Therapy For Treatment Of Lung Cancer Research Articles

2471: Microbeam radiation therapy for lung cancer treatment: a systematic review of the literature

2471: Microbeam radiation therapy for lung cancer treatment: a systematic review of the literature

Silencing circLDLRAD3 Inhibits Lung Cancer Progression by Regulating the miR-497-5p/PFKP Axis.

Lung cancer is one of the leading causes of death worldwide. Recent studies have shown that circular RNAs are dysregulated in a variety of cancers, but the mechanism in lung cancer is still indistinct. In our work, we explored the action mechanism of circLDLRAD3 in lung cancer. The abundance of circLDLRAD3, microRNA-497-5p (miR-497-5p) and platelet-type PFK (PFKP) was measured by real-time quantitative polymerase chain reaction (RT-qPCR) in lung cancer. Meanwhile, the level of PFKP was quantified by western blot. Cell counting kit-8 (CCK-8), 5-Ethynyl-2'-deoxyuridine (EdU) assay, transwell assay, wound healing assay, flow cytometry, western blot, immunohistochemical (IHC) assay and glycolysis metabolism analysis were performed for functional analyses. Furthermore, the interplay between miR-497-5p and circLDLRAD3 or FKPF was detected by the dual-luciferase reporter and RNA Immunoprecipitation (RIP) assays. Eventually, the in vivo experiments were applied to measure the role of circLDLRAD3. The levels of circLDLRAD3 and PFKP were increased. Silencing circLDLRAD3 inhibited cell viability, proliferation, migration, invasion and glycolysis metabolism and promoted cell apoptosis in lung cancer cells. In mechanism, circLDLRAD3 regulated PFKP level as a miR-497-5p sponge. MiR-497-5p suppressed the progression of lung cancer by inhibiting PFKP. In addition, circLDLRAD3 knockdown also inhibited tumor growth in vivo. CircLDLRAD3 promoted the development of lung cancer through increasing PFKP expression by regulating miR-497-5p, which also provided a potential targeted therapy for lung cancer treatment.

Harnessing p53 to Improve Immunotherapy for Lung Cancer Treatment.

Immunotherapy, especially immune checkpoint blockade (ICB), has become a critical therapy for lung cancer treatment in recent years. Tumor mutational burden (TMB) is one of the decisive biomarkers for predicting ICB effect. Writing in Cancer Cell, Zhu and colleagues use autochthonous and syngeneic mouse models to show that p53 mutation and tumor heterogeneity may be responsible for resistance in patients with lung cancer. Pole-induced high TMB shows enhanced immunogenicity in KrasG12D mice, however, loss of p53 in KrasG12D PoleP286/+ mice can lead to an immune suppressive profile of lung tumors, which diminishes immune response to ICB. Moreover, high TMB causes high shared mutations, which helps promote immune protection and immune memory. Heterogeneity can drive immune escape to tumor cells causing resistance to ICB. Decreased cGAS/STING signaling may explain possible resistance to ICB. On the basis of the new model found by Zhu and colleagues for lung cancer, combined ICB with STING agonists or p53 inducers may be new therapeutic options to improve the efficacy of ICB for patients with lung cancer with high TMB.

Nonlinear free convective pulsatile magnetohydrodynamic flow in a nonlinearly radiated and Ohmic heated porous channel filled with third-grade fluid properties and combinations of nanoparticles: Entropy generation

This work explores the effect of Ohmic heating, thermal radiation, and viscous dissipation on the third-grade hybrid nanofluid’s magnetohydrodynamic pulsatile flow in a porous channel. While alumina and Gold are nanoparticles, blood was recognized as a third-grade fluid. The significance of mathematical modelling of biological fluids is evident in many medical disciplines, using magnetic fields to regulate blood flow during surgery and radiation therapy for lung cancer treatment. In Maple 2018, a system of ODE was created from the governing PDE, and then shooting approach was used to resolve the scenario. The important characteristics of emergent factors are presented through graphical representations. The findings show that the velocity falls when the non-Newtonian parameter and Hartmann number increase. As the viscous dissipation rate grows, the temperature of the nanofluid increases whereas heat transfer rate also improved. But heat transfer rate was reduced when the thermal radiation and magnetic field was increased.

Exacerbation of symptoms of rheumatoid arthritis in the course of immunotherapy of non-small cell lung cancer - an analysis of medical cases and a review of the literature

Background: Lung cancer has been at the forefront of cancers with the highest incidence and mortality rates. Nowadays, there are available more effective forms of treatment such as immunotherapy. In the case of cancer cells expressing the PD-L1 receptor, pembrolizumab, atezolizumab and nivolmab are of particular use. While these drugs have the great benefit of stabilizing the disease, they are not without side effects, especially inflammatory changes in the joints. The aim of the study is to show the risk of immunotherapy in the form of exacerbation of inflammatory symptoms in patients with rheumatoid arthritis (RA) as a concomitant disease. Case report: Lung cancer (PD-L1 +) was diagnosed in three patients with a history of RA. After meeting the criteria of the drug program, the patients started molecularly targeted therapy with pembrolizumab and atezolizumab. The applied treatment brought a great benefit in the form of stabilization the neoplastic disease. Over time an exacerbation of inflammatory changes within the joints was noted, which significantly impeded everyday functioning in two patients. Due to this situation, immunotherapy was discontinued. Conlusions: Studies show that as many as 1/4 of patients treated with PD-L1 inhibitors experience side effects related to the autoimmune system. In the case of people suffering from RA, the use of immunotherapy may intensify inflammatory changes and increase pain, which significantly reduce the quality of life. Therefore, the risk of RA exacerbation as a side effect of biological therapy for lung cancer treatment should be popularized. This awareness will enable quick intervention and minimize the number of interrupted immunotherapies.

Bio-magnetic pulsatile CuO−Fe3O4 hybrid nanofluid flow in a vertical irregular channel in a suspension of body acceleration

Mathematical modelling of biological fluids is essential in various medical disciplines. The current work has many biomechanical applications, including radiation therapy for lung cancer treatment and magnetic field strength to regulate blood flow during surgery. The current model deals with the pulsatile hybrid nanofluid flow in a vertically permeable irregular channel under the influence of externally applied body acceleration. Thermal radiation and heat source have been included in the heat transfer analysis. The velocity, temperature, heat transfer rate, and isothermal lines are produced using the perturbation approach to evaluate coupled equations with the nonlinear problem. In addition, response surface method is executed to probe the sensitivity of effective flow field parameters on the heat transfer rate. It is found that the hybrid nanoparticles expose a lower blood temperature than the mono nanoparticles; as a result, the hybrid nanoparticles have better drug delivery performance. The blood velocity decreases with increasing the values of the body force parameter. In addition, the blood flow is higher for CuO nanofluid than the CuO-Fe3O4 hybrid nanofluid, but this case is quite the opposite for lower values of frequency parameter.

Hydroquinone 5-O-Cinnamoyl Ester of Renieramycin M Suppresses Lung Cancer Stem Cells by Targeting Akt and Destabilizes c-Myc.

Cancer stem cells (CSCs) are distinct cancer populations with tumorigenic and self-renewal abilities. CSCs are drivers of cancer initiation, progression, therapeutic failure, and disease recurrence. Thereby, novel compounds targeting CSCs offer a promising way to control cancer. In this study, the hydroquinone 5-O-cinnamoyl ester of renieramycin M (CIN-RM) was demonstrated to suppress lung cancer CSCs. CIN-RM was toxic to lung cancer cells with a half-maximal inhibitory concentration of around 15 µM. CIN-RM suppressed CSCs by inhibiting colony and tumor spheroid formation. In addition, the CSC population was isolated and treated and the CSCs were dispatched in response to CIN-RM within 24 h. CIN-RM was shown to abolish cellular c-Myc, a central survival and stem cell regulatory protein, with the depletion of CSC markers and stem cell transcription factors ALDH1A1, Oct4, Nanog, and Sox2. For up-stream regulation, we found that CIN-RM significantly inhibited Akt and consequently decreased the pluripotent transcription factors. CIN-RM also inhibited mTOR, while slightly decreasing p-GSK3β (Ser9) but rarely affected the protein kinase C (PKC) signal. Inhibiting Akt/mTOR induced ubiquitination of c-Myc and promoted degradation. The mechanism of how Akt regulates the stability of c-Myc was validated with the Akt inhibitor wortmannin. The computational analysis further confirmed the strong interaction between CIN-RM and the Akt protein with a binding affinity of −10.9 kcal/mol at its critical active site. Taken together, we utilized molecular experiments, the CSC phenotype, and molecular docking methods to reveal the novel suppressing the activity of this compound on CSCs to benefit CSC-targeted therapy for lung cancer treatment.

A Review of Chemotherapy and Photodynamic Therapy for Lung Cancer Treatment

A Review of Chemotherapy and Photodynamic Therapy for Lung Cancer Treatment

A Review of Chemotherapy and Photodynamic Therapy for Lung Cancer Treatment

A Review of Chemotherapy and Photodynamic Therapy for Lung Cancer Treatment

Novel Frog Skin-Derived Peptide Dermaseptin-PP for Lung Cancer Treatment: In vitro/vivo Evaluation and Anti-tumor Mechanisms Study.

Lung cancer is the major cause of cancer deaths worldwide, and it has the highest incidence and mortality rate of any cancer among men and women in China. The first-line therapy for lung cancer treatment is platinum-based chemotherapy drugs such as cisplatin. However, the application of present chemotherapies is limited by severe side effects, which stimulates the discovery of new drugs with new anti-tumor mechanisms and fewer side effects. Beneficially, many antimicrobial peptides (AMPs) from frog skin have been reported to exhibit potent anti-cancer activities with low toxicity, high selectivity and a low propensity to induce resistance. In this study, we first reported an AMP named Dermaseptin-PP, from a rarely studied frog species, Phyllomedusa palliata. Dermaseptin-PP exhibited selective cytotoxicity on H157, MCF-7, PC-3, and U251 MG cancer cells instead of normal HMEC-1 cells with low hemolytic effect. Furthermore, on subcutaneous H157 tumor model of nude mice, Dermaseptin-PP was found to display potent in vivo anti-tumor activity in a dose-related manner without obvious hepatopulmonary side effects. It is widely accepted that AMPs usually work through a membrane disruptive mode, and the confocal laser microscope observation confirmed that Dermaseptin-PP could destroy H157 cell membranes. Further investigation of mechanisms by flow cytometry assay and immunohistochemical analysis unraveled that Dermaseptin-PP also exerted its anti-tumor activity by inducing H157 cell apoptosis via both endogenous mitochondrial apoptosis pathway and exogenous death receptor apoptosis pathway. Herein, we emphasize that the membrane disrupting and the apoptosis activation effects of Dermaseptin-PP both depend on its concentration. Overall, a novel frog skin-derived AMP, named Dermaseptin-PP, was identified for the first time. It possesses strong antimicrobial activity and effective anti-tumor activity by distinct mechanisms. This study revealed the possibility of Dermaseptin-PP for lung cancer treatment and provided a new perspective for designing novel AMP-based anti-tumor candidates with low risk of cytotoxicity.

A Review of Chemotherapy and Photodynamic Therapy for Lung Cancer Treatment

Cancer is among the leading causes of mortality and morbidity worldwide. Among the different types of cancers, lung cancer is considered to be the leading cause of death related to cancer and the most commonly diagnosed form of such disease. Chemotherapy remains a dominant treatment modality for many types of cancers at different stages. However, in many cases, cancer cells develop drug resistance and become nonresponsive to chemotherapy, thus, necessitating the exploration of alternative and /or complementary treatment modalities. Photodynamic Therapy (PDT) has emerged as an effective treatment modality for various malignant neoplasia and tumors. In PDT, the photochemical interaction of light, Photosensitizer (PS) and molecular oxygen produces Reactive Oxygen Species (ROS), which induces cell death. Combination therapy, by using PDT and chemotherapy, can promote synergistic effect against this fatal disease with the elimination of drug resistance, and enhancement of the efficacy of cancer eradication. In this review, we give an overview of chemotherapeutic modalities, PDT, and the different types of drugs associated with each therapy. Furthermore, we also explored the combined use of chemotherapy and PDT in the course of lung cancer treatment and how this approach could be the last resort for thousands of patients that have been diagnosed by this fatal disease.

Miniature Non-thermal Plasma Induced Cell Cycle Arrest and Apoptosis in Lung Carcinoma Cells

Non-thermal plasma has been a promising new cancer treatment modality in plasma oncology field. It generates extracellular and intracellular reactive species which are key factors for the treatment of cancer cells. In this study, we investigated the differential effect of non-thermal plasma on both A549 lung adenocarcinoma and MRC-5 lung fibroblast cells. Extracellular generation of reactive species in both A549 lung cancer and MRC-5 normal lung fibroblast cells were similar, whereas intracellular penetration of reactive species generated by plasma in A549 cancer cells were almost fourfold higher than the normal cells. Interestingly, A549 cancer cells treated for shorter (15 and 30 s) and longer durations (60 and 120 s) get arrested in S-phase (19%) and G2/M phase (28%) respectively. In a healthy MRC-5 cells, few cells arrested in S and G2/M phase in relative to A549 cells for all treatment time. Finally, we evaluated the expression of apoptosis-related genes, H2AX, BAX, P53, Caspase-8, and ATM on normal and cancer cells. There was a higher expression of BAX gene for 120 s plasma treated A549 cell samples at day 1 relative to MRC-5 cells. These findings demonstrate that non-thermal plasma generated reactive species creates intracellular stress, that arrests cell cycle and induces apoptosis in cancer cells. This study suggests that non-thermal plasma could be a potential therapy for lung cancer treatment.

Role of Anti-EGFR Targeted Therapies in Stage III Locally Advanced Non-small Cell Lung Cancer: Give or Not to Give?

Identification of targetable mutations such as EGFR has allowed opportunity for Tyrosine Kinase Inhibitor (TKI) therapy for lung cancer treatment. EGFR-TKIs have revolutionized treatment of advanced EGFR mutant Non-Small Cell Lung Cancer (NSCLC), but there is little evidence that EGFR-TKI treatment is effective in stage III NSCLC. Here we discuss recent evidence supporting the use of EGFR-TKI therapy in combination with chemotherapy and radiation in stage III NSCLC. Recent results of small trials testing EGFR-TKI therapy in combination with chemoradiation showed promising efficacy, improved outcomes, and a tolerable toxicity profile when administered to patients with EGFR mutant stage III NSCLC. However, strong supporting evidence regarding EGFR-TKI therapy in stage III NSCLC is lacking because previous trials involved a small patient population or were terminated due to slow participant accrual. Despite the lack of large randomized clinical trials, results from early-stage trials highlight promising future directions for investigating the use of EGFR-TKI therapy in stage III NSCLC treatment.

Abstract 3751: Apoptosis inducer gene delivery by polylysine-calcium complexes attenuates mouse lung carcinoma allograft growth after intravenous injection or intratracheal spray

Abstract Transfection efficiency and toxicity concerns remain a challenge for gene therapy. Nanoparticle-based gene delivery technique potentially overcomes these concerns and may be applicable to cancer gene therapy. Cell penetrating peptides (CPPs) have been broadly investigated to improve the transfection of genetic material (e.g., pDNA and siRNA). Our previous study demonstrated that an apoptosis inducer, angiotensin II type 2 receptor plasmid DNA (pAT2R) encapsulated in a modified HIV-1 TAT peptide (dTAT-pAT2R), significantly attenuated the growth of Lewis lung carcinoma (LLC) allograft in mouse lungs (Kawabata et al., Cancer Res, 2012). Here, we report a newly synthesized polylysine CPP (K9 peptide)-based gene therapy for lung cancer treatment. The pAT2R and K9 peptide (K9-pAT2R) complexes were condensed using calcium chloride (K9-pAT2R-Ca2+). The resulting complexes were small (∼150 nm) and showed high levels of gene expression in vitro. This simple non-viral formulation approach showed negligible cytotoxicity in several different human and mouse cell lines (human cervix, breast, kidney, and human and mouse lung cell lines). Additionally, this K9-pDNA-Ca2+ complex demonstrated cancer targeted gene delivery when administered via intravenous (IV) injection or intratracheal (IT) spray into LLC orthotopic allograft-bearing mice. Average lung weights (mg) of the K9-pAT2R-Ca2+ IT (190.6±48.3) and the K9-pAT2R-Ca2+ IV (201.6±67.0) treated groups were significantly smaller than that of the control PBS group (325.7±69.4, P<0.05). In histological examination of tumors in H&E stained lung, average numbers of tumor nodules in the lungs in the K9-pAT2R-Ca2+ IT (6.0±4.2) and the K9-pAT2R-Ca2+ IV (4.6±3.4) groups were also significantly smaller than that of the control PBS group (17.8±6.0, P<0.01). This tumor attenuating effect was not observed in K9-pLUC-Ca2+ IT and K9-pLUC-Ca2+ IV treatment, thus it is suggested that LLC tumor growth was attenuated by apoptosis inducer gene, pAT2R, delivery. Immunohistochemical analysis confirmed that the complex effectively delivered pAT2R to the cancer cells, where it was expressed mainly in cancer cells along with bronchial epithelial cells. A single administration of these complexes markedly attenuated lung cancer growth offering preclinical proof of concept for a novel non-viral gene delivery method exhibiting effective lung tumor gene therapy via either IV or IT administration. This work is supported in part by Savara Pharmaceuticals (CB and MT), Faculty of Pharmacy of King Abdulaziz University, Jeddah, Saudi Arabia (NAA), University of Kansas Macromolecule and Vaccine Stabilization Center (CB), Kansas State University Johnson Cancer Research Center (MT), NIH grants U43 CA165462 (MT), P20 GM103418 (MT), and Kansas Bioscience Authority Collaborative Cancer Research grant (MT). Citation Format: Susumu Ishiguro, Nabil A. Alhakamy, Deepthi Uppalapati, Cory J. Berkland, Masaaki Tamura. Apoptosis inducer gene delivery by polylysine-calcium complexes attenuates mouse lung carcinoma allograft growth after intravenous injection or intratracheal spray. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3751.

Abstract 1726: CRM1 is overexpressed in lung tumorigenesis and represents an adjuvant target for lung cancer treatment

Abstract In spite of extensive investigations, the molecular mechanisms of lung tumorigenesis have not been completely understood, and the effective therapy for lung cancer is in great demand. Studies have shown that chromosome region maintenance 1 (CRM1), a nuclear export receptor for various cancer-associated ‘cargo’ proteins, overexpressed in several human cancers. The objectives of the present study are to evaluate the involvement of CRM1 in lung carcinogenesis and lung cancer treatment. First, we have analyzed the importance of CRM1 overexpression in lung cancer development. We showed that CRM1 was overexpressed in lung tumor tissues from lung cancer patients and lung adenocarcinoma in mice induced by a tobacco carcinogen, as well as lung cancer cell lines. The increased CRM1 expression levels in these lung cancer tissues and cells were associated with an increased phosphorylation level at threonine residue 55 of the p53 protein. Furthermore, CRM1 overexpression in lung cancer cells seemed to be p53-dependent. Stable overexpression of CRM1 in BEAS-2B cells led to malignant cellular transformation and p53 cytoplasmic localization. Moreover, as compared to A549 cells, cancer-related genes significantly altered in A549 cells with stable CRM1 knockdown. Second, we have evaluated targeting CRM1 as an adjuvant therapy for lung cancer treatment using both in vitro and in vivo models. We found that CRM1-siRNA could inhibit A549 cell growth and A549 cells with stable CRM1 knockdown showed more pronounced cytotoxic effects to cisplatin than A549 cells. In addition, A549 cells treated with cisplatin and a low non-toxic dose of leptomycin B (a CRM1 inhibitor) had a remarkably enhanced cytotoxicity compared to cisplatin. This increased therapeutic effect from leptomycin B and cisplatin was further validated using an in vivo xenograft mouse model. The findings of this study reveal the significance of CRM1 in lung carcinogenesis and lung cancer adjuvant therapy. Citation Format: Weimin Gao, Chuanwen Lu, Lixia Chen, Phouthone Keohavong. CRM1 is overexpressed in lung tumorigenesis and represents an adjuvant target for lung cancer treatment. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1726. doi:10.1158/1538-7445.AM2015-1726

First-, Second- and Third-Line Lung Cancer Treatment Patterns And Associated Costs in a US Healthcare Claims Database

Aim: To identify the most common first, second, and third lines of therapy and associated costs among patients treated for lung cancer. Methods: This retrospective analysis of healthcare claims identified patients treated for lung cancer from January 2007 through April 2012. Patients were enrolled in first-, second-, or third-line therapy cohorts and stratified by the number of discrete treatments received or by the specific chemotherapy or biologically targeted agent or combination of agents. Results: Of patients receiving first-line treatment (either chemotherapy or biologically targeted therapies), 18.3% and 4.4% received second-line and third-line treatment, respectively. Pemetrexed, topotecan, docetaxel, and erlotinib were the most commonly second-line regimens; pemetrexed and erlotinib were the most common third-line regimens. While total costs increased with increasing lines of treatment, costs per patient per month remained stable or decreased overall. Conclusion: Platinum/taxane combined treatment is still the mainstay of first-line therapy for lung cancer treatment for those with advanced disease. Second- and third-line therapy is still prescribed infrequently, although newer agents are more commonly used in this setting.

Dosimetric verification of stereotactic body radiation therapy for lung cancer treatment plans using flattening filter-free beams.

This study aimed to analyze the dose distribution using different dosimetric tools in conducting pretreatment quality assurance for lung cancer stereotactic body radiation therapy (SBRT) plans with flattening filter free (FFF) beams. Nine patients with lung cancer treated via SBRT were randomly selected, and their treatment plans were generated using the Eclipse treatment planning system (TPS) with FFF beams. For each patient, the same plan was applied to the Delta4 phantom and MatriXX by the TPS, which calculated the dose distribution. The Delta4 and MatriXX phantoms were then used to measure the actual dose distribution at the linear accelerator, and these measured doses were compared to with the calculated doses. Gamma analysis was employed in verifying the correspondence between the dose distributions. The absolute point doses were measured by a 0.016 mL Microchamber with the RW3 phantom and Thorax phantom. The absolute point doses measured by the 0.016 mL Microchamber were within ±3% of the calculated results for the central point of the RW3 and Thorax phantoms. The Delta4 and MatriXX dose distributions agreed well with the measured and calculated doses, over 98%, based on the 3% maximum dose and 3 mm gamma criteria. Both measured and calculated doses for the Delta4 and MatriXX phantoms agreed well for each patient with lung cancer. The absolute point dose measurements using the 0.016 mL Microchamber exhibited excellent agreement with the TPS calculated between the RW3 and Thorax phantoms.

Effect of deformable registration on the dose calculated in radiation therapy planning CT scans of lung cancer patients.

To characterize the effects of deformable image registration of serial computed tomography (CT) scans on the radiation dose calculated from a treatment planning scan. Eighteen patients who received curative doses (≥ 60 Gy, 2 Gy/fraction) of photon radiation therapy for lung cancer treatment were retrospectively identified. For each patient, a diagnostic-quality pretherapy (4-75 days) CT scan and a treatment planning scan with an associated dose map were collected. To establish correspondence between scan pairs, a researcher manually identified anatomically corresponding landmark point pairs between the two scans. Pretherapy scans then were coregistered with planning scans (and associated dose maps) using the demons deformable registration algorithm and two variants of the Fraunhofer MEVIS algorithm ("Fast" and "EMPIRE10"). Landmark points in each pretherapy scan were automatically mapped to the planning scan using the displacement vector field output from each of the three algorithms. The Euclidean distance between manually and automatically mapped landmark points (dE) and the absolute difference in planned dose (|ΔD|) were calculated. Using regression modeling, |ΔD| was modeled as a function of dE, dose (D), dose standard deviation (SD(dose)) in an eight-pixel neighborhood, and the registration algorithm used. Over 1400 landmark point pairs were identified, with 58-93 (median: 84) points identified per patient. Average |ΔD| across patients was 3.5 Gy (range: 0.9-10.6 Gy). Registration accuracy was highest using the Fraunhofer MEVIS EMPIRE10 algorithm, with an average dE across patients of 5.2 mm (compared with >7 mm for the other two algorithms). Consequently, average |ΔD| was also lowest using the Fraunhofer MEVIS EMPIRE10 algorithm. |ΔD| increased significantly as a function of dE (0.42 Gy/mm), D (0.05 Gy/Gy), SD(dose) (1.4 Gy/Gy), and the algorithm used (≤ 1 Gy). An average error of <4 Gy in radiation dose was introduced when points were mapped between CT scan pairs using deformable registration, with the majority of points yielding dose-mapping error <2 Gy (approximately 3% of the total prescribed dose). Registration accuracy was highest using the Fraunhofer MEVIS EMPIRE10 algorithm, resulting in the smallest errors in mapped dose. Dose differences following registration increased significantly with increasing spatial registration errors, dose, and dose gradient (i.e., SDdose). This model provides a measurement of the uncertainty in the radiation dose when points are mapped between serial CT scans through deformable registration.

TU‐F‐BRF‐03: Effect of Radiation Therapy Planning Scan Registration On the Dose in Lung Cancer Patient CT Scans

Purpose:To characterize the effect of deformable registration of serial computed tomography (CT) scans on the radiation dose calculated from a treatment planning scan.Methods:Eighteen patients who received curative doses (≥60Gy, 2Gy/fraction) of photon radiation therapy for lung cancer treatment were retrospectively identified. For each patient, a diagnostic‐quality pre‐therapy (4–75 days) CT scan and a treatment planning scan with an associated dose map calculated in Pinnacle were collected. To establish baseline correspondence between scan pairs, a researcher manually identified anatomically corresponding landmark point pairs between the two scans. Pre‐therapy scans were co‐registered with planning scans (and associated dose maps) using the Plastimatch demons and Fraunhofer MEVIS deformable registration algorithms. Landmark points in each pretherapy scan were automatically mapped to the planning scan using the displacement vector field output from both registration algorithms. The absolute difference in planned dose (|ΔD|) between manually and automatically mapped landmark points was calculated. Using regression modeling, |ΔD| was modeled as a function of the distance between manually and automatically matched points (registration error, E), the dose standard deviation (SD_dose) in the eight‐pixel neighborhood, and the registration algorithm used.Results:52–92 landmark point pairs (median: 82) were identified in each patient's scans. Average |ΔD| across patients was 3.66Gy (range: 1.2–7.2Gy). |ΔD| was significantly reduced by 0.53Gy using Plastimatch demons compared with Fraunhofer MEVIS. |ΔD| increased significantly as a function of E (0.39Gy/mm) and SD_dose (2.23Gy/Gy).Conclusion:An average error of &lt;4Gy in radiation dose was introduced when points were mapped between CT scan pairs using deformable registration. Dose differences following registration were significantly increased when the Fraunhofer MEVIS registration algorithm was used, spatial registration errors were larger, and dose gradient was higher (i.e., higher SD_dose). To our knowledge, this is the first study to directly compute dose errors following deformable registration of lung CT scans.

Oxidative Stress-Regulated Lentiviral TK/GCV Gene Therapy for Lung Cancer Treatment

Nuclear factor erythroid-2 related factor 2 (Nrf2) is a transcription factor that regulates protection against a wide variety of toxic insults to cells, including cytotoxic cancer chemotherapeutic drugs. Many lung cancer cells harbor a mutation in either Nrf2 or its inhibitor Keap1 resulting in permanent activation of Nrf2 and chemoresistance. In this study, we sought to examine whether this attribute could be exploited in cancer suicide gene therapy by using a lentiviral (LV) vector expressing herpes simplex virus thymidine kinase (HSV-TK/GCV) under the regulation of antioxidant response element (ARE), a cis-acting enhancer sequence that binds Nrf2. In human lung adenocarcinoma cells in which Nrf2 is constitutively overexpressed, ARE activity was found to be high under basal conditions. In this setting, ARE-HSV-TK was more effective than a vector in which HSV-TK expression was driven by a constitutively active promoter. In a mouse xenograft model of lung cancer, suicide gene therapy with LV-ARE-TK/GCV was effective compared with LV-PGK-TK/GCV in reducing tumor size. We conclude that ARE-regulated HSV-TK/GCV therapy offers a promising approach for suicide cancer gene therapy in cells with high constitutive ARE activity, permitting a greater degree of therapeutic targeting to those cells.