[show abstract][hide abstract] ABSTRACT: A major solar particle event (SPE) may place astronauts at significant risk for the acute radiation syndrome (ARS), which may be exacerbated when combined with other space flight stressors, such that the mission or crew health may be compromised. The National Space Biomedical Research Institute (NSBRI) Center of Acute Radiation Research (CARR) is focused on the assessment of risks of adverse biological effects related to the ARS in animals exposed to space flight stressors combined with the types of radiation expected during an SPE. The CARR studies are focused on the adverse biological effects resulting from exposure to the types of radiation, at the appropriate energies, doses and dose-rates, present during an SPE (and standard reference radiations: gamma rays or electrons). All animal studies described have been approved by the University of PA IACUC. Some conclusions from recent CARR investigations are as follows: (i) the relative biological effectiveness (RBE) values for SPE-like protons compared with standard reference radiations (gammas or electrons) for white blood cells (WBCs) vary greatly between mice, ferrets and pigs, with the RBE values being greater in ferrets than those in mice, and considerably greater in pigs compared with those in ferrets or mice [1, 2]. This trend for the data suggests that the RBE values for WBCs in humans could be considerably greater than those observed in small mammals, and SPE proton radiation may be far more hazardous to humans than previously estimated from small animal studies. (ii) Very low doses of SPE proton radiation (25 cGy) increase blood clotting times in ferrets, and the low SPE-like dose rate has more severe effects than high dose rate radiation . (iii) Results from pig and ferret studies suggest that disseminated intravascular coagulation is a major cause of death at doses near the LD50 level for SPE-like proton and gamma radiation. (iv) Exposure to SPE-like proton or gamma radiation, in combination with simulated microgravity (hindlimb suspension), leads to a very high level of morbidity/mortality in mice given a bacterial challenge with non-toxic levels of Pseudomonas aeruginosa or Klebsiella pneumoniae; the threshold for this effect was 1.5 Gy. (v) T-cell activation was reduced in mice exposed to SPE-like radiation with or without simulated hypogravity (either partial weight suspension or hindlimb suspension) (e.g. ). (vi) Radiation and simulated hypogravity had synergistic effects on immune system biological endpoints (e.g. ). (vii) Pigs exposed to simulated SPE radiation exhibited increases in intracranial pressure that remained elevated over the 90-day experimental period. (viii) A major sparing effect of SPE-like low dose rate radiation (compared with the results for high dose rate radiation) was observed for ferret emesis parameters, such that the differences between the results for ferret exposure to low dose rate radiation (50 cGy/h) and controls were not statistically significant (for doses up to 2 Gy). For high dose rate SPE proton radiation, the threshold value for retching was 75 cGy, and for ferret vomiting, it was 1 Gy.
Journal of Radiation Research 03/2014; 55 Suppl 1:i66-i67. · 1.45 Impact Factor
[show abstract][hide abstract] ABSTRACT: The space radiation environment imposes increased dangers of exposure to ionizing radiation, particularly during a solar particle event (SPE). These events consist primarily of low energy protons that produce a highly inhomogeneous dose distribution. Due to this inherent dose heterogeneity, experiments designed to investigate the radiobiological effects of SPE radiation present difficulties in evaluating and interpreting dose to sensitive organs. To address this challenge, we used the Geant4 Monte Carlo simulation framework to develop dosimetry software that uses computed tomography (CT) images and provides radiation transport simulations incorporating all relevant physical interaction processes. We found that this simulation accurately predicts measured data in phantoms and can be applied to model dose in radiobiological experiments with animal models exposed to charged particle (electron and proton) beams. This study clearly demonstrates the value of Monte Carlo radiation transport methods for two critically interrelated uses: (i) determining the overall dose distribution and dose levels to specific organ systems for animal experiments with SPE-like radiation, and (ii) interpreting the effect of random and systematic variations in experimental variables (e.g. animal movement during long exposures) on the dose distributions and consequent biological effects from SPE-like radiation exposure. The software developed and validated in this study represents a critically important new tool that allows integration of computational and biological modeling for evaluating the biological outcomes of exposures to inhomogeneous SPE-like radiation dose distributions, and has potential applications for other environmental and therapeutic exposure simulations.
Journal of Radiation Research 12/2013; · 1.45 Impact Factor
[show abstract][hide abstract] ABSTRACT: The present study was undertaken to determine relative biological effectiveness (RBE) values for simulated solar particle event (SPE) radiation on peripheral blood cells using Yucatan minipigs and electron-simulated SPE as the reference radiation. The results demonstrated a generally downward trend in the RBE values with increasing doses of simulated SPE radiation for leukocytes in the irradiated animals. The fitted RBE values for white blood cells (WBCs), lymphocytes, neutrophils, monocytes and eosinophils were above 1.0 in all three radiation dose groups at all time-points evaluated, and the lower limits of the 95% confidence intervals were > 1.0 in the majority of the dose groups at different time-points, which together suggest that proton-simulated SPE radiation is more effective than electron-simulated SPE radiation in reducing the number of peripheral WBCs, lymphocytes, neutrophils, monocytes and eosinophils, especially at the low end of the 5-10 Gy dose range evaluated. Other than the RBE values, the responses of leukocytes to electron-simulated SPE radiation and proton-simulated SPE radiation exposure are highly similar with respect to the time-course, the most radiosensitive cell type (the lymphocytes), and the shape of the dose-response curves, which is generally log-linear. These findings provide additional evidence that electron-simulated SPE radiation is an appropriate reference radiation for determination of RBE values for the simulated SPE radiations, and the RBE estimations using electron-simulated SPE radiation as the reference radiation are not complicated by other characteristics of the leukocyte response to radiation exposure.
Journal of Radiation Research 09/2013; · 1.45 Impact Factor
[show abstract][hide abstract] ABSTRACT: The standard of care in Locally-Advanced Non-Small Cell Lung Cancer (LA-NSCLC) is chemotherapy and radiation; however, Radiation-Induced Lung Injury (RILI), which may be prevented by the anti-inflammatory and anti-oxidant properties of Flaxseed (FS), impedes its maximum benefit.
Patients with LA-NSCLC requiring definitive RT were randomized to one FS or control muffin daily from start to 2 weeks after RT. Blood and urine were collected to quantify plasma FS metabolites, Enterodione (ED) and Enterolactone (EL), and urinary oxidative stress biomarkers, 8, 12-iso-iPF2a-VI (isoprostane) and 8-oxo-7,8-dihydro-2'deoxyguanosine (8-oxo-dGuo). Tolerability was defined as consuming ≥ 75% of the intended muffins and no ≥ grade 3 gastrointestinal toxicities.
Fourteen patients (control,7; FS,7) were enrolled. The tolerability rates were 42.9 versus 71.4% (p=0.59) for FS and control, respectively. Mean percentages of intended number of muffins consumed were 37% versus 73% (p=0.12). ED and EL increased at onset of FS and decreased with discontinuation, confirming bioavailability. Isoprostane and 8-oxo-dGuo were detectable. There was a trend towards decreased rates of pneumonitis in FS.
This is the first study to report FS bioavailability and quantify oxidative stress markers in NSCLC patients. FS in the administered muffin formulation did not meet tolerability criteria. Given the promising mechanism of FS as a radioprotectant, further investigations should focus on the optimal method for administration of FS.
Journal of pulmonary & respiratory medicine. 08/2013; 3(4):154.
[show abstract][hide abstract] ABSTRACT: Acute radiation sickness (ARS) is expected to occur in astronauts during large solar particle events (SPEs). One parameter associated with ARS is the hematopoietic syndrome, which can result from decreased numbers of circulating blood cells in those exposed to radiation. The peripheral blood cells are critical for an adequate immune response, and low blood cell counts can result in an increased susceptibility to infection. In this study, Yucatan minipigs were exposed to proton radiation within a range of skin dose levels expected for an SPE (estimated from previous SPEs). The proton-radiation exposure resulted in significant decreases in total white blood cell count (WBC) within 1 day of exposure, 60% below baseline control value or preirradiation values. At the lowest level of the blood cell counts, lymphocytes, neutrophils, monocytes and eosinophils were decreased up to 89.5%, 60.4%, 73.2% and 75.5%, respectively, from the preirradiation values. Monocytes and lymphocytes were decreased by an average of 70% (compared to preirradiation values) as early as 4 h after radiation exposure. Skin doses greater than 5 Gy resulted in decreased blood cell counts up to 90 days after exposure. The results reported here are similar to studies of ARS using the nonhuman primate model, supporting the use of the Yucatan minipig as an alternative. In addition, the high prevalence of hematologic abnormalities resulting from exposure to acute, whole-body SPE-like proton radiation warrants the development of appropriate countermeasures to prevent or treat ARS occurring in astronauts during space travel.
[show abstract][hide abstract] ABSTRACT: BACKGROUND: Wholegrain flaxseed (FS), and its lignan component (FLC) consisting mainly of secoisolariciresinol diglucoside (SDG), have potent lung radioprotective properties while not abrogating the efficacy of radiotherapy. However, while the whole grain was recently shown to also have potent mitigating properties in a thoracic radiation pneumonopathy model, the bioactive component in the grain responsible for the mitigation of lung damage was never identified. Lungs may be exposed to radiation therapeutically for thoracic malignancies or incidentally following detonation of a radiological dispersion device. This could potentially lead to pulmonary inflammation, oxidative tissue injury, and fibrosis. This study aimed to evaluate the radiation mitigating effects of FLC in a mouse model of radiation pneumonopathy. METHODS: We evaluated FLC-supplemented diets containing SDG lignan levels comparable to those in 10% and 20% whole grain diets. 10% or 20% FLC diets as compared to an isocaloric control diet (0% FLC) were given to mice (C57/BL6) (n=15-30 mice/group) at 24, 48, or 72-hours after single-dose (13.5 Gy) thoracic x-ray treatment (XRT). Mice were evaluated 4 months post-XRT for blood oxygenation, lung inflammation, fibrosis, cytokine and oxidative damage levels, and survival. RESULTS: FLC significantly mitigated radiation-related animal death. Specifically, mice fed 0% FLC demonstrated 36.7% survival 4 months post-XRT compared to 60--73.3% survival in mice fed 10%-20% FLC initiated 24--72 hours post-XRT. FLC also mitigated radiation-induced lung fibrosis whereby 10% FLC initiated 24-hours post-XRT significantly decreased fibrosis as compared to mice fed control diet while the corresponding TGF-beta1 levels detected immunohistochemically were also decreased. Additionally, 10-20% FLC initiated at any time point post radiation exposure, mitigated radiation-induced lung injury evidenced by decreased bronchoalveolar lavage (BAL) protein and inflammatory cytokine/chemokine release at 16 weeks post-XRT. Importantly, neutrophilic and overall inflammatory cell infiltrate in airways and levels of nitrotyrosine and malondialdehyde (protein and lipid oxidation, respectively) were also mitigated by the lignan diet. CONCLUSIONS: Dietary FLC given early post-XRT mitigated radiation effects by decreasing inflammation, lung injury and eventual fibrosis while improving survival. FLC may be a useful agent, mitigating adverse effects of radiation in individuals exposed to incidental radiation, inhaled radioisotopes or even after the initiation of radiation therapy to treat malignancy.
BMC Cancer 04/2013; 13(1):179. · 3.33 Impact Factor
[show abstract][hide abstract] ABSTRACT: Radiation therapy is a common treatment regimen for cancer patients. However, its adverse effects on the neighboring bone could lead to fractures with a great impact on quality of life. The underlying mechanism is still elusive and there is no preventive or curative solution for this bone loss. Parathyroid hormone (PTH) is a current therapy for osteoporosis that has potent anabolic effects on bone. In this study, we found that focal radiation from frequent scans of the right tibiae in 1-month-old rats by micro-computed tomography severely decreased trabecular bone mass and deteriorated bone structure. Interestingly, PTH daily injections remarkably improved trabecular bone in the radiated tibiae with increases in trabecular number, thickness, connectivity, structure model index and stiffness, and a decrease in trabecular separation. Histomorphometric analysis revealed that radiation mainly decreased the number of osteoblasts and impaired their mineralization activity but had little effects on osteoclasts. PTH reversed these adverse effects and greatly increased bone formation to a similar level in both radiated and non-radiated bones. Furthermore, PTH protects bone marrow mesenchymal stem cells from radiation-induced damage, including a decrease in number and an increase in adipogenic differentiation. While radiation generated the same amount of free radicals in the bone marrow of vehicle-treated and PTH-treated animals, the percentage of apoptotic bone marrow cells was significantly attenuated in the PTH group. Taken together, our data demonstrate a radioprotective effect of PTH on bone structure and bone marrow and shed new light on a possible clinical application of anabolic treatment in radiotherapy.
[show abstract][hide abstract] ABSTRACT: Pleural photodynamic therapy (PDT) has been used as an adjuvant
treatment with lung-sparing surgical treatment for mesothelioma with
remarkable results. In the current intrapleural PDT protocol, a moving
fiber-based point source is used to deliver the light and the light dose
are monitored by 7 detectors placed in the pleural cavity. To improve
the delivery of light dose uniformity, an infrared (IR) camera system is
used to track the motion of the light sources. A treatment planning
system uses feedback from the detectors as well as the IR camera to
update light fluence distribution in real-time, which is used to guide
the light source motion for uniform light dose distribution. We have
improved the GUI of the light dose calculation engine to provide
real-time light fluence distribution suitable for guiding the surgery to
delivery light more uniformly. A dual-correction method is used in the
feedback system, so that fluence calculation can match detector readings
using both direct and scatter light models. An improved measurement
device is developed to automatically acquire laser position for the
point source. Comparison of the effects of the guidance is presented in
[show abstract][hide abstract] ABSTRACT: OBJECTIVE: Proton therapy can result in clinically significant radiation dermatitis. In some clinical scenarios, such as lung or breast cancer, the risk of severe radiation dermatitis may limit beam arrangement and prescription doses. Patients undergoing proton therapy for prostate cancer commonly develop mild radiation dermatitis. Herein, we report the outcomes of two prostate cancer patients whose radiation dermatitis appears to have been substantially diminished by transparent film dressings (Beekley stickers). METHODS: This is a descriptive report of the skin toxicity observed in two patients undergoing proton therapy for prostate cancer at a single institution in 2011. A phantom dosimetric study was performed to evaluate the impact of a transparent film dressing on a beam's spread out Bragg peak (SOBP). RESULTS: Two patients with low risk prostate cancer were treated with proton therapy to a total dose of 79.2Gy (RBE) in 1.8 Gy (RBE) fractions using two opposed lateral beams daily. Both patients had small circular (2.5 cm diameter) transparent adhesive markers placed on their skin to assist with daily alignment. Patient 1 had markers in place bilaterally for the entirety of treatment. Patient 2 had a marker in place for three weeks on one side and six weeks on the other. Over the course of therapy, both men developed typical Grade 1 radiation dermatitis (asymptomatic erythema) on their hips; however, in both patients, the erythema was substantially decreased beneath the markers. Patient 2 demonstrated less attenuation and thus greater erythema in the skin covered for three weeks compared to the skin covered for six weeks. The difference in skin changes between the covered and uncovered skin persisted for at least 1 month. A phantom study of double scattered beam SOBP with and without the marker in the beam path showed no gross dosimetric effect. CONCLUSIONS: Transparent adhesive markers appear to have attenuated radiation dermatitis in these two patients without affecting the SOBP. One patient may have exhibited a dose--response effect. The reproducibility and underlying mechanisms are unclear. However, the potential to leverage this effect to improve proton-related radiation dermatitis in other clinical scenarios is intriguing. Exploratory animal studies are underway.
[show abstract][hide abstract] ABSTRACT: While dietary wholegrain Flaxseed (FS) has potent anti-inflammatory, anti-fibrotic and antioxidant properties in murine models of acute and chronic lung injury, the main bioactive ingredient that contributes to these protective effects remains unknown. This study evaluated the lignan complex of FS (FLC) enriched in secoisolariciresinol diglucoside with respect to lung radioprotective and tumor radiosensitizing efficacy using a mouse model of thoracic radiation-induced pneumonopathy. C57/Bl6 mice were fed 0% FS, 10% FS, 10% FLC or 20% FLC for 3 weeks, then irradiated with a single fraction (13.5 Gy) of X-ray radiation treatment (XRT). Mouse survival was monitored for 4 months after irradiation and inflammatory lung parameters were evaluated in bronchoalveolar lavage (BAL) fluid. Gene and protein levels of protective antioxidant and phase II enzymes were evaluated in lung tissue using qPCR and protein levels were verified by immunoblotting. Prolonged administration of the FLC diet was well tolerated and was not associated with any toxicity. Importantly, comparable to the whole grain 10% FS diet, irradiated mice fed 10% and 20% FLC diets displayed improved survival. Improved hemodynamic measurements were also recorded in irradiated mice fed 10% FS or 10% FLC diet compared to irradiated 0% FS fed mice. Flaxseed lignan complex diet also attenuated polymorphonuclear infiltration and overall lung inflammation to levels comparable to those in nonirradiated mice. Flaxseed lignan complex, similarly to FS, up-regulated gene expression as well as protein levels of protective antioxidant enzymes such as heme oxygenase-1 (HO-1) and NAD(P)H quinone oxidoreductase 1 (NQO1). Dietary FLC induced radiosensitizing effects in our murine model of metastatic lung cancer. Importantly, protection of normal tissue does not thwart tumor cell death by radiation treatment. The dietary lignan complex of FS, mainly consisting of the phenolic secoisolariciresinol, is protective against radiation pneumonopathy in vivo while not hindering the tumoricidal effects of radiotherapy.
[show abstract][hide abstract] ABSTRACT: Patients with serosal (pleural or peritoneal) spread of malignancy have few definitive treatment options and consequently have a very poor prognosis. We have previously shown that photodynamic therapy (PDT) can be an effective treatment for these patients, but that the therapeutic index is relatively narrow. Here, we test the hypothesis that EGFR and STAT3 activation increase survival following PDT and that inhibiting these pathways leads to increased PDT-mediated direct cellular cytotoxicity by examining BPD-PDT in OvCa and NSCLC cells. We found that BPD-mediated PDT stimulated EGFR tyrosine phosphorylation and nuclear translocation and that EGFR inhibition by erlotinib resulted in reduction of PDT-mediated EGFR activation and nuclear translocation. Nuclear translocation and PDT-mediated activation of EGFR was also observed in response to BPD-mediated PDT in multiple cell lines, including OvCa, NSCLC and head and neck cancer cells and was observed to occur in response to porfimer sodium-mediated PDT. In addition, we found that PDT stimulates nuclear translocation of STAT3 and STAT3/EGFR association and that inhibiting STAT3 signaling prior to PDT leads to increased PDT cytotoxicity. Finally, we found that inhibition of EGFR signaling lead to increased PDT cytotoxicity through a mechanism that involves increased apoptotic cell death. Taken together, these results demonstrate that PDT stimulates the nuclear accumulation both EGFR and STAT3 and that targeting these survival pathways is a potentially promising strategy that could be adapted for clinical trials of PDT for patients with serosal spread of malignancy.
Cancer biology & therapy 09/2012; 13(14). · 3.29 Impact Factor
[show abstract][hide abstract] ABSTRACT: A major solar particle event (SPE) may place astronauts at significant
risk for the acute radiation syndrome (ARS), which may be exacerbated
when combined with other space flight stressors, such that the mission
or crew health may be compromised. The National Space Biomedical
Research Institute (NSBRI) Center of Acute Radiation Research (CARR) is
focused on the assessment of risks of adverse biological effects related
to the ARS in animal models exposed to space flight stressors combined
with the types of radiation expected during an SPE. As part of this
program, FDA-approved drugs that may prevent and/or mitigate ARS
symptoms are being evaluated. The CARR studies are focused on the
adverse biological effects resulting from exposure to the types of
radiation, at the appropriate energies, doses and dose-rates, present
during an SPE (and standard reference radiations, gamma rays or
electrons). The ARS is a phased syndrome which often includes vomiting
and fatigue. Other acute adverse biologic effects of concern are the
loss of hematopoietic cells, which can result in compromised bone marrow
and immune cell functions. There is also concern for skin damage from
high SPE radiation doses, including burns, and resulting immune system
dysfunction. Using 3 separate animal model systems (ferrets, mice and
pigs), the major ARS biologic endpoints being evaluated are: 1)
vomiting/retching and fatigue, 2) hematologic changes (with focus on
white blood cells) and immune system changes resulting from exposure to
SPE radiation with and without reduced weightbearing conditions, and 3)
skin injury and related immune system functions. In all of these areas
of research, statistically significant adverse health effects have been
observed in animals exposed to SPE-like radiation. Countermeasures for
the management of ARS symptoms are being evaluated. New research
findings from the past grant year will be discussed. Acknowledgements:
This research is supported by the NSBRI Center of Acute Radiation
Research (CARR) grant; NSBRI is funded through NASA NCC 9-58. Recent
Publications: Cengel K. A. et al. (2010) Radiat Environ Biophys
49(4): 715-21.  Ware J. H. et al. (2010) Radiation Res 174: 325-330.
 Davis J. G. et al. (2010) Radiation Res 173(3):353-61.  Sanzari
J.K. et al. (2011) Radiation Res 175(5):650-6.  Ni H. et al. (2011)
Radiation Res 175(4): 485-92.  Mao X. W. et al. (2011) Radiation Res
176: 187-197.  Maks C. J. et al. (2011) Radiation Res 176: 170-6. 
Kennedy A. R. et al. (2011) Radiation Res 176: 62-70.  Sanzari J. K.
et al. (2011) Int J Radiat Biol 87: 1033-8.  Wilson J. M. et al.
(2011) Radiation Res 176(5):649-59.  Kennedy A. R. and Wan X. S.
(2011) Advances in Space Res 48: 1460-1479.  Gridley D. S. et al.
(2011) Int J Radiat Biol 2011 87(12): 1173-81,  York J. M., et al.
(2012) Brain Behav Immun 26(2): 218-27, Wilson J. M. et al. (2012)
Advances in Space Res 49: 237-248.  Krigsfeld, G.S. et al. Int J
Radiat Biol 2012 Feb 6 [Epub ahead of print]
[show abstract][hide abstract] ABSTRACT: Use of individually ventilated caging (IVC) systems for mouse-based laboratory investigation has dramatically increased. We found that without mice present, intra-cage oxygen concentration was comparable (21%) between IVC housing and ambient environment caging (AEC) that used wire top lids. However, when mice were housed 4-to-a-cage for 1week, intra-cage oxygen dropped to 20.5% in IVC housing as compared to 21% for AEC housing. IVC intra-cage humidity was also elevated relative to AEC housing. Mice raised in IVC housing as compared to mice raised in AEC housing had higher RBC mass, hematocrit and hemoglobin concentrations. They also had elevated platelet counts but lower white blood cell counts. IVC mice, relative to AEC mice, had increased saccharin preference and increased fluid consumption but similar locomotion, food intake, social exploration and novel object recognition when tested in an AEC environment. Taken together, these data indicate that ventilated caging systems can have a 0.5% reduction from ambient oxygen concentration that is coupled to mouse red blood cell indices indicative of chronic exposure to a hypoxia. Importantly, IVC housing can impact behavioral testing for depressive-like behavior.
Brain Behavior and Immunity 05/2012; 26(6):951-8. · 5.61 Impact Factor
[show abstract][hide abstract] ABSTRACT: Radical pleurectomy (RP) for mesothelioma is often considered either technically unfeasible or an operation limited to patients who would not tolerate a pneumonectomy. The purpose of this study was to review our experience using RP and intraoperative photodynamic therapy (PDT) for mesothelioma.
Thirty-eight patients (42-81 years) underwent RP-PDT. Thirty five of 38 (92%) patients also received systemic therapy. Standard statistical techniques were used for analysis.
Thirty seven of 38 (97%) patients had stage III/IV cancer (according to the American Joint Committee on Cancer [AJCC manual 7th Edition, 2010]) and 7/38 (18%) patients had nonepithelial subtypes. Macroscopic complete resection was achieved in 37/38 (97%) patients. There was 1 postoperative mortality (stroke). At a median follow-up of 34.4 months, the median survival was 31.7 months for all 38 patients, 41.2 months for the 31/38 (82%) patients with epithelial subtypes, and 6.8 months for the 7/38 (18%) patients with nonepithelial subtypes. Median progression-free survival (PFS) was 9.6, 15.1, and 4.8 months, respectively. The median survival and PFS for the 20/31 (64%) patients with N2 epithelial disease were 31.7 and 15.1 months, respectively.
It was possible to achieve a macroscopic complete resection using lung-sparing surgery in 97% of these patients with stage III/IV disease. The survival we observed with this approach was unusually long for the patients with the epithelial subtype but, interestingly, the PFS was not. The reason for this prolonged survival despite recurrence is not clear but is potentially related to preservation of the lung or some PDT-induced effect, or both. We conclude that the results of this lung-sparing approach are safe, encouraging, and warrant further investigation.
The Annals of thoracic surgery 05/2012; 93(5):1658-65; discussion 1665-7. · 3.74 Impact Factor
[show abstract][hide abstract] ABSTRACT: In patients with malignant pheochromocytoma and paraganglioma, 131I-MIBG radiotherapy can achieve an objective response rate of 30-50% with the dose limiting toxicity being hematologic. Patients with disseminated disease, who also have a few index bulky or symptomatic lesions, may benefit from the addition of targeted external beam radiotherapy alone or in combination with systemic 131I-MIBG. The records of patients with malignant paraganglioma who were treated with external beam radiotherapy at the University of Pennsylvania from February 1973 to February 2011 were reviewed in an institutional review board approved retrospective study. Of the 17 patients with tumors in the thorax, abdomen, or pelvis, 76% had local control or clinically significant symptomatic relief for at least 1 year or until death. As expected, the predominant toxicity was due to irradiation of tumor-adjacent normal tissues without clinically significant hematologic toxicity. Due to widespread systemic metastases with areas of bulky, symptomatic tumor, 5 of the 17 patients were treated with sequential 131I-MIBG (2 mCi/kg per treatment) and external beam radiotherapy to 9 sites. In these patients, all areas that were irradiated with external beam radiotherapy showed durable objective response despite all patients eventually experiencing out-of-field systemic progression requiring other treatment. Four of these patients remain alive with excellent performance status 16, 18, 23, and 24 months after external beam radiotherapy. External beam radiotherapy can be highly effective in local management of malignant paraganglioma and can be used in conjunction with 131I-MIBG due to nonoverlapping toxicities with excellent control of locally bulky tumors.
Hormone and Metabolic Research 05/2012; 44(5):405-10. · 2.15 Impact Factor
[show abstract][hide abstract] ABSTRACT: Proton beam therapy (PBT) is a novel method for treating malignant disease with radiotherapy. The purpose of this work was to evaluate the state of the science of PBT and arrive at a recommendation for the use of PBT. The emerging technology committee of the American Society of Radiation Oncology (ASTRO) routinely evaluates new modalities in radiotherapy and assesses the published evidence to determine recommendations for the society as a whole. In 2007, a Proton Task Force was assembled to evaluate the state of the art of PBT. This report reflects evidence collected up to November 2009. Data was reviewed for PBT in central nervous system tumors, gastrointestinal malignancies, lung, head and neck, prostate, and pediatric tumors. Current data do not provide sufficient evidence to recommend PBT in lung cancer, head and neck cancer, GI malignancies, and pediatric non-CNS malignancies. In hepatocellular carcinoma and prostate cancer and there is evidence for the efficacy of PBT but no suggestion that it is superior to photon based approaches. In pediatric CNS malignancies PBT appears superior to photon approaches but more data is needed. In large ocular melanomas and chordomas, we believe that there is evidence for a benefit of PBT over photon approaches. PBT is an important new technology in radiotherapy. Current evidence provides a limited indication for PBT. More robust prospective clinical trials are needed to determine the appropriate clinical setting for PBT.
Radiotherapy and Oncology 03/2012; 103(1):8-11. · 4.52 Impact Factor
[show abstract][hide abstract] ABSTRACT: Intrapleural photodynamic therapy (PDT) has been used as an adjuvant
treatment with lung-sparing surgical treatment for mesothelioma. In the
current intrapleural PDT protocol, a moving fiber-based point source is
used to deliver the light and the light dose are monitored by 7
detectors placed in the pleural cavity. To improve the delivery of light
dose uniformity, an infrared (IR) camera system is used to track the
motion of the light sources. A treatment planning system uses feedback
from the detectors as well as the IR camera to update light fluence
distribution in real-time, which is used to guide the light source
motion for uniform light dose distribution. We have reported previously
the success of using IR camera to passively monitor the light fluence
rate distribution. In this study, the real-time feedback has been
implemented in the current system prototype, by transferring data from
the IR camera to a computer at a rate of 20 Hz, and by
calculation/displaying using Matlab. A dual-correction method is used in
the feedback system, so that fluence calculation can match detector
readings. Preliminary data from a phantom showed superior light
uniformity using this method. Light fluence uniformity from patient
treatments is also shown using the correction method dose model.
[show abstract][hide abstract] ABSTRACT: Photodynamic therapy is increasingly being utilized to treat thoracic malignancies. For patients with early-stage non-small cell lung cancer, photodynamic therapy is primarily employed as an endobronchial therapy to definitely treat endobronchial, roentgenographically occult, or synchronous primary carcinomas. As definitive monotherapy, photodynamic therapy is most effective in treating bronchoscopically visible lung cancers ≤1 cm with no extracartilaginous invasion. For patients with advanced-stage non-small cell lung cancer, photodynamic therapy can be used to palliate obstructing endobronchial lesions, as a component of definitive multi-modality therapy, or to increase operability or reduce the extent of operation required. A review of the available medical literature detailing all published studies utilizing photodynamic therapy to treat at least 10 patients with non-small cell lung cancer is performed, and treatment recommendations and summaries for photodynamic therapy applications are described.
[show abstract][hide abstract] ABSTRACT: In the clinical setting, repeated exposures (10-30) to low-doses of ionizing radiation (≤200 cGy), as seen in radiotherapy for cancer, causes fatigue. Almost nothing is known, however, about the fatigue inducing effects of a single exposure to environmental low-dose ionizing radiation that might occur during high-altitude commercial air flight, a nuclear reactor accident or a solar particle event (SPE). To investigate the short-term impact of low-dose ionizing radiation on mouse biobehaviors and neuroimmunity, male CD-1 mice were whole body irradiated with 50 cGy or 200 cGy of gamma or proton radiation. Gamma radiation was found to reduce spontaneous locomotor activity by 35% and 36%, respectively, 6 h post irradiation. In contrast, the motivated behavior of social exploration was un-impacted by gamma radiation. Examination of pro-inflammatory cytokine gene transcripts in the brain demonstrated that gamma radiation increased hippocampal TNF-α expression as early as 4 h post-irradiation. This was coupled to subsequent increases in IL-1RA (8 and 12 h post irradiation) in the cortex and hippocampus and reductions in activity-regulated cytoskeleton-associated protein (Arc) (24 h post irradiation) in the cortex. Finally, restraint stress was a significant modulator of the neuroimmune response to radiation blocking the ability of 200 cGy gamma radiation from impairing locomotor activity and altering the brain-based inflammatory response to irradiation. Taken together, these findings indicate that low-dose ionizing radiation rapidly activates the neuroimmune system potentially causing early onset fatigue-like symptoms in mice.
Brain Behavior and Immunity 09/2011; 26(2):218-27. · 5.61 Impact Factor