[Show abstract][Hide abstract] ABSTRACT: Purpose To compare the interobserver and intermodality differences in image-based identification of head and neck primary site gross tumor volumes (GTV). Modalities compared include: contrast-enhanced CT, F-18 fluorodeoxyglucose positron emission tomography (PET/CT) and contrast-enhanced MRI. Methods and Materials Fourteen patients were simulated after immobilization for all 3 imaging modalities (CT, PET/CT, MRI). Three radiation oncologists (RO) contoured GTVs as seen on each modality. The GTV was contoured first on the contrast-enhanced CT (considered the standard), then on PET/CT, and finally on post-contrast T1 MRI. Interobserver and intermodality variability were analyzed by volume, intersection, union, and volume overlap ratio (VOR). Results Analysis of RO contours revealed the average volume for CT-, PET/CT-, and MRI-derived GTVs were 45cc, 35cc and 49cc, respectively. In 93% of cases PET/CT-derived GTVs had the smallest volume and in 57% of cases MRI-derived GTVs had the largest volume. CT showed the largest variation in target definition (standard deviation amongst observers 35%) compared to PET/CT (28%) and MRI (27%). The VOR was largest (indicating greatest interobserver agreement) in PET/CT (46%), followed by MRI (36%), followed by CT (34%). For each observer, the least agreement in GTV definition occurred between MRI & PET/CT (average VOR = 41%), compared to CT & PET/CT (48%) and CT & MRI (47%).
Conclusions A non-significant interobserver difference in GTVs for each modality was seen. Among three modalities, CT was least consistent, while PET/CT-derived GTVs had the smallest volumes and were most consistent. MRI combined with PET/CT provided the least agreement in GTVs generated. The significance of these differences for head & neck cancer is important to explore as we move to volume-based treatment planning based on multi-modality imaging as a standard method for treatment delivery.
[Show abstract][Hide abstract] ABSTRACT: To determine the risk of radiation-induced malignancy after prophylactic treatment for heterotopic ossification (HO).
A matched case-control study was conducted within a population-based cohort of 3489 patients treated either for acetabular fractures with acetabular open reduction internal fixation or who underwent total hip arthroplasty from 1990 to 2009. Record-linkage techniques identified patients who were diagnosed with a malignancy from our state health registry. Patients with a prior history of malignancy were excluded from the cohort. For each documented case of cancer, 2 controls were selected by stratified random sampling from the cohort that did not develop a malignancy. Matching factors were sex, age at time of hip treatment, and duration of follow-up.
A total of 243 patients were diagnosed with a malignancy after hip treatment. Five patients were excluded owing to inadequate follow-up time in the corresponding control cohort. A cohort of 238 cases (control, 476 patients) was included. Mean follow-up was 10 years, 12 years in the control group. In the cancer cohort, 4% of patients had radiation therapy (RT), compared with 7% in the control group. Of the 9 patients diagnosed with cancer after RT, none occurred within the field. The mean latency period was 5.9 years in the patients who received RT and 6.6 years in the patients who did not. Median (range) age at time of cancer diagnosis in patients who received RT was 62 (43-75) years, compared with 70 (32-92) years in the non-RT patients. An ad hoc analysis was subsequently performed in all 2749 patients who were not matched and found neither an increased incidence of malignancy nor a difference in distribution of type of malignancy.
We were unable to demonstrate an increased risk of malignancy in patients who were treated with RT for HO prophylaxis compared with those who were not.
International journal of radiation oncology, biology, physics 05/2014; · 4.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background: Adenoid cystic carcinoma (ACCs) are malignant salivary gland tumors noteworthy for high rates of late failure with limited salvage therapy options. We have previously shown increased Akt signaling is common in ACC and the HIV protease inhibitor nelfinavir (NFV) inhibits in vitro tumor growth by suppressing Akt signaling. This phase II trial was conducted to determine progression free survival in response to NFV in patients with recurrent/end stage ACC who have failed standard therapies. Methods: Eligible patients had recurrent or end stage ACC and measureable disease per Response Evaluation Criteria in Solid Tumors (RECIST) criteria. NFV was provided at 1250 mg twice daily. Results: Among 15 trial participants, median progression free survival was 5.5 months (lower 95% bound 4.4 months). No patient achieved a RECIST partial or complete response to therapy. Conclusion: NFV monotherapy does not result in a meaningful improvement in clinical outcomes among patients with recurrent ACC. Head Neck, 2014
[Show abstract][Hide abstract] ABSTRACT: To quantify the dosimetric impact of applicator displacements and applicator reconstruction-uncertainties through simulated planning studies of virtual applicator shifts.
Twenty randomly selected high-dose-rate (HDR) titanium tandem-and-ovoid (T&O) plans were retrospectively studied. MRI-guided, conformal brachytherapy (MRIG-CBT) plans were retrospectively generated. To simulate T&O displacement, the whole T&O set was virtually shifted on treatment planning system in the cranial (+) and the caudal (-) direction after each dose calculation. Each shifted plan was compared to an unshifted plan. To simulate T&O reconstruction-uncertainties, each tandem and ovoid was separately shifted along its axis before performing the dose calculation. After the dose calculation, the calculated isodose lines and T&O were moved back to unshifted T&O position. Shifted and shifted-back plan were compared.
Regarding the dosimetric impact of the simulated T&O displacements, rectal D2cc values were observed as being the most sensitive to change due to T&O displacement among all dosimetric metrics regardless of point A (p < 0.013) or MRIG-CBT plans (p < 0.0277). To avoid more than 10% change, ± 1.5 mm T&O displacements were accommodated for both point A and MRIG-CBT plans. The dosimetric impact of T&O displacements on sigmoid (p < 0.0005), bladder (p < 0.0001), HR-CTV (p < 0.0036), and point A (p < 0.0015) were significantly larger in the MRIG-CBT plans than point A plans. Regarding the dosimetric impact of T&O reconstruction-uncertainties, less than ± 3.0 mm reconstruction-uncertainties were also required in order to avoid more than 10% dosimetric change in either the point A or MRIG-CBT plans.
The dosimetric impact of simulated T&O displacements was significantly larger in the MRIG-CBT plans than in the point A plans. Either ± 3 mm T&O displacement or a ± 4.5 mm T&O reconstruction-uncertainty could cause greater than 10% dosimetric change for both point A plans and MRIG-CBT plans.
Journal of Contemporary Brachytherapy 12/2013; 5(4):250-7.
[Show abstract][Hide abstract] ABSTRACT: In this treatment planning study, the potential benefits of a rotating shield brachytherapy (RSBT) technique based on a partially-shielded electronic brachytherapy source were assessed for treating cervical cancer. Conventional intracavitary brachytherapy (ICBT), intracavitary plus supplementary interstitial (IS+ICBT), and RSBT treatment plans for azimuthal emission angles of 180° (RSBT-180) and 45° (RSBT-45) were generated for five patients. For each patient, high-risk clinical target volume (HR-CTV) equivalent dose in 2 Gy fractions (EQD2) (α/β = 10 Gy) was escalated until bladder, rectum, or sigmoid colon tolerance EQD2 values were reached. External beam radiotherapy dose (1.8 Gy × 25) was accounted for, and brachytherapy was assumed to have been delivered in 5 fractions. IS+ICBT provided a greater HR-CTV D90 (minimum EQD2 to the hottest 90%) than ICBT. D90 was greater for RSBT-45 than IS+ICBT for all five patients, and greater for RSBT-180 than IS+ICBT for two patients. When the RSBT-45/180 plan with the lowest HR-CTV D90 that was greater than the D90 the ICBT or IS+ICBT plan was selected, the average (range) of D90 increases for RSBT over ICBT and IS+ICBT were 16.2 (6.3-27.2)and 8.5 (0.03-20.16) Gy, respectively. The average (range) treatment time increase per fraction of RSBT was 34.56 (3.68-70.41) min over ICBT and 34.59 (3.57-70.13) min over IS+ICBT. RSBT can increase D90 over ICBT and IS+ICBT without compromising organ-at-risk sparing. The D90 and treatment time improvements from RSBT depend on the patient and shield emission angle.
Physics in Medicine and Biology 06/2013; 58(11):3931-41. · 2.92 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: PET-CT images have been widely used in clinical practice for radiotherapy treatment planning of the radiotherapy. Many existing segmentation approaches only work for a single imaging modality, which suffer from the low spatial resolution in PET or low contrast in CT. In this work we propose a novel method for the co-segmentation of the tumor in both PET and CT images, which makes use of advantages from each modality: the functionality information from PET and the anatomical structure information from CT. The approach formulates the segmentation problem as a minimization problem of a Markov Random Field (MRF) model, which encodes the information from both modalities. The optimization is solved using a graph-cut based method. Two sub-graphs are constructed for the segmentation of the PET and the CT images, respectively. To achieve consistent results in two modalities, an adaptive context cost is enforced by adding context arcs between the two subgraphs. An optimal solution can be obtained by solving a single maximum flow problem, which leads to simultaneous segmentation of the tumor volumes in both modalities. The proposed algorithm was validated in robust delineation of lung tumors on 23 PET-CT datasets and two head-and-neck cancer subjects. Both qualitative and quantitative results show significant improvement compared to the graph cut methods solely using PET or CT.
[Show abstract][Hide abstract] ABSTRACT: Purpose: The authors present a rapid emission angle selection (REAS) method that enables the efficient selection of the azimuthal shield angle for rotating shield brachytherapy (RSBT). The REAS method produces a Pareto curve from which a potential RSBT user can select a treatment plan that balances the tradeoff between delivery time and tumor dose conformity.Methods: Two cervical cancer patients were considered as test cases for the REAS method. The RSBT source considered was a Xoft Axxent(TM) electronic brachytherapy source, partially shielded with 0.5 mm of tungsten, which traveled inside a tandem intrauterine applicator. Three anchor RSBT plans were generated for each case using dose-volume optimization, with azimuthal shield emission angles of 90°, 180°, and 270°. The REAS method converts the anchor plans to treatment plans for all possible emission angles by combining neighboring beamlets to form beamlets for larger emission angles. Treatment plans based on exhaustive dose-volume optimization (ERVO) and exhaustive surface optimization (ERSO) were also generated for both cases. Uniform dwell-time scaling was applied to all plans such that that high-risk clinical target volume D90 was maximized without violating the D2cc tolerances of the rectum, bladder, and sigmoid colon.Results: By choosing three azimuthal emission angles out of 32 potential angles, the REAS method performs about 10 times faster than the ERVO method. By setting D90 to 85-100 Gy10, the delivery times used by REAS generated plans are 21.0% and 19.5% less than exhaustive surface optimized plans used by the two clinical cases. By setting the delivery time budget to 5-25 and 10-30 min∕fx, respectively, for two the cases, the D90 contributions for REAS are improved by 5.8% and 5.1% compared to the ERSO plans. The ranges used in this comparison were selected in order to keep both D90 and the delivery time within acceptable limits.Conclusions: The REAS method enables efficient RSBT treatment planning and delivery and provides treatment plans with comparable quality to those generated by exhaustive replanning with dose-volume optimization.
Medical Physics 05/2013; 40(5):051720. · 3.01 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To evaluate tumor volume changes that occurred during courses of high-dose-rate brachytherapy (HDR) using high resolution (3.0 Tesla) magnetic resonance imaging (MRI), along with the regression after external beam radiation therapy (EBRT).
Fourteen patients with International Federation of Gynecology and Obstetrics stage IB1-IV cervical cancer were studied retrospectively. All patients underwent EBRT with concurrent chemotherapy followed by HDR brachytherapy. Gross tumor volume (GTV) and high-risk clinical target volume (HR-CTV) were contoured on a 3.0 Tesla MRI on the day of the HDR and on diagnostic MRI (1.5 Tesla) prior to EBRT. Two physicians independently contoured the GTV and HR-CTV on a total of 46 MRI data sets for the HDR plans. The percent volume changes of GTV and HR-CTV were quantified after EBRT and again after each HDR. The conformity indices (CIs) of the 2 contours were assessed.
GTV and HR-CTV considerably regressed after the first ( --31.7% ± 19.3% and --26.4% ± 6.9%, respectively) and the second (--26.8% ± 14.3% and --23.8% ± 11.0%) fraction of HDR while relatively small regressions were observed after the third (--16.3% ± 14.2% and --10.6% ± 13.4%) and the fourth (--8.0% ± 3.4% and --9.0% ± 8.0%) fractions. The lymph node-positive on positron emission tomography (PET) and stage III or IV group showed, on average, more than 200% larger GTV and HR-CTV before EBRT than those of the other patients. The GTV and HR-CTV for the group were larger on average more than 150% after EBRT and before the first HDR fraction than the other group. Interobserver CI did not vary significantly (0.75 ± 0.11) for HR-CTV, although a smaller CI (0.56 ± 0.21) was found for GTV.
Larger tumor regressions were observed after the first and second fractions of HDR than after all subsequent fractions. The PET-identified lymph node-positive patient group and stage III or higher tumors showed larger tumor volumes before and after EBRT than other cases.
[Show abstract][Hide abstract] ABSTRACT: The purpose of this work was to develop and validate fully automated methods for uptake measurement of cerebellum, liver, and aortic arch in full-body PET/CT scans. Such measurements are of interest in the context of uptake normalization for quantitative assessment of metabolic activity and/or automated image quality control.
Cerebellum, liver, and aortic arch regions were segmented with different automated approaches. Cerebella were segmented in PET volumes by means of a robust active shape model (ASM) based method. For liver segmentation, a largest possible hyperellipsoid was fitted to the liver in PET scans. The aortic arch was first segmented in CT images of a PET/CT scan by a tubular structure analysis approach, and the segmented result was then mapped to the corresponding PET scan. For each of the segmented structures, the average standardized uptake value (SUV) was calculated. To generate an independent reference standard for method validation, expert image analysts were asked to segment several cross sections of each of the three structures in 134 F-18 fluorodeoxyglucose (FDG) PET/CT scans. For each case, the true average SUV was estimated by utilizing statistical models and served as the independent reference standard.
For automated aorta and liver SUV measurements, no statistically significant scale or shift differences were observed between automated results and the independent standard. In the case of the cerebellum, the scale and shift were not significantly different, if measured in the same cross sections that were utilized for generating the reference. In contrast, automated results were scaled 5% lower on average although not shifted, if FDG uptake was calculated from the whole segmented cerebellum volume. The estimated reduction in total SUV measurement error ranged between 54.7% and 99.2%, and the reduction was found to be statistically significant for cerebellum and aortic arch.
With the proposed methods, the authors have demonstrated that automated SUV uptake measurements in cerebellum, liver, and aortic arch agree with expert-defined independent standards. The proposed methods were found to be accurate and showed less intra- and interobserver variability, compared to manual analysis. The approach provides an alternative to manual uptake quantification, which is time-consuming. Such an approach will be important for application of quantitative PET imaging to large scale clinical trials.
Medical Physics 06/2012; 39(6):3112-23. · 3.01 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Overexpression of manganese superoxide dismutase (MnSOD), when combined with certain chemicals that inhibit peroxide removal, increases cancer cell cytotoxicity. Elevating MnSOD levels in cells enhances the conversion of superoxide (O(2)(*-)) to hydrogen peroxide (H(2)O(2)), combined with inhibiting the removal of H(2)O(2), further increases H(2)O(2) levels, leading to increased cytotoxicity. We hypothesized that increasing endogenous O(2)(*-) production in cells that were pretreated with adenoviral MnSOD (AdMnSOD) plus 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) would lead to an increased level of intracellular H(2)O(2) accumulation and increased cell killing. The cytotoxic effects of Adriamycin or radiation, agents known to produce O(2)(*-), were determined in MDA-MB-231 breast cancer cells pretreated with AdMnSOD plus BCNU both in vitro and in vivo. In vitro, AdMnSOD plus BCNU sensitized cells to the cytotoxicity of Adriamycin or radiation. In vivo, AdMnSOD, BCNU, and Adriamycin or ionizing radiation inhibited tumor growth and prolonged survival. The results suggest that agents that produce O(2)(*-) in combination with AdMnSOD plus BCNU may represent a powerful new antitumor regimen against breast cancer.
Cancer Research 05/2009; 69(10):4294-300. · 9.28 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: AP-2alpha and c-MYC are important transcription factors involved in multiple cellular processes. They each display the paradoxical capacities to stimulate both cell proliferation and apoptosis under different conditions. In the present study we found that over expression of c-MYC was associated with accumulation of reactive oxygen species (ROS) and apoptosis in human keratinocytes, both of which were significantly inhibited by co-expression of AP-2. The effects of AP-2 on c-MYC were active at several levels. First, AP-2 and c-MYC were confirmed to interact at the protein level as previously described. In addition, forced expression of AP-2 significantly decreased steady state levels of c-MYC mRNA and protein. These findings suggested that AP-2 may have a direct effect on the c-myc gene. Chromatin immunoprecipitation assays demonstrated that AP-2 proteins bound to a cluster of AP-2 binding sites located within a 2 kb upstream regulatory region of c-myc These results suggest that the negative regulation of AP-2 on c-MYC activity was achieved through binding of AP-2 protein to the c-myc gene. The effects of AP-2 on c-MYC induced ROS accumulation and apoptosis in epidermal keratinocytes are likely to play an important role in cell growth, differentiation and carcinogenesis of the skin.
[Show abstract][Hide abstract] ABSTRACT: Superoxide dismutases (SODs) have been found to decrease tumor formation and angiogenesis. SOD gene therapy, as with many other gene transfer strategies, may not completely inhibit tumor growth on its own. Thus, concomitant therapies are necessary to completely control the spread of this disease. We hypothesized that intratumoral injection of AdSOD in combination with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) chemotherapy would synergistically inhibit breast cancer growth. Our data indicate that BCNU when combined with SOD overexpression increased oxidative stress as suggested by elevated glutathione disulfide (GSSG) production in one of three breast cancer cell lines tested, at least in part due to glutathione reductase (GR) inactivation. The increased oxidative stress caused by BCNU combined with adenovirally expressed SODs, manganese or copper zinc SOD, decreased growth and survival in the three cell lines tested in vitro, but had the largest effect in the MDA-MB231 cell line, which showed the largest amount of oxidative stress. Delivery of MnSOD and BCNU intratumorally completely inhibited MDA-MB231 xenograft growth and increased nude mouse survival in vivo. Intravenous (iv) BCNU, recapitulating clinical usage, and intratumoral AdMnSOD delivery, to provide tumor specificity, provided similar decreased growth and survival in our nude mouse model. This cancer therapy produced impressive results, suggesting the potential use of oxidative stress-induced growth inhibitory treatments for breast cancer patients.
Free Radical Biology and Medicine 04/2008; 44(5):856-67. · 5.71 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The aim of the present study was to compare the effects of the three different forms of the antioxidant enzyme superoxide dismutase [i.e., manganese superoxide dismutase (MnSOD), copper zinc superoxide dismutase (CuZnSOD), and extracellular superoxide dismutase (EcSOD)] on the malignant phenotype of human pancreatic cancer.
Human pancreatic cancer cell lines were infected with adenoviral vectors containing the cDNAs for three different forms of the antioxidant enzyme SOD. Intratumoral injections of the adenoviral vectors were used in nude mice with human tumor xenografts.
Increases in immunoreactive protein and enzymatic activity were seen after infections with the AdMnSOD, AdCuZnSOD, or AdEcSOD constructs. Increased SOD activity decreased superoxide levels and increased hydrogen peroxide levels. Increasing SOD levels correlated with increased doubling time. Cell growth and plating efficiency decreased with increasing amounts of the adenoviral constructs, with the AdCuZnSOD vector having the greatest effect in decreasing in vitro tumor growth. In contrast, inhibiting endogenous SOD with small interfering RNA increased superoxide levels and promoted tumor growth. Of the three SODs, tumors grew the slowest and survival was increased the greatest in nude mice injected with the AdEcSOD construct.
Scavenging plasma membrane-generated superoxide may prove beneficial for suppression of pancreatic cancer growth.
Clinical Cancer Research 01/2008; 13(24):7441-50. · 8.19 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Phospholipid glutathione peroxidase (PhGPx) reduces lipid hydroperoxides generated in biomembranes and also uses a wide range of reducing cofactors in addition to glutathione. PhGPx is synthesized as a mitochondrial PhGPx form (L-form) and as a nonmitochondrial PhGPx form (S-form). Our aims were to determine whether overexpression of PhGPx altered pancreatic tumor cell behavior. Pancreatic cancer cell lines were found by Western blotting to have diminished levels of PhGPx-immunoreactive protein compared with normal human pancreas. To normalize the levels of this protein, PhGPx was overexpressed in MIA PaCa-2 and AsPC-1 human pancreatic cancer cells by infection with an adenovirus-PhGPx L-form construct (AdPhGPx- L-form) (0-200 MOI) or with an adenovirus-PhGPx S-form construct (AdPhGPx-S-form) (0-200 MOI), and cell growth, plating efficiency, and growth in soft agar were determined. Pancreatic cancer cells were also injected subcutaneously into nude mice and tumor volume was calculated. Single direct injections of the adenoviral- PhGPx constructs were made into preestablished tumors. In vitro, AdPhGPx-S-form demonstrated 80% tumor growth inhibition, whereas AdPhGPx-L-form demonstrated 95% tumor growth inhibition. Ad- PhGPx-L-form or AdPhGPx-S-form also decreased plating efficiency and growth in soft agar. AdPhGPx-Lform decreased in vivo tumor growth to a greater extent than did AdPhGPx-S-form. Because of the growthinhibitory effects of PhGPx, lipid hydroperoxides may play an important role in the growth of pancreatic cancer.
Human Gene Therapy 02/2006; 17(1):105-16. · 3.62 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Pancreatic cancer has low levels of antioxidant enzymes including manganese superoxide dismutase (MnSOD), which converts superoxide radical (O(2)(*-)) into hydrogen peroxide (H(2)O(2)), and glutathione peroxidase (GPx), which converts H(2)O(2) into water. Recent studies have demonstrated that overexpression of MnSOD has a tumor-suppressive effect in pancreatic cancer. However, GPx overexpression has been shown to reverse the tumor cell growth inhibition caused by MnSOD overexpression in other types of cancer. Our aims were to determine if overexpression of GPx alters in vitro pancreatic cancer cell behavior and if delivering the GPx gene directly to tumor xenografts alters growth and survival. In vitro, AdGPx slowed tumor growth by 39% and AdMnSOD slowed tumor growth by 35%. AdGPx also decreased plating efficiency and growth in soft agar. The combination of AdGPx and AdMnSOD had the greatest effect on tumor cell growth suppression with a 71% reduction in cell growth compared to controls. In vivo, either AdGPx or AdMnSOD alone slowed tumor growth by 51% and 54%, respectively, while the combination of AdGPx and AdMnSOD potentiated tumor growth suppression by 81% of controls and increased animal survival. GPx may be a tumor suppressor gene in pancreatic cancer. Delivery of the GPx gene alone or in combination with the MnSOD gene may prove beneficial for treatment of pancreatic cancer.
Human Gene Therapy 04/2004; 15(3):239-50. · 3.62 Impact Factor