss, and 5 patients had grade 1 dry eye. Conclusion: IMRT is an effective method for treating meningiomas causing ophthalmologic deficits, and toxicity is minimal. Thorough ophthalmologic assessment is important because clinical responses often occur in the absence of radiological change.« less

Method of enhancing radiation response of radiation detection materials

DOEpatents

Miller, Steven D.

1997-01-01

The present invention is a method of increasing radiation response of a radiation detection material for a given radiation signal by first pressurizing the radiation detection material. Pressurization may be accomplished by any means including mechanical and/or hydraulic. In this application, the term "pressure" includes fluid pressure and/or mechanical stress.

A Prospective Study of Proton Beam Reirradiation for Esophageal Cancer.

PubMed

Fernandes, Annemarie; Berman, Abigail T; Mick, Rosemarie; Both, Stefan; Lelionis, Kristi; Lukens, John N; Ben-Josef, Edgar; Metz, James M; Plastaras, John P

2016-05-01

Reirradiation to the esophagus carries a significant risk of complications. Proton therapy may offer an advantage in the reirradiation setting due to the lack of exit dose and potential sparing of previously radiated normal tissues. Between June 2010 and February 2014, 14 patients with a history of thoracic radiation and newly diagnosed or locally recurrent esophageal cancer began proton beam reirradiation on a prospective trial. Primary endpoints were feasibility and acute toxicity. Toxicity was graded according Common Toxicity Criteria version 4.0. The median follow-up was 10 months (2-25 months) from the start of reirradiation. Eleven patients received concurrent chemotherapy. The median interval between radiation courses was 32 months (10-307 months). The median reirradiation prescription dose was 54.0 Gy (relative biological effectiveness [RBE]) (50.4-61.2 Gy[RBE]), and the median cumulative prescription dose was 109.8 Gy (76-129.4 Gy). Of the 10 patients who presented with symptomatic disease, 4 patients had complete resolution of symptoms, and 4 had diminished or stable symptoms. Two patients had progressive symptoms. The median time to symptom recurrence was 10 months. Maximum acute nonhematologic toxicity attributable to radiation was grade 2 (64%, N=9), 3 (29%, N=4), 4 (0%), and 5 (7%, N=1). The acute grade 5 toxicity was an esophagopleural fistula more likely related to tumor progression than radiation. Grade 3 nonhematologic acute toxicities included dysphagia, dehydration, and pneumonia. There was 1 late grade 5 esophageal ulcer more likely related to tumor progression than radiation. There were 4 late grade 3 toxicities: heart failure, esophageal stenosis requiring dilation, esophageal ulceration from tumor, and percutaneous endoscopic gastrostomy tube dependence. The median time to local failure was 10 months, and the median overall survival was 14 months. Our data demonstrate that proton reirradiation is feasible, with an encouraging symptom control rate, modest radiation-related toxicity, and favorable survival in this high-risk population. Copyright © 2016 Elsevier Inc. All rights reserved.

Induction therapy with carboplatin/paclitaxel followed by concurrent carboplatin/paclitaxel and dose-escalating conformal radiotherapy in the treatment of locally advanced, unresectable non-small cell lung cancer: preliminary report of a phase I trial.

PubMed

Socinski, M A; Clark, J A; Halle, J; Steagall, A; Kaluzny, B; Rosenman, J G

1997-08-01

Locally advanced non-small cell lung cancer is optimally managed with chemotherapy and thoracic irradiation, although the most appropriate strategy is not yet defined. In this phase I trial, we use two 21-day cycles of induction chemotherapy with paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) (225 mg/m2 over 3 hours) and carboplatin (area under the concentration-time curve = 6) followed by concurrent weekly paclitaxel (45 mg/m2/wk x 6) and carboplatin (area under the concentration-time curve = 2/wk x 6) and thoracic irradiation. Patients undergo three-dimensional treatment planning (conformal radiotherapy) to define the cancer target volume precisely. The phase I question being addressed in this study is the maximum tolerated radiation dose given concurrently with low-dose paclitaxel and carboplatin. The initial radiation dose is 60 Gy, with dose escalations to 66 Gy, 70 Gy, and 74 Gy being planned. Ten patients have been entered thus far (eight men and two women). Their median age is 67 years (range, 59 to 78 years), and none of the patients has had greater than 5% pretreatment weight loss. Seven of 10 are evaluable for response to induction carboplatin and paclitaxel, with a response rate of 57% (three partial responses and one minor response). Three patients had stable disease and none of the patients had evidence of progressive disease during induction chemotherapy. Three patients have completed all treatment at 60 Gy and one has completed all treatment at 66 Gy. Three of the four patients have had partial responses (75%), with the remaining patient having stable disease. Toxicity in the concurrent chemoradiotherapy portion of the trial thus far has consisted of grade 3 neutropenia in one patient and grade 4 lymphocytopenia in all four patients. No grade 3 or 4 nonhematologic toxicity has been seen. The trial data are not yet mature enough to report on survival. Accrual and treatment is continuing at the 66 Gy radiation dose level.

The Impact of Chemotherapy, Radiation and Epigenetic Modifiers in Cancer Cell Expression of Immune Inhibitory and Stimulatory Molecules and Anti-Tumor Efficacy

PubMed Central

Chacon, Jessica Ann; Schutsky, Keith; Powell, Daniel J.

2016-01-01

Genomic destabilizers, such as radiation and chemotherapy, and epigenetic modifiers are used for the treatment of cancer due to their apoptotic effects on the aberrant cells. However, these therapies may also induce widespread changes within the immune system and cancer cells, which may enable tumors to avoid immune surveillance and escape from host anti-tumor immunity. Genomic destabilizers can induce immunogenic death of tumor cells, but also induce upregulation of immune inhibitory ligands on drug-resistant cells, resulting in tumor progression. While administration of immunomodulatory antibodies that block the interactions between inhibitory receptors on immune cells and their ligands on tumor cells can mediate cancer regression in a subset of treated patients, it is crucial to understand how genomic destabilizers alter the immune system and malignant cells, including which inhibitory molecules, receptors and/or ligands are upregulated in response to genotoxic stress. Knowledge gained in this area will aid in the rational design of trials that combine genomic destabilizers, epigenetic modifiers and immunotherapeutic agents that may be synergized to improve clinical responses and prevent tumor escape from the immune system. Our review article describes the impact genomic destabilizers, such as radiation and chemotherapy, and epigenetic modifiers have on anti-tumor immunity and the tumor microenvironment. Although genomic destabilizers cause DNA damage on cancer cells, these therapies can also have diverse effects on the immune system, promote immunogenic cell death or survival and alter the cancer cell expression of immune inhibitor molecules. PMID:27854240

Mechanisms and biological importance of photon-induced bystander responses: do they have an impact on low-dose radiation responses

PubMed Central

Tomita, Masanori; Maeda, Munetoshi

2015-01-01

Abstract Elucidating the biological effect of low linear energy transfer (LET), low-dose and/or low-dose-rate ionizing radiation is essential in ensuring radiation safety. Over the past two decades, non-targeted effects, which are not only a direct consequence of radiation-induced initial lesions produced in cellular DNA but also of intra- and inter-cellular communications involving both targeted and non-targeted cells, have been reported and are currently defining a new paradigm in radiation biology. These effects include radiation-induced adaptive response, low-dose hypersensitivity, genomic instability, and radiation-induced bystander response (RIBR). RIBR is generally defined as a cellular response that is induced in non-irradiated cells that receive bystander signals from directly irradiated cells. RIBR could thus play an important biological role in low-dose irradiation conditions. However, this suggestion was mainly based on findings obtained using high-LET charged-particle radiations. The human population (especially the Japanese, who are exposed to lower doses of radon than the world average) is more frequently exposed to low-LET photons (X-rays or γ-rays) than to high-LET charged-particle radiation on a daily basis. There are currently a growing number of reports describing a distinguishing feature between photon-induced bystander response and high-LET RIBR. In particular, photon-induced bystander response is strongly influenced by irradiation dose, the irradiated region of the targeted cells, and p53 status. The present review focuses on the photon-induced bystander response, and discusses its impact on the low-dose radiation effect. PMID:25361549

[Combined palliative hypofractionated radiation and carboplatin chemotherapy of intranasal tumours in dogs].

PubMed

Schwietzer, A; Kessler, M; Kandel-Tschiederer, B

2012-10-17

Combination therapy of intranasal tumours in dogs with palliative 60 cobalt radiation and carboplatin chemotherapy. Twenty-five dogs with intranasal tumours were treated in the Hofheim Veterinary Hospital (Germany) from 2004 to 2006 with a total radiation dose of 24Gy (3 fractions of 8 Gy on days 0, 7 and 21) and five doses of Carboplatin (270-300 mg/m² BSA i.v. every 21-28 days). In 88% patients, clinical symptoms subsided partially or completely resulting in improvement in quality of life. Computed tomography revealed partial (5/25) or complete (5/25) tumour remissions. Chemotherapy was well tolerated. Radiation therapy caused no or minimal side effects except for 3 dogs (12%), which experienced serious ocular side effects resulting in loss of vision of the affected eye and one dog with epileptic seizures. Survival times ranged from 10-639 days with a median of 156 days. There was no statistically significant correlation between the parameters breed, age, sex, brain invasion or tumour stage and survival time or progression free interval. Survival time and progression free interval were significantly correlated with the degree of tumour remission. It can be concluded from this study that palliative radiation therapy combined with chemotherapy results in excellent palliation of clinical symptoms and acceptable survival times. There was no advantage of combined therapy (radiation with carboplatin) when compared to literature data on results of radiation therapy alone.

Randomized phase II--study evaluating EGFR targeting therapy with cetuximab in combination with radiotherapy and chemotherapy for patients with locally advanced pancreatic cancer--PARC: study protocol [ISRCTN56652283].

PubMed

Krempien, R; Muenter, M W; Huber, P E; Nill, S; Friess, H; Timke, C; Didinger, B; Buechler, P; Heeger, S; Herfarth, K K; Abdollahi, A; Buchler, M W; Debus, J

2005-10-11

Pancreatic cancer is the fourth commonest cause of death from cancer in men and women. Advantages in surgical techniques, radiation therapy techniques, chemotherapeutic regimes, and different combined-modality approaches have yielded only a modest impact on the prognosis of patients with pancreatic cancer. Thus there is clearly a need for additional strategies. One approach involves using the identification of a number of molecular targets that may be responsible for the resistance of cancer cells to radiation or to other cytotoxic agents. As such, these molecular determinants may serve as targets for augmentation of the radiotherapy or chemotherapy response. Of these, the epidermal growth factor receptor (EGFR) has been a molecular target of considerable interest and investigation, and there has been a tremendous surge of interest in pursuing targeted therapy of cancers via inhibition of the EGFR. The PARC study is designed as an open, controlled, prospective, randomized phase II trial. Patients in study arm A will be treated with chemoradiation using intensity modulated radiation therapy (IMRT) combined with gemcitabine and simultaneous cetuximab infusions. After chemoradiation the patients receive gemcitabine infusions weekly over 4 weeks. Patients in study arm B will be treated with chemoradiation using intensity modulated radiation therapy (IMRT) combined with gemcitabine and simultaneous cetuximab infusions. After chemoradiation the patients receive gemcitabine weekly over 4 weeks and cetuximab infusions over 12 weeks. A total of 66 patients with locally advanced adenocarcinoma of the pancreas will be enrolled. An interim analysis for patient safety reasons will be done one year after start of recruitment. Evaluation of the primary endpoint will be performed two years after the last patient's enrollment. The primary objective of this study is to evaluate the feasibility and the toxicity profile of trimodal therapy in pancreatic adenocarcinoma with chemoradiation therapy with gemcitabine and intensity modulated radiation therapy (IMRT) and EGFR-targeted therapy using cetuximab and to compare between two different methods of cetuximab treatment schedules (concomitant versus concomitant and sequential cetuximab treatment). Secondary objectives are to determine the role and the mechanism of cetuximab in patient's chemoradiation regimen, the response rate, the potential of this combined modality treatment to concert locally advanced lesions to potentially resectable lesions, the time to progression interval and the quality of life.

Intensity Modulated Radiation Therapy With Simultaneous Integrated Boost in Patients With Brain Oligometastases: A Phase 1 Study (ISIDE-BM-1)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ferro, Marica; Chiesa, Silvia; Macchia, Gabriella, E-mail: gmacchia@rm.unicatt.it

Purpose: To investigate the maximum tolerated dose of intensity modulated radiation therapy simultaneous integrated boost whole-brain radiation therapy for palliative treatment of patients with <5 brain metastases using a standard linear accelerator. Materials and Methods: The whole brain plus 3-mm margin was defined as the planning target volume (PTV{sub wb}), whereas each brain metastasis, defined as the contrast-enhancing tumor on MRI T1 scans, plus a 3-mm isotropic margin, was defined as metastases PTV (PTV{sub m}). Radiation therapy was delivered in 10 daily fractions (2 weeks). Only the dose to PTV{sub m} was progressively increased in the patient cohorts (35 Gy, 40 Gy, 45 Gy, 50 Gy),more » whereas the PTV{sub wb} was always treated with 30 Gy (3 Gy per fraction) in all patients. The dose-limiting toxicity was evaluated providing that 3 months of follow-up had occurred after the treatment of a 6-patient cohort. Results: Thirty patients were enrolled in the study (dose PTV{sub m}: 35 Gy, 8 patients; 40 Gy, 6 patients; 45 Gy, 6 patients; 50 Gy, 10 patients). The number of treated brain metastases was 1 in 18 patients, 2 in 5 patients, 3 in 6 patients, and 4 in 1 patient. Three patients experienced dose-limiting toxicity: 1 patient at dose level 2 presented grade 3 (G3) skin toxicity; 1 patient at dose level 4 presented G3 neurologic toxicity; and 1 patient at the same level showed brain hemorrhage. Most patients showed G1 to 2 acute toxicity, in most cases skin (n=19) or neurologic (n=10). Twenty-seven were evaluable for response: 6 (22%) stable disease, 18 (67%) partial response, and 3 (11%) complete response. Median survival and 1-year overall survival were 12 months and 53%, respectively. No patient showed late toxicity. Conclusions: In this first prospective trial on the use of intensity modulated radiation therapy simultaneous integrated boost delivered with a standard linear accelerator in patients with brain oligometastases, a boost dose up to 50 Gy in 10 fractions was tolerable according to the study design.« less

Accumulated Delivered Dose Response of Stereotactic Body Radiation Therapy for Liver Metastases

DOE Office of Scientific and Technical Information (OSTI.GOV)

Swaminath, Anand; Massey, Christine; Brierley, James D.

2015-11-01

Purpose: To determine whether the accumulated dose using image guided radiation therapy is a stronger predictor of clinical outcomes than the planned dose in stereotactic body radiation therapy (SBRT) for liver metastases. Methods and Materials: From 2003 to 2009, 81 patients with 142 metastases were treated in institutional review board–approved SBRT studies (5-10 fractions). Patients were treated during free breathing (with or without abdominal compression) or with controlled exhale breath-holding. SBRT was planned on a static exhale computed tomography (CT) scan, and the minimum planning target volume dose to 0.5 cm{sup 3} (minPTV) was recorded. The accumulated minimum dose to themore » 0.5 cm{sup 3} gross tumor volume (accGTV) was calculated after performing dose accumulation from exported image guided radiation therapy data sets registered to the planning CT using rigid (2-dimensional MV/kV orthogonal) or deformable (3-dimensional/4-dimensional cone beam CT) image registration. Univariate and multivariate Cox regression models assessed the factors influencing the time to local progression (TTLP). Hazard ratios for accGTV and minPTV were compared using model goodness-of-fit and bootstrapping. Results: Overall, the accGTV dose exceeded the minPTV dose in 98% of the lesions. For 5 to 6 fractions, accGTV doses of >45 Gy were associated with 1-year local control of 86%. On univariate analysis, the cancer subtype (breast), smaller tumor volume, and increased dose were significant predictors for improved TTLP. The dose and volume were uncorrelated; the accGTV dose and minPTV dose were correlated and were tested separately on multivariate models. Breast cancer subtype, accGTV dose (P<.001), and minPTV dose (P=.02) retained significance in the multivariate models. The univariate hazard ratio for TTLP for 5-Gy increases in accGTV versus minPTV was 0.67 versus 0.74 (all patients; 95% confidence interval of difference 0.03-0.14). Goodness-of-fit testing confirmed the accGTV dose as a stronger dose–response predictor than the minPTV dose. Conclusions: The accGTV dose is a better predictor of TTLP than the minPTV dose for liver metastasis SBRT. The use of modern image guided radiation therapy in future analyses of dose–response outcomes should increase the concordance between the planned and delivered doses.« less

Food irradiation: after 35 years, have we made progress. A government perspective.

PubMed

Young, Alvin L

2003-01-01

The use of irradiation to improve the safety, protect the nutritional benefits, and preserve the quality of fresh and processed foods is a well established and proven technology. Over the past 35 years, the United States Government has invested in the science to confirm safety and in the technology to show application. The United States Department of Agriculture (USDA) and the Food and Drug Administration have approved sources of ionizing radiation for the treatment of foods, and their application to most meats, fruits, vegetables, and spices. Despite the value of this technology to the food industry and to the health and welfare of the public, only minimal application of this technology occurs. This underscores the importance of increasing the public's understanding of radiation risks relative to other hazards. Accordingly, in 1995, the Committee on Interagency Radiation Research and Policy Coordination of the Executive Office of the President made recommendations for the creation of a centralized National Radiation Information Center that would work closely with Federal departments and agencies in responding to public queries about radiation issues and Federal programs. This article updates a commentary published in 1996 (Young 1996). In the past six years, some progress has been made, including the establishment of a government operated Food Irradiation Information Center, and the completion of final rule making by USDA, thus permitting the safe treatment of meats and poultry. Despite these actions, little progress has been made on the public acceptance of this technology. The need for an informed public and for a better understanding of risks, i.e., risk communication, is noted.

Targeting the cMET pathway augments radiation response without adverse effect on hearing in NF2 schwannoma models.

PubMed

Zhao, Yingchao; Liu, Pinan; Zhang, Na; Chen, Jie; Landegger, Lukas D; Wu, Limeng; Zhao, Fu; Zhao, Yanxia; Zhang, Yanling; Zhang, Jing; Fujita, Takeshi; Stemmer-Rachamimov, Anat; Ferraro, Gino B; Liu, Hao; Muzikansky, Alona; Plotkin, Scott R; Stankovic, Konstantina M; Jain, Rakesh K; Xu, Lei

2018-02-27

Neurofibromatosis type II (NF2) is a disease that needs new solutions. Vestibular schwannoma (VS) growth causes progressive hearing loss, and the standard treatment, including surgery and radiotherapy, can further damage the nerve. There is an urgent need to identify an adjunct therapy that, by enhancing the efficacy of radiation, can help lower the radiation dose and preserve hearing. The mechanisms underlying deafness in NF2 are still unclear. One of the major limitations in studying tumor-induced hearing loss is the lack of mouse models that allow hearing testing. Here, we developed a cerebellopontine angle (CPA) schwannoma model that faithfully recapitulates the tumor-induced hearing loss. Using this model, we discovered that cMET blockade by crizotinib (CRZ) enhanced schwannoma radiosensitivity by enhancing DNA damage, and CRZ treatment combined with low-dose radiation was as effective as high-dose radiation. CRZ treatment had no adverse effect on hearing; however, it did not affect tumor-induced hearing loss, presumably because cMET blockade did not change tumor hepatocyte growth factor (HGF) levels. This cMET gene knockdown study independently confirmed the role of the cMET pathway in mediating the effect of CRZ. Furthermore, we evaluated the translational potential of cMET blockade in human schwannomas. We found that human NF2-associated and sporadic VSs showed significantly elevated HGF expression and cMET activation compared with normal nerves, which correlated with tumor growth and cyst formation. Using organoid brain slice culture, cMET blockade inhibited the growth of patient-derived schwannomas. Our findings provide the rationale and necessary data for the clinical translation of combined cMET blockade with radiation therapy in patients with NF2.

Whole-brain hippocampal sparing radiation therapy: Volume-modulated arc therapy vs intensity-modulated radiation therapy case study.

PubMed

Lee, Katrina; Lenards, Nishele; Holson, Janice

2016-01-01

The hippocampus is responsible for memory and cognitive function. An ongoing phase II clinical trial suggests that sparing dose to the hippocampus during whole-brain radiation therapy can help preserve a patient׳s neurocognitive function. Progressive research and advancements in treatment techniques have made treatment planning more sophisticated but beneficial for patients undergoing treatment. The aim of this study is to evaluate and compare hippocampal sparing whole-brain (HS-WB) radiation therapy treatment planning techniques using volume-modulated arc therapy (VMAT) and intensity-modulated radiation therapy (IMRT). We randomly selected 3 patients to compare different treatment techniques that could be used for reducing dose to the hippocampal region. We created 2 treatment plans, a VMAT and an IMRT, from each patient׳s data set and planned on the Eclipse 11.0 treatment planning system (TPS). A total of 6 plans (3 IMRT and 3 VMAT) were created and evaluated for this case study. The physician contoured the hippocampus as per the Radiation Therapy Oncology Group (RTOG) 0933 protocol atlas. The organs at risk (OR) were contoured and evaluated for the plan comparison, which included the spinal cord, optic chiasm, the right and left eyes, lenses, and optic nerves. Both treatment plans produced adequate coverage on the planning target volume (PTV) while significantly reducing dose to the hippocampal region. The VMAT treatment plans produced a more homogenous dose distribution throughout the PTV while decreasing the maximum point dose to the target. However, both treatment techniques demonstrated hippocampal sparing when irradiating the whole brain. Copyright © 2016 American Association of Medical Dosimetrists. Published by Elsevier Inc. All rights reserved.

Low-dose energetic protons induce adaptive and bystander effects that protect human cells against DNA damage caused by a subsequent exposure to energetic iron ions

PubMed Central

Buonanno, Manuela; De Toledo, Sonia M.; Howell, Roger W.; Azzam, Edouard I.

2015-01-01

During interplanetary missions, astronauts are exposed to mixed types of ionizing radiation. The low ‘flux’ of the high atomic number and high energy (HZE) radiations relative to the higher ‘flux’ of low linear energy transfer (LET) protons makes it highly probable that for any given cell in the body, proton events will precede any HZE event. Whereas progress has been made in our understanding of the biological effects of low-LET protons and high-LET HZE particles, the interplay between the biochemical processes modulated by these radiations is unclear. Here we show that exposure of normal human fibroblasts to a low mean absorbed dose of 20 cGy of 0.05 or 1-GeV protons (LET ∼ 1.25 or 0.2 keV/μm, respectively) protects the irradiated cells (P < 0.0001) against chromosomal damage induced by a subsequent exposure to a mean absorbed dose of 50 cGy from 1 GeV/u iron ions (LET ∼ 151 keV/μm). Surprisingly, unirradiated (i.e. bystander) cells with which the proton-irradiated cells were co-cultured were also significantly protected from the DNA-damaging effects of the challenge dose. The mitigating effect persisted for at least 24 h. These results highlight the interactions of biological effects due to direct cellular traversal by radiation with those due to bystander effects in cell populations exposed to mixed radiation fields. They show that protective adaptive responses can spread from cells targeted by low-LET space radiation to bystander cells in their vicinity. The findings are relevant to understanding the health hazards of space travel. PMID:25805407

Thirty year celebration of journal publications on radiation oncology medical physics.

PubMed

Oliver, L D

2007-03-01

The Australasian Physical & Engineering Sciences in Medicine Journal (APESM) is an avenue for the profession to report scientific work in medicine; provide a facility for the publication of current work, new research and new techniques developed or reviewed; report on professional news from elsewhere and; publish the Australasian College of Physical Scientists and Engineers in Medicine (ACPSEM) policies and protocols. The journal is a vital instrument within the ACPSEM organisation with a worldwide circulation. This review of APESM on medical physics in radiation oncology is meant to be a progress summary of work in that specialty. Even so, it has become a lengthy appraisal due to the many years involved. In considering publications related to medical physics in radiation oncology, this review has shown the progression of the College journal to an international journal. There is an increase in the number of papers contributed from Asia and other countries world wide for this discipline. Growth in the number of contributions should continue to rise. In order to provide some appreciation of where the present medical physics activity arose from, this article commences its discussion in 1959 and progresses towards the present, describing along the way, from radiation oncology papers published in APESM, the use of linear accelerators, brachytherapy, the medical physics workforce, the formation of the ACPSEM, and the more modern developments in radiotherapy such as 3-D treatment planning and IMRT.

Ionizing radiation and cell cycle progression in ataxia telangiectasia

DOE Office of Scientific and Technical Information (OSTI.GOV)

Beamish, H.; Khanna, K.K.; Lavin, M.F.

1994-04-01

Exposure of mammalian cells to ionizing radiation causes delay in normal progress through the cell cycle at a number of different checkpoints. Abnormalities in these checkpoints have been described for ataxia telangiectasia cells after irradiation. In this report we show that these abnormalities occur at different phases in the cell cycle in several ataxia telangiectasia lymphoblastoid cells. Ataxia telangiectasia cells, synchronized in late G{sub 1} phase with either mimosine or aphidicolin and exposed to radiation, showed a reduced delay in entering S phase compared to irradiated control cells. Failure to exhibit G{sub 1}-phase delay in ataxia telangiectasia cells is accompaniedmore » by a reduced ability of radiation to activate the product of the tumor suppressor gene p53, a protein involved in G{sub 1}/S-phase delay. When the progress of irradiated G{sub 1}-phase cells was followed into the subsequent G{sub 2} and G{sub 1} phases ataxia telangiectasia cells showed a more pronounced accumulation in G{sub 2} phase than control cells. When cells were irradiated in S phase and extent of delay was more evident in G{sub 2} phase and ataxia telangiectasia cells were delayed to a greater extent. These results suggest that the lack of initial delay in both G{sub 1} and S phases to the radiosensitivity observed in this syndrome. 26 refs., 3 figs., 2 tabs.« less

TU-D-207B-01: A Prediction Model for Distinguishing Radiation Necrosis From Tumor Progression After Gamma Knife Radiosurgery Based On Radiomics Features From MR Images

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, Z; MD Anderson Cancer Center, Houston, TX; Ho, A

Purpose: To develop and validate a prediction model using radiomics features extracted from MR images to distinguish radiation necrosis from tumor progression for brain metastases treated with Gamma knife radiosurgery. Methods: The images used to develop the model were T1 post-contrast MR scans from 71 patients who had had pathologic confirmation of necrosis or progression; 1 lesion was identified per patient (17 necrosis and 54 progression). Radiomics features were extracted from 2 images at 2 time points per patient, both obtained prior to resection. Each lesion was manually contoured on each image, and 282 radiomics features were calculated for eachmore » lesion. The correlation for each radiomics feature between two time points was calculated within each group to identify a subset of features with distinct values between two groups. The delta of this subset of radiomics features, characterizing changes from the earlier time to the later one, was included as a covariate to build a prediction model using support vector machines with a cubic polynomial kernel function. The model was evaluated with a 10-fold cross-validation. Results: Forty radiomics features were selected based on consistent correlation values of approximately 0 for the necrosis group and >0.2 for the progression group. In performing the 10-fold cross-validation, we narrowed this number down to 11 delta radiomics features for the model. This 11-delta-feature model showed an overall prediction accuracy of 83.1%, with a true positive rate of 58.8% in predicting necrosis and 90.7% for predicting tumor progression. The area under the curve for the prediction model was 0.79. Conclusion: These delta radiomics features extracted from MR scans showed potential for distinguishing radiation necrosis from tumor progression. This tool may be a useful, noninvasive means of determining the status of an enlarging lesion after radiosurgery, aiding decision-making regarding surgical resection versus conservative medical management.« less

Comparative transcriptome analysis of rice seedlings induced by different doses of heavy ion radiation

NASA Astrophysics Data System (ADS)

Zhao, Qian; Sun, Yeqing; Wang, Wei

2016-07-01

Highly ionizing radiation (HZE) in space is considered as a main factor causing biological effects on plant seeds. To investigate the different effects on genome-wide gene expression of low-dose and high-dose ion radiation, we carried out ground-base carbon particle HZE experiments with different cumulative doses (0Gy, 0.2Gy, 2Gy) to rice seeds and then performed comparative transcriptome analysis of the rice seedlings. We identified a total of 2551 and 1464 differentially expressed genes (DEGs) in low-dose and high-dose radiation groups, respectively. Gene ontology analyses indicated that low-dose and high-dose ion radiation both led to multiple physiological and biochemical activities changes in rice. By Gene Ontology analyses, the results showed that only one process-oxidation reduction process was enriched in the biological process category after high-dose ion radiation, while more processes such as response to biotic stimulus, heme binding, tetrapyrrole binding, oxidoreductase activity, catalytic activity and oxidoreductase activity were significantly enriched after low-dose ion radiation. The results indicated that the rice plants only focused on the process of oxidation reduction to response to high-dose ion radiation, whereas it was a coordination of multiple biological processes to response to low-dose ion radiation. To elucidate the transcriptional regulation of radiation stress-responsive genes, we identified several DEGs-encoding TFs. AP2/EREBP, bHLH, C2H2, MYB and WRKY TF families were altered significantly in response to ion radiation. Mapman analysis speculated that the biological effects on rice seedlings caused by the radiation stress might share similar mechanisms with the biotic stress. Our findings highlight important alterations in the expression of radiation response genes, metabolic pathways, and TF-encoding genes in rice seedlings exposed to low-dose and high-dose ion radiation.

Treatment of Vascular Soft Tissue Sarcomas With Razoxane, Vindesine, and Radiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rhomberg, Walter; Wink, Anna; Pokrajac, Boris

2009-05-01

Purpose: In previous studies, razoxane and vindesine together with radiotherapy was proved to be effective in soft tissue sarcomas (STS). Because razoxane leads to a redifferentiation of pathological tumor blood vessels, it was of particular interest to study the influence of this drug combination in vascular soft tissue sarcomas. Methods and Materials: This open multicenter Phase II study was performed by the Austrian Society of Radiooncology. Among 13 evaluable patients (10 angiosarcomas and 3 hemangio-pericytomas), 9 had unresectable measurable disease, 3 showed microscopic residuals, and 1 had a resection with clear margins. They received a basic treatment with razoxane andmore » vindesine supported by radiation therapy. Outcome measures were objective response rates, survival time, and the incidence of distant metastases. Results: In nine patients with measurable vascular soft tissue sarcomas (eight angiosarcomas and one hemangiopericytoma), 6 complete remissions, 2 partial remissions, and 1 minor remission were achieved, corresponding to a major response rate of 89%. A maintenance therapy with razoxane and vindesine of 1 year or longer led to a suppression of distant metastases. The median survival time from the start of the treatment is 23+ months (range, 3-120+) for 12 patients with macroscopic and microscopic residual disease. The progression-free survival at 6 months was 75%. The combined treatment was associated with a low general toxicity, but attention must be given to increased normal tissue reactions. Conclusions: This trimodal treatment leads to excellent response rates, and it suppresses distant metastases when given as maintenance therapy.« less

Increased oxidative phosphorylation in response to acute and chronic DNA damage

PubMed Central

Brace, Lear E; Vose, Sarah C; Stanya, Kristopher; Gathungu, Rose M; Marur, Vasant R; Longchamp, Alban; Treviño-Villarreal, Humberto; Mejia, Pedro; Vargas, Dorathy; Inouye, Karen; Bronson, Roderick T; Lee, Chih-Hao; Neilan, Edward; Kristal, Bruce S; Mitchell, James R

2016-01-01

Accumulation of DNA damage is intricately linked to aging, aging-related diseases and progeroid syndromes such as Cockayne syndrome (CS). Free radicals from endogenous oxidative energy metabolism can damage DNA, however the potential of acute or chronic DNA damage to modulate cellular and/or organismal energy metabolism remains largely unexplored. We modeled chronic endogenous genotoxic stress using a DNA repair-deficient Csa−/−|Xpa−/− mouse model of CS. Exogenous genotoxic stress was modeled in mice in vivo and primary cells in vitro treated with different genotoxins giving rise to diverse spectrums of lesions, including ultraviolet radiation, intrastrand crosslinking agents and ionizing radiation. Both chronic endogenous and acute exogenous genotoxic stress increased mitochondrial fatty acid oxidation (FAO) on the organismal level, manifested by increased oxygen consumption, reduced respiratory exchange ratio, progressive adipose loss and increased FAO in tissues ex vivo. In multiple primary cell types, the metabolic response to different genotoxins manifested as a cell-autonomous increase in oxidative phosphorylation (OXPHOS) subsequent to a transient decline in steady-state NAD+ and ATP levels, and required the DNA damage sensor PARP-1 and energy-sensing kinase AMPK. We conclude that increased FAO/OXPHOS is a general, beneficial, adaptive response to DNA damage on cellular and organismal levels, illustrating a fundamental link between genotoxic stress and energy metabolism driven by the energetic cost of DNA damage. Our study points to therapeutic opportunities to mitigate detrimental effects of DNA damage on primary cells in the context of radio/chemotherapy or progeroid syndromes. PMID:28721274

Simulated Hydrologic Responses to Climate Variations and Change in the Merced, Carson, and American River Basins, Sierra Nevada, California, 1900-2099

NASA Astrophysics Data System (ADS)

Dettinger, M. D.; Cayan, D. R.; Cayan, D. R.; Meyer, M. K.

2001-12-01

Sensitivities of river basins in the Sierra Nevada of California to historical and future climate variations and changes are analyzed by simulating daily streamflow and water-balance responses to simulated climate variations over a continuous 200-year period. The coupled atmosphere-ocean-ice-land Parallel Climate Model provides the simulated climate histories, and existing hydrologic models of the Merced, Carson, and American Rivers are used to simulate the basin responses. The historical simulations yield stationary climate and hydrologic variations through the first part of the 20th Century until about 1975, when temperatures begin to warm noticeably and when snowmelt and streamflow peaks begin to occur progressively earlier within the seasonal cycle. A future climate simulated with business-as-usual increases in greenhouse-gas and aerosol radiative forcings continues those recent trends through the 21st Century with an attendant +2.5ºC warming and a hastening of snowmelt and streamflow within the seasonal cycle by almost a month. In contrast, a control simulation in which radiative forcings are held constant at 1995 levels for the 50 years following 1995, yields climate and streamflow-timing conditions much like the 1980s and 1990s throughout its duration. Long-term average totals of streamflow and other hydrologic fluxes remain similar to the historical mean in all three simulations. The various projected trends in the business-as-usual simulations become readily visible above simulated natural climatic and hydrologic variability by about 2020.

C/EBPα expression is downregulated in human nonmelanoma skin cancers and inactivation of C/EBPα confers susceptibility to UVB-induced skin squamous cell carcinomas.

PubMed

Thompson, Elizabeth A; Zhu, Songyun; Hall, Jonathan R; House, John S; Ranjan, Rakesh; Burr, Jeanne A; He, Yu-Ying; Owens, David M; Smart, Robert C

2011-06-01

Human epidermis is routinely subjected to DNA damage induced by UVB solar radiation. Cell culture studies have revealed an unexpected role for C/EBPα (CCAAT/enhancer-binding protein-α) in the DNA damage response network, where C/EBPα is induced following UVB DNA damage, regulates the G(1) checkpoint, and diminished or ablated expression of C/EBPα results in G(1) checkpoint failure. In the current study we observed that C/EBPα is induced in normal human epidermal keratinocytes and in the epidermis of human subjects exposed to UVB radiation. The analysis of human skin precancerous and cancerous lesions (47 cases) for C/EBPα expression was conducted. Actinic keratoses, a precancerous benign skin growth and precursor to squamous cell carcinoma (SCC), expressed levels of C/EBPα similar to normal epidermis. Strikingly, all invasive SCCs no longer expressed detectable levels of C/EBPα. To determine the significance of C/EBPα in UVB-induced skin cancer, SKH-1 mice lacking epidermal C/EBPα (CKOα) were exposed to UVB. CKOα mice were highly susceptible to UVB-induced SCCs and exhibited accelerated tumor progression. CKOα mice displayed keratinocyte cell cycle checkpoint failure in vivo in response to UVB that was characterized by abnormal entry of keratinocytes into S phase. Our results demonstrate that C/EBPα is silenced in human SCC and loss of C/EBPα confers susceptibility to UVB-induced skin SCCs involving defective cell cycle arrest in response to UVB.

C/EBPα Expression Is Downregulated in Human Nonmelanoma Skin Cancers and Inactivation of C/EBPα Confers Susceptibility to UVB-Induced Skin Squamous Cell Carcinomas

PubMed Central

Thompson, Elizabeth A.; Zhu, Songyun; Hall, Jonathan R.; House, John S.; Ranjan, Rakesh; Burr, Jeanne A.; He, Yu-Ying; Owens, David M.; Smart, Robert C.

2012-01-01

Human epidermis is routinely subjected to DNA damage induced by UVB solar radiation. Cell culture studies have revealed an unexpected role for C/EBPα (CCAAT/enhancer-binding protein-α) in the DNA damage response network, where C/EBPα is induced following UVB DNA damage, regulates the G1 checkpoint, and diminished or ablated expression of C/EBPα results in G1 checkpoint failure. In the current study we observed that C/EBPα is induced in normal human epidermal keratinocytes and in the epidermis of human subjects exposed to UVB radiation. The analysis of human skin precancerous and cancerous lesions (47 cases) for C/EBPα expression was conducted. Actinic keratoses, a precancerous benign skin growth and precursor to squamous cell carcinoma (SCC), expressed levels of C/EBPα similar to normal epidermis. Strikingly, all invasive SCCs no longer expressed detectable levels of C/EBPα. To determine the significance of C/EBPα in UVB-induced skin cancer, SKH-1 mice lacking epidermal C/EBPα (CKOα) were exposed to UVB. CKOα mice were highly susceptible to UVB-induced SCCs and exhibited accelerated tumor progression. CKOα mice displayed keratinocyte cell cycle checkpoint failure in vivo in response to UVB that was characterized by abnormal entry of keratinocytes into S phase. Our results demonstrate that C/EBPα is silenced in human SCC and loss of C/EBPα confers susceptibility to UVB-induced skin SCCs involving defective cell cycle arrest in response to UVB. PMID:21346772

Health and Safety Research Division progress report, April 1, 1981-September 30, 1982

DOE Office of Scientific and Technical Information (OSTI.GOV)

Not Available

1983-02-01

Research progress for the reporting period is briefly summarized for the following sections: (1) health studies, (2) technology assessments, (3) biological and radiation physics, (4) chemical physics, (5) Office of Risk Analysis, and (6) health and environmental risk and analysis. (ACR)

Tumour response endpoints in the BA1112 rat sarcoma.

PubMed Central

Martin, D. F.; Moulder, J. E.; Fischer, J. J.

1980-01-01

The rat rhabdomyosarcoma BA1112 has a number of features which make it a useful model for the study of tumour response to radiation therapy. It is a transplantable tumour, isologous to an inbred line of WAG/Rij rats and it elicits no demonstrable host immune response. The tumour grows locally at the implantation site and rarely metastasizes. It is known to contain hypoxic cells which reoxygenate during a prolonged course of fractionated radiation therapy. The growth and radiation response characteristics of the tumour have remained stable for over 15 years. A newly developed in vitro assay for tumour cell clonogenicity greatly facilitates the measurement of radiation dose-response curves and the monitoring of cell response following in vivo treatment. The in vivo response of the tumour to fractionated radiation therapy is analysed in terms of cellular response, reoxygenation and cell proliferation. PMID:6932936

The Tripartite Seminars at the Russian Methodological and Training Center: An Overview of Progress in Nuclear Materials Control and Accounting in the Russian Federation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pshakin, Gennady; Dickman, Deborah A.; Ryazanov, Boris

2003-09-16

The development of the Russian Methodological and Training Center (RMTC) has been an important element of collaboration between the Russian Federation (RF), the European Union and the US. The RMTC, located at the Institute of Physics and Power Engineering (IPPE) in Obninsk, Russia has been designated by the Russian Ministry of Atomic Energy (Minatom) to provide nuclear materials protection, control and Accounting training to Minatom and the Federal Nuclear and Radiation Safety Authority (Gosatomnadzor) personnel. In addition, the RMTC was chartered with the responsibility of providing a venue for exchange of experiences and information between Russian and international specialists.

Sun exposure: what molecular photodermatology tells us about its good and bad sides.

PubMed

Krutmann, Jean; Morita, Akimichi; Chung, Jin Ho

2012-03-01

The health consequences of sun exposure have concerned mankind for more than 100 years. Recent molecular studies in photodermatology have greatly advanced our understanding of this important topic. We will illustrate this progress by focusing on the following selected topics: (i) the nature of the DNA damage-independent part of the UVB response of human skin and the role of the arylhydrocarbon receptor in cutaneous biology, (ii) the contribution of wavelengths beyond the UV spectrum to solar radiation-induced skin damage, (iii) the emerging evidence that subcutaneous fat is a target tissue for sunlight, and (iv) the most recent insight into the mode of action of phototherapy.

Low-dose energetic protons induce adaptive and bystander effects that protect human cells against DNA damage caused by a subsequent exposure to energetic iron ions.

PubMed

Buonanno, Manuela; De Toledo, Sonia M; Howell, Roger W; Azzam, Edouard I

2015-05-01

During interplanetary missions, astronauts are exposed to mixed types of ionizing radiation. The low 'flux' of the high atomic number and high energy (HZE) radiations relative to the higher 'flux' of low linear energy transfer (LET) protons makes it highly probable that for any given cell in the body, proton events will precede any HZE event. Whereas progress has been made in our understanding of the biological effects of low-LET protons and high-LET HZE particles, the interplay between the biochemical processes modulated by these radiations is unclear. Here we show that exposure of normal human fibroblasts to a low mean absorbed dose of 20 cGy of 0.05 or 1-GeV protons (LET ∼ 1.25 or 0.2 keV/μm, respectively) protects the irradiated cells (P < 0.0001) against chromosomal damage induced by a subsequent exposure to a mean absorbed dose of 50 cGy from 1 GeV/u iron ions (LET ∼ 151 keV/μm). Surprisingly, unirradiated (i.e. bystander) cells with which the proton-irradiated cells were co-cultured were also significantly protected from the DNA-damaging effects of the challenge dose. The mitigating effect persisted for at least 24 h. These results highlight the interactions of biological effects due to direct cellular traversal by radiation with those due to bystander effects in cell populations exposed to mixed radiation fields. They show that protective adaptive responses can spread from cells targeted by low-LET space radiation to bystander cells in their vicinity. The findings are relevant to understanding the health hazards of space travel. © The Author 2015. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.

Local control rates of metastatic renal cell carcinoma (RCC) to the bone using stereotactic body radiation therapy: Is RCC truly radioresistant?

PubMed

Amini, Arya; Altoos, Basel; Bourlon, Maria T; Bedrick, Edward; Bhatia, Shilpa; Kessler, Elizabeth R; Flaig, Thomas W; Fisher, Christine M; Kavanagh, Brian D; Lam, Elaine T; Karam, Sana D

2015-01-01

We report the radiographic and clinical response rate of stereotactic body radiation therapy (SBRT) compared with conventional fractionated external beam radiation therapy (CF-EBRT) for renal cell carcinoma (RCC) bone lesions treated at our institution. Forty-six consecutive patients were included in the study, with 95 total lesions treated (50 SBRT, 45 CF-EBRT). We included patients who had histologic confirmation of primary RCC and radiographic evidence of metastatic bone lesions. The most common SBRT regimen used was 27 Gy in 3 fractions. Median follow-up was 10 months (range, 1-64 months). Median time to symptom control between SBRT and CF-EBRT were 2 (range, 0-6 weeks) and 4 weeks (range, 0-7 weeks), respectively. Symptom control rates with SBRT and CF-EBRT were significantly different (P = .020) with control rates at 10, 12, and 24 months of 74.9% versus 44.1%, 74.9% versus 39.9%, and 74.9% versus 35.7%, respectively. The median time to radiographic failure and unadjusted pain progression was 7 months in both groups. When controlling for gross tumor volume, dose per fraction, smoking, and the use of systemic therapy, biologically effective dose ≥80 Gy was significant for clinical response (hazard ratio [HR], 0.204; 95% confidence interval [CI], 0.043-0.963; P = .046) and radiographic (HR, 0.075; 95% CI, 0.013-0.430; P = .004). When controlling for gross tumor volume and total dose, biologically effective dose ≥80 Gy was again predictive of clinical local control (HR, 0.140; 95% CI, 0.025-0.787; P = .026). Toxicity rates were low and equivalent in both groups, with no grade 4 or 5 toxicity reported. SBRT is both safe and effective for treating RCC bone metastases, with rapid improvement in symptoms after treatment and more durable clinical and radiographic response rate. Future prospective trials are needed to further define efficacy and toxicity of treatment, especially in the setting of targeted agents. Copyright © 2015 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.

Radiation-induced leukemia: lessons from history.

PubMed

Finch, Stuart C

2007-03-01

Beginning in 1895, with the discovery of x-rays, alpha and beta radiation, uranium, radium, thorium, and polonium, the fascinating story of the beginning of knowledge concerning the existence of ionizing radiation unfolds. This brief history of radiation and leukemia is divided into two main parts: the first 50 years, which deals with the confusion regarding radiation effects and the failure to clearly recognize that exposure to ionizing radiation may induce leukemia. The second part focuses on the last 60 years, when the radiation induction of leukemia was accepted and some progress achieved in understanding the clinical and pathophysiological characteristics of radiation-induced leukemia. Particular attention in this is paid to the effects of radiation on the survivors of Hiroshima and Nagasaki. The discussion in this section also covers some concepts of radiation-induced cell damage and ruminations on unanswered questions.

Study of radiation effects on mammalian cells in vitro

NASA Technical Reports Server (NTRS)

Sinclair, W. K.

1968-01-01

Radiation effect on single cells and cell populations of Chinese hamster lung tissue is studied in vitro. The rate and position as the cell progresses through the generation cycle shows division delay, changes in some biochemical processes in the cell, chromosomal changes, colony size changes, and loss of reproductive capacity.

ABVD chemotherapy with reduced radiation therapy rates in children, adolescents and young adults with all stages of Hodgkin lymphoma.

PubMed

Marr, K C; Connors, J M; Savage, K J; Goddard, K J; Deyell, R J

2017-04-01

We adopted ABVD chemotherapy with risk-adapted radiation therapy (RT) as first-line therapy for children, adolescents and young adults with Hodgkin lymphoma (HL) in British Columbia in 2004. Patients ≤ 25 years diagnosed from 2004 to 2013 with all stages of HL who received ABVD as initial therapy were included. Among 55 children (age < 18 year) and 154 young adults (18-25 year), there were no significant differences among age groups for sex, histologic subtype, tumour bulk, B symptoms, prognostic risk groups or treatment received. The rates of complete response, partial response and progressive disease were 84%, 7% and 10% for children and 95%, 4% and 1% for young adults (P=0.01), respectively. Treatment failures in children all occurred within one year of completion, while 8/21 (38%) relapses in young adults occurred later (P=0.04). With a median follow-up of 66 months the 5-year progression-free (PFS) and overall survival (OS) were 85 ± 3% and 97 ± 1%, respectively. For limited stage disease, PFS was 90 ± 7% for children and 93 ± 3% for young adults (P=0.65); OS was 100% for both. For advanced stage patients, PFS and OS were also similar for the children and young adults (77 ± 7% versus 81 ± 4%; P=0.38 and OS 90 ± 6% versus 97 ± 2%; P=0.17). The rate of consolidative RT was low (21%) and did not differ between age groups. ABVD is an effective treatment in children, adolescents and young adults with HL. Children were less likely to achieve complete response and demonstrated earlier relapses compared to young adults. RT may be omitted for the majority of patients while maintaining excellent 5-year OS. © The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Radiation-induced genomic instability and bystander effects: related inflammatory-type responses to radiation-induced stress and injury? A review.

PubMed

Lorimore, S A; Wright, E G

2003-01-01

To review studies of radiation responses in the haemopoietic system in the context of radiation-induced genomic instability, bystander effects and inflammatory-type processes. There is considerable evidence that cells that themselves are not exposed to ionizing radiation but are the progeny of cells irradiated many cell divisions previously may express a high frequency of gene mutations, chromosomal aberrations and cell death. These effects are collectively known as radiation-induced genomic instability. A second untargeted effect results in non-irradiated cells exhibiting responses typically associated with direct radiation exposure but occurs as a consequence of contact with irradiated cells or by receiving soluble signals from irradiated cells. These effects are collectively known as radiation-induced bystander effects. Reported effects include increases or decreases in damage-inducible and stress-related proteins; increases or decreases in reactive oxygen species, cell death or cell proliferation, and induction of mutations and chromosome aberrations. This array of responses is reminiscent of effects mediated by cytokines and other similar regulatory factors that may involve, but do not necessarily require, gap junction-mediated transfer, have multiple inducers and a variety of context-dependent consequences in different cell systems. That chromosomal instability in haemopoietic cells can be induced by an indirect bystander-type mechanism both in vitro and in vivo provides a potential link between these two untargeted effects and there are radiation responses in vivo consistent with the microenvironment contributing secondary cell damage as a consequence of an inflammatory-type response to radiation-induced injury. Intercellular signalling, production of cytokines and free radicals are features of inflammatory responses that have the potential for both bystander-mediated and persisting damage as well as for conferring a predisposition to malignancy. The induction of bystander effects and instabilities may reflect interrelated aspects of a non-specific inflammatory-type response to radiation-induced stress and injury and be involved in a variety of the pathological consequences of radiation exposures.

Alternative perspective on the control of transpiration by radiation.

PubMed

Mott, Keith A; Peak, David

2011-12-06

Stomatal responses to light are important determinants for plant water use efficiency and for general circulation models, but a mechanistic understanding of these responses remains elusive. A recent study [Pieruschka R, Huber G, Berry JA (2010) Proc Natl Acad Sci USA 107:13372-13377] concluded that stomata respond to total absorbed radiation rather than red and blue light as previously thought. We tested this idea by reexamining stomatal responses to red and blue light and to IR radiation. We show that responses to red and blue light are not consistent with a response to total absorbed radiation and that apparent stomatal responses to IR radiation are explainable as experimental artifacts. In addition, our data and analysis provide a method for accurately determining the internal temperature of a leaf.

Systemic effects of ionizing radiation at the proteome and metabolome levels in the blood of cancer patients treated with radiotherapy: the influence of inflammation and radiation toxicity.

PubMed

Jelonek, Karol; Pietrowska, Monika; Widlak, Piotr

2017-07-01

Blood is the most common replacement tissue used to study systemic responses of organisms to different types of pathological conditions and environmental insults. Local irradiation during cancer radiotherapy induces whole body responses that can be observed at the blood proteome and metabolome levels. Hence, comparative blood proteomics and metabolomics are emerging approaches used in the discovery of radiation biomarkers. These techniques enable the simultaneous measurement of hundreds of molecules and the identification of sets of components that can discriminate different physiological states of the human body. Radiation-induced changes are affected by the dose and volume of irradiated tissues; hence, the molecular composition of blood is a hypothetical source of biomarkers for dose assessment and the prediction and monitoring of systemic responses to radiation. This review aims to provide a comprehensive overview on the available evidence regarding molecular responses to ionizing radiation detected at the level of the human blood proteome and metabolome. It focuses on patients exposed to radiation during cancer radiotherapy and emphasizes effects related to radiation-induced toxicity and inflammation. Systemic responses to radiation detected at the blood proteome and metabolome levels are primarily related to the intensity of radiation-induced toxicity, including inflammatory responses. Thus, several inflammation-associated molecules can be used to monitor or even predict radiation-induced toxicity. However, these abundant molecular features have a rather limited applicability as universal biomarkers for dose assessment, reflecting the individual predisposition of the immune system and tissue-specific mechanisms involved in radiation-induced damage.

A progress report of the Marshall Islands nationwide thyroid study: an international cooperative scientific study.

PubMed

Takahashi, T; Simon, S L; Trott, K R; Fujimori, K; Nakashima, N; Arisawa, K; Schoemaker, M J

1999-04-01

The objective of this report is to present a summary of progress of the Marshall Islands Nationwide Thyroid Study. As well known, the US atomic weapons testing program in the Pacific was conducted primarily between 1946 and 1958 in the Marshall Islands. The nuclear tests resulted in radioactive contamination of a number of atolls and resulted in exposure of Marshallese to undefined levels before our study. Little information has been paid to health consequences among residents of the nearly twenty inhibited atolls except for some information about nodular thyroid disease which was reported on by an US group. In a cooperative agreement with the Government of the Marshall Islands, between 1993 and 1997 we studied the prevalence of both thyroid nodules and thyroid cancer among 4766 Marshallese potentially exposed to radioiodines from bomb test fallout. That group represents more than 65% of the population at risk. We diagnosed 45 thyroid cancers and 1398 benign thyroid nodules. In addition, 23 study participants had been operated on prior to our study for thyroid cancer. Presently, we are developing a database of information to estimate radiation doses and planning a statistical analysis to determine if a dose-response relationship exists. These data will be important for the health promotion of exposed people all over the world including Hiroshima, Nagasaki, Semipalatinsk, Chernobyl and other locations. A timely completion is important for purpose of assisting Marshallese as well as to add the global understanding of radiation induced thyroid cancer.

NASA Self-Assessment of Space Radiation Research

NASA Technical Reports Server (NTRS)

Cucinotta, Francis A.

2010-01-01

Space exploration involves unavoidable exposures to high-energy galactic cosmic rays whose penetration power and associated secondary radiation makes radiation shielding ineffective and cost prohibitive. NASA recognizing the possible health dangers from cosmic rays notified the U.S. Congress as early as 1959 of the need for a dedicated heavy ion accelerator to study the largely unknown biological effects of galactic cosmic rays on astronauts. Information and scientific tools to study radiation health effects expanded over the new decades as NASA exploration programs to the moon and preparations for Mars exploration were carried out. In the 1970 s through the early 1990 s a more than 3-fold increase over earlier estimates of fatal cancer risks from gamma-rays, and new knowledge of the biological dangers of high LET radiation were obtained. Other research has increased concern for degenerative risks to the central nervous system and other tissues at lower doses compared to earlier estimates. In 1996 a review by the National Academy of Sciences Space Science Board re-iterated the need for a dedicated ground-based accelerator facility capable of providing up to 2000 research hours per year to reduce uncertainties in risks projections and develop effective mitigation measures. In 1998 NASA appropriated funds for construction of a dedicated research facility and the NASA Space Radiation Laboratory (NSRL) opened for research in October of 2003. This year marks the 8th year of NSRL research were about 1000 research hours per year have been utilized. In anticipation of the approaching ten year milestone, funded investigators and selected others are invited to participate in a critical self-assessment of NSRL research progress towards NASA s goals in space radiation research. A Blue and Red Team Assessment format has been integrated into meeting posters and special plenary sessions to allow for a critical debate on the progress of the research and major gaps areas. Blue teams will highlight progress and important new knowledge gained. Red teams will challenge the Blue teams on proposed highlights and point to Gaps not considered. We will review the current space radiation Risks and Gaps under investigation at NASA, critical data sets and research highlights anticipated, and possible goals for future research at NSRL.

Review of GEM Radiation Belt Dropout and Buildup Challenges

NASA Astrophysics Data System (ADS)

Tu, Weichao; Li, Wen; Morley, Steve; Albert, Jay

2017-04-01

In Summer 2015 the US NSF GEM (Geospace Environment Modeling) focus group named "Quantitative Assessment of Radiation Belt Modeling" started the "RB dropout" and "RB buildup" challenges, focused on quantitative modeling of the radiation belt buildups and dropouts. This is a community effort which includes selecting challenge events, gathering model inputs that are required to model the radiation belt dynamics during these events (e.g., various magnetospheric waves, plasmapause and density models, electron phase space density data), simulating the challenge events using different types of radiation belt models, and validating the model results by comparison to in situ observations of radiation belt electrons (from Van Allen Probes, THEMIS, GOES, LANL/GEO, etc). The goal is to quantitatively assess the relative importance of various acceleration, transport, and loss processes in the observed radiation belt dropouts and buildups. Since 2015, the community has selected four "challenge" events under four different categories: "storm-time enhancements", "non-storm enhancements", "storm-time dropouts", and "non-storm dropouts". Model inputs and data for each selected event have been coordinated and shared within the community to establish a common basis for simulations and testing. Modelers within and outside US with different types of radiation belt models (diffusion-type, diffusion-convection-type, test particle codes, etc.) have participated in our challenge and shared their simulation results and comparison with spacecraft measurements. Significant progress has been made in quantitative modeling of the radiation belt buildups and dropouts as well as accessing the modeling with new measures of model performance. In this presentation, I will review the activities from our "RB dropout" and "RB buildup" challenges and the progresses achieved in understanding radiation belt physics and improving model validation and verification.

Biology Division annual progress report for period ending December 31, 1968

DOE Office of Scientific and Technical Information (OSTI.GOV)

None

1969-07-01

Brief summaries are presented of research in progress in the fields of radiobiology, genetics, hematology, immunology, physsiology, biochemistry, bacteriology, enzymology, microbiology, photosynthesis, biophysics, radiation protection, and related fields. A list is included of 212 publications in the world literature that report results of completed studies. (CH)

Health and Safety Research Division. Progress report, October 1, 1979-March 31, 1981

DOE Office of Scientific and Technical Information (OSTI.GOV)

Not Available

1981-08-01

Research progress for the period October 1, 1979 through March 31, 1981 is reported. Research conducted by the Office of Integrated Assessments and Policy Analysis, Health Studies Section, Technology Assessments Section, Biological and Radiation Physics Section, and Chemical Physics Section is summarized. (ACR)

High LET, passive space radiation dosimetry and spectrometry

NASA Technical Reports Server (NTRS)

Benton, E. V.; Frank, A. L.; Benton, E. R.; Keegan, R. P.; Frigo, L. A.; Sanner, D.; Rowe, V.

1995-01-01

The development of high linear energy transfer (LET), passive radiation dosimetry and spectrometry is needed for the purpose of accurate determination of equivalent doses and assessment of health risks to astronauts on long duration missions. Progress in the following research areas is summerized: intercomparisons of cosmic ray equivalent dose and LET spectra measurements between STS missions and between astronauts; increases LET spectra measurement accuracy with ATAS; space radiation measurements for intercomparisons of passive (PNTD, TLD, TRND, Emulsion) and active (TEPC, RME-111) dosimeters; interaction of cosmic ray particles with nuclei in matter; radiation measurements after long duration space exposures; ground based dosimeter calibrations; neutron detector calibrations; radiation measurements on Soviet/Russian spacecraft; space radiation measurements under thin shielding; and space radiation.

Joint Services Electronics Program.

DTIC Science & Technology

1984-06-01

INTEGRATION •6 1.1 Properties of Materials: Application of Channeling Radiation to a Study of the Properties 6 of Materials 1.1.1 Scientific...Objectives 6 1.1.2 Progress 7 1.1.2.1 Channeling Radiation from Si with an Oxygen Platelet Impurity 7 1.1.2.2 Calculated Potentials and Eigenvalues in GaAs...AIGaAs, and AlAs 11 1.1.2.3 Low Temperature Channeling Radiation 14 1.1.2.4 Electron Channeling Radiation from LiH and UD 14 1.1.2.5 12.6 MeV Electron

Radiation response and electrical properties of polymer energy storage capacitors: PVF2, Polysulfone, and Mylar

NASA Technical Reports Server (NTRS)

Edwards, L. R.

1981-01-01

Efforts were made to develop a polymer film capacitor that is tolerant to radiation. The capacitors are to be utilized in a high voltage pulse discharge application. Radiation response data at high dose/dose rate levels are presented for polyvinylidene fluoride (PVF2), polysulfone, and Mylar. The results show that PVF2 is the most radiation tolerant while Mylar is the least tolerant. The data also show that the radiation response is quite dependent on operating electric stress.

10 CFR 35.24 - Authority and responsibilities for the radiation protection program.

Code of Federal Regulations, 2012 CFR

2012-01-01

... protection program. (a) In addition to the radiation protection program requirements of § 20.1101 of this...) Radiation protection program changes that do not require a license amendment and are permitted under § 35.26... responsible for implementing the radiation protection program. The licensee, through the Radiation Safety...

10 CFR 35.24 - Authority and responsibilities for the radiation protection program.

Code of Federal Regulations, 2014 CFR

2014-01-01

... protection program. (a) In addition to the radiation protection program requirements of § 20.1101 of this...) Radiation protection program changes that do not require a license amendment and are permitted under § 35.26... responsible for implementing the radiation protection program. The licensee, through the Radiation Safety...

10 CFR 35.24 - Authority and responsibilities for the radiation protection program.

Code of Federal Regulations, 2011 CFR

2011-01-01

... protection program. (a) In addition to the radiation protection program requirements of § 20.1101 of this...) Radiation protection program changes that do not require a license amendment and are permitted under § 35.26... responsible for implementing the radiation protection program. The licensee, through the Radiation Safety...

10 CFR 35.24 - Authority and responsibilities for the radiation protection program.

Code of Federal Regulations, 2010 CFR

2010-01-01

... protection program. (a) In addition to the radiation protection program requirements of § 20.1101 of this...) Radiation protection program changes that do not require a license amendment and are permitted under § 35.26... responsible for implementing the radiation protection program. The licensee, through the Radiation Safety...

10 CFR 35.24 - Authority and responsibilities for the radiation protection program.

Code of Federal Regulations, 2013 CFR

2013-01-01

... protection program. (a) In addition to the radiation protection program requirements of § 20.1101 of this...) Radiation protection program changes that do not require a license amendment and are permitted under § 35.26... responsible for implementing the radiation protection program. The licensee, through the Radiation Safety...

CAPIRI-IMRT: a phase II study of concurrent capecitabine and irinotecan with intensity-modulated radiation therapy for the treatment of recurrent rectal cancer.

PubMed

Cai, Gang; Zhu, Ji; Palmer, Joshua D; Xu, Ye; Hu, Weigang; Gu, Weilie; Cai, Sanjun; Zhang, Zhen

2015-02-28

This study investigated the local effect and acute toxicity of irinotecan and capecitabine with concurrent intensity-modulated radiation therapy (IMRT) for the treatment of recurrent rectal cancer without prior pelvic irradiation. Seventy-one patients diagnosed with recurrent rectal cancer who did not previously receive pelvic irradiation were treated in our hospital from October 2009 to July 2012. Radiotherapy was delivered to the pelvis, and IMRT of 45 Gy (1.8 Gy per fraction), followed by a boost of 10 Gy to 16 Gy (2 Gy per fraction), was delivered to the recurrent sites. The concurrent chemotherapy regimen was 50 mg/m(2) irinotecan weekly and 625 mg/m(2) capecitabine twice daily (Mon-Fri). Radical surgery was recommended for medically fit patients without extra-pelvic metastases. The patients were followed up every 3 months. Tumor response was evaluated using CT/MRIs according to the RECIST criteria or postoperative pathological findings. NCI-CTC 3.0 was used to score the toxicities. Forty-eight patients (67.6%) had confirmed recurrent rectal cancer without extra pelvic metastases, and 23 patients (32.4%) had extra pelvic metastases. Fourteen patients (19.7%) underwent radical resections (R0) post-chemoradiation. A pathologic complete response was observed in 7 of 14 patients. A clinical complete response was observed in 4 patients (5.6%), and a partial response was observed in 22 patients (31.0%). Only 5 patients (7.0%) showed progressive disease during or shortly after treatment. Of 53 symptomatic patients, clinical complete and partial symptom relief with chemoradiation was achieved in 56.6% and 32.1% of patients, respectively. Only 2 patients (2.8%) experienced grade 4 leukopenia. The most common grade 3 toxicity was diarrhea (16 [22.5%] patients). The median follow-up was 31 months. The cumulative local progression-free survival rate was 74.2% and 33.9% at 1 and 3 years after chemoradiation, respectively. The cumulative total survival rate was 80.1% and 36.5% at 1 and 3 years after chemoradiation, respectively. This study revealed that concurrent irinotecan and capecitabine with IMRT significantly relieves local symptoms and exhibits promising efficacy with manageable toxicities in recurrent rectal cancer without prior pelvic irradiation. Improving the rate of R0 resections will be investigated in a future study.

Clinical outcomes and prognostic factors of cyberknife stereotactic body radiation therapy for unresectable hepatocellular carcinoma.

PubMed

Que, Jenny; Kuo, Hsing-Tao; Lin, Li-Ching; Lin, Kuei-Li; Lin, Chia-Hui; Lin, Yu-Wei; Yang, Ching-Chieh

2016-07-12

Stereotactic body radiation therapy (SBRT) has been an emerging non-invasive treatment modality for patients with hepatocellular carcinoma (HCC) when curative treatments cannot be applied. In this study, we report our clinical experience with Cyberknife SBRT for unresectable HCC and evaluate the efficacy and clinical outcomes of this highly sophisticated treatment technology. Between 2008 and 2012, 115 patients with unresectable HCC treated with Cyberknife SBRT were retrospectively analyzed. Doses ranged from 26 Gy to 40 Gy were given in 3 to 5 fractions for 3 to 5 consecutive days. The cumulative probability of survival was calculated according to the Kaplan-Meier method and compared using log-rank test. Univariate and multivariate analysis were performed using Cox proportional hazard models. The median follow-up was 15.5 months (range, 2-60 months). Based on Response Evaluation and Criteria in Solid Tumors (RECIST). We found that 48.7 % of patients achieved a complete response and 40 % achieved a partial response. Median survival was 15 months (4-25 months). Overall survival (OS) at 1- and 2-years was 63.5 %(54-71.5 %) and 41.3 % (31.6-50.6 %), respectively, while 1- and 2- years Progression-free Survival (PFS) rates were 42.8 %(33.0-52.2 %) and 38.8 % (29.0-48.4 %). Median progression was 6 months (3-16 months). In-field recurrence free survival at 1 and 2 years was 85.3 % (76.2-91.1 %) and 81.6 % (72.2-88.6 %), respectively, while the 1- and 2-years out-field recurrence free survival were 52.5 % (41.2-60.8 %) and 49.5 %(38.9-59.2 %), respectively. Multivariate analysis revealed that Child-Pugh score (A vs. B), Portal vein tumor thrombosis (positive vs. negative), Tumor size (≤4 cm vs >4-9 cm /≥10 cm), and tumor response after SBRT (CR vs. PR/stable) were independent predictors of OS. Acute toxicity was mostly transient and tolerable. Cyberknife SBRT appears to be an effective non-invasive treatment for local unresectable HCC with low risk of severe toxicity. These results suggested that Cyberknife SBRT can be a good alternative treatment for unresectable HCC unsuitable for standard treatment.

Lessons Learned Through the Follow-up of the Long-Term Effects of Over-Exposure to an Ir192 Industrial Radiography Source in Bangladesh

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jalil, A.; Rabbani, G.; Hossain, M. K.

2003-02-24

An industrial radiographer was accidentally over-exposed while taking the radiograph of weld-joints of gas pipe-lines in 1985 in Bangladesh. Symptoms of high radiation exposure occurred immediately after the accident and skin erythema developed leading to progressive tissue deterioration. The consequences of this over-exposure is being followed up to assess the long-term effects of ionizing radiation on the victim. Progressive tissue deteriorations have already led to multiple surgeries and successive amputations of the finger-tips so far. Lessons learned from this accident are also reported in this paper.

FAS Death Receptor: A Breast Cancer Subtype-Specific Radiation Response Biomarker and Potential Therapeutic Target

PubMed Central

Horton, Janet K.; Siamakpour-Reihani, Sharareh; Lee, Chen-Ting; Zhou, Ying; Chen, Wei; Geradts, Joseph; Fels, Diane R.; Hoang, Peter; Ashcraft, Kathleen A.; Groth, Jeff; Kung, Hsiu-Ni; Dewhirst, Mark W.; Chi, Jen-Tsan A.

2015-01-01

Although a standardized approach to radiotherapy has been used to treat breast cancer, regardless of subtype (e.g., luminal, basal), recent clinical data suggest that radiation response may vary significantly among subtypes. We hypothesized that this clinical variability may be due, in part, to differences in cellular radiation response. In this study, we utilized RNA samples for microarray analysis from two sources: 1. Paired pre- and postirradiation breast tumor tissue from 32 early-stage breast cancer patients treated in our unique preoperative radiation Phase I trial; and 2. Sixteen biologically diverse breast tumor cell lines exposed to 0 and 5 Gy irradiation. The transcriptome response to radiation exposure was derived by comparing gene expression in samples before and after irradiation. Genes with the highest coefficient of variation were selected for further evaluation and validated at the RNA and protein level. Gene editing and agonistic antibody treatment were performed to assess the impact of gene modulation on radiation response. Gene expression in our cohort of luminal breast cancer patients was distinctly different before and after irradiation. Further, two distinct patterns of gene expression were observed in our biologically diverse group of breast cancer cell lines pre- versus postirradiation. Cell lines that showed significant change after irradiation were largely luminal subtype, while gene expression in the basal and HER2+ cell lines was minimally impacted. The 100 genes with the most significant response to radiation in patients were identified and analyzed for differential patterns of expression in the radiation-responsive versus nonresponsive cell lines. Fourteen genes were identified as significant, including FAS, a member of the tumor necrosis factor receptor family known to play a critical role in programed cell death. Modulation of FAS in breast cancer cell lines altered radiation response phenotype and enhanced radiation sensitivity in radioresistant basal cell lines. Our findings suggest that cell-type-specific, radiation-induced FAS contributes to subtype-specific breast cancer radiation response and that activation of FAS pathways may be exploited for biologically tailored radiotherapy. PMID:26488758

{sup 18}F-Fluorodeoxyglucose/Positron Emission Tomography Predicts Patterns of Failure After Definitive Chemoradiation Therapy for Locally Advanced Non-Small Cell Lung Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ohri, Nitin, E-mail: ohri.nitin@gmail.com; Bodner, William R.; Halmos, Balazs

Background: We previously reported that pretreatment positron emission tomography (PET) identifies lesions at high risk for progression after concurrent chemoradiation therapy (CRT) for locally advanced non-small cell lung cancer (NSCLC). Here we validate those findings and generate tumor control probability (TCP) models. Methods: We identified patients treated with definitive, concurrent CRT for locally advanced NSCLC who underwent staging {sup 18}F-fluorodeoxyglucose/PET/computed tomography. Visible hypermetabolic lesions (primary tumors and lymph nodes) were delineated on each patient's pretreatment PET scan. Posttreatment imaging was reviewed to identify locations of disease progression. Competing risks analyses were performed to examine metabolic tumor volume (MTV) and radiation therapymore » dose as predictors of local disease progression. TCP modeling was performed to describe the likelihood of local disease control as a function of lesion size. Results: Eighty-nine patients with 259 hypermetabolic lesions (83 primary tumors and 176 regional lymph nodes) met the inclusion criteria. Twenty-eight patients were included in our previous report, and the remaining 61 constituted our validation cohort. The median follow-up time was 22.7 months for living patients. In 20 patients, the first site of progression was a primary tumor or lymph node treated with radiation therapy. The median time to progression for those patients was 11.5 months. Data from our validation cohort confirmed that lesion MTV predicts local progression, with a 30-month cumulative incidence rate of 23% for lesions above 25 cc compared with 4% for lesions below 25 cc (P=.008). We found no evidence that radiation therapy dose was associated with local progression risk. TCP modeling yielded predicted 30-month local control rates of 98% for a 1-cc lesion, 94% for a 10-cc lesion, and 74% for a 50-cc lesion. Conclusion: Pretreatment FDG-PET identifies lesions at risk for progression after CRT for locally advanced NSCLC. Strategies to improve local control should be tested on high-risk lesions, and treatment deintensification for low-risk lesions should be explored.« less

Stereotactic Radiosurgery and Fractionated Stereotactic Radiation Therapy for the Treatment of Uveal Melanoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yazici, Gozde; Kiratli, Hayyam; Ozyigit, Gokhan

Purpose: To evaluate treatment results of stereotactic radiosurgery or fractionated stereotactic radiation therapy (SRS/FSRT) for uveal melanoma. Methods and Materials: We retrospectively evaluated 181 patients with 182 uveal melanomas receiving SRS/FSRT between 2007 and 2013. Treatment was administered with CyberKnife. Results: According to Collaborative Ocular Melanoma Study criteria, tumor size was small in 1%, medium in 49.5%, and large in 49.5% of the patients. Seventy-one tumors received <45 Gy, and 111 received ≥45 Gy. Median follow-up time was 24 months. Complete and partial response was observed in 8 and 104 eyes, respectively. The rate of 5-year overall survival was 98%, disease-free survival 57%,more » local recurrence-free survival 73%, distant metastasis-free survival 69%, and enucleation-free survival 73%. There was a significant correlation between tumor size and disease-free survival, SRS/FSRT dose and enucleation-free survival; and both were prognostic for local recurrence-free survival. Enucleation was performed in 41 eyes owing to progression in 26 and complications in 11. Conclusions: The radiation therapy dose is of great importance for local control and eye retention; the best treatment outcome was achieved using ≥45 Gy in 3 fractions.« less

JASMIN: Japanese-American study of muon interactions and neutron detection

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nakashima, Hiroshi; /JAEA, Ibaraki; Mokhov, N.V.

Experimental studies of shielding and radiation effects at Fermi National Accelerator Laboratory (FNAL) have been carried out under collaboration between FNAL and Japan, aiming at benchmarking of simulation codes and study of irradiation effects for upgrade and design of new high-energy accelerator facilities. The purposes of this collaboration are (1) acquisition of shielding data in a proton beam energy domain above 100GeV; (2) further evaluation of predictive accuracy of the PHITS and MARS codes; (3) modification of physics models and data in these codes if needed; (4) establishment of irradiation field for radiation effect tests; and (5) development of amore » code module for improved description of radiation effects. A series of experiments has been performed at the Pbar target station and NuMI facility, using irradiation of targets with 120 GeV protons for antiproton and neutrino production, as well as the M-test beam line (M-test) for measuring nuclear data and detector responses. Various nuclear and shielding data have been measured by activation methods with chemical separation techniques as well as by other detectors such as a Bonner ball counter. Analyses with the experimental data are in progress for benchmarking the PHITS and MARS15 codes. In this presentation recent activities and results are reviewed.« less

Management of salivary gland tumors.

PubMed

Andry, Guy; Hamoir, Marc; Locati, Laura D; Licitra, Lisa; Langendijk, Johannes A

2012-09-01

Surgery after proper imaging (MRI or CT scan) is the main stay of treatment for salivary gland tumors. Although excision margins should be ≥5 mm for malignant tumors in cases of parotid gland carcinoma, the facial nerve should be preserved whenever it is not infiltrated. Adjuvant external radiation is indicated for malignant tumors with high-risk features such as close (or invaded) margins, perineural speed, lymphatic and/or vascular invasion, lymph-node involvement and high-grade histology. A Phase II trial testing adjuvant concomitant cisplatin plus radiation therapy versus adjuvant radiation therapy alone after surgery is currently under investigation for high-risk salivary gland cancer. For inoperable cancers, photons combined with proton boost seem to be a valuable option. Even if protons or carbon ions are promising, access to the latter is limited for usual treatment. For recurrent and/or metastatic cancer, polychemotherapy (cisplatin based) gives a 25% response rate in adenoid cystic carcinoma and should be used when the disease is overtly in progression. Targeted therapies with anti-EGF receptor molecules, antiangiogenic agents and tyrosine kinase inhibitors are ongoing, but more trials are needed to establish their efficacy, as is the use of bortezomib followed by doxorubicin. The products of fusion oncogenes, which have a pathogenic role in some adenoid cystic carcinoma and mucoepidermoid carcinomas, are of interest as potential therapeutic targets.

Influence of inhomogeneous surface heat capacity on the estimation of radiative response coefficients in a two-zone energy balance model

NASA Astrophysics Data System (ADS)

Park, Jungmin; Choi, Yong-Sang

2018-04-01

Observationally constrained values of the global radiative response coefficient are pivotal to assess the reliability of modeled climate feedbacks. A widely used approach is to measure transient global radiative imbalance related to surface temperature changes. However, in this approach, a potential error in the estimate of radiative response coefficients may arise from surface inhomogeneity in the climate system. We examined this issue theoretically using a simple two-zone energy balance model. Here, we dealt with the potential error by subtracting the prescribed radiative response coefficient from those calculated within the two-zone framework. Each zone was characterized by the different magnitude of the radiative response coefficient and the surface heat capacity, and the dynamical heat transport in the atmosphere between the zones was parameterized as a linear function of the temperature difference between the zones. Then, the model system was forced by randomly generated monthly varying forcing mimicking time-varying forcing like an observation. The repeated simulations showed that inhomogeneous surface heat capacity causes considerable miscalculation (down to -1.4 W m-2 K-1 equivalent to 31.3% of the prescribed value) in the global radiative response coefficient. Also, the dynamical heat transport reduced this miscalculation driven by inhomogeneity of surface heat capacity. Therefore, the estimation of radiative response coefficients using the surface temperature-radiation relation is appropriate for homogeneous surface areas least affected by the exterior.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Komaki, Ritsuko, E-mail: rkomaki@mdanderson.org; Allen, Pamela K.; Wei, Xiong

Purpose: To test, in a single-arm, prospective, phase 2 trial, whether adding the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib to concurrent chemoradiotherapy for previously untreated, locally advanced, inoperable non-small cell lung cancer would improve survival and disease control without increasing toxicity. Methods and Materials: Forty-eight patients with previously untreated non-small cell lung cancer received intensity modulated radiation therapy (63 Gy/35 fractions) on Monday through Friday, with chemotherapy (paclitaxel 45 mg/m², carboplatin area under the curve [AUC] = 2) on Mondays, for 7 weeks. All patients also received the EGFR tyrosine kinase inhibitor erlotinib (150 mg orally 1/d) on Tuesday-Sunday for 7 weeks, followedmore » by consolidation paclitaxel–carboplatin. The primary endpoint was time to progression; secondary endpoints were overall survival (OS), toxicity, response, and disease control and whether any endpoint differed by EGFR mutation status. Results: Of 46 patients evaluable for response, 40 were former or never-smokers, and 41 were evaluable for EGFR mutations (37 wild-type [WT] and 4 mutated [all adenocarcinoma]). Median time to progression was 14.0 months and did not differ by EGFR status. Toxicity was acceptable (no grade 5, 1 grade 4, 11 grade 3). Twelve patients (26%) had complete responses (10 WT, 2 mutated), 27 (59%) partial (21 WT, 2 mutated, 4 unknown), and 7 (15%) none (6 WT, 2 mutated, 1 unknown) (P=.610). At 37.0 months' follow-up (range, 3.6-76.5 months) for all patients, median OS time was 36.5 months, and 1-, 2-, and 5-year OS rates were 82.6%, 67.4%, and 35.9%, respectively; none differed by mutation status. Twelve patients had no progression, and 34 had local and/or distant failure. Eleven of 27 distant failures were in the brain (7 WT, 3 mutated, 1 unknown). Conclusions: Toxicity and OS were promising, but time to progression did not meet expectations. The prevalence of distant failures underscores the need for effective systemic therapy.« less

Physiological Imaging-Defined, Response-Driven Subvolumes of a Tumor

DOE Office of Scientific and Technical Information (OSTI.GOV)

Farjam, Reza; Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan; Tsien, Christina I.

2013-04-01

Purpose: To develop an image analysis framework to delineate the physiological imaging-defined subvolumes of a tumor in relating to treatment response and outcome. Methods and Materials: Our proposed approach delineates the subvolumes of a tumor based on its heterogeneous distributions of physiological imaging parameters. The method assigns each voxel a probabilistic membership function belonging to the physiological parameter classes defined in a sample of tumors, and then calculates the related subvolumes in each tumor. We applied our approach to regional cerebral blood volume (rCBV) and Gd-DTPA transfer constant (K{sup trans}) images of patients who had brain metastases and were treatedmore » by whole-brain radiation therapy (WBRT). A total of 45 lesions were included in the analysis. Changes in the rCBV (or K{sup trans})–defined subvolumes of the tumors from pre-RT to 2 weeks after the start of WBRT (2W) were evaluated for differentiation of responsive, stable, and progressive tumors using the Mann-Whitney U test. Performance of the newly developed metrics for predicting tumor response to WBRT was evaluated by receiver operating characteristic (ROC) curve analysis. Results: The percentage decrease in the high-CBV-defined subvolumes of the tumors from pre-RT to 2W was significantly greater in the group of responsive tumors than in the group of stable and progressive tumors (P<.007). The change in the high-CBV-defined subvolumes of the tumors from pre-RT to 2W was a predictor for post-RT response significantly better than change in the gross tumor volume observed during the same time interval (P=.012), suggesting that the physiological change occurs before the volumetric change. Also, K{sup trans} did not add significant discriminatory information for assessing response with respect to rCBV. Conclusion: The physiological imaging-defined subvolumes of the tumors delineated by our method could be candidates for boost target, for which further development and evaluation is warranted.« less

Final Report for Annex II--Assessment of Solar Radiation Resources In Saudi Arabia, 1998-2000

DOE Office of Scientific and Technical Information (OSTI.GOV)

Myers, D. R.; Wilcox, S. M.; Marion, W. F.

2002-04-01

The Final Report for Annex II - Assessment of Solar Radiation Resources in Saudi Arabia 1998-2000 summarizes the accomplishment of work performed, results achieved, and products produced under Annex II, a project established under the Agreement for Cooperation in the Field of Renewable Energy Research and Development between the Kingdom of Saudi Arabia and the United States. The report covers work and accomplishments from January 1998 to December 2000. A previous progress report, Progress Report for Annex II - Assessment of Solar Radiation Resources in Saudi Arabia 1993-1997, NREL/TP-560-29374, summarizes earlier work and technical transfer of information under the project.more » The work was performed in at the National Renewable Energy Laboratory (NREL) in Golden, Colorado, at the King Abdulaziz City for Science and Technology (KACST) in Riyadh, Saudi Arabia, and at selected weather stations of the Saudi Meteorological and Environmental Protection Administration (MEPA).« less

Mechanisms for radiation damage in DNA. Progress report, January 1, 1980-December 31, 1980

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sevilla, M D

1980-09-01

In this project several mechanisms are proposed for radiation damage to DNA constituents and DNA, and a series of experiments detailed utilizing electron spin resonance spectrometry to test the proposed mechanisms. Under current investigation are irradiated systems of DNA constituents which may shed light on indirect effects. In addition, studies of radiation effects on lipids have been undertaken which will shed light on the only other proposed site for cell kill, the membrane. Studies completed during the past year are: (1) ..pi.. cations produced in DNA bases by attack of oxidizing radicals; (2) INDO studies of radicals produced in peptidesmore » and carboxylic acid model compounds; (3) electron reactions with carboxylic acids, ketones and aldehydes; and (4) ..gamma..-irradiation of esters and triglycerides. Progress has been made this year in a study of radicals generated in model compounds for the sugar-phosphate backbone.« less

Research in cosmic and gamma ray astrophysics: Cosmic physics portion

NASA Technical Reports Server (NTRS)

Stone, Edward C.; Mewaldt, Richard A.; Schindler, Stephen

1993-01-01

Research in particle astrophysics at the Space Radiation Laboratory (SRL) of the California Institute of Technology is supported under NASA Grant NAGW-1919. A three-year proposal for continuation of support was submitted a year ago and put into effect 1 October 1992. This report is the combined progress report and continuation application called for under the Federal Demonstration Project. Gamma-ray Astrophysics at SRL is separately supported under NAGW-1919 and will be separately summarized and proposed. This report will document progress and plans for our particle spectroscopy activities and for related data analysis, calibration, and community service activities. A bibliography and a budget will be attached as appendices. The Caltech SRL research program includes a heavy emphasis on elemental and isotopic spectroscopy of energetic particles in the cosmic radiation; in solar, interplanetary, and anomalous 'cosmic' radiation; and in planetary magnetospheres as discussed.

Clinical study and numerical simulation of brain cancer dynamics under radiotherapy

NASA Astrophysics Data System (ADS)

Nawrocki, S.; Zubik-Kowal, B.

2015-05-01

We perform a clinical and numerical study of the progression of brain cancer tumor growth dynamics coupled with the effects of radiotherapy. We obtained clinical data from a sample of brain cancer patients undergoing radiotherapy and compare it to our numerical simulations to a mathematical model of brain tumor cell population growth influenced by radiation treatment. We model how the body biologically receives a physically delivered dose of radiation to the affected tumorous area in the form of a generalized LQ model, modified to account for the conversion process of sublethal lesions into lethal lesions at high radiation doses. We obtain good agreement between our clinical data and our numerical simulations of brain cancer progression given by the mathematical model, which couples tumor growth dynamics and the effect of irradiation. The correlation, spanning a wide dataset, demonstrates the potential of the mathematical model to describe the dynamics of brain tumor growth influenced by radiotherapy.

Phosphoproteomics profiling of human skin fibroblast cells reveals pathways and proteins affected by low doses of ionizing radiation.

PubMed

Yang, Feng; Waters, Katrina M; Miller, John H; Gritsenko, Marina A; Zhao, Rui; Du, Xiuxia; Livesay, Eric A; Purvine, Samuel O; Monroe, Matthew E; Wang, Yingchun; Camp, David G; Smith, Richard D; Stenoien, David L

2010-11-30

High doses of ionizing radiation result in biological damage; however, the precise relationships between long-term health effects, including cancer, and low-dose exposures remain poorly understood and are currently extrapolated using high-dose exposure data. Identifying the signaling pathways and individual proteins affected at the post-translational level by radiation should shed valuable insight into the molecular mechanisms that regulate dose-dependent responses to radiation. We have identified 7117 unique phosphopeptides (2566 phosphoproteins) from control and irradiated (2 and 50 cGy) primary human skin fibroblasts 1 h post-exposure. Semi-quantitative label-free analyses were performed to identify phosphopeptides that are apparently altered by radiation exposure. This screen identified phosphorylation sites on proteins with known roles in radiation responses including TP53BP1 as well as previously unidentified radiation-responsive proteins such as the candidate tumor suppressor SASH1. Bioinformatic analyses suggest that low and high doses of radiation affect both overlapping and unique biological processes and suggest a role for MAP kinase and protein kinase A (PKA) signaling in the radiation response as well as differential regulation of p53 networks at low and high doses of radiation. Our results represent the most comprehensive analysis of the phosphoproteomes of human primary fibroblasts exposed to multiple doses of ionizing radiation published to date and provide a basis for the systems-level identification of biological processes, molecular pathways and individual proteins regulated in a dose dependent manner by ionizing radiation. Further study of these modified proteins and affected networks should help to define the molecular mechanisms that regulate biological responses to radiation at different radiation doses and elucidate the impact of low-dose radiation exposure on human health.

Phosphoproteomics Profiling of Human Skin Fibroblast Cells Reveals Pathways and Proteins Affected by Low Doses of Ionizing Radiation

PubMed Central

Yang, Feng; Waters, Katrina M.; Miller, John H.; Gritsenko, Marina A.; Zhao, Rui; Du, Xiuxia; Livesay, Eric A.; Purvine, Samuel O.; Monroe, Matthew E.; Wang, Yingchun; Camp, David G.; Smith, Richard D.; Stenoien, David L.

2010-01-01

Background High doses of ionizing radiation result in biological damage; however, the precise relationships between long-term health effects, including cancer, and low-dose exposures remain poorly understood and are currently extrapolated using high-dose exposure data. Identifying the signaling pathways and individual proteins affected at the post-translational level by radiation should shed valuable insight into the molecular mechanisms that regulate dose-dependent responses to radiation. Principal Findings We have identified 7117 unique phosphopeptides (2566 phosphoproteins) from control and irradiated (2 and 50 cGy) primary human skin fibroblasts 1 h post-exposure. Semi-quantitative label-free analyses were performed to identify phosphopeptides that are apparently altered by radiation exposure. This screen identified phosphorylation sites on proteins with known roles in radiation responses including TP53BP1 as well as previously unidentified radiation-responsive proteins such as the candidate tumor suppressor SASH1. Bioinformatic analyses suggest that low and high doses of radiation affect both overlapping and unique biological processes and suggest a role for MAP kinase and protein kinase A (PKA) signaling in the radiation response as well as differential regulation of p53 networks at low and high doses of radiation. Conclusions Our results represent the most comprehensive analysis of the phosphoproteomes of human primary fibroblasts exposed to multiple doses of ionizing radiation published to date and provide a basis for the systems-level identification of biological processes, molecular pathways and individual proteins regulated in a dose dependent manner by ionizing radiation. Further study of these modified proteins and affected networks should help to define the molecular mechanisms that regulate biological responses to radiation at different radiation doses and elucidate the impact of low-dose radiation exposure on human health. PMID:21152398

Ionizing radiation calculations and comparisons with LDEF data

NASA Technical Reports Server (NTRS)

Armstrong, T. W.; Colborn, B. L.; Watts, J. W., Jr.

1992-01-01

In conjunction with the analysis of LDEF ionizing radiation dosimetry data, a calculational program is in progress to aid in data interpretation and to assess the accuracy of current radiation models for future mission applications. To estimate the ionizing radiation environment at the LDEF dosimeter locations, scoping calculations for a simplified (one dimensional) LDEF mass model were made of the primary and secondary radiations produced as a function of shielding thickness due to trapped proton, galactic proton, and atmospheric (neutron and proton cosmic ray albedo) exposures. Preliminary comparisons of predictions with LDEF induced radioactivity and dose measurements were made to test a recently developed model of trapped proton anisotropy.

RADIATION STERILIZATION OF COCOA POWDERS. Report No. 3 (Progress), November 18, 1959-May 17, 1960

DOE Office of Scientific and Technical Information (OSTI.GOV)

McCombs, C.J.

1961-10-31

A summary is given of the results and conclusions of a study of the effects of radiation doses of O.1 x 10/sup 6/ and 0.5 x 10/sup 6/ rads on the blooming characteristics and general quality of chocolate coatings. (B.O.G.)

Effects of Radiation on the Microbiota and Intestinal Inflammatory Disease

DTIC Science & Technology

2017-09-01

microbial communities induced by intestinal radiation exposure. Currently, we demonstrate that these changes correlate with increased sensitivity to...Accomplishment: Place a description of the latest scientific accomplishment here. Limit the comments to three lines or less to make them fit; be succinct. These comments are valuable since they show progress.

Second Annual Progress Report on Radiation Tolerance of Controlled Fusion Welds in High Temperature Oxidation Resistant FeCrAl Alloys

DOE Office of Scientific and Technical Information (OSTI.GOV)

Field, Kevin G.; Gussev, Maxim N.; Yamamoto, Yukinori

2016-12-30

The present report summarizes and discusses the current results and on-going activity towards developing a modern, nuclear grade FeCrAl alloy designed to have enhanced radiation tolerance and weldability under the Department of Energy (DOE) Nuclear Energy Enabling Technologies (NEET) program.

Low-Dose, Ionizing Radiation and Age-Related Changes in Skeletal Microarchitecture

DOE PAGES

Alwood, Joshua S.; Kumar, Akhilesh; Tran, Luan H.; ...

2012-01-01

Osteoporosis can profoundly affect the aged as a consequence of progressive bone loss; high-dose ionizing radiation can cause similar changes, although less is known about lower doses (≤100 cGy). We hypothesized that exposure to relatively low doses of gamma radiation accelerates structural changes characteristic of skeletal aging. Mice (C57BL/6J-10 wk old, male) were irradiated (total body; 0-sham, 1, 10 or 100 cGy 137 Cs) and tissues harvested on the day of irradiation, 1 or 4 months later. Microcomputed tomography was used to quantify microarchitecture of high turnover, cancellous bone. Irradiation at 100 cGy caused transient microarchitectural changes over one month that were only evident atmore » longer times in controls (4 months). Ex vivo bone cell differentiation from the marrow was unaffected by gamma radiation. In conclusion, acute ionizing gamma irradiation at 100 cGy (but not at 1 cGy or 10 cGy) exacerbated microarchitectural changes normally found during progressive, postpubertal aging prior to the onset of age-related osteoporosis.« less

Low-Dose, Ionizing Radiation and Age-Related Changes in Skeletal Microarchitecture

DOE Office of Scientific and Technical Information (OSTI.GOV)

Alwood, Joshua S.; Kumar, Akhilesh; Tran, Luan H.

Osteoporosis can profoundly affect the aged as a consequence of progressive bone loss; high-dose ionizing radiation can cause similar changes, although less is known about lower doses (≤100 cGy). We hypothesized that exposure to relatively low doses of gamma radiation accelerates structural changes characteristic of skeletal aging. Mice (C57BL/6J-10 wk old, male) were irradiated (total body; 0-sham, 1, 10 or 100 cGy 137 Cs) and tissues harvested on the day of irradiation, 1 or 4 months later. Microcomputed tomography was used to quantify microarchitecture of high turnover, cancellous bone. Irradiation at 100 cGy caused transient microarchitectural changes over one month that were only evident atmore » longer times in controls (4 months). Ex vivo bone cell differentiation from the marrow was unaffected by gamma radiation. In conclusion, acute ionizing gamma irradiation at 100 cGy (but not at 1 cGy or 10 cGy) exacerbated microarchitectural changes normally found during progressive, postpubertal aging prior to the onset of age-related osteoporosis.« less

Common Progress Monitoring Graph Omissions: Missing Goal and Goal Line. Progress Monitoring Brief #2

ERIC Educational Resources Information Center

National Center on Response to Intervention, 2013

2013-01-01

Progress monitoring assessment is one of the four essential components of Response to Intervention (RTI), as defined by the National Center on Response to Intervention (NCRTI). Progress data allow teachers to evaluate the academic performance of students over time, quantify rates of improvement or responsiveness to instruction, and evaluate…

Radiosensitizing Pancreatic Cancer Xenografts by an Implantable Micro-Oxygen Generator.

PubMed

Cao, Ning; Song, Seung Hyun; Maleki, Teimour; Shaffer, Michael; Stantz, Keith M; Cao, Minsong; Kao, Chinghai; Mendonca, Marc S; Ziaie, Babak; Ko, Song-Chu

2016-04-01

Over the past decades, little progress has been made to improve the extremely low survival rates in pancreatic cancer patients. Extreme hypoxia observed in pancreatic tumors contributes to the aggressive and metastatic characteristics of this tumor and can reduce the effectiveness of conventional radiation therapy and chemotherapy. In an attempt to reduce hypoxia-induced obstacles to effective radiation treatment, we used a novel device, the implantable micro-oxygen generator (IMOG), for in situ tumor oxygenation. After subcutaneous implantation of human pancreatic xenograft tumors in athymic rats, the IMOG was wirelessly powered by ultrasonic waves, producing 30 μA of direct current (at 2.5 V), which was then utilized to electrolyze water and produce oxygen within the tumor. Significant oxygen production by the IMOG was observed and corroborated using the NeoFox oxygen sensor dynamically. To test the radiosensitization effect of the newly generated oxygen, the human pancreatic xenograft tumors were subcutaneously implanted in nude mice with either a functional or inactivated IMOG device. The tumors in the mice were then exposed to ultrasonic power for 10 min, followed by a single fraction of 5 Gy radiation, and tumor growth was monitored thereafter. The 5 Gy irradiated tumors containing the functional IMOG exhibited tumor growth inhibition equivalent to that of 7 Gy irradiated tumors that did not contain an IMOG. Our study confirmed that an activated IMOG is able to produce sufficient oxygen to radiosensitize pancreatic tumors, enhancing response to single-dose radiation therapy.

Synergistic effect of Ebselen and gamma radiation on breast cancer cells.

PubMed

Thabet, Noura M; Moustafa, Enas M

2017-08-01

To explore the synergistic effect of a seleno-organic compound Ebselen (Ebs) and/or γ-radiation to exert antitumor effects on human breast cancer (MCF-7) cell line in vitro. Ebs cytotoxicity at various concentrations (10, 25, 50 and 75 μg), cell proliferation and clonogenic assay of Ebs and/or γ-radiation (at 1, 3 and 6 Gy), expression of p-IκBα and NF-κB, inflammatory cytokines levels (TNF-α, IL-2, INF-γ, IL-10 and TGF-β), apoptotic factors (Caspase-3, Granzyme-B and TRAIL) and angiogenic factor (VEGF) were investigated. The results showed that the effective dosage of this combination was observed at 25 μg/ml of Ebs with γ-radiation at 6 Gy. Data displayed a significant reduction in NF-κB mRNA along with an elevation in granzyme-B mRNA and TRAIL mRNA expression. Furthermore, protein expression of caspase-3 was elevated, whereas p-IκBα and p-NF-κB(p65) protein expression was reduced significantly. Also, a significant decline in TNF-α, IL-2, INF-γ, TGF-β with a significant increase in IL-10 levels were revealed. Meanwhile, a significant decrease in VEGF level and proliferation capacity were observed. We conclude that a combination of Ebs with radiotherapy has a major antitumor efficiency in inducing apoptosis and inhibiting cancer cell progression, due to the synergistic effect in regulating gene and protein expression, and in a modulating response of pro-and anti-inflammatory cytokines.

Current Developments in Future Planetary Probe Sensors for TPS

NASA Technical Reports Server (NTRS)

Martinez, Ed; Venkatapathy, Ethiraj; Oishu, Tomo

2003-01-01

In-situ Thermal Protection System (TPS) sensors are required to provide traceability of TPS performance and sizing tools. Traceability will lead to higher fidelity design tools, which in turn will lead to lower design safety margins, and decreased heatshield mass. Decreasing TPS mass will enable certain missions that are not otherwise feasible, and directly increase science payload. NASA Ames is currently developing two flight measurements as essential to advancing the state of TPS traceability for material modeling and aerothermal simulation: heat flux and surface recession (for ablators). The heat flux gage is applicable to both ablators and non-ablators and is therefore the more generalized sensor concept of the two with wider applicability to mission scenarios. This paper describes the development of a microsensor capable of surface and in-depth temperature and heat flux measurements for TPS materials appropriate to Titan, Neptune, and Mars aerocapture, and direct entry. The thermal sensor will be monolithic solid state devices composed of thick film platinum RTD on an alumina substrate. Choice of materials and critical dimensions are used to tailor gage response, determined during calibration activities, to specific (forebody vs. aftbody) heating environments. Current design has maximum operating temperature of 1500 K, and allowable constant heat flux of q=28.7 watts per square centimeter, and time constants between 0.05 and 0.2 seconds. The catalytic and radiative response of these heat flux gages can also be changed through the use of appropriate coatings. By using several co-located gages with various surface coatings, data can be obtained to isolate surface heat flux components due to radiation, catalycity and convection. Selectivity to radiative heat flux is a useful feature even for an in-depth gage, as radiative transport may be a significant heat transport mechanism for porous TPS materials in Titan aerocapture. This paper also reports on progress to adapt a previously flown surface recession sensor, based on the Jupiter probe Galileo Analog Resistance Ablation Detector (ARAD), to appropriate aerocapture conditions.

Synergy between Prkdc and Trp53 regulates stem cell proliferation and GI-ARS after irradiation.

PubMed

Gurley, Kay E; Ashley, Amanda K; Moser, Russell D; Kemp, Christopher J

2017-11-01

Ionizing radiation (IR) is one of the most widely used treatments for cancer. However, acute damage to the gastrointestinal tract or gastrointestinal acute radiation syndrome (GI-ARS) is a major dose-limiting side effect, and the mechanisms that underlie this remain unclear. Here we use mouse models to explore the relative roles of DNA repair, apoptosis, and cell cycle arrest in radiation response. IR induces DNA double strand breaks and DNA-PK mutant Prkdc scid/scid mice are sensitive to GI-ARS due to an inability to repair these breaks. IR also activates the tumor suppressor p53 to trigger apoptotic cell death within intestinal crypt cells and p53 deficient mice are resistant to apoptosis. To determine if DNA-PK and p53 interact to govern radiosensitivity, we compared the response of single and compound mutant mice to 8 Gy IR. Compound mutant Prkdc scid/scid /Trp53 -/- mice died earliest due to severe GI-ARS. While both Prkdc scid/scid and Prkdc scid/scid /Trp53 -/- mutant mice had higher levels of IR-induced DNA damage, particularly within the stem cell compartment of the intestinal crypt, in Prkdc scid/scid /Trp53 -/- mice these damaged cells abnormally progressed through the cell cycle resulting in mitotic cell death. This led to a loss of Paneth cells and a failure to regenerate the differentiated epithelial cells required for intestinal function. IR-induced apoptosis did not correlate with radiosensitivity. Overall, these data reveal that DNA repair, mediated by DNA-PK, and cell cycle arrest, mediated by p53, cooperate to protect the stem cell niche after DNA damage, suggesting combination approaches to modulate both pathways may be beneficial to reduce GI-ARS. As many cancers harbor p53 mutations, this also suggests targeting DNA-PK may be effective to enhance sensitivity of p53 mutant tumors to radiation.

Definitive Management of Oligometastatic Melanoma in a Murine Model Using Combined Ablative Radiation Therapy and Viral Immunotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Blanchard, Miran; Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota; Shim, Kevin G.

Purpose: The oligometastatic state is an intermediate state between a malignancy that can be completely eradicated with conventional modalities and one in which a palliative approach is undertaken. Clinically, high rates of local tumor control are possible with stereotactic ablative radiation therapy (SABR), using precisely targeted, high-dose, low-fraction radiation therapy. However, in oligometastatic melanoma, virtually all patients develop progression systemically at sites not initially treated with ablative radiation therapy that cannot be managed with conventional chemotherapy and immunotherapy. We have demonstrated in mice that intravenous administration of vesicular stomatitis virus (VSV) expressing defined tumor-associated antigens (TAAs) generates systemic immune responsesmore » capable of clearing established tumors. Therefore, in the present preclinical study, we tested whether the combination of systemic VSV-mediated antigen delivery and SABR would be effective against oligometastatic disease. Methods and Materials: We generated a model of oligometastatic melanoma in C57BL/6 immunocompetent mice and then used a combination of SABR and systemically administered VSV-TAA viral immunotherapy to treat both local and systemic disease. Results: Our data showed that SABR generates excellent control or cure of local, clinically detectable, and accessible tumor through direct cell ablation. Also, the immunotherapeutic activity of systemically administered VSV-TAA generated T-cell responses that cleared subclinical metastatic tumors. We also showed that SABR induced weak T-cell-mediated tumor responses, which, particularly if boosted by VSV-TAA, might contribute to control of local and systemic disease. In addition, VSV-TAA therapy alone had significant effects on control of both local and metastatic tumors. Conclusions: We have shown in the present preliminary murine study using a single tumor model that this approach represents an effective, complementary combination therapy model that addresses the need for both systemic and local control in oligometastatic melanoma.« less

Phosphoprotein profiles of candidate markers for early cellular responses to low-dose γ-radiation in normal human fibroblast cells

PubMed Central

Yim, Ji-Hye; Yun, Jung Mi; Kim, Ji Young; Lee, In Kyung; Nam, Seon Young

2017-01-01

Abstract Ionizing radiation causes biological damage that leads to severe health effects. However, the effects and subsequent health implications caused by exposure to low-dose radiation are unclear. The objective of this study was to determine phosphoprotein profiles in normal human fibroblast cell lines in response to low-dose and high-dose γ-radiation. We examined the cellular response in MRC-5 cells 0.5 h after exposure to 0.05 or 2 Gy. Using 1318 antibodies by antibody array, we observed ≥1.3-fold increases in a number of identified phosphoproteins in cells subjected to low-dose (0.05 Gy) and high-dose (2 Gy) radiation, suggesting that both radiation levels stimulate distinct signaling pathways. Low-dose radiation induced nucleic acid–binding transcription factor activity, developmental processes, and multicellular organismal processes. By contrast, high-dose radiation stimulated apoptotic processes, cell adhesion and regulation, and cellular organization and biogenesis. We found that phospho-BTK (Tyr550) and phospho-Gab2 (Tyr643) protein levels at 0.5 h after treatment were higher in cells subjected to low-dose radiation than in cells treated with high-dose radiation. We also determined that the phosphorylation of BTK and Gab2 in response to ionizing radiation was regulated in a dose-dependent manner in MRC-5 and NHDF cells. Our study provides new insights into the biological responses to low-dose γ-radiation and identifies potential candidate markers for monitoring exposure to low-dose ionizing radiation. PMID:28122968

A metabolomics and mouse models approach to study inflammatory and immune responses to radiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fornace, Albert J.; Li, Henghong

2013-12-02

The three-year project entitled "A Metabolomics and Mouse Models Approach to Study Inflammatory and Immune Responses to Radiation" was initiated in September 2009. The overall objectives of this project were to investigate the acute and persistent effects of low dose radiation on T cell lymphocyte function and physiology, as well the contributions of these cells to radiation-induced inflammatory responses. Inflammation after ionizing radiation (IR), even at low doses, may impact a variety of disease processes, including infectious disease, cardiovascular disease, cancer, and other potentially inflammatory disorders. There were three overall specific aims: 1. To investigate acute and persistent effects ofmore » low dose radiation on T cell subsets and function; 2. A genetic approach with mouse models to investigate p38 MAPK pathways that are involved in radiation-induced inflammatory signaling; 3. To investigate the effect of radiation quality on the inflammatory response. We have completed the work proposed in these aims.« less

Radiation therapy in the management of head-and-neck cancer of unknown primary origin: how does the addition of concurrent chemotherapy affect the therapeutic ratio?

PubMed

Chen, Allen M; Farwell, D Gregory; Lau, Derick H; Li, Bao-Qing; Luu, Quang; Donald, Paul J

2011-10-01

To determine how the addition of cisplatin-based concurrent chemotherapy to radiation therapy influences outcomes among a cohort of patients treated for head-and-neck cancer of unknown primary origin. The medical records of 60 consecutive patients treated by radiation therapy for squamous cell carcinoma of the head and neck presenting as cervical lymph node metastasis of occult primary origin were reviewed. Thirty-two patients (53%) were treated by concurrent chemoradiation, and 28 patients (47%) were treated by radiation therapy alone. Forty-five patients (75%) received radiation therapy after surgical resection, and 15 patients (25%) received primary radiation therapy. Thirty-five patients (58%) were treated by intensity-modulated radiotherapy. The 2-year estimates of overall survival, local-regional control, and progression-free survival were 89%, 89%, and 79%, respectively, among patients treated by chemoradiation, compared to 90%, 92%, and 83%, respectively, among patients treated by radiation therapy alone (p > 0.05, for all). Exploratory analysis failed to identify any subset of patients who benefited from the addition of concurrent chemotherapy to radiation therapy. The use of concurrent chemotherapy was associated with a significantly increased incidence of Grade 3+ acute and late toxicity (p < 0.001, for both). Concurrent chemoradiation is associated with significant toxicity without a clear advantage to overall survival, local-regional control, and progression-free survival in the treatment of head-and-neck cancer of unknown primary origin. Although selection bias cannot be ignored, prospective data are needed to further address this question. Copyright © 2011 Elsevier Inc. All rights reserved.

Climate change and maize yield in southern Africa: what can farm management do?

PubMed

Rurinda, Jairos; van Wijk, Mark T; Mapfumo, Paul; Descheemaeker, Katrien; Supit, Iwan; Giller, Ken E

2015-12-01

There is concern that food insecurity will increase in southern Africa due to climate change. We quantified the response of maize yield to projected climate change and to three key management options - planting date, fertilizer use and cultivar choice - using the crop simulation model, agricultural production systems simulator (APSIM), at two contrasting sites in Zimbabwe. Three climate periods up to 2100 were selected to cover both near- and long-term climates. Future climate data under two radiative forcing scenarios were generated from five global circulation models. The temperature is projected to increase significantly in Zimbabwe by 2100 with no significant change in mean annual total rainfall. When planting before mid-December with a high fertilizer rate, the simulated average grain yield for all three maize cultivars declined by 13% for the periods 2010-2039 and 2040-2069 and by 20% for 2070-2099 compared with the baseline climate, under low radiative forcing. Larger declines in yield of up to 32% were predicted for 2070-2099 with high radiative forcing. Despite differences in annual rainfall, similar trends in yield changes were observed for the two sites studied, Hwedza and Makoni. The yield response to delay in planting was nonlinear. Fertilizer increased yield significantly under both baseline and future climates. The response of maize to mineral nitrogen decreased with progressing climate change, implying a decrease in the optimal fertilizer rate in the future. Our results suggest that in the near future, improved crop and soil fertility management will remain important for enhanced maize yield. Towards the end of the 21st century, however, none of the farm management options tested in the study can avoid large yield losses in southern Africa due to climate change. There is a need to transform the current cropping systems of southern Africa to offset the negative impacts of climate change. © 2015 John Wiley & Sons Ltd.

Next Steps Toward Understanding Human Habitation of Space: Environmental Impacts and Mechanisms

NASA Technical Reports Server (NTRS)

Globus, Ruth

2016-01-01

Entry into low earth orbit and beyond causes profound shifts in environmental conditions that have the potential to influence human productivity, long term health, and even survival. We now have evidence that microgravity, radiation and/or confinement in space can lead to demonstrably detrimental changes in the cardiovascular (e.g. vessel function, orthostatic intolerance), musculoskeletal (muscle atrophy, bone loss) and nervous (eye, neurovestibular) systems of astronauts. Because of both the limited number of astronauts who have flown (especially females) and the high degree of individual variability in the human population, important unanswered questions about responses to the space environment remain: What are the sex differences with respect to specific physiological systems? Are the responses age-dependent and/or reversible after return to Earth? Do observed detrimental changes that resemble accelerated aging progress continuously over time or plateau? What are the mechanisms of the biological responses? Answering these important questions certainly demands a multi-pronged approach, and the study of multicellular model organisms (such as rodents and flies) already has provided opportunities for exploring those questions in some detail. Recent long duration spaceflight experiments with rodents show that mice in space provide a mammalian model that uniquely combines the influence of reduced gravitational loading with increased physical activity. In addition, multiple investigators have shown that ground-based models that simulate aspects of spaceflight (including rodent hind limb unloading to mimic weightlessness and exposure to ionizing radiation), cause various transient and persistent detrimental consequences in multiple physiological systems. In general, we have found that adverse skeletal effects of simulated weightlessness and space radiation when combined, can be quantitatively, if not qualitatively, different from the influence of each environmental factor alone implying at least some shared underlying mechanisms. Thus, both ground based and spaceflight research utilizing model organisms provide the opportunity to better understand environmental factors and biological mechanisms that contribute to human health and survival in space.

Feasibility of Using Bevacizumab With Radiation Therapy and Temozolomide in Newly Diagnosed High-Grade Glioma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Narayana, Ashwatha; Golfinos, John G.; Fischer, Ingeborg

2008-10-01

Introduction: Bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), has shown promise in the treatment of patients with recurrent high-grade glioma. The purpose of this study is to test the feasibility of using bevacizumab with chemoradiation in the primary management of high-grade glioma. Methods and Materials: Fifteen patients with high-grade glioma were treated with involved field radiation therapy to a dose of 59.4 Gy at 1.8 Gy/fraction with bevacizumab 10 mg/kg on Days 14 and 28 and temozolomide 75 mg/m{sup 2}. Subsequently, bevacizumab 10 mg/kg was continued every 2 weeks with temozolomide 150 mg/m{sup 2} for 12 months.more » Changes in relative cerebral blood volume, perfusion-permeability index, and tumor volume measurement were measured to assess the therapeutic response. Immunohistochemistry for phosphorylated VEGF receptor 2 (pVEGFR2) was performed. Results: Thirteen patients (86.6%) completed the planned bevacizumab and chemoradiation therapy. Four Grade III/IV nonhematologic toxicities were seen. Radiographic responses were noted in 13 of 14 assessable patients (92.8%). The pVEGFR2 staining was seen in 7 of 8 patients (87.5%) at the time of initial diagnosis. Six patients have experienced relapse, 3 at the primary site and 3 as diffuse disease. One patient showed loss of pVEGFR2 expression at relapse. One-year progression-free survival and overall survival rates were 59.3% and 86.7%, respectively. Conclusion: Use of antiangiogenic therapy with radiation and temozolomide in the primary management of high-grade glioma is feasible. Perfusion imaging with relative cerebral blood volume, perfusion-permeability index, and pVEGFR2 expression may be used as a potential predictor of therapeutic response. Toxicities and patterns of relapse need to be monitored closely.« less

Cytogenetic damage, oncogenic transformation and p53 induction in human epithelial cells in response to irradiation

NASA Astrophysics Data System (ADS)

Armitage, Mark

Ionizing radiation can have several different effects on cells, some are almost instantaneous such as the generation of DNA damage, other cellular responses take a matter of minutes or hours - DNA repair protein induction/activation, and others may take months or even years to be manifested - carcinogenesis. Human epithelial cell lines derived from both normal, non-neoplastic tissues and from a malignant source were cultured in order to examine several effects of ionizing radiation on such cell types. Cells not from a malignant source were previously immortalized by viral infection or by transfection with viral sequences. Simian virus 40 immortalised uroepithelial cells (SV-HUC) were found to be approximately a factor of two fold more radioresistant than cells of malignant origin (T24) in terms of unrepaired clastogenic damage i.e. assessment of micronuclei levels following irradiation. SV-HUC lines unlike T24 cells are non-tumourigenic when inoculated into nude athymic mice. SV-HUC lines proved very resistant to full oncogenic transformation using radiation and chemical carcinogens. However, morphological alterations and decreased anchorage dependant growth was observed in post carcinogen treated cells after appropriate cell culture conditions were utilized. The progression from this phenotype to a fully tumourigenic one was not recorded in this study. The ability of ionizing radiation to induce increased levels of the nuclear phosphoprotein p53 was also assessed using several different cell lines. SV- HUC and T24 cell lines failed to exhibit any increased p53 stabilization following irradiation. One cell line, a human papilloma virus transformed line (HPV) did show an approximate two fold increase of the wild type p53 protein after treatment with radiation. Only the cell line HPV showed any cell cycle delay, resulting in accumulation of cells in the G2/M compartment in post irradiation cell cycle analysis. The status of p53 was also assessed i.e. wild type or mutant conformation in all the above cells lines and two other control lines HOS (a human osteosarcoma cell line) and H Tori-3 (SV40 immortalised thyroid epithelial cells).

Deconvolving the temporal response of photoelectric x-ray detectors for the diagnosis of pulsed radiations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zou, Shiyang; Song, Peng; Pei, Wenbing

2013-09-15

Based on the conjugate gradient method, a simple algorithm is presented for deconvolving the temporal response of photoelectric x-ray detectors (XRDs) to reconstruct the resolved time-dependent x-ray fluxes. With this algorithm, we have studied the impact of temporal response of XRD on the radiation diagnosis of hohlraum heated by a short intense laser pulse. It is found that the limiting temporal response of XRD not only postpones the rising edge and peak position of x-ray pulses but also smoothes the possible fluctuations of radiation fluxes. Without a proper consideration of the temporal response of XRD, the measured radiation flux canmore » be largely misinterpreted for radiation pulses of a hohlraum heated by short or shaped laser pulses.« less

Cardiovascular changes in atherosclerotic ApoE-deficient mice exposed to Co60 (γ) radiation.

PubMed

Kumarathasan, Prem; Vincent, Renaud; Blais, Erica; Saravanamuthu, Anu; Gupta, Pallavi; Wyatt, Heather; Mitchel, Ronald; Hannan, Mohammed; Trivedi, Akilesh; Whitman, Stewart

2013-01-01

There is evidence for a role of ionizing radiation in cardiovascular diseases. The goal of this work was to identify changes in oxidative and nitrative stress pathways and the status of the endothelinergic system during progression of atherosclerosis in ApoE-deficient mice after single and repeated exposure to ionizing radiation. B6.129P2-ApoE tmlUnc mice on a low-fat diet were acutely exposed (whole body) to Co60 (γ) (single dose 0, 0.5, and 2 Gy) at a dose rate of 36.32 cGy/min, or repeatedly (cumulative dose 0 and 2 Gy) at a dose-rate of 0.1 cGy/min for 5 d/wk, over a period of 4 weeks. Biological endpoints were investigated after 3-6 months of recovery post-radiation. The nitrative stress marker 3-nitrotyrosine and the vasoregulator peptides endothelin-1 and endothelin-3 in plasma were increased (p<0.05) in a dose-dependent manner 3-6 months after acute or chronic exposure to radiation. The oxidative stress marker 8-isoprostane was not affected by radiation, while plasma 8-hydroxydeoxyguanosine and L-3,4-dihydroxyphenylalanine decreased (p<0.05) after treatment. At 2Gy radiation dose, serum cholesterol was increased (p = 0.008) relative to controls. Percent lesion area increased (p = 0.005) with age of animal, but not with radiation treatment. Our observations are consistent with persistent nitrative stress and activation of the endothelinergic system in ApoE-/- mice after low-level ionizing radiation exposures. These mechanisms are known factors in the progression of atherosclerosis and other cardiovascular diseases.

Recent progress in the transition radiation detector techniques

NASA Technical Reports Server (NTRS)

Yuan, L. C. L.

1973-01-01

A list of some of the major experimental achievements involving charged particles in the relativistic region are presented. With the emphasis mainly directed to the X-ray region, certain modes of application of the transition radiation for the identification and separation of relativistic charged particles are discussed. Some recent developments in detection techniques and improvements in detector performances are presented. Experiments were also carried out to detect the dynamic radiation, but no evidence of such an effect was observed.

Mitigating HZE Radiation-Induced Deficits in Marrow-Derived Mesenchymal Progenitor Cells and Skeletal Structure

NASA Technical Reports Server (NTRS)

Globus, Ruth K.; Schreurs, Ann-Sofie; Shirazi-Fard, Yasaman; Terada, Masahiro; Alwood, Joshua; Halloran, Bernard; Tahimic, Candice

2016-01-01

Future long-duration space exploration beyond the earths magnetosphere will increase human exposure to space radiation and associated risks to skeletal health. We hypothesize that oxidative stress resulting from radiation exposure causes progressive bone loss and dysfunction in associated tissue. In animal studies, increased free radical formation is associated with pathological changes in bone structure, enhanced bone resorption, reduced bone formation and decreased bone mineral density, which can lead to skeletal fragility.

Assessing Spectral Shortwave Cloud Observations at the Southern Great Plains Facility

NASA Technical Reports Server (NTRS)

McBride, P. J.; Marshak, A.; Wiscombe, W. J.; Flynn, C. J.; Vogelmann, A. M.

2012-01-01

The Atmospheric Radiation Measurement (ARM) program (now Atmospheric System Research) was established, in part, to improve radiation models so that they could be used reliably to compute radiation fluxes through the atmosphere, given knowledge of the surface albedo, atmospheric gases, and the aerosol and cloud properties. Despite years of observations, discrepancies still exist between radiative transfer models and observations, particularly in the presence of clouds. Progress has been made at closing discrepancies in the spectral region beyond 3 micron, but the progress lags at shorter wavelengths. Ratios of observed visible and near infrared cloud albedo from aircraft and satellite have shown both localized and global discrepancies between model and observations that are, thus far, unexplained. The capabilities of shortwave surface spectrometry have been improved in recent years at the Southern Great Plains facility (SGP) of the ARM Climate Research Facility through the addition of new instrumentation, the Shortwave Array Spectroradiometer, and upgrades to existing instrumentation, the Shortwave Spectroradiometer and the Rotating Shadowband Spectroradiometer. An airborne-based instrument, the HydroRad Spectroradiometer, was also deployed at the ARM site during the Routine ARM Aerial Facility Clouds with Low Optical Water Depths (CLOWD) Optical Radiative Observations (RACORO) field campaign. Using the new and upgraded spectral observations along with radiative transfer models, cloud scenes at the SGP are presented with the goal of characterizing the instrumentation and the cloud fields themselves.

Comprehensive Craniospinal Radiation for Controlling Central Nervous System Leukemia

DOE Office of Scientific and Technical Information (OSTI.GOV)

Walker, Gary V.; Shihadeh, Ferial; Kantarjian, Hagop

Purpose: To determine the benefit of radiation therapy (RT) in resolution of neurologic symptoms and deficits and whether the type of RT fields influences central nervous system (CNS) control in adults with CNS leukemia. Methods and Materials: A total of 163 adults from 1996 to 2012 were retrospectively analyzed. Potential associations between use of radiation and outcome were investigated by univariate and multivariate analysis. Results: The median survival time was 3.8 months after RT. Common presenting symptoms were headache in 79 patients (49%), cranial nerve VII deficit in 46 (28%), and cranial nerve II deficit in 44 (27%). RT was deliveredmore » to the base of skull in 48 patients (29%), to the whole brain (WB) in 67 (41%), and to the craniospinal axis (CS) in 48 (29%). Among 149 patients with a total of 233 deficits, resolution was observed in 34 deficits (15%), improvement in 126 deficits (54%), stability in 34 deficits (15%), and progression in 39 deficits (17%). The 12-month CNS progression-free survival was 77% among those receiving CS/WB and 51% among those receiving base of skull RT (P=.02). On multivariate analysis, patients who did not undergo stem cell transplantation after RT and base of skull RT were associated with worse CNS progression-free survival. Conclusions: Improvement or resolution of symptoms occurred in two thirds of deficits after RT. Comprehensive radiation to the WB or CS seems to offer a better outcome, especially in isolated CNS involvement.« less

Radiation-induced synthesis and swelling properties of p(2-hydroxyethyl methacrylate/itaconic acid/oligo (ethylene glycol) acrylate) terpolymeric hydrogels

NASA Astrophysics Data System (ADS)

Micic, M.; Stamenic, D.; Suljovrujic, E.

2012-09-01

Since it is presumed that by incorporation of pH-responsive (IA) and temperature-responsive (OEGA) co-monomers, it is possible to prepare P(HEMA/IA/OEGA) hydrogels with dual (pH and thermo) responsiveness, the main purpose of our study is to investigate the influence of different mole fractions of IA and especially OEGA on the diversity of the swelling properties of the obtained hydrogels. For that reason, a series of terpolymeric hydrogels with different mole ratios of 2-hydroxyethyl methacrylate (HEMA), itaconic acid (IA) and oligo(ethylene glycol) acrylates (OEGA) was synthesised by gamma radiation. The obtained hydrogels were characterised by swelling studies in the wide pH (2.2-9.0) and temperature range (20-70 °C), confirming dual (pH and thermo) responsiveness and a large variation in the swelling capability. It was observed that the equilibrium swelling of P(HEMA/IA/OEGA) hydrogels, for a constant amount of IA, increased progressively with an increase in OEGA share. On the other hand, the dissociation of carboxyl groups from IA occurs at pH>4; therefore, small mole fractions of IA render good pH sensitivity and a large increase in the swelling capacity of these hydrogels at higher pH values. Additional characterisation of structure and properties was conducted by Fourier transform infrared (FTIR) spectroscopy, scanning electron microscopy (SEM) and mechanical measurements, confirming that the inherent properties of P(HEMA/IA/OEGA) hydrogels can be significantly tuned by variation in their composition. According to all presented, it seems that the obtained hydrogels can be a beneficial synergetic combination for controlled delivery of bioactive molecules such as drugs, peptides, proteins, etc.

Simulated hydrologic responses to climate variations and change in the Merced, Carson, and American River basins, Sierra Nevada, California, 1900-2099 *

USGS Publications Warehouse

Dettinger, M.D.; Cayan, D.R.; Meyer, M.K.; Jeton, A.

2004-01-01

Hydrologic responses of river basins in the Sierra Nevada of California to historical and future climate variations and changes are assessed by simulating daily streamflow and water-balance responses to simulated climate variations over a continuous 200-yr period. The coupled atmosphere-ocean-ice-land Parallel Climate Model provides the simulated climate histories, and existing hydrologic models of the Merced, Carson, and American Rivers are used to simulate the basin responses. The historical simulations yield stationary climate and hydrologic variations through the first part of the 20th century until about 1975 when temperatures begin to warm noticeably and when snowmelt and streamflow peaks begin to occur progressively earlier within the seasonal cycle. A future climate simulated with business-as-usual increases in greenhouse-gas and aerosol radiative forcings continues those recent trends through the 21st century with an attendant +2.5??C warming and a hastening of snowmelt and streamflow within the seasonal cycle by almost a month. The various projected trends in the business-as-usual simulations become readily visible despite realistic simulated natural climatic and hydrologic variability by about 2025. In contrast to these changes that are mostly associated with streamflow timing, long-term average totals of streamflow and other hydrologic fluxes remain similar to the historical mean in all three simulations. A control simulation in which radiative forcings are held constant at 1995 levels for the 50 years following 1995 yields climate and streamflow timing conditions much like the 1980s and 1990s throughout its duration. The availability of continuous climate-change projection outputs and careful design of initial conditions and control experiments, like those utilized here, promise to improve the quality and usability of future climate-change impact assessments.

Single-fraction Radiosurgery for Presumed Intracranial Meningiomas: Efficacy and Complications From a 22-Year Experience

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pollock, Bruce E., E-mail: pollock.bruce@mayo.edu; Department of Radiation Oncology, Mayo Clinic College of Medicine, Rochester, MN; Stafford, Scott L.

Purpose: To define the rate of tumor control and factors associated with radiation-related complications after single-fraction radiosurgery (SRS) for patients with imaging defined intracranial meningiomas. Materials and Methods: Retrospective review of 251 patients (192 women, 59 men) having SRS for imaging-defined intracranial meningiomas between 1990 and 2008. Excluded were patients with radiation-induced tumors, meningiomatosis, or neurofibromatosis. The mean patient age was 58.6 {+-} 13.4 years. The majority of tumors involved the skull base/tentorium (n = 210, 83.7%). The mean treatment volume was 7.7 {+-} 6.2 cm{sup 3}; the mean tumor margin dose was 15.8 {+-} 2.0 Gy. Follow-up (mean, 62.9more » {+-} 43.9 months) was censored at last evaluation (n = 224), death (n = 22), or tumor resection (n = 5). Results: No patient died from tumor progression or radiation-related complications. Tumor size decreased in 181 patients (72.1%) and was unchanged in 67 patients (26.7%). Three patients (1.2%) had in-field tumor progression noted at 28, 145, and 150 months, respectively. No patient had a marginal tumor progression. The 3- and 10-year local control rate was 99.4%. One patient had distant tumor progression at 105 months and underwent repeat SRS. Thirty-one patients (12.4%) had either temporary (n = 8, 3.2%) or permanent (n = 23, 9.2%) symptomatic radiation-related complications including cranial nerve deficits (n = 14), headaches (n = 5), hemiparesis (n = 5), new/worsened seizure (n = 4), cyst-formation (n = 1), hemifacial spasm (n = 1), and stroke (n = 1). The 1- and 5-year complication rates were 8.3% and 11.5%, respectively. Radiation-related complications were associated with convexity/falx tumors (HR = 2.8, 95% CI 1.3-6.1, p = 0.009) and increasing tumor volume (HR = 1.05, 95% CI 1.0-1.1, p = 0.04) on multivariate analysis. No patient developed a radiation-induced tumor. Conclusions: Single-fraction SRS at the used dose range provides a high rate of tumor control for patients with imaging defined intracranial meningiomas. However, treatment failures were noted after 10 years emphasizing the need for long-term imaging follow-up after meningioma SRS.« less

Acoustic attraction, repulsion and radiation force cancellation on a pair of rigid particles with arbitrary cross-sections in 2D: Circular cylinders example

NASA Astrophysics Data System (ADS)

Mitri, F. G.

2017-11-01

The acoustic radiation forces arising on a pair of sound impenetrable cylindrical particles of arbitrary cross-sections are derived. Plane progressive, standing or quasi-standing waves with an arbitrary incidence angle are considered. Multiple scattering effects are described using the multipole expansion formalism and the addition theorem of cylindrical wave functions. An effective incident acoustic field on a particular object is determined, and used with the scattered field to derive closed-form analytical expressions for the radiation force vector components. The mathematical expressions for the radiation force components are exact, and have been formulated in partial-wave series expansions in cylindrical coordinates involving the angle of incidence, the reflection coefficient forming the progressive or the (quasi)standing wave field, the addition theorem, and the expansion coefficients. Numerical examples illustrate the analysis for two rigid circular cross-sections immersed in a non-viscous fluid. Computations for the dimensionless radiation force functions are performed with emphasis on varying the angle of incidence, the interparticle distance, the sizes of the particles as well as the characteristics of the incident field. Depending on the interparticle distance and angle of incidence, one of the particles yields neutrality; it experiences no force and becomes unresponsive (i.e., ;invisible;) to the linear momentum transfer of the effective incident field due to multiple scattering cancellation effects. Moreover, attractive or repulsive forces between the two particles may arise depending on the interparticle distance, the angle of incidence and size parameters of the particles. This study provides a complete analytical method and computations for the axial and transverse radiation force components in multiple acoustic scattering encompassing the cases of plane progressive, standing or quasi-standing waves of arbitrary incidence by a pair of scatterers. Potential applications concern the prediction of the forces used in acoustically-engineered metamaterials with reconfigurable periodicities, cloaking devices, and liquid crystals to name a few examples.

Dietary Supplement Attenuates Radiation-Induced Osteoclastogenic and Oxidative Stress-Related Responses and Protects Adult Mice from Radiation-Induced Bone Loss

NASA Technical Reports Server (NTRS)

Globus, Ruth; Schreurs, Ann-Sofie; Tahimic, Candice; Shirazi-Fard, Yasaman; Alwood, Joshua; Shahnazari, Mohammed; Halloran, Bernard

2015-01-01

Our central hypothesis is that oxidative stress plays a key role in cell dysfunction and progressive bone loss caused by radiation exposure during spaceflight. In animal studies, excess free radical formation is associated with pathological changes in bone structure, enhanced bone resorption, reduced bone formation and decreased bone mineral density, which can lead to skeletal fragility. We previously reported that exposure to low or high-LET radiation rapidly increases expression levels of pro-osteoclastogenic and oxidative stress-related genes in bone and marrow, followed by pathological changes in skeletal structure. To screen various antioxidants for radioprotective effects on bone, 4 month old, male C57Bl6/J mice were treated with a dietary antioxidant cocktail, injectable alpha-lipoic acid, or a dried plum-enriched diet (DP). Mice were then exposed to 2Gy 137Cs total body radiation and one day later marrow cells were collected and the relevant genes analyzed for expression levels. Of the candidates tested, DP was most effective in reducing bone resorption-related gene expression. Microcomputed tomography revealed that DP also prevented the radiation-induced deterioration of skeletal microarchitecture, as indicated by percent bone volume, trabecular spacing and trabecular number. DP had similar protective effects on skeletal structure after sequential exposure to protons (0.5 Gy, 150MeV/n) and 56Fe 0.5Gy, 600 MeV/n). When cultured ex vivo under osteogenic conditions, bone marrow-derived cells from DP-fed animals exhibited increased colony numbers compared to control diet-fed animals. These findings suggest that DP exerted pro-osteogenic effects apart from previously identified anti-resorptive actions, which may contribute to radioprotection of skeletal tissue. In conclusion, a diet enriched in certain types of antioxidants and polyphenols such as DP may be useful as an intervention to protect tissues from degenerative effects of ionizing radiation.

High LET Radiation Can Enhance TGF(Beta) Induced EMT and Cross-Talk with ATM Pathways

NASA Technical Reports Server (NTRS)

Wang, Minli; Hada, Megumi; Huff, Janice; Pluth, Janice M.; Anderson, Janniffer; ONeill, Peter; Cucinotta, Francis A.

2010-01-01

The TGF(Beta) pathway has been shown to regulate or directly interact with the ATM pathway in the response to radiation in mammary epithelial cells. We investigated possible interactions between the TGF(Beta) and ATM pathways following simulated space radiation using hTERT immortalized human esophageal epithelial cells (EPC-hTERT), mink lung epithelial cells (Mv1lu), and several human fibroblast cell lines. TGF(Beta) is a key modulator of the Epithelial-Mesenchymal Transition (EMT), important in cancer progression and metastasis. The implication of EMT by radiation also has several lines of developing evidence, however is poorly understood. The identification of TGF(Beta) induced EMT can be shown in changes to morphology, related gene over expression or down regulation, which can be detected by RT-PCR, and immunostaining and western blotting. In this study, we have observed morphologic and molecular alternations consistent with EMT after Mv1lu cells were treated with TGF(Beta) High LET radiation enhanced TGF(Beta) mediated EMT with a dose as low as 0.1Gy. In order to consider the TGF(Beta) interaction with ATM we used a potent ATM inhibitor Ku55933 and investigated gene expression changes and Smad signaling kinetics. Ku559933 was observed to reverse TGF(Beta) induced EMT, while this was not observed in dual treated cells (radiation+TGF(Beta)). In EPC-hTERT cells, TGF(Beta) alone was not able to induce EMT after 3 days of application. A combined treatment with high LET, however, significantly caused the alteration of EMT markers. To study the function of p53 in the process of EMT, we knocked down P53 through RNA interference. Morphology changes associated with EMT were observed in epithelial cells with silenced p53. Our study indicates: high LET radiation can enhance TGF(Beta) induced EMT; while ATM is triggering the process of TGF(Beta)-induced EMT, p53 might be an essential repressor for EMT phenotypes.

Radiation-induced lung fibrosis in a tumor-bearing mouse model is associated with enhanced Type-2 immunity.

PubMed

Chen, Jing; Wang, Yacheng; Mei, Zijie; Zhang, Shimin; Yang, Jie; Li, Xin; Yao, Ye; Xie, Conghua

2016-03-01

Lung fibrosis may be associated with Type-2 polarized inflammation. Herein, we aim to investigate whether radiation can initiate a Type-2 immune response and contribute to the progression of pulmonary fibrosis in tumor-bearing animals. We developed a tumor-bearing mouse model with Lewis lung cancer to receive either radiation therapy alone or radiation combined with Th1 immunomodulator unmethylated cytosine-phosphorothioate-guanine containing oligodeoxynucleotide (CpG-ODN). The Type-2 immune phenotype in tumors and the histological grade of lung fibrosis were evaluated in mice sacrificed three weeks after irradiation. Mouse lung tissues were analyzed for hydroxyproline and the expression of Type-1/Type-2 key transcription factors (T-bet/GATA-3). The concentration of Type-1/Type-2 cytokines in serum was measured by cytometric bead array. Lung fibrosis was observed to be more serious in tumor-bearing mice than in normal mice post-irradiation. The fibrosis score in irradiated tumor-bearing mice on Day 21 was 4.33 ± 0.82, which was higher than that of normal mice (2.00 ± 0.63; P < 0.05). Hydroxyproline and GATA-3 expression were increased in the lung tissues of tumor-bearing mice following irradiation. CpG-ODN attenuated fibrosis by markedly decreasing GATA-3 expression. Serum IL-13 and IL-5 were elevated, whereas INF-γ and IL-12 expression were decreased in irradiated tumor-bearing mice. These changes were reversed after CpG-ODN treatment. Thus, Type-2 immunity in tumors appeared to affect the outcome of radiation damage and might be of interest for future studies on developing approaches in which Type-1-related immunotherapy and radiotherapy are used in combination. © The Author 2015. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.

High dose radiation with chemotherapy followed by salvage esophagectomy among patients with locally advanced esophageal squamous cell carcinoma.

PubMed

Lertbutsayanukul, Chawalit; Tharavej, Chadin; Klaikeaw, Naruemon; Prayongrat, Anussara; Lowanitchai, Chutinan; Sriuranpong, Virote

2017-05-01

Locoregional failure is a major problem associated with chemoradiation treatment for squamous cell esophageal carcinoma. The aim of this study was to assess the feasibility, efficacy, and toxicity of preoperative radiation (dose > 50 Gy) with platinum-based chemotherapy followed by esophagectomy in locally advanced squamous cell carcinoma. Data of patients with cT2-cT4 or node positive squamous cell carcinoma of the esophagus who received trimodality treatment between February 2006 and June 2015 were reviewed. Forty-four patients were treated with intensity-modulated radiation therapy, volumetric-modulated arc therapy or three-dimensional radiation therapy. The median radiation dose was 60 Gy. The average volume of the lungs receiving 10 Gy was 48.1%, 20 Gy was 24.5%, and the average mean lung dose was 14 Gy. After chemoradiation, R0 resection was achieved in 31 patients (71%). Patients who received >60 Gy had a higher pathologic complete remission rate than those in the lower dose group (59.1% vs. 36.4%). R0 resection and radiation dose >60 Gy were associated with better overall survival in Cox proportional hazards regression analysis. The median follow-up duration was 22.4 months and median survival was 25.6 months. Two-year overall, progression-free survival and locoregional control rates were 55.9%, 28.6%, and 56%, respectively. The most common grade 3-4 toxicities were esophagitis (63.6%) and neutropenia (25%). Grade 3-4 postoperative morbidities included surgical wound infection (2.3%), acute renal failure (2.3%), and anastomosis stricture (2.3%). Trimodality treatment with a high preoperative radiation dose and chemotherapy yielded a good pathologic complete response rate, and long-term survival with low toxicities. © 2017 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.

The c-Abl signaling network in the radioadaptive response

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chi-Min, Yuan

2014-01-28

The radioadaptive response, or radiation hormesis, i.e. a low dose of radiation can protect cells and organisms from the effects of a subsequent higher dose, is a widely recognized phenomenon. Mechanisms underlying such radiation hormesis, however, remain largely unclear. Preliminary studies indicate an important role of c-Abl signaling in mediating the radioadaptive response. We propose to investigate how c-Abl regulates the crosstalk between p53 and NFκB in response to low doses irradiation. We found in our recent study that low dose IR induces a reciprocal p53 suppression and NFκB activation, which induces HIF-a and subsequently a metabolic reprogramming resulting inmore » a transition from oxidative phosphorylation to glycolysis. Of importance is that this glycolytic switch is essential for the radioadaptive response. This low-dose radiationinduced HIF1α activation was in sharp contrast with the high-dose IR-induced p53 activation and HIF1α inhibition. HIF1α and p53 seem to play distinct roles in mediating the radiation dose-dependent metabolic response. The induction of HIF1α-mediated glycolysis is restricted to a low dose range of radiation, which may have important implications in assessing the level of radiation exposure and its potential health risk. Our results support a dose-dependent metabolic response to IR. When IR doses are below the threshold of causing detectable DNA damage (<0.2Gy) and thus little p53 activation, HIF1α is induced resulting in induction of glycolysis and increased radiation resistance. When the radiation dose reaches levels eliciting DNA damage, p53 is activated and diminishes the activity of HIF1α and glycolysis, leading to the induction of cell death. Our work challenges the LNT model of radiation exposure risk and provides a metabolic mechanism of radioadaptive response. The study supports a need for determining the p53 and HIF1α activity as a potential reliable biological readout of radiation exposure in humans. The exquisite sensitivity of cellular metabolism to low doses of radiation could also serve as a valuable biomarker for estimating the health effects of low-level radiation exposure.« less

Clinical significance of post-surgical residual tumor burden and radiation therapy in treating patients with lacrimal adenoid cystic carcinoma.

PubMed

Noh, Jae Myoung; Lee, Eonju; Ahn, Yong Chan; Oh, Dongryul; Kim, Yoon-Duck; Woo, Kyung In; Ko, Young-Hyeh; Kim, Seokhwi

2016-09-13

Retrospective analyses were done on 19 lacrimal adenoid cystic carcinoma (ACC) patients who underwent curative treatment between 1997 and 2013. Nine patients (47.4%) had T1-2 disease and ten (52.6%) had T4 disease. Surgical procedures were globe-preserving tumor resection in 11 patients (57.9%), incisional biopsy in five (26.3%), and orbital exenteration was undertaken in three (15.8%). Residual tumor burdens were R0/1 in 12 patients (63.2%) and R2 in seven (36.8%). Radiation therapy (RT) was recommended to all patients, and 16 (84.2%) completed RT (median 60 Gy). After median follow-up of 57.5 months, seven (36.8%) developed progression and three (15.8%) died. Local recurrence occurred in four patients (21.1%), distant metastasis in one (5.3%), and combined local recurrence and distant metastasis in two (10.5%). Progression-free survival and overall survival rates at 5-years were 64.5% and 82.6%, respectively. Among 12 patients following R0/1 resection, two (16.7%) developed local recurrence and none died, while among seven following R2 resection, five (71.4%) developed progression and three (42.9%) died. RT following R0/R1 resection could reduce progression. Globe-preserving surgery and RT seemed optimal strategy for T1-2 disease. Careful attention should to be paid to minimize residual tumor burden at surgery and effort for safe radiation dose escalation would be desired.

Opposite Roles for p38MAPK-Driven Responses and Reactive Oxygen Species in the Persistence and Resolution of Radiation-Induced Genomic Instability

PubMed Central

Werner, Erica; Wang, Huichen; Doetsch, Paul W.

2014-01-01

We report the functional and temporal relationship between cellular phenotypes such as oxidative stress, p38MAPK-dependent responses and genomic instability persisting in the progeny of cells exposed to sparsely ionizing low-Linear Energy Transfer (LET) radiation such as X-rays or high-charge and high-energy (HZE) particle high-LET radiation such as 56Fe ions. We found that exposure to low and high-LET radiation increased reactive oxygen species (ROS) levels as a threshold-like response induced independently of radiation quality and dose. This response was sustained for two weeks, which is the period of time when genomic instability is evidenced by increased micronucleus formation frequency and DNA damage associated foci. Indicators for another persisting response sharing phenotypes with stress-induced senescence, including beta galactosidase induction, increased nuclear size, p38MAPK activation and IL-8 production, were induced in the absence of cell proliferation arrest during the first, but not the second week following exposure to high-LET radiation. This response was driven by a p38MAPK-dependent mechanism and was affected by radiation quality and dose. This stress response and elevation of ROS affected genomic instability by distinct pathways. Through interference with p38MAPK activity, we show that radiation-induced stress phenotypes promote genomic instability. In contrast, exposure to physiologically relevant doses of hydrogen peroxide or increasing endogenous ROS levels with a catalase inhibitor reduced the level of genomic instability. Our results implicate persistently elevated ROS following exposure to radiation as a factor contributing to genome stabilization. PMID:25271419

Influence of ionizing radiation on the immune response

DOE Office of Scientific and Technical Information (OSTI.GOV)

Brocadeszaalberg, O.

1974-01-01

The effects of ionizing radiation on the immune response are reviewed. Following an introduction on the function of the immune apparatus, the effect of radiation in the different cell types of the immune system is described. The possible consequences of these effects on the prognosis of radiation victims are discussed. (GRA)

ULTRAVIOLET PROTECTIVE PIGMENTS AND DNA DIMER INDUCTION AS RESPONSES TO ULTRAVIOLET RADIATION

EPA Science Inventory

Life on Earth has evolved adaptations to many environmental stresses over the epochs. One consistent stress has been exposure to ultraviolet (UV) radiation. The most basic effect of UV radiation on biological systems is damage to DNA. In response to UV radiation organisms have ad...

Angiogenic Blockade and Radiotherapy in Hepatocellular Carcinoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chi, Kwan-Hwa, E-mail: M006565@ms.skh.org.t; Institute of Radiation Science and School of Medicine, National Yang-Ming University, Taipei, Taiwan; Liao, Chao-Sheng

2010-09-01

Purpose: We report our preliminary experience of combining sunitinib and helical tomotherapy in patients with advanced HCC. Methods and Materials: Records of patients with advanced hepatocellular carcinoma (HCC) treated with helical tomotherapy and sunitinib after radiation therapy (RT) from March 2007 to August 2008 were retrospectively reviewed. We report acute toxicities, radiologic response, serial {alpha}-fetoprotein (AFP) kinetics, and survival. Results: Of 23 evaluable patients, 60% had {>=}2 hepatic lesions, extrahepatic disease was present in 5 (21.7%), and all received 2 tablets (25 mg) of sunitinib at least 1 week before, during, and 2 weeks after RT. Thirteen patients continued maintenancemore » sunitinib after RT until disease progression. Hypofractionated RT with a median target dose of 52.5 Gy/15 fractions was delivered. An objective response was achieved in 74% of patients. The 1-year survival rate was 70%, with median survival of 16 months. Multivariate analysis showed that maintenance sunitinib was the most significant factor for survival. The time to progression was 10 months in the maintenance group compared with 4 months in the control group. Eighteen out of 21 patients with elevated AFP (85.7%) had {>=}50% decline of AFP within 2 months after RT. There were three episodes of upper gastrointestinal bleeding and one episode of pancreatitis; 10 patients had {>=}Grade 2 elevation of liver enzymes, and 15 had {>=}Grade 2 thrombocytopenia. Conclusions: These preliminary results suggest that sunitinib and helical tomotherapy yield high Response Evaluation Criteria in Solid Tumors (RECIST) and AFP response rates in advanced HCC with an acceptable safety profile. Maintenance sunitinib after RT potentially prolongs survival. A randomized trial is warranted.« less

Alectinib: a review of its use in advanced ALK-rearranged non-small cell lung cancer.

PubMed

McKeage, Kate

2015-01-01

Alectinib (Alecensa(®)) is a second-generation, orally active, potent and highly selective inhibitor of anaplastic lymphoma kinase (ALK). Alectinib is approved for the treatment of ALK fusion-gene positive, unresectable, advanced or recurrent non-small cell lung cancer (NSCLC) in Japan, where it has been given orphan drug designation. Approval was based on a phase 1-2 study in ALK inhibitor-naive patients with ALK-rearranged advanced NSCLC who received twice-daily alectinib 300 mg. In the phase 2 portion, 93.5 % of patients achieved an objective response. Treatment response was rapid, with a partial response achieved in two-thirds of patients within 3 weeks (cycle 1). Patient follow-up is ongoing, and after approximately 2 years, 19.6 % of patients had achieved a complete response, and the 2-year progression-free survival rate is 76 %. During treatment with alectinib (median follow-up approximately 8 months), there was no progression of CNS lesions among patients with known CNS metastases at baseline (although prior radiation therapy may have confounded results). In preclinical models, alectinib was active against most ALK fusion-gene mutations related to crizotinib resistance, and preliminary results from clinical trials indicate efficacy in crizotinib-refractory NSCLC. Alectinib was generally well tolerated in clinical trials, and there were no treatment-related grade 4 adverse events or deaths. The most common grade 3 treatment-related adverse events were decreased neutrophil counts and increased creatinine phosphokinase. While more data are needed to confirm the efficacy of alectinib and to evaluate its activity in crizotinib-resistant disease, the drug provides a very promising option for the treatment of ALK-rearranged advanced NSCLC.

A phase II evaluation of ixabepilone in the treatment of recurrent/persistent carcinosarcoma of the uterus, an NRG Oncology/Gynecologic Oncology Group study.

PubMed

McCourt, Carolyn K; Deng, Wei; Dizon, Don S; Lankes, Heather A; Birrer, Michael J; Lomme, Michele M; Powell, Matthew A; Kendrick, James E; Saltzman, Joel N; Warshal, David; Tenney, Meaghan E; Kushner, David M; Aghajanian, Carol

2017-01-01

The primary objectives were to determine the objective response rate (ORR) and safety profile of ixabepilone in women with recurrent or persistent uterine carcinosarcoma (UCS). Secondary objectives included progression-free survival (PFS) and overall survival (OS). Exploratory translational objectives included characterization of class III beta tubulin expression and its association with response, PFS, and OS. Patients had measurable disease; up to two prior chemotherapeutic regimens were allowed, but must have included a taxane. Women received ixabepilone 40mg/m 2 as a 3hour IV infusion on day 1 of a 21daycycle. Treatment was continued until disease progression or unacceptable toxicity occurred. Forty-two women were enrolled, with 34 eligible and evaluable. Median age was 68years. ECOG performance status was 0 in 56% of women, 38% had received radiation, and 15% had received 2 lines of chemotherapy. Overall ORR was 11.8% (4/34, 90% CI 4.2-25.1%); all were partial responses. Stable disease for at least 8weeks was achieved in 8 patients (23.5%). Median PFS and OS were 1.7mo and 7.7mo, respectively, with a median follow-up of 37mo. Six month PFS was 20.6%. Major grade≥3 toxicities were neutropenia (47%), fatigue (15%), dehydration (15%), hypertension (15%), and hyponatremia (15%); grade 2 peripheral neuropathy was reported in 18%. In this small sample size, class III beta tubulin expression in the primary tumor was not associated with the response to ixabepilone, PFS, or OS. In this cohort of women, single agent ixabepilone showed modest but insufficient clinical activity. Copyright © 2016. Published by Elsevier Inc.

A phase II evaluation of ixabepilone in the treatment of recurrent/persistent carcinosarcom a of the uterus, an NRG Oncology/Gynecologic Oncology Group study☆

PubMed Central

McCourt, Carolyn K.; Deng, Wei; Dizon, Don S.; Lankes, Heather A.; Birrer, Michael J.; Lomme, Michele M.; Powell, Matthew A.; Kendrick, James E.; Saltzman, Joel N.; Warshal, David; Tenney, Meaghan E.; Kushner, David M.; Aghajanian, Carol

2017-01-01

Background The primary objectives were to determine the objective response rate (ORR) and safety profile of ixabepilone in women with recurrent or persistent uterine carcinosarcoma (UCS). Secondary objectives included progression-free survival (PFS) and overall survival (OS). Exploratory translational objectives included characterization of class III beta tubulin expression and its association with response, PFS, and OS. Methods Patients had measurable disease; up to two prior chemotherapeutic regimens were allowed, but must have included a taxane. Women received ixabepilone 40 mg/m2 as a 3 hour IV infusion on day 1 of a 21 day cycle. Treatment was continued until disease progression or unacceptable toxicity occurred. Results Forty-two women were enrolled, with 34 eligible and evaluable. Median age was 68 years. ECOGperformance status was 0 in 56% of women, 38% had received radiation, and 15% had received 2 lines of chemotherapy. Overall ORR was 11.8%(4/34, 90%CI 4.2–25.1%); all were partial responses. Stable disease for at least 8 weeks was achieved in 8 patients (23.5%). Median PFS and OS were 1.7 mo and 7.7 mo, respectively, with a median follow-up of 37 mo. Six month PFS was 20.6%. Major grade ≥ 3 toxicities were neutropenia (47%), fatigue (15%), dehydration (15%), hypertension (15%), and hyponatremia (15%); grade 2 peripheral neuropathy was reported in 18%. In this small sample size, class III beta tubulin expression in the primary tumor was not associated with the response to ixabepilone, PFS, or OS. Conclusion In this cohort of women, single agent ixabepilone showed modest but insufficient clinical activity. PMID:28029447

Modeling microenvironmental regulation of glioblastoma stem cells: a biomaterials perspective

NASA Astrophysics Data System (ADS)

Heffernan, John M.; Sirianni, Rachael W.

2018-02-01

Following diagnosis of a glioblastoma (GBM) brain tumor, surgical resection, chemotherapy and radiation together yield a median patient survival of only 15 months. Importantly, standard treatments fail to address the dynamic regulation of the brain tumor microenvironment that actively supports tumor progression and treatment resistance. It is becoming increasingly recognized that specialized niches within the tumor microenvironment maintain a population of highly malignant glioblastoma stem-like cells (GSCs). GSCs are resistant to traditional chemotherapy and radiation therapy, suggesting that they may be responsible for the near universal rates of tumor recurrence and associated morbidity in GBM. Thus, disrupting microenvironmental support for GSCs could be critical to developing more effective GBM therapies. Three-dimensional (3D) culture models of the tumor microenvironment are powerful tools for identifying key biochemical and biophysical inputs that impact malignant behaviors. Such systems have been used effectively to identify conditions that regulate GSC proliferation, invasion, stem-specific phenotypes, and treatment resistance. Considering the significant role that GSC microenvironments play in regulating this tumorigenic sub-population, these models may be essential for uncovering mechanisms that limit GSCs malignancy.

Mouse brain responses to charged particle radiation

NASA Astrophysics Data System (ADS)

Nelson, Gregory; Nelson, Gregory; Chang, Polly; Favre, Cecile; Fike, John; Mao, Xiao-Wen; Obenaus, Andre; Pecaut, Michael; Vlkolinsky, Roman; Song, Sheng-Kwei; Spigelman, Igor; Stampanoni, Marco

CHANGES IN DISEASE LATENCY AND HOMEOSTASIS: 1) APP23 transgenic mice exhibit many of the pathological features of Alzheimer's Disease, and the disease progression is continuous over several months. Electrophysiological measurements have shown that disease-related decreases in synaptic efficacy occur earlier in irradiated APP23 animals. 2) Using vascular polymer cast technology combined with micro-tomographic imaging, microvasculature changes following irradiation have been detected and are consistent with loss of vessels and an increased spacing between them. The time course of vessel changes to control and irradiated animals is being constructed. 3) In order to assess the ability of the brain to respond to external environmental shocks and restore orderly normal function (homeostasis), we apply a controlled septic shock by treating animals with lipopolysaccharide (LPS). We find that in irradiated animals, the patterns of electrophysiological changes associated with reactions to lipopolysaccharide (LPS) are complex and unlike those of either LPS or irradiation alone. They further suggest that the brain continues to remodel for up to 6 months following radiation. This is consistent with the idea that irradiation may potentiate the risks from late secondary insults.

Environmental Measurements Laboratory 1994 annual report

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chieco, N.A.; Krey, P.W.; Beck, H.L.

1995-08-01

This report summarizes the activities of the Environmental Measurements Laboratory (EML) for the calendar year 1994 and it serves as an annual report to the Director of the Office of Energy Research (ER), the Associate Director and staff of the Office of Health and Environmental Research (OHER), the manager and staff of the Chicago Field Office, and the authors colleagues. Emphasized are the progress and accomplishments of the year, rather than future plans or expectations. The technical summaries are grouped according to the following seven general program areas: environmental radiation and radioactivity; radiation transport and dosimetry; environmental radon, thoron, andmore » related aerosols; atmospheric and surface pollutant studies related to global climate change; atmospheric chemistry; metrology, consultation, and emergency response; environmental management. EML`s mission is to address important scientific questions concerning human health and environmental impacts. Through its multidisciplinary staff, EML conducts experimental and theoretical research on radioactive and other energy-related pollutants, and provides DOE and other federal agencies with the in-house capability to respond effectively and efficiently with regard to quality assurance activities, environmental issues and related national security issues.« less

AMF 1 Site Science

DOE Office of Scientific and Technical Information (OSTI.GOV)

Miller, Mark Alan

This report documents progress on DOE Grant# DE-FG02-08ER64531 funded by the Department of Energy’s Atmospheric Systems Research (ASR) program covering the period between its inception in 2008 and its conclusion in 2014. The Atmospheric Radiation Measurement (ARM) Program’s Mobile Facility #1 (AMF#1) is a collection of state-of-the art atmospheric sensing systems including remote and in situ instrumentation designed to characterize the atmospheric column above and in the immediate vicinity of the deployment location. The grant discussed in this report funded the activities of the AMF#1 Site Scientist Team. Broad responsibilities of this team included examining new deployment sites and recommendingmore » instrument deployment configurations; data quality control during the early stages of deployments and for certain instruments through the course of the deployment; scientific outreach in the host country or location (particularly international deployments); scientific research oriented toward basic questions about cloud physics and radiation transfer in the deployment region; and training of Ph.D. students to conduct future research relevant to the Atmospheric Systems Research (ASR) program.« less

Low dose radiation adaptive protection to control neurodegenerative diseases.

PubMed

Doss, Mohan

2014-05-01

Concerns have been expressed recently regarding the observed increased DNA damage from activities such as thinking and exercise. Such concerns have arisen from an incomplete accounting of the full effects of the increased oxidative damage. When the effects of the induced adaptive protective responses such as increased antioxidants and DNA repair enzymes are taken into consideration, there would be less endogenous DNA damage during the subsequent period of enhanced defenses, resulting in improved health from the thinking and exercise activities. Low dose radiation (LDR), which causes oxidative stress and increased DNA damage, upregulates adaptive protection systems that may decrease diseases in an analogous manner. Though there are ongoing debates regarding LDR's carcinogenicity, with two recent advisory committee reports coming to opposite conclusions, data published since the time of the reports have overwhelmingly ruled out its carcinogenicity, paving the way for consideration of its potential use for disease reduction. LDR adaptive protection is a promising approach to control neurodegenerative diseases, for which there are no methods of prevention or cure. Preparation of a compelling ethics case would pave the way for LDR clinical studies and progress in dealing with neurodegenerative diseases.

Tumor-Endothelial Cell Three-dimensional Spheroids: New Aspects to Enhance Radiation and Drug Therapeutics12

PubMed Central

Upreti, Meenakshi; Jamshidi-Parsian, Azemat; Koonce, Nathan A; Webber, Jessica S; Sharma, Sunil K; Asea, Alexzander AA; Mader, Mathew J; Griffin, Robert J

2011-01-01

Classic cancer research for several decades has focused on understanding the biology of tumor cells in vitro. However, extending these findings to in vivo settings has been impeded owing to limited insights on the impact of microenvironment on tumor cells. We hypothesized that tumor cell biology and treatment response would be more informative when done in the presence of stromal components, like endothelial cells, which exist in the tumor microenvironment. To that end, we have developed a system to grow three-dimensional cultures of GFP-4T1 mouse mammary tumor and 2H11 murine endothelial cells in hanging drops of medium in vitro. The presence of 2H11 endothelial cells in these three-dimensional cocultures was found to sensitize 4T1-GFP tumor cells to chemotherapy (Taxol) and, at the same time, protect cells from ionizing radiation. These spheroidal cultures can also be implanted into the dorsal skinfold window chamber of mice for fluorescence imaging of vascularization and disease progression/treatment response. We observed rapid neovascularization of the tumor-endothelial spheroids in comparison to tumor spheroids grown in nude mice. Molecular analysis revealed pronounced up-regulation of several proangiogenic factors in the tumor tissue derived from the tumor-endothelial spheroids compared with tumor-only spheroids. Furthermore, the rate of tumor growth from tumor-endothelial spheroids in mice was faster than the tumor cell-only spheroids, resulting in greater metastasis to the lung. This three-dimensional coculture model presents an improved way to investigate more pertinent aspects of the therapeutic potential for radiation and/or chemotherapy alone and in combination with antiangiogenic agents. PMID:22191001

Tumor-Endothelial Cell Three-dimensional Spheroids: New Aspects to Enhance Radiation and Drug Therapeutics.

PubMed

Upreti, Meenakshi; Jamshidi-Parsian, Azemat; Koonce, Nathan A; Webber, Jessica S; Sharma, Sunil K; Asea, Alexzander Aa; Mader, Mathew J; Griffin, Robert J

2011-12-01

Classic cancer research for several decades has focused on understanding the biology of tumor cells in vitro. However, extending these findings to in vivo settings has been impeded owing to limited insights on the impact of microenvironment on tumor cells. We hypothesized that tumor cell biology and treatment response would be more informative when done in the presence of stromal components, like endothelial cells, which exist in the tumor microenvironment. To that end, we have developed a system to grow three-dimensional cultures of GFP-4T1 mouse mammary tumor and 2H11 murine endothelial cells in hanging drops of medium in vitro. The presence of 2H11 endothelial cells in these three-dimensional cocultures was found to sensitize 4T1-GFP tumor cells to chemotherapy (Taxol) and, at the same time, protect cells from ionizing radiation. These spheroidal cultures can also be implanted into the dorsal skinfold window chamber of mice for fluorescence imaging of vascularization and disease progression/treatment response. We observed rapid neovascularization of the tumor-endothelial spheroids in comparison to tumor spheroids grown in nude mice. Molecular analysis revealed pronounced up-regulation of several proangiogenic factors in the tumor tissue derived from the tumor-endothelial spheroids compared with tumor-only spheroids. Furthermore, the rate of tumor growth from tumor-endothelial spheroids in mice was faster than the tumor cell-only spheroids, resulting in greater metastasis to the lung. This three-dimensional coculture model presents an improved way to investigate more pertinent aspects of the therapeutic potential for radiation and/or chemotherapy alone and in combination with antiangiogenic agents.

Studying the physical basis of global warming: thermal effects of the interaction between radiation and matter and greenhouse effect

NASA Astrophysics Data System (ADS)

Besson, Ugo; De Ambrosis, Anna; Mascheretti, Paolo

2010-03-01

We present a teaching module dealing with the thermal effects of interaction between radiation and matter, the infrared emission of bodies and the greenhouse effect devoted to university level and teacher education. The module stresses the dependence of the optical properties of materials (transparency, absorptivity and emissivity) on radiation frequency, as a result of interaction between matter and radiation. Multiple experiences are suggested to favour a progressive construction of knowledge on the physical aspects necessary to understand the greenhouse effect and global warming. Some results obtained with university students are briefly reported.

10 CFR 35.2024 - Records of authority and responsibilities for radiation protection programs.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 10 Energy 1 2014-01-01 2014-01-01 false Records of authority and responsibilities for radiation protection programs. 35.2024 Section 35.2024 Energy NUCLEAR REGULATORY COMMISSION MEDICAL USE OF BYPRODUCT MATERIAL Records § 35.2024 Records of authority and responsibilities for radiation protection programs. (a...

10 CFR 35.2024 - Records of authority and responsibilities for radiation protection programs.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 10 Energy 1 2013-01-01 2013-01-01 false Records of authority and responsibilities for radiation protection programs. 35.2024 Section 35.2024 Energy NUCLEAR REGULATORY COMMISSION MEDICAL USE OF BYPRODUCT MATERIAL Records § 35.2024 Records of authority and responsibilities for radiation protection programs. (a...

10 CFR 35.2024 - Records of authority and responsibilities for radiation protection programs.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 10 Energy 1 2010-01-01 2010-01-01 false Records of authority and responsibilities for radiation protection programs. 35.2024 Section 35.2024 Energy NUCLEAR REGULATORY COMMISSION MEDICAL USE OF BYPRODUCT MATERIAL Records § 35.2024 Records of authority and responsibilities for radiation protection programs. (a...

10 CFR 35.2024 - Records of authority and responsibilities for radiation protection programs.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 10 Energy 1 2011-01-01 2011-01-01 false Records of authority and responsibilities for radiation protection programs. 35.2024 Section 35.2024 Energy NUCLEAR REGULATORY COMMISSION MEDICAL USE OF BYPRODUCT MATERIAL Records § 35.2024 Records of authority and responsibilities for radiation protection programs. (a...

10 CFR 35.2024 - Records of authority and responsibilities for radiation protection programs.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 10 Energy 1 2012-01-01 2012-01-01 false Records of authority and responsibilities for radiation protection programs. 35.2024 Section 35.2024 Energy NUCLEAR REGULATORY COMMISSION MEDICAL USE OF BYPRODUCT MATERIAL Records § 35.2024 Records of authority and responsibilities for radiation protection programs. (a...

A Prospective Study of Proton Beam Reirradiation for Esophageal Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fernandes, Annemarie, E-mail: Annemarie.fernandes@gmail.com; Berman, Abigail T.; Mick, Rosemarie

Purpose: Reirradiation to the esophagus carries a significant risk of complications. Proton therapy may offer an advantage in the reirradiation setting due to the lack of exit dose and potential sparing of previously radiated normal tissues. Methods and Materials: Between June 2010 and February 2014, 14 patients with a history of thoracic radiation and newly diagnosed or locally recurrent esophageal cancer began proton beam reirradiation on a prospective trial. Primary endpoints were feasibility and acute toxicity. Toxicity was graded according Common Toxicity Criteria version 4.0. Results: The median follow-up was 10 months (2-25 months) from the start of reirradiation. Eleven patients receivedmore » concurrent chemotherapy. The median interval between radiation courses was 32 months (10-307 months). The median reirradiation prescription dose was 54.0 Gy (relative biological effectiveness [RBE]) (50.4-61.2 Gy[RBE]), and the median cumulative prescription dose was 109.8 Gy (76-129.4 Gy). Of the 10 patients who presented with symptomatic disease, 4 patients had complete resolution of symptoms, and 4 had diminished or stable symptoms. Two patients had progressive symptoms. The median time to symptom recurrence was 10 months. Maximum acute nonhematologic toxicity attributable to radiation was grade 2 (64%, N=9), 3 (29%, N=4), 4 (0%), and 5 (7%, N=1). The acute grade 5 toxicity was an esophagopleural fistula more likely related to tumor progression than radiation. Grade 3 nonhematologic acute toxicities included dysphagia, dehydration, and pneumonia. There was 1 late grade 5 esophageal ulcer more likely related to tumor progression than radiation. There were 4 late grade 3 toxicities: heart failure, esophageal stenosis requiring dilation, esophageal ulceration from tumor, and percutaneous endoscopic gastrostomy tube dependence. The median time to local failure was 10 months, and the median overall survival was 14 months. Conclusions: Our data demonstrate that proton reirradiation is feasible, with an encouraging symptom control rate, modest radiation-related toxicity, and favorable survival in this high-risk population.« less

Intake of high-fat diet stimulates the risk of ultraviolet radiation-induced skin tumors and malignant progression of papillomas to carcinoma in SKH-1 hairless mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Vaid, Mudit; Singh, Tripti; Prasad, Ram

Previously, we showed that administration of a high-fat diet (HF-diet) to C57BL/6 mice exacerbates their response to short-term UVB radiation-induced inflammation in the skin. To explore the effects of an HF-diet on UVB-induced tumorigenesis, we have used the SKH-1 hairless mouse model in which the mice are exposed to UVB radiation (180 mJ/cm{sup 2}) three times a week for 24 weeks. The development of UVB-induced skin tumors was rapid and the tumor multiplicity and tumor size were significantly higher (P < 0.01–0.005) in the mice fed an HF-diet than the mice fed a control-diet (C-diet). Moreover, the malignant progression ofmore » UVB-induced papillomas to carcinomas was higher in HF-diet-fed mice. On analysis of tumors and tumor-uninvolved skin samples from the tumor-bearing mice, we found that administration of an HF-diet significantly enhanced the levels of UVB-induced expression of cyclooxygenase-2 (COX-2), prostaglandin E{sub 2} (P < 0.01), and PGE{sub 2} receptors, and activation of NF-κB in the UVB-exposed skin as well as in tumors. In addition the HF-diet enhanced the expression of proinflammatory cytokines, including tumor necrosis factor-α (P < 0.01), interleukin (IL)-1β (P < 0.01) and IL-6 (P < 0.05) in the UVB-exposed skin as well as in tumors. Western blot analysis revealed that HF-diet enhanced the levels of epidermal cell proliferation, phosphatidylinositol 3-kinase and phosphorylation of Akt at Ser{sup 473} in UVB-exposed skin and skin tumors. Collectively, these data demonstrate that the regular consumption of an HF-diet increases the risk of photocarcinogenesis in mice and that this is associated with enhanced expression of inflammatory mediators in the UVB-exposed skin and tumors. - Highlights: • Consumption of high-fat diet increases UVB-induced skin tumor development in mice. • Intake of high-fat diet stimulates progression of UV-induced papilloma to carcinoma. • Intake of high-fat diet enhances inflammation in UV-exposed skin • Regular consumption of low-fat diet may inhibit the risk of photocarcinogenesis.« less

Can anti-vascular endothelial growth factor antibody reverse radiation necrosis? A preclinical investigation.

PubMed

Duan, Chong; Perez-Torres, Carlos J; Yuan, Liya; Engelbach, John A; Beeman, Scott C; Tsien, Christina I; Rich, Keith M; Schmidt, Robert E; Ackerman, Joseph J H; Garbow, Joel R

2017-05-01

Anti-vascular endothelial growth factor (anti-VEGF) antibodies are a promising new treatment for late time-to-onset radiation-induced necrosis (RN). We sought to evaluate and validate the response to anti-VEGF antibody in a mouse model of RN. Mice were irradiated with the Leksell Gamma Knife Perfexion™ and then treated with anti-VEGF antibody, beginning at post-irradiation (PIR) week 8. RN progression was monitored via anatomic and diffusion MRI from weeks 4-12 PIR. Standard histology, using haematoxylin and eosin (H&E), and immunohistochemistry staining were used to validate the response to treatment. After treatment, both post-contrast T1-weighted and T2-weighted image-derived lesion volumes decreased (P < 0.001), while the lesion volumes for the control group increased. The abnormally high apparent diffusion coefficient (ADC) for RN also returned to the ADC range for normal brain following treatment (P < 0.001). However, typical RN pathology was still present histologically. Large areas of focal calcification were observed in ~50% of treated mouse brains. Additionally, VEGF and hypoxia-inducible factor 1-alpha (HIF-1α) were continually upregulated in both the anti-VEGF and control groups. Despite improvements observed radiographically following anti-VEGF treatment, lesions were not completely resolved histologically. The subsequent calcification and the continued upregulation of VEGF and HIF-1α merit further preclinical/clinical investigation.

Nucks1 synergizes with Trp53 to promote radiation lymphomagenesis in mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yue, Yangbo; Leung, Stanley G.; Liu, Yueyong

NUCKS1 is a 27 kD vertebrate-specific protein, with a role in the DNA damage response. Here, we show that after 4 Gy total-body X-irradiation, Trp53+/- Nucks1+/- mice more rapidly developed tumors, particularly thymic lymphoma (TL), than Trp53+/- mice. TLs in both cohorts showed loss of heterozygosity (LOH) of the Trp53+ allele in essentially all cases. In contrast, LOH of the Nucks1+ allele was rare. Nucks1 expression correlated well with Nucks1 gene dosage in normal thymi, but was increased in the majority of TLs from Trp53+/- Nucks1+/- mice, suggesting that elevated Nucks1 message may be associated with progression towards malignancy inmore » vivo. Trp53+/- Nucks1+/- mice frequently succumbed to CD4- CD8- TLs harboring translocations involving Igh but not Tcra/d, indicating TLs in Trp53+/- Nucks1+/- mice mostly originated prior to the double positive stage and at earlier lineage than TLs in Trp53+/- mice. Monoclonal rearrangements at Tcrb were more prevalent in TLs from Trp53+/- Nucks1+/- mice, as was infiltration of primary TL cells to distant organs (liver, kidney and spleen). We propose that, in the context of Trp53 deficiency, wild type levels of Nucks1 are required to suppress radiation-induced TL, likely through the role of the NUCKS1 protein in the DNA damage response.« less

Can anti-Vascular Endothelial Growth Factor Antibody Reverse Radiation Necrosis? A Preclinical Investigation

PubMed Central

Duan, Chong; Perez-Torres, Carlos J; Yuan, Liya; Engelbach, John A; Beeman, Scott C; Tsien, Christina I; Rich, Keith M; Schmidt, Robert E; Ackerman, Joseph JH; Garbow, Joel R

2017-01-01

Anti-vascular endothelial growth factor (anti-VEGF) antibodies are a promising new treatment for late time-to-onset radiation-induced necrosis (RN). We sought to evaluate and validate the response to anti-VEGF antibody in a mouse model of RN. Mice were irradiated with the Leksell Gamma Knife PerfexionTM and then treated with anti-VEGF antibody, beginning at post-irradiation (PIR) week 8. RN progression was monitored via anatomic and diffusion MRI from weeks 4 to 12 PIR. Standard histology, using haematoxylin and eosin (H&E), and immunohistochemistry staining were used to validate the response to treatment. After treatment, both post-contrast T1-weighted and T2-weighted image-derived lesion volumes decreased (P<0.001), while the lesion volumes for the control group increased. The abnormally high apparent diffusion coefficient (ADC) for RN also returned to the ADC range for normal brain following treatment (P<0.001). However, typical RN pathology was still present histologically. Large areas of focal calcification were observed in ~50% of treated mouse brains. Additionally, VEGF and hypoxia-inducible factor 1-alpha (HIF-1α) were continually upregulated in both the anti-VEGF and control groups. Despite improvements observed radiographically following anti-VEGF treatment, lesions were not completely resolved histologically. The subsequent calcification and the continued upregulation of VEGF and HIF-1α merit further preclinical/clinical investigation. PMID:28425047

Nucks1 synergizes with Trp53 to promote radiation lymphomagenesis in mice

DOE PAGES

Yue, Yangbo; Leung, Stanley G.; Liu, Yueyong; ...

2016-08-16

NUCKS1 is a 27 kD vertebrate-specific protein, with a role in the DNA damage response. Here, we show that after 4 Gy total-body X-irradiation, Trp53+/- Nucks1+/- mice more rapidly developed tumors, particularly thymic lymphoma (TL), than Trp53+/- mice. TLs in both cohorts showed loss of heterozygosity (LOH) of the Trp53+ allele in essentially all cases. In contrast, LOH of the Nucks1+ allele was rare. Nucks1 expression correlated well with Nucks1 gene dosage in normal thymi, but was increased in the majority of TLs from Trp53+/- Nucks1+/- mice, suggesting that elevated Nucks1 message may be associated with progression towards malignancy inmore » vivo. Trp53+/- Nucks1+/- mice frequently succumbed to CD4- CD8- TLs harboring translocations involving Igh but not Tcra/d, indicating TLs in Trp53+/- Nucks1+/- mice mostly originated prior to the double positive stage and at earlier lineage than TLs in Trp53+/- mice. Monoclonal rearrangements at Tcrb were more prevalent in TLs from Trp53+/- Nucks1+/- mice, as was infiltration of primary TL cells to distant organs (liver, kidney and spleen). We propose that, in the context of Trp53 deficiency, wild type levels of Nucks1 are required to suppress radiation-induced TL, likely through the role of the NUCKS1 protein in the DNA damage response.« less

Transcription factors and stress response gene alterations in human keratinocytes following Solar Simulated Ultra Violet Radiation.

PubMed

Marais, Thomas L Des; Kluz, Thomas; Xu, Dazhong; Zhang, Xiaoru; Gesumaria, Lisa; Matsui, Mary S; Costa, Max; Sun, Hong

2017-10-19

Ultraviolet radiation (UVR) from sunlight is the major effector for skin aging and carcinogenesis. However, genes and pathways altered by solar-simulated UVR (ssUVR), a mixture of UVA and UVB, are not well characterized. Here we report global changes in gene expression as well as associated pathways and upstream transcription factors in human keratinocytes exposed to ssUVR. Human HaCaT keratinocytes were exposed to either a single dose or 5 repetitive doses of ssUVR. Comprehensive analyses of gene expression profiles as well as functional annotation were performed at 24 hours post irradiation. Our results revealed that ssUVR modulated genes with diverse cellular functions changed in a dose-dependent manner. Gene expression in cells exposed to a single dose of ssUVR differed significantly from those that underwent repetitive exposures. While single ssUVR caused a significant inhibition in genes involved in cell cycle progression, especially G2/M checkpoint and mitotic regulation, repetitive ssUVR led to extensive changes in genes related to cell signaling and metabolism. We have also identified a panel of ssUVR target genes that exhibited persistent changes in gene expression even at 1 week after irradiation. These results revealed a complex network of transcriptional regulators and pathways that orchestrate the cellular response to ssUVR.

Effects of heavy ions on visual function and electrophysiology of rodents: the ALTEA-MICE project

NASA Technical Reports Server (NTRS)

Sannita, W. G.; Acquaviva, M.; Ball, S. L.; Belli, F.; Bisti, S.; Bidoli, V.; Carozzo, S.; Casolino, M.; Cucinotta, F.; De Pascale, M. P.;

Mid-Infrared Reflectance Imaging of Thermal-Barrier Coatings

NASA Technical Reports Server (NTRS)

Edlridge, Jeffrey I.; Martin, Richard E.

2009-01-01

An apparatus for mid-infrared reflectance imaging has been developed as means of inspecting for subsurface damage in thermal-barrier coatings (TBCs). The apparatus is designed, more specifically, for imaging the progression of buried delamination cracks in plasma-sprayed yttria-stabilized zirconia coatings on turbine-engine components. Progression of TBC delamination occurs by the formation of buried cracks that grow and then link together to produce eventual TBC spallation. The mid-infrared reflectance imaging system described here makes it possible to see delamination progression that is invisible to the unaided eye, and therefore give sufficiently advanced warning before delamination progression adversely affects engine performance and safety. The apparatus (see figure) includes a commercial mid-infrared camera that contains a liquid-nitrogen-cooled focal plane indium antimonide photodetector array, and imaging is restricted by a narrow bandpass centered at wavelength of 4 microns. This narrow wavelength range centered at 4 microns was chosen because (1) it enables avoidance of interfering absorptions by atmospheric OH and CO2 at 3 and 4.25 microns, respectively; and (2) the coating material exhibits maximum transparency in this wavelength range. Delamination contrast is produced in the midinfrared reflectance images because the introduction of cracks into the TBC creates an internal TBC/air-gap interface with a high diffuse reflectivity of 0.81, resulting in substantially higher reflectance of mid-infrared radiation in regions that contain buried delamination cracks. The camera is positioned a short distance (.12 cm) from the specimen. The mid-infrared illumination is generated by a 50-watt silicon carbide source positioned to the side of the mid-infrared camera, and the illumination is collimated and reflected onto the specimen by a 6.35-cm-diameter off-axis paraboloidal mirror. Because the collected images are of a steady-state reflected intensity (in contrast to the transient thermal response observed in infrared thermography), collection times can be lengthened to whatever extent needed to achieve desired signal-to-noise ratios. Each image is digitized, and the resulting data are processed in several steps to obtain a true mid-infrared reflectance image. The raw image includes thermal radiation emitted by the specimen in addition to the desired reflected radiation. The thermal-radiation contribution is eliminated by subtracting the image obtained with the illumination off from the image obtained with the illumination on. A flat-field correction is then made to remove the effects of non-uniformities in the illumination level and pixel-to-pixel variations in sensitivity. This correction is performed by normalizing to an image of a standard object that has a known reflectance at a wavelength of 4 microns. After correction, each pixel value is proportional to the reflectance (at a wavelength of 4-microns) at the corresponding location on the specimen. Mid-infrared reflectance imaging of specimens that were thermally cyc led for different numbers of cycles was performed and demonstrated t hat mid-infrared reflectance imaging was able to monitor the gradual delamination progression that occurs with continued thermal cycling . Reproducible values were obtained for the reflectance associated w ith an attached and fully delaminated TBC, so that intermediate refle ctance values could be interpreted to successfully predict the numbe r of thermal cycles to failure.

Unusual progression and subsequent improvement in cystic lung disease in a child with radiation-induced lung injury

PubMed Central

Wolf, Michael S.; Chadha, Ashley D.; Carroll, Clinton M.; Borinstein, Scott C.

2014-01-01

Radiation-induced lung disease is a known complication of therapeutic lung irradiation, but the features have not been well described in children. We report the clinical, radiologic and histologic features of interstitial lung disease (ILD) in a 4-year-old child who had previously received lung irradiation as part of successful treatment for metastatic Wilms tumor. Her radiologic abnormalities and clinical symptoms developed in an indolent manner. Clinical improvement gradually occurred with corticosteroid therapy. However, the observed radiologic progression from interstitial and reticulonodular opacities to diffuse cystic lung disease, with subsequent improvement, is striking and has not been previously described in children. PMID:25434733

Factors modifying the response of large animals to low-intensity radiation exposure

NASA Technical Reports Server (NTRS)

Page, N. P.; Still, E. T.

1972-01-01

In assessing the biological response to space radiation, two of the most important modifying factors are dose protraction and dose distribution to the body. Studies are reported in which sheep and swine were used to compare the hematology and lethality response resulting from radiation exposure encountered in a variety of forms, including acute (high dose-rate), chronic (low dose-rate), combinations of acute and chronic, and whether received as a continuous or as fractionated exposure. While sheep and swine are basically similar in response to acute radiation, their sensitivity to chronic irradiation is markedly different. Sheep remain relatively sensitive as the radiation exposure is protracted while swine are more resistant and capable of surviving extremely large doses of chronic irradiation. This response to chronic irradiation correlated well with changes in radiosensitivity and recovery following an acute, sublethal exposure.

Metal oxide composite dosimeter method and material

DOEpatents

Miller, Steven D.

1998-01-01

The present invention is a method of measuring a radiation dose wherein a radiation responsive material consisting essentially of metal oxide is first exposed to ionizing radiation. The metal oxide is then stimulating with light thereby causing the radiation responsive material to photoluminesce. Photons emitted from the metal oxide as a result of photoluminescence may be counted to provide a measure of the ionizing radiation.

Planning Guidance for Response to a Nuclear Detonation

DTIC Science & Technology

2009-01-16

Radiation and Fallout One of the primary outputs from a nuclear explosion is radiation . Intense radiation is...dose rates based on the quantity of visible fallout. Therefore, visible fallout may possibly be used as an indicator of a direct radiation hazard...to survivors and response workers.15 The National Council on Radiation Protection and Measurements (NCRP) has recommended 10 R/hour (R/hour) as a

Developing vascular and hypoxia based theranostics in solid tumors

NASA Astrophysics Data System (ADS)

Koonce, Nathan A.

Tissue hypoxia was recognized for its biological attenuating effects on ionizing radiation over a century ago and is a characteristic feature of many solid tumors. Clinical and experimental evidence indicates tumor hypoxia plays diverse and key roles in tumor progression, angiogenesis, and resistance to chemotherapy/radiotherapy. Hypoxia has known effects on progression and resistance to several standard treatment approaches and the significant history of study might suggest diagnostic imaging and therapeutic interventions would be routine in oncological practice. Curiously, this is not the case and the research results involved in this report will attempt to better understand and contribute to why this gap in knowledge exists and a rationale for harnessing the potential of detecting and targeting hypoxia. Despite the addition of oxygen and reversal of hypoxia being known as the best radiosensitizer, hypoxia remains unexploited in clinical cancer therapy. The studies reported herein detail development of a novel imaging technique to detect a subtype of tumor hypoxia, vascular hypoxia or hypoxemia, with a 17-fold increase (p<0.05) in uptake of pimonidazole targeted microbubbles observed compared to controls. This technique creates the potential to study the role of hypoxemia in progression and therapeutic response. Additionally, description of a nanoparticle-based therapy that targets tumor areas associated with tumor hypoxia and the tumor microenvironment in general is reported. TNF-loaded nanoparticles combined with radiotherapy resulted in a 5.25-fold growth delay that was found to be synergistic (p<0.05) and suggests clinical evaluation is warranted. An additional study to evaluate an approach to use thermal ablation of intratumoral hypoxia by an image-guided technique developed in our group is described along with a sequence dependence of radiation preceding ablation. A final study on the use of galectin-1 antagonist to significantly decrease (p<0.05) hypoxia in the tumor microenvironment by altering tumor vessel characteristics is illustrated in Chapter 5. Overall, this thesis details imaging approaches of tumor hypoxia and its detection, quantification and targeting in therapeutic approaches.

Develop real-time dosimetry concepts and instrumentation for long term missions

NASA Technical Reports Server (NTRS)

Braby, L. A.

1981-01-01

The development of a rugged portable dosimetry system, based on microdosimetry techniques, which will measure dose and evaluate dose equivalent in a mixed radiation field is described. Progress in the desired dosimetry system can be divided into three distinct areas: development of the radiation detector, and electron system are presented. The mathematical techniques required are investigated.

Radiation-Induced Liver Injury in Three-Dimensional Conformal Radiation Therapy (3D-CRT) for Postoperative or Locoregional Recurrent Gastric Cancer: Risk Factors and Dose Limitations.

PubMed

Li, Guichao; Wang, Jiazhou; Hu, Weigang; Zhang, Zhen

2015-01-01

This study examined the status of radiation-induced liver injury in adjuvant or palliative gastric cancer radiation therapy (RT), identified risk factors of radiation-induced liver injury in gastric cancer RT, analysed the dose-volume effects of liver injury, and developed a liver dose limitation reference for gastric cancer RT. Data for 56 post-operative gastric cancer patients and 6 locoregional recurrent gastric cancer patients treated with three-dimensional conformal radiation therapy (3D-CRT) or intensity-modulated radiation therapy (IMRT) from Sep 2007 to Sep 2009 were analysed. Forty patients (65%) were administered concurrent chemotherapy. Pre- and post-radiation chemotherapy were given to 61 patients and 43 patients, respectively. The radiation dose was 45-50.4 Gy in 25-28 fractions. Clinical parameters, including gender, age, hepatic B virus status, concurrent chemotherapy, and the total number of chemotherapy cycles, were included in the analysis. Univariate analyses with a non-parametric rank test (Mann-Whitney test) and logistic regression test and a multivariate analysis using a logistic regression test were completed. We also analysed the correlation between RT and the changes in serum chemistry parameters [including total bilirubin, (TB), direct bilirubin (D-TB), alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST) and serum albumin (ALB)] after RT. The Child-Pugh grade progressed from grade A to grade B after radiotherapy in 10 patients. A total of 16 cases of classic radiation-induced liver disease (RILD) were observed, and 2 patients had both Child-Pugh grade progression and classic RILD. No cases of non-classic radiation liver injury occurred in the study population. Among the tested clinical parameters, the total number of chemotherapy cycles correlated with liver function injury. V35 and ALP levels were significant predictive factors for radiation liver injury. In 3D-CRT for gastric cancer patients, radiation-induced liver injury may occur and affect the overall treatment plan. The total number of chemotherapy cycles correlated with liver function injury, and V35 and ALP are significant predictive factors for radiation-induced liver injury. Our dose limitation reference for liver protection is feasible.

Hypofractionated Palliative Radiotherapy with Concurrent Radiosensitizing Chemotherapy for Advanced Head and Neck Cancer Using the "QUAD-SHOT Regimen".

PubMed

Gamez, Mauricio E; Agarwal, Manuj; Hu, Kenneth S; Lukens, John N; Harrison, Louis B

2017-02-01

To analyze the outcomes using the hypofractionated palliative radiotherapy regimen "QUAD-Shot" with concurrent radiosensitizing chemotherapy for advanced head and neck cancer. We analyzed twenty-one patients with newly-diagnosed or recurrent head and neck cancer treated with palliative hypofractionated concurrent chemoradiation using the QUAD-Shot regimen. All patients received at least one cycle of RT, with sixteen patients (76%) completing all three cycles. 85.7 % of patients had objective response to therapy with five patients (23.8%) demonstrating complete response (CR) and thirteen patients (61.9%) demonstrating partial response (PR). Palliation of symptoms was achieved in all (100%) of the sixteen patients that completed the three cycles. Median overall survival and median progression-free survival were 7 and 4 months, respectively. QUAD-Shot palliative radiation therapy coupled with radiosensitizing chemotherapy is efficacious and well-tolerated in patients with newly-diagnosed or recurrent head and neck cancer not amenable to curative therapy. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Comparative study of microwave radiation-induced magnetoresistive oscillations induced by circularly- and linearly- polarized photo-excitation

PubMed Central

Ye, Tianyu; Liu, Han-Chun; Wang, Zhuo; Wegscheider, W.; Mani, Ramesh G.

2015-01-01

A comparative study of the radiation-induced magnetoresistance oscillations in the high mobility GaAs/AlGaAs heterostructure two dimensional electron system (2DES) under linearly- and circularly- polarized microwave excitation indicates a profound difference in the response observed upon rotating the microwave launcher for the two cases, although circularly polarized microwave radiation induced magnetoresistance oscillations observed at low magnetic fields are similar to the oscillations observed with linearly polarized radiation. For the linearly polarized radiation, the magnetoresistive response is a strong sinusoidal function of the launcher rotation (or linear polarization) angle, θ. For circularly polarized radiation, the oscillatory magnetoresistive response is hardly sensitive to θ. PMID:26450679

Comparative study of microwave radiation-induced magnetoresistive oscillations induced by circularly- and linearly- polarized photo-excitation.

PubMed

Ye, Tianyu; Liu, Han-Chun; Wang, Zhuo; Wegscheider, W; Mani, Ramesh G

2015-10-09

A comparative study of the radiation-induced magnetoresistance oscillations in the high mobility GaAs/AlGaAs heterostructure two dimensional electron system (2DES) under linearly- and circularly- polarized microwave excitation indicates a profound difference in the response observed upon rotating the microwave launcher for the two cases, although circularly polarized microwave radiation induced magnetoresistance oscillations observed at low magnetic fields are similar to the oscillations observed with linearly polarized radiation. For the linearly polarized radiation, the magnetoresistive response is a strong sinusoidal function of the launcher rotation (or linear polarization) angle, θ. For circularly polarized radiation, the oscillatory magnetoresistive response is hardly sensitive to θ.