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ABSTRACT: In the wake of the 9/11 terrorist attacks and the recent Level 7 nuclear event at the Fukushima Daiichi plant, there has been heightened awareness of the possibility of radiological terrorism and accidents and the need for techniques to estimate radiation levels after such events. A number of approaches to monitoring radiation using biological markers have been published, including physical techniques, cytogenetic approaches, and direct, DNA-analysis approaches. Each approach has the potential to provide information that may be applied to the triage of an exposed population, but problems with development and application of devices or lengthy analyses limit their potential for widespread application. We present a post-irradiation observation with the potential for development into a rapid point-of-care device. Using simple mitochondrial proteomic analysis, we investigated irradiated and nonirradiated murine mitochondria and identified a protein mobility shift occurring at 2-3 Gy. We discuss the implications of this finding both in terms of possible mechanisms and potential applications in bio-radiation monitoring.
Advances in experimental medicine and biology 01/2013; 765:139-45. · 1.09 Impact Factor
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ABSTRACT: Tumor hypoxia is probably the most important not yet measurable factor that predicts the outcome of cancer therapy. Hypoxic tumors are resistant to radiation, chemotherapy, and surgery. They signal tumor cells to grow, invade, survive cytotoxic-factor assault, and increase metastatic activity. Therapies aimed at reversing hypoxia-related treatment resistance or normalizing hypoxia are proven effective with level 1 evidence. The weak link remains the lack of satisfactory methods of measurement of tumor oxygenation.
Advances in experimental medicine and biology 01/2013; 765:195-201. · 1.09 Impact Factor
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Jun Ma,
Deping Han,
Mei Zhang,
Chun Chen,
Bingrong Zhang,
Zhenhuan Zhang,
Xiaohui Wang,
Shanmin Yang,
Yansong Guo, Paul Okunieff,
Lurong Zhang
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ABSTRACT: Although glycoproteins possess a variety of functional and structural roles in intracellular and intercellular activities, the effect of ionizing radiation (IR) on glycosylation is largely unknown. To explore this effect, we established a sandwich assay in which PHA-L, a phytohaemagglutinin that agglutinates leukocytes, was used as a coating layer to capture glycoproteins containing complex oligosaccharides; the bound glycoproteins were then measured. C57BL/6 mice were exposed to 0, 3, 6, or 10 Gy, and the plasma was collected at 6, 12, 18, 24, 48, 72, or 168 h and then analyzed for galactose/N-acetylgalactosamine (Gal/GalNAc) containing proteins. We found that (1) the sandwich assay accurately measured the level of glycoproteins, (2) 6-12 h after IR, the amount of glycoproteins containing GalNAc increased, and (3) at 72 and 168 h, 10 Gy was associated with a decrease in Gal/GalNAc. These IR-induced alterations might relate to the release of glycoproteins into the blood and the damage of the proteins and genes that are related to the glycosylation process.
Advances in experimental medicine and biology 01/2013; 765:147-53. · 1.09 Impact Factor
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Jun Ma,
Yanqian Hou,
Deping Han,
Mei Zhang,
Chun Chen,
Bingrong Zhang,
Zhenhuan Zhang,
Xiaohui Wang,
Shanmin Yang,
Yansong Guo, Paul Okunieff,
Lurong Zhang
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ABSTRACT: Various members of the fibroblast growth factor (FGF) family mitigate radiation-induced damage. We designed and synthesized the binding domain peptide of FGF-2 (FGF-P) with a dimer form resistant to peptidase and examined its mitigatory effect on murine bone marrow cells. NIH Swiss mice were exposed to different doses of total body irradiation (TBI) and treated with ten doses of 5 mg/kg FGF-P. We achieved the following results: (1) FGF-P stimulated the growth of bone marrow cells harvested from mice exposed to 3 Gy; (2) on day 25 after 6 Gy TBI, the number of leukocytes and granulocytes was higher in the FGF-P group than in the vehicle-alone group; (3) FGF-P significantly increased the number of pro-B and pre-B cells; and (4) FGF-P treatment in vivo increased the long-term hematopoietic stem cells (LT-HSC) in bone marrow. These data reveal the underlying mechanism by which FGF-P rescued a significant percentage of the exposed mice. The increase of LT-HSC in bone marrow leads to a concomitant increase of pro-B and pre-B cells followed by leukocytes and granulocytes, which in turn enhance immunity against infection.
Advances in experimental medicine and biology 01/2013; 765:155-61. · 1.09 Impact Factor
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Zhenyu Xiao,
Shanmin Yang,
Ying Su,
Wei Wang,
Hengshan Zhang,
Mei Zhang,
Kunzhong Zhang,
Yeping Tian,
Yongbing Cao,
Liangjie Yin,
Lurong Zhang, Paul Okunieff
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ABSTRACT: Inflammatory molecules (IMs) play an important role in ionizing radiation (IR)-induced soft tissue damage. The alteration of IMs as a function of time was studied with a protein array containing 62 IMs in mouse cutaneous soft tissues exposed to 30 Gy. The results showed that: (1) 2 days after irradiation, the levels of TGF-β1, MIP-1γ, IL-1α, and sTNF RI increased, while IGFBP-3, CXCL16, and IL-1β decreased in IR skin as compared to control skin; (2) 21 days after IR, TGF-β1, and MIP-1 γ, IL-1α remained high, while CXCL16 and IL-1β remained low; (3) 3 months after IR, the cytokine pattern exhibited reversals. The levels of MIP-1γ decreased, while VCAM-1, IGFBP-3, and TGF-β1 production increased. The data indicated that: (a) IMs change as a function of time after soft tissue irradiation; (b) changing IM levels may reflect the altered balance of the cytokine network, leading to imbalance or homeostasis; and (c) an antibody-based protein array can be used to assess multiple IMs simultaneously, making it useful for bulk screening for changes in tissue cytokine levels.
Advances in experimental medicine and biology 01/2013; 765:335-41. · 1.09 Impact Factor
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Mei Zhang,
Bingrong Zhang,
Yansong Guo,
Lei Zhang,
Shanmin Yang,
Liangjie Yin,
Sadasivan Vidyasagar,
David Maguire,
Steve Swarts,
Zhenhuan Zhang,
Amy Zhang,
Lurong Zhang, Paul Okunieff
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ABSTRACT: Mitochondrial DNA (mtDNA) is maternally inherited and controls the oxygen-related production of adenosine-5'-triphosphate, which is transported from the mitochondria to other cellular compartments and used as energy for cellular activities. The mtDNA is physically separated from nuclear DNA (nDNA). Ionizing radiation (IR) causes the release of both mtDNA and nDNA into circulation. Our previous study demonstrated that nDNA has potential to be a biodosimeter. In this study, branched DNA technology was used to explore the alteration pattern of mtDNA after IR. C57BL/6 mice were exposed to 0, 1.5, 3, 6, 8, or 10 Gy total body irradiation; thereafter, plasma mtDNA was assessed with samples collected at 3, 6, 9, 15, 24, 48, 72, or 168 h. We found that: (1) the designed probesets were specific for mtDNA extracted from the liver, and they recognized the small amount of mtDNA mixed in the nDNA; (2) plasma mtDNA exhibited a statistically significant increase only at 6 h after 8 Gy irradiation. The alteration of mtDNA was not dose-dependent or time-dependent; hence, it is unlikely to be an effective biodosimeter.
Advances in experimental medicine and biology 01/2013; 765:371-7. · 1.09 Impact Factor
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Chun Chen,
Shanmin Yang,
Mei Zhang,
Zhenhuan Zhang,
Bingrong Zhang,
Deping Han,
Jun Ma,
Xiaohui Wang,
Jingshen Hong,
Yansong Guo, Paul Okunieff,
Lurong Zhang
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ABSTRACT: In this study, we compared two in vitro collagen production assays ([(3)H]-proline incorporation and Sirius Red) for their ability to determine the pattern shift from soluble to deposited collagen. The effect of the antifibrotic agent, triptolide (TPL), on collagen production was also studied. The results showed that: (1) 48 h after NIH 3T3 (murine embryo fibroblast) and HFL-1(human fetal lung fibroblast) were exposed to transforming growth factor-beta 1 (TGF-β), there was an increase in soluble collagen in the culture medium; (2) on day 4, soluble collagen declined, whereas deposited collagen increased; (3) Sirius Red was easier to use than [(3)H]-proline incorporation and more consistently reflected the collagen pattern shift from soluble to deposited; (4) the in vitro Sirius Red assay took less time than the in vivo assay to determine the effect of TPL. Our results suggest that: (a) the newly synthesized soluble collagen can sensitively evaluate an agent's capacity for collagen production and (b) Sirius Red is more useful than [(3)H]-proline because it is easier to use, more convenient, less time consuming, and does not require radioactive material.
Advances in experimental medicine and biology 01/2013; 765:47-53. · 1.09 Impact Factor
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Yaacov Richard Lawrence,
Bhadrasain Vikram,
James J Dignam,
Arnab Chakravarti,
Mitchell Machtay,
Boris Freidlin,
Naoko Takebe,
Walter J Curran,
Soren M Bentzen, Paul Okunieff,
C Norman Coleman,
Adam P Dicker
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ABSTRACT: 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.
CancerSpectrum Knowledge Environment 12/2012; · 14.07 Impact Factor
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Feng Ming Spring Kong,
Timothy Ritter,
Douglas Quint,
Lon Marsh,
Suresh Senan,
Laurie Gaspar,
Ritsuko Komaki,
Coen Hurkmans,
Robert Timmerman,
Hak Choy,
Andrea Bezjak,
Jeffrey Bradley,
Benjamin Mosvas, Paul Okunieff,
Walter Curran
International journal of radiation oncology, biology, physics 10/2012; 84(2):305-6. · 4.59 Impact Factor
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Mei Zhang,
Liangjie Yin,
Kunzhong Zhang,
Weimin Sun,
Shanmin Yang,
Bingrong Zhang,
Peter Salzman,
Wei Wang,
Chaomei Liu,
Sadasivan Vidyasagar,
Lei Zhang,
Shaoqing Ju, Paul Okunieff,
Lurong Zhang
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ABSTRACT: To determine the plasma concentrations of acute responding cytokines/chemokines following 9-Gy ionizing radiation in C57BL/6 (radiation tolerant) and C3H/HeN (radiation sensitive) murine strains.
Mice (5/group) received 9-Gy total body irradiation (TBI), and the plasma from each mouse was collected at 6h or 1, 2, 4, or 10 days after TBI. A multiplex bead array was used to assess the levels of 32 cytokines/chemokines in plasma to determine their common and strain-specific temporal responses.
The plasma levels of five cytokines/chemokines (Axl, FasL, ICAM-1, TARC, and TSLP) were beyond the detectable level. Five (VEGF, IL-2, IL-5, IL-17, and CD30) were unaffected by irradiation in either strain. Temporal patterns were similar in both murine strains for 10 of the cytokines tested, including G-CSF, IL-6, TCA-3, MCP-1, MIP-1γ, KC, CXCL 13, CXCL 16, MDC, and TIMP-1; the other 12 molecules (GM-CSF, IL-3, SCF, IL-1β, IL-4, IL-10, IL-12p70, MIP-1α, Eotaxin, TNF-α, sTNF-R1, and CD40) showed strain-specific response patterns. While a number of cytokines had temporal response patterns following TBI, the strains exhibited quantitatively different results.
The levels of 27 of the 32 plasma cytokines measured indicate the following: (1) different cytokine concentrations and temporal patterns in the two strains may partly explain different radiation sensitivities and sequelae following irradiation; (2) many of the cytokines/chemokines exhibit similar temporal responses in the two strains. These responses suggest the potential value of using a panel of cytokine/chemokine temporal patterns for radiation dosimetry. Although radiation doses will be difficult to quantitate due to the large variation in levels and temporal responses exhibited in the two murine strains, serial measurements of cytokines might help identify subjects exposed to radiation.
Cytokine 01/2012; 58(2):169-77. · 3.02 Impact Factor
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Deping Han,
Mei Zhang,
Jun Ma,
Jingshen Hong,
Chun Chen,
Bingrong Zhang,
Luqiang Huang,
Wenlong Lv,
Liangjie Yin,
Amy Zhang,
Hengshan Zhang,
Zhenhuan Zhang,
Sadasivan Vidyasagar, Paul Okunieff,
Lurong Zhang
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ABSTRACT: Little is known about the effects of ionizing radiation on the transition and the related signal transduction of progenitor B cells in the bone marrow. Thus, using an NIH Swiss mouse model, we explored the impact of ionizing radiation on the early stage of B-cell development via an examination of the transition of CLP to pro-B to pre-B cells within bone marrow as a function of radiation doses and times. Our results showed that while the total number of bone marrow lymphoid cells at different stages were greatly reduced by subtotal body irradiation (sub-TBI), the surviving cells continued to transition from common lymphoid progenitors to pro-B and then to pre-B in a reproducible temporal pattern. The rearrangement of the immunoglobulin heavy chain increased significantly 1-2 weeks after irradiation, but no change occurred after 3-4 weeks. The rearrangement of the immunoglobulin light chain decreased significantly 1-2 weeks after sub-TBI but increased dramatically after 3-4 weeks. In addition, several key transcription factors and signaling pathways were involved in B-precursor transitions after sub-TBI. The data indicate that week 2 after irradiation is a critical time for the transition from pro-B cells to pre-B cells, reflecting that the functional processes for different B-cell stages are well preserved even after high-dose irradiation.
PLoS ONE 01/2012; 7(10):e46560. · 4.09 Impact Factor
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Steven B Zhang,
Mei Zhang,
Yongbing Cao,
Shanmin Yang,
Amy P Zhang,
Liangjie Yin,
Yeping Tian,
Kuzhong Zhang,
Yangsong Guo,
Xiaohui Wang,
Chun Chen,
Jun Ma,
Deping Han,
Alexandra Litvinchuk,
Steven Swarts,
Sadasivan Vidyasagar,
David Maguire,
Lurong Zhang, Paul Okunieff
Advances in experimental medicine and biology 01/2012; 737:139-45. · 1.09 Impact Factor
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Lei Zhang,
Mei Zhang,
Bingrong Zhang,
Yongbing Cao,
Shanmin Yang,
Liangjie Yin,
Yeping Tian,
Kunzhong Zhang,
Lulu Zhang,
Steven Swarts, Paul Okunieff,
Lurong Zhang
Advances in experimental medicine and biology 01/2012; 737:147-53. · 1.09 Impact Factor
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ABSTRACT: To analyze the long-term survival and tumor control outcomes after stereotactic body radiotherapy (SBRT) for metastases limited in number and extent.
We prospectively analyzed the long-term overall survival (OS) and cancer control outcomes of 121 patients with five or fewer clinically detectable metastases, from any primary site, metastatic to one to three organ sites, and treated with SBRT. Freedom from widespread distant metastasis (FFDM) was defined as metastatic disease not amenable to local therapy (i.e., resection or SBRT). Prognostic variables were assessed using log-rank and Cox regression analyses.
For breast cancer patients, the median follow-up was 4.5 years (7.1 years for 16 of 39 patients alive at the last follow-up visit). The 2-year OS, FFDM, and local control (LC) rate was 74%, 52%, and 87%, respectively. The 6-year OS, FFDM, and LC rate was 47%, 36%, and 87%, respectively. From the multivariate analyses, the variables of bone metastases (p = .057) and one vs. more than one metastasis (p = .055) were associated with a fourfold and threefold reduced hazard of death, respectively. None of the 17 bone lesions from breast cancer recurred after SBRT vs. 10 of 68 lesions from other organs that recurred (p = .095). For patients with nonbreast cancers, the median follow-up was 1.7 years (7.3 years for 7 of 82 patients alive at the last follow-up visit). The 2-year OS, FFDM, and LC rate was 39%, 28%, and 74%, respectively. The 6-year OS, FFDM, and LC rate was 9%, 13%, and 65%, respectively. For nonbreast cancers, a greater SBRT target volume was significantly adverse for OS (p = .012) and lesion LC (p < .0001). Patients whose metastatic lesions, before SBRT, demonstrated radiographic progression after systemic therapy experienced significantly worse OS compared with patients with stable or regressing disease.
Select patients with limited metastases treated with SBRT are long-term survivors. Future research should address the therapeutic benefit of SBRT for these patients.
International journal of radiation oncology, biology, physics 12/2011; 83(3):878-86. · 4.59 Impact Factor
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ABSTRACT: Standard therapy for metastatic non small cell lung cancer (NSCLC) includes palliative systemic chemotherapy and/or radiotherapy. Recent studies of patients with limited metastases treated with curative-intent stereotactic body radiation therapy (SBRT) have shown encouraging survival. We hypothesized that patients treated with SBRT for limited metastases have comparable outcomes with those treated with curative-intent radiation for Stage III NSCLC.
We retrospectively reviewed the records of NSCLC patients treated with curative-intent radiotherapy at the University of Rochester from 2000-2008. We identified 3 groups of patients with NSCLC: stage III, stage IV, and recurrent stage IV (initial stage I-II). All stage IV NSCLC patients treated with SBRT had ≤ 8 lesions.
Of 146 patients, 88% had KPS ≥ 80%, 30% had > 5% weight loss, and 95% were smokers. The 5-year OS from date of NSCLC diagnosis for stage III, initial stage IV and recurrent stage IV was 7%, 14%, and 27% respectively. The 5-year OS from date of metastatic diagnosis was significantly (p < 0.00001) superior among those with limited metastases (≤ 8 lesions) versus stage III patients who developed extensive metastases not amenable to SBRT (14% vs. 0%).
Stage IV NSCLC is a heterogeneous patient population, with a selected cohort apparently faring better than Stage III patients. Though patients with limited metastases are favorably selected by virtue of more indolent disease and/or less bulky disease burden, perhaps staging these patients differently is appropriate for prognostic and treatment characterization. Aggressive local therapy may be indicated in these patients, though prospective clinical studies are needed.
Radiation Oncology 06/2011; 6:80. · 2.32 Impact Factor
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ABSTRACT: While secretagogue-induced diarrhea is rich in chloride (Cl(-)) and bicarbonate (HCO(3) (-)) anions, little is known about diarrhea or its anionic composition following irradiation. We performed studies to characterize the differences between cyclic adenosine monophosphate (cAMP)-stimulated anion secretions in irradiated and non-irradiated mice.
HCO(3) (-) secretion was examined in basal, cAMP-stimulated, and irradiated jejunal tissues from BALB/c (Bagg albino) mice. The abdomens of the mice were γ-irradiated using a caesium-137 source.
Ussing-chamber experiments performed in an HCO(3)(-)-containing, Cl(-)-free solution on the bath side showed inhibition of HCO(3)(-) in irradiated mice. Non-irradiated mice exhibited bumetanide-sensitive and insensitive current, while irradiated mice displayed bumetanide-sensitive current. pH-stat experiments showed inhibition of basal and cAMP-stimulated HCO(3)(-) secretions in irradiated mice. Immunohistochemistry and Western blot analysis displayed a sodium-bicarbonate cotransporter expression in the villus and not the crypt of non-irradiated mice, while its expression and protein levels decreased in irradiated mice.
Anion secretions in irradiated mice, being primarily Cl(-) and minimally HCO(3)(-), differ from that of secretagogue-induced anion secretions. Understanding anion loss will help us correct electrolyte imbalances, while reduced HCO(3)(-) secretion in the upper-gastrointestinal tract might also have implications for irradiation-induced nausea and vomiting.
International Journal of Radiation Biology 06/2011; 87(8):878-88. · 2.28 Impact Factor
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ABSTRACT: Epidermal keratinocytes, which can be severely damaged after ionizing radiation (IR), are rapid turnover cells that function as a barrier, protecting the host from pathogenic invasion and fluid loss. We tested fibroblast growth factor-peptide (FGF-P), a small peptide derived from the receptor-binding domain of FGF-2, as a potential mitigator of radiation effects via proliferation and the barrier function of keratinocytes.
Keratinocytes isolated from neonatal foreskin were grown on transwells. After being exposed to 0, 5, or 10 Gy IR, the cells were treated with a vehicle or FGF-P. The permeability of IR cells was assessed by using transepithelial electrical resistance (TEER) and a paracellular tracer flux of fluorescein isothiocyanate-conjugated bovine serum albumin (FITC-BSA) with Ussing chambers. The cell proliferation was measured with yellow tetrazolium salt (MTT) and tritiated thymidine ([3H]-TdR) assays. The phosphorylation of extracellular signal-regulated kinases (ERK) was measured in an enzyme-linked immunosorbent (ELISA)-like assay, and the proteins related to tight junctions (TJ) and adherens junctions (AJ) were examined with Western blotting. We used a mouse model to assess the ability of FGF-P to promote the healing of skin β burns created with a strontium applicator.
We found (1) FGF-P reduced the permeability of irradiated keratinocytes, as evidenced by increased TEER and decreased diffusion of FITC-BSA, both associated with the regulation of different proteins and levels of TJ and AJ; and (2) FGF-P enhanced the proliferation of irradiated keratinocytes, as evidenced by increased MTT activity and [3H]-TdR incorporation, which was associated with activation of the ERK pathway; and (3) FGF-P promoted the healing of skin β burns.
FGF-P enhances the barrier function, including up-regulation of TJ proteins, increases proliferation of human keratinocytes, and accelerates the healing of skin β burns. FGF-P is a promising mitigator that improves the proliferation and barrier function of keratinocytes after IR.
International journal of radiation oncology, biology, physics 04/2011; 81(1):248-54. · 4.59 Impact Factor
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ABSTRACT: Treatment of patients who have locally advanced non-small-cell lung cancer and compromised performance status or weight loss (WL) is challenging. This study was conducted to test a low toxicity treatment regimen in this cohort.
Patients were treated with concurrent celecoxib and thoracic radiation therapy to 45 Gy in 15 fractions or 60 to 66 Gy in 30 to 33 fractions. Eligible patients had inoperable or unresectable stage IIB, IIIA/B NSCLC, performance status 2 and/or greater than 5% WL. In the phase I portion of the study, the starting dose of celecoxib was 200 mg twice daily with one dose escalation to 400 mg twice daily. Celecoxib was continued for 2 years or until progression.
The phase I component accrued eight patients each at 200 mg twice daily and 400 mg twice daily. Twice daily 400 mg was chosen for the phase II component, which enrolled five patients and was closed early because of poor accrual. We were able to analyze 18 patients. Performance status ratings were 0, 1, and 2 in 7, 7, and 4 patients, respectively. Median age was 72 years. WL of greater than 5% was noted in 10 patients (56%). Four of 10 had WL greater than or equal to 20%. Median follow-up and survival was 10 months. Overall survival rates at 1 and 2 years were 44.4% [95% confidence interval (CI), 21.6%-65.1%] and 22.2% (95% CI, 6.9%-42.9%), respectively. Progression-free survival at 1 year was 33.3% (95% CI, 13.7%-54.5%). Toxicities matched those expected with thoracic radiotherapy alone.
Concurrent thoracic radiation therapy and celecoxib was well tolerated. The sample size was too small to draw conclusions regarding efficacy.
Clinical Lung Cancer 03/2011; 12(2):125-30. · 2.94 Impact Factor
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Clifton D Fuller,
Jasper Nijkamp,
Joop C Duppen,
Coen R N Rasch,
Charles R Thomas,
Samuel J Wang, Paul Okunieff,
William E Jones,
Daniel Baseman,
Shilpen Patel, [......],
Benjamin D Smith,
Alan W Katz,
Camille McGann,
Jennifer L Harper,
Daniel T Chang,
Stephen Smalley,
David T Marshall,
Karyn A Goodman,
Niko Papanikolaou,
Lisa A Kachnic
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ABSTRACT: Variations in target volume delineation represent a significant hurdle in clinical trials involving conformal radiotherapy. We sought to determine the effect of a consensus guideline-based visual atlas on contouring the target volumes.
A representative case was contoured (Scan 1) by 14 physician observers and a reference expert with and without target volume delineation instructions derived from a proposed rectal cancer clinical trial involving conformal radiotherapy. The gross tumor volume (GTV), and two clinical target volumes (CTVA, including the internal iliac, presacral, and perirectal nodes, and CTVB, which included the external iliac nodes) were contoured. The observers were randomly assigned to receipt (Group A) or nonreceipt (Group B) of a consensus guideline and atlas for anorectal cancers and then instructed to recontour the same case/images (Scan 2). Observer variation was analyzed volumetrically using the conformation number (CN, where CN = 1 equals total agreement).
Of 14 evaluable contour sets (1 expert and 7 Group A and 6 Group B observers), greater agreement was found for the GTV (mean CN, 0.75) than for the CTVs (mean CN, 0.46-0.65). Atlas exposure for Group A led to significantly increased interobserver agreement for CTVA (mean initial CN, 0.68, after atlas use, 0.76; p = .03) and increased agreement with the expert reference (initial mean CN, 0.58; after atlas use, 0.69; p = .02). For the GTV and CTVB, neither the interobserver nor the expert agreement was altered after atlas exposure.
Consensus guideline atlas implementation resulted in a detectable difference in interobserver agreement and a greater approximation of expert volumes for the CTVA but not for the GTV or CTVB in the specified case. Visual atlas inclusion should be considered as a feature in future clinical trials incorporating conformal RT.
International journal of radiation oncology, biology, physics 02/2011; 79(2):481-9. · 4.59 Impact Factor
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ABSTRACT: Mitochondria play pivotal roles in cellular handling of oxygen and in apoptosis, the ordered suicide response of cells to irradiation. The involvement of expression products from the 16.5 kb human mitochondrial genome in these activities has been studied widely. However, little is known about effects of irradiation on mammalian mitochondrial DNA (mtDNA). The relative lack of mtDNA repair mechanisms compared with nuclear DNA (nDNA) predicts particular vulnerability to irradiation. Using a technique developed to ascertain mtDNA:nDNA ratios, we previously showed that this ratio increases dramatically in murine small bowel within 48 hours following whole body irradiation. We now report that those levels continue to rise for four days and remain elevated at close to that level beyond 30 days after 5 Gy of irradiation.We further demonstrate that levels of the mtDNA-specific DNA polymerase-γ (Pol-γ ) also show a sharp and sustained increase during this time course after a 2-Gy dose. Paradoxically, transcription factor A (TFAM), exhibited the directly opposite response.
Advances in experimental medicine and biology 01/2011; 701:201-6. · 1.09 Impact Factor
