Dose coverage impacts local control in ultra-central lung oligometastases treated with stereotactic radiotherapy.

INTRODUCTION: The use of Stereotactic Body Radiotherapy (SBRT) is controversial in Ultra-Central lung tumors, a subset of central lung tumors characterized by proximity to critical mediastinal structures. This is of interest in oligometastatic (≤3 metastases) patients, who can yield survival benefit from local treatments. The aim of our study is to assess the determinants of efficacy and toxicity in this setting. MATERIALS AND METHODS: Clinical and dosimetric parameters were reviewed in a cohort of oligometastatic patients treated with SBRT for ultra-central tumors. Local control rate (LC) and toxicity were assessed. Statistical Analysis was carried out to assess the impact of those predictors on local recurrence and adverse events. RESULTS: One-hundred-nine consecutive patients were included. A median Biologic Effective Dose (BED) of 105 (75-132) Gy10 was prescribed. At a median follow-up of 17 (range 3-78) months, 2-year LC was 87%. Improved LC was correlated to Planning Treatment Volume (PTV) covered by 95% of the prescription dose (V95% PTV) > 85% (HR 0.15, 95%CI 0.05-0.49, p = 0.0017) and to Gross Tumor Volume (GTV) < 90 cm3 (HR 0.2, 95%CI 0.07-0.56, p = 0.0021). Overall and grade ≥ 3 toxicity incidence was 20% and 5%, respectively. Patients experiencing acute and late toxicities received significantly higher dose to 1 cm3 (D1cm3) of esophagus and lung volume receiving ≥5 Gy (V5Gy) (p = 0.016 and p = 0.013), and higher dose to 0.1 cm3 (D0.1cm3) of heart (p = 0.036), respectively. CONCLUSION: V95% PTV > 85% and GTV < 90 cm3 are independent predictors of LC. Dose to esophagus, lung and heart should be carefully assessed to minimize treatment-related toxicities.

Cytotoxicity and genotoxicity of light emitted by incandescent, halogen, and LED bulbs on ARPE-19 and BEAS-2B cell lines.

LED technology has the extraordinary ability to reduce energy consumption, constituting an economic and ecological advantage, so it is planned to replace incandescent, halogen and other inefficient bulbs for public and domestic lighting with LEDs. LEDs present specific spectral and energetic characteristics compared with those of other domestic light sources, so the potential risks for human health of these bulbs need to be explored. The aim of this study was to assess cytotoxicity and genotoxicity of light emitted by different commercial light bulbs: incandescent, halogen, and two LED bulbs with different correlated color temperatures. The evaluation was done on ARPE-19 as a specific cell model for eye toxicity and on BEAS-2B as a good cell model for toxicology tests. Light induced mainly cytotoxic effects on ARPE-19 and DNA damage on BEAS-2B, so different cell lines showed different biological responses. Moreover, our findings indicate that among the four bulbs, cold LED caused the highest cytotoxic effect on ARPE-19 and the highest genotoxic and oxidative effect on BEAS-2B. Cold LED is probably able to cause more cellular damage because it contains more high-energy radiations (blue). These results suggest that LED technology could be a safe alternative to older technologies, but the use of warm LED should be preferred to cold LED, which can potentially cause adverse effects on retinal cells.

Effectiveness of bronchial thermoplasty in patients with severe refractory asthma: Clinical and histopathologic correlations.

BACKGROUND: The effectiveness of bronchial thermoplasty (BT) has been reported in patients with severe asthma, yet its effect on different bronchial structures remains unknown. OBJECTIVE: We sought to examine the effect of BT on bronchial structures and to explore the association with clinical outcome in patients with severe refractory asthma. METHODS: Bronchial biopsy specimens (n = 300) were collected from 15 patients with severe uncontrolled asthma before and 3 months after BT. Immunostained sections were assessed for airway smooth muscle (ASM) area, subepithelial basement membrane thickness, nerve fibers, and epithelial neuroendocrine cells. Histopathologic findings were correlated with clinical parameters. RESULTS: BT significantly improved asthma control and quality of life at both 3 and 12 months and decreased the numbers of severe exacerbations and the dose of oral corticosteroids. At 3 months, this clinical benefit was accompanied by a reduction in ASM area (median values before and after BT, respectively: 19.7% [25th-75th interquartile range (IQR), 15.9% to 22.4%] and 5.3% [25th-75th IQR], 3.5% to 10.1%, P < .001), subepithelial basement membrane thickening (4.4 µm [25th-75th IQR, 4.0-4.7 µm] and 3.9 µm [25th-75th IQR, 3.7-4.6 µm], P = 0.02), submucosal nerves (1.0 ‰ [25th-75th IQR, 0.7-1.3 ‰] immunoreactivity and 0.3 ‰ [25th-75th IQR, 0.1-0.5 ‰] immunoreactivity, P < .001), ASM-associated nerves (452.6 [25th-75th IQR, 196.0-811.2] immunoreactive pixels per mm2 and 62.7 [25th-75th IQR, 0.0-230.3] immunoreactive pixels per mm2, P = .02), and epithelial neuroendocrine cells (4.9/mm2 [25th-75th IQR, 0-16.4/mm2] and 0.0/mm2 [25th-75th IQR, 0-0/mm2], P = .02). Histopathologic parameters were associated based on Asthma Control Test scores, numbers of exacerbations, and visits to the emergency department (all P ≤ .02) 3 and 12 months after BT. CONCLUSION: BT is a treatment option in patients with severe therapy-refractory asthma that downregulates selectively structural abnormalities involved in airway narrowing and bronchial reactivity, particularly ASM, neuroendocrine epithelial cells, and bronchial nerve endings.

Establishment of detailed respiratory tract model and Monte Carlo simulation of radon progeny caused dose.

As radon is one of the most important natural radiation sources, its radiation hazard has always been a concern. α and ß particles emitted by short-lived radioactive radon progeny nuclides could result in a high local dose and induce radiation damage to the respiratory tract. A detailed respiratory tract model needs to be built and dose distribution in the respiratory tract should be studied to reflect the characteristics of energy deposition caused by radon and its progeny. Therefore, in the present work, a dosimetric study was conducted on the respiratory tract and non-uniform dose distribution in the bronchial region was studied. First, a detailed voxel respiratory tract model was established based on the anatomic bronchial parameters of an adult Chinese male. The dimensional parameters of the tracheo-bronchial tree of an adult male adopted in ICRP Publication 66 (ICRP 1994 Human Respiratory Tract Model for Radiological Protection ICRP Publication 66 (Oxford: Pergamon)), featured by consecutive 16 generations of bronchi structures to express the irregular structure of the respiratory tract and the radiosensitive tissues in the bronchial region, were also built for dosimetric study. Then the deposition and clearance models recommended by ICRP were used to analyse the regional deposition and transfer in the respiratory tract, and a fluid dynamic simulation was used to obtain 3D distribution of radon progeny aerosol particles in the bronchial region. The result showed that the highest deposition fraction density occurs at the first and second generations of bronchi. Furthermore, the detailed voxel respiratory tract model along with the Monte Carlo method were used to obtain dose distribution in the BB region. It was found that the dose distribution in the respiratory tract is very non-uniform and the maximum voxel dose is about 30 times higher than the average voxel dose. The dose conversion factor (DCF) for lung in the home environment derived with the dosimetry method in the present work is 9.86 mSv·WLM-1. Sensitivity analysis was performed for the parameters involved in the DCF calculation and it was found that the unattached fraction and breathing rate influence the DCF the most.

Effect of high laser output on the central bronchi and pulmonary artery.

A diode-pump Nd:YAG high-power laser (wavelength 1320 nm, power 100 W) is routinely used to surgically remove lung metastases. Even pulmonary lesions in central locations are resectable via this method, yet it also carries a potential risk of damaging the larger bronchi and vessels in the vicinity. Studies investigating the safety of using high-power lasers are lacking. We therefore aimed to examine the direct effects of a 100-watt laser on the bronchi and pulmonary artery at a standard working velocity. From freshly slaughtered pigs, we isolated cylindrical specimens of the trachea, the main and lobar bronchi, and the central pulmonary artery from the both lungs. These specimens were fixed consecutively in rows behind each other on a Styrofoam surface in the laboratory. The laser's handle was clamped into a hydraulic feed unit so that the laser was focused at constant distance perpendicular to the tissue and would move at 10 mm/s over the specimens. The Nd:YAG Laser LIMAX® 120 functioned at a consistent power of 100 W during all the experiments. The lasered specimens were examined macroscopically and histologically for tissue damage. None of the trachea or bronchial walls were perforated. Compared to the pulmonary parenchyma, we observed no vaporization effects-only minor superficial coagulation (with a mean depth of 2.1 ± 0.8 mm). This finding was histologically confirmed in each specimen, which revealed mild superficial coagulation and no damage to the cartilage. In the presence of a residual peribronchial fatty tissue, the laser effect was even attenuated. The pulmonary arteries presented no lumen openings whatsoever, merely a discrete trace of coagulation. The vessel wall revealed increased vacuolization without alteration of the remaining vessel wall. In conclusion, laser resection at 100 W of the central lung areas is safe with respect to airways and blood vessels and the laser output does not need to be reduced when treating these areas.

Analysis of the miRNA-mRNA networks in malignant transformation BEAS-2B cells induced by alpha-particles.

The aim of this study was to determine the toxicity induced by irradiation with alpha-particles on malignant transformation of immortalized human bronchial epithelial cells (BEAS-2B) using miRNA-mRNA networks. The expression of BEAS-2B cells was determined by measuring colony formation, mtDNA, mitochondrial membrane potential (MMP), and ROS levels. Changes in BEAS-2B cell gene expression were observed and quantified using microarrays that included an increase in 157 mRNA and 20 miRNA expression and a decrease in 77 mRNA and 48 miRNA. Bioinformatic software was used to analyze these different mRNA and miRNA, which indicated that miR-107 and miR-494 play an important role in alpha-particles-mediated cellular malignant transformation processes. The pathways related to systemic lupus erythematosus, cytokine-cytokine receptor interaction, MAPK signaling pathway, regulation of actin cytoskeleton, and cell adhesion molecules (CAMs) were stimulated, while those of ribosome, transforming growth factor (TGF)-beta signaling pathway, and metabolic pathways were inhibited. Data suggest that miRNA and mRNA play a crucial role in alpha-particles-mediated malignant transformation processes. It is worth noting that three target genes associated with lung cancer were identified and upregulated PEG 10 (paternally expressed gene 10), ARHGAP26, and IRS1.

Radon induced hyperplasia: effective adaptation reducing the local doses in the bronchial epithelium.

There is experimental and histological evidence that chronic irritation and cell death may cause hyperplasia in the exposed tissue. As the heterogeneous deposition of inhaled radon progeny results in high local doses at the peak of the bronchial bifurcations, it was proposed earlier that hyperplasia occurs in these deposition hot spots upon chronic radon exposure. The objective of the present study is to quantify how the induction of basal cell hyperplasia modulates the microdosimetric consequences of a given radon exposure. For this purpose, computational epithelium models were constructed with spherical cell nuclei of six different cell types based on histological data. Basal cell hyperplasia was modelled by epithelium models with additional basal cells and increased epithelium thickness. Microdosimetry for alpha-particles was performed by an own-developed Monte-Carlo code. Results show that the average tissue dose, and the average hit number and dose of basal cells decrease by the increase of the measure of hyperplasia. Hit and dose distribution reveal that the induction of hyperplasia may result in a basal cell pool which is shielded from alpha-radiation. It highlights that the exposure history affects the microdosimetric consequences of a present exposure, while the biological and health effects may also depend on previous exposures. The induction of hyperplasia can be considered as a radioadaptive response at the tissue level. Such an adaptation of the tissue challenges the validity of the application of the dose and dose rate effectiveness factor from a mechanistic point of view. As the location of radiosensitive target cells may change due to previous exposures, dosimetry models considering the tissue geometry characteristic of normal conditions may be inappropriate for dose estimation in case of protracted exposures. As internal exposures are frequently chronic, such changes in tissue geometry may be highly relevant for other incorporated radionuclides.

Stochastic rat lung dosimetry for inhaled radon progeny: a surrogate for the human lung for lung cancer risk assessment.

Laboratory rats are frequently used in inhalation studies as a surrogate for human exposures. The objective of the present study was therefore to develop a stochastic dosimetry model for inhaled radon progeny in the rat lung, to predict bronchial dose distributions and to compare them with corresponding dose distributions in the human lung. The most significant difference between human and rat lungs is the branching structure of the bronchial tree, which is relatively symmetric in the human lung, but monopodial in the rat lung. Radon progeny aerosol characteristics used in the present study encompass conditions typical for PNNL and COGEMA rat inhalation studies, as well as uranium miners and human indoor exposure conditions. It is shown here that depending on exposure conditions and modeling assumptions, average bronchial doses in the rat lung ranged from 5.4 to 7.3 mGy WLM(-1). If plotted as a function of airway generation, bronchial dose distributions exhibit a significant maximum in large bronchial airways. If, however, plotted as a function of airway diameter, then bronchial doses are much more uniformly distributed throughout the bronchial tree. Comparisons between human and rat exposures indicate that rat bronchial doses are slightly higher than human bronchial doses by about a factor of 1.3, while lung doses, averaged over the bronchial (BB), bronchiolar (bb) and alveolar-interstitial (AI) regions, are higher by about a factor of about 1.6. This supports the current view that the rat lung is indeed an appropriate surrogate for the human lung in case of radon-induced lung cancers. Furthermore, airway diameter seems to be a more appropriate morphometric parameter than airway generations to relate bronchial doses to bronchial carcinomas.

Long-term low-dose α-particle enhanced the potential of malignant transformation in human bronchial epithelial cells through MAPK/Akt pathway.

Since the wide usage of ionizing radiation, the cancer risk of low dose radiation (LDR) (<0.1 Gy) has become attractive for a long time. However, most results are derived from epidemiologic studies on atomic-bomb survivors and nuclear accidents surrounding population, and the molecular mechanism of this risk is elusive. To explore the potential of a long-term LDR-induced malignant transformation, human bronchial epithelial cells Beas-2B were fractionally irradiated with 0.025 Gy α-particles for 8 times in total and then further cultured for 1-2 months. It was found that the cell proliferation, the abilities of adhesion and invasion, and the protein expressions of p-ERK, p-Akt, especially p-P38 were not only increased in the multiply-irradiated cells but also in their offspring 1-2 months after the final exposure, indicating high potentiality of cell malignant transformation. On opposite, the expressions of p-JNK and p-P66 were diminished in the subcultures of irradiated cells and thus may play a role of negative regulation in canceration. When the cells were transferred with p38 siRNA, the LDR-induced enhancements of cell adhesion and invasion were significantly reduced. These findings suggest that long-term LDR of α-particles could enhance the potential of malignant transformation incidence in human bronchial epithelial cells through MAPK/Akt pathway.

[Bronchial thermoplasty: a real advancement in the treatment of asthma]. / Thermoplastie bronchique: une réelle avancée dans le traitement de l'asthme.

New treatments are needed to improve the care of severe asthmatic patients. Bronchial thermoplasty aims to lessen the airway smooth muscles via the heating of bronchial walls by radiofrequency. The preliminary studies showed a good tolerance and some good efficacy. Randomized controlled trials have been undertaken on moderate to severe asthmatic patients, demonstrating an improvement in quality of life, rate of severe exacerbations and unscheduled medical visits. The main side-effects consist of asthma exacerbations, atelectasis and infections. Bronchial thermoplasty is an innovative treatment with good efficacy and acceptable tolerance for moderate to severe asthmatic patients. More studies are needed to better understand its mechanism of action and more clearly delineate the precise indications of this innovative technique.

[Morphologic changes in mice trachea, bronchi and lungs after prolonged combined radiation and inhaled chemical exposure].

Investigations of morphology and morphometry of the breathing organs (trachea, bronchi and lungs) and immunogenesis of mice subject to a combined sequential exposure to fractionated external γ-irradiation by the total dose of 350 cGy and a mix of acetone, ethanol and acetaldehyde in MPCs for piloted spacecrafts simulating the estimated levels in crewed exploration missions were conducted. Morphologic changes in the breathing organs of animals after space missions point to immunogenesis activation and appearance of a "structural trace" as a chronic inflammation with the growth of fibrous connective tissue in tracheal, bronchial and lung walls, increase in volume fractions of glands and vessels and reduction in loose fibrous connective tissue. Formation of the fibrous connective tissue was particularly noticeable in respiratory parts of the breathing organs suggesting a high risk of long-term adverse effects.

Relative proximity of chromosome territories influences chromosome exchange partners in radiation-induced chromosome rearrangements in primary human bronchial epithelial cells.

It is well established that chromosomes exist in discrete territories (CTs) in interphase and are positioned in a cell-type specific probabilistic manner. The relative localisation of individual CTs within cell nuclei remains poorly understood, yet many cancers are associated with specific chromosome rearrangements and there is good evidence that relative territorial position influences their frequency of exchange. To examine this further, we characterised the complexity of radiation-induced chromosome exchanges in normal human bronchial epithelial (NHBE) cells by M-FISH analysis of PCC spreads and correlated the exchanges induced with their preferred interphase position, as determined by 1/2-colour 2D-FISH analysis, at the time of irradiation. We found that the frequency and complexity of aberrations induced were reduced in ellipsoid NHBE cells in comparison to previous observations in spherical cells, consistent with aberration complexity being dependent upon the number and proximity of damaged CTs, i.e. lesion proximity. To ask if particular chromosome neighbourhoods could be identified we analysed all radiation-induced pair-wise exchanges using SCHIP (statistics for chromosome interphase positioning) and found that exchanges between chromosomes (1;13), (9;17), (9;18), (12;18) and (16;21) all occurred more often than expected assuming randomness. All of these pairs were also found to be either sharing similar preferred positions in interphase and/or sharing neighbouring territory boundaries. We also analysed a human small cell lung cancer cell line, DMS53, by M-FISH observing the genome to be highly rearranged, yet possessing rearrangements also involving chromosomes (1;13) and (9;17). Our findings show evidence for the occurrence of non-random exchanges that may reflect the territorial organisation of chromosomes in interphase at time of damage and highlight the importance of cellular geometry for the induction of aberrations of varying complexity after exposure to both low and high-LET radiation.

Expanded HILUS Trial: A Pooled Analysis of Risk Factors for Toxicity From Stereotactic Body Radiation Therapy of Central and Ultracentral Lung Tumors.

PURPOSE: Stereotactic body radiation therapy for tumors near the central airways implies high-grade toxic effects, as concluded from the HILUS trial. However, the small sample size and relatively few events limited the statistical power of the study. We therefore pooled data from the prospective HILUS trial with retrospective data from patients in the Nordic countries treated outside the prospective study to evaluate toxicity and risk factors for high-grade toxic effects. METHODS AND MATERIALS: All patients were treated with 56 Gy in 8 fractions. Tumors within 2 cm of the trachea, the mainstem bronchi, the intermediate bronchus, or the lobar bronchi were included. The primary endpoint was toxicity, and the secondary endpoints were local control and overall survival. Clinical and dosimetric risk factors were analyzed for treatment-related fatal toxicity in univariable and multivariable Cox regression analyses. RESULTS: Of 230 patients evaluated, grade 5 toxicity developed in 30 patients (13%), of whom 20 patients had fatal bronchopulmonary bleeding. The multivariable analysis revealed tumor compression of the tracheobronchial tree and maximum dose to the mainstem or intermediate bronchus as significant risk factors for grade 5 bleeding and grade 5 toxicity. The 3-year local control and overall survival rates were 84% (95% CI, 80%-90%) and 40% (95% CI, 34%-47%), respectively. CONCLUSIONS: Tumor compression of the tracheobronchial tree and high maximum dose to the mainstem or intermediate bronchus increase the risk of fatal toxicity after stereotactic body radiation therapy in 8 fractions for central lung tumors. Similar dose constraints should be applied to the intermediate bronchus as to the mainstem bronchi.

Radon-induced reduced apoptosis in human bronchial epithelial cells with knockdown of mitochondria DNA.

Radon and radon progeny inhalation exposure are recognized to induce lung cancer. To explore the role of mitochondria in radon-induced carcinogenesis in humans, an in vitro partially depleted mitochondrial DNA (mtDNA) cell line (ρ-) was generated by treatment of human bronchial epithelial (HBE) cells (ρ+) with ethidium bromide (EB). The characterization of ρ- cells indicated the presence of dysfunctional mitochondria and might thus serve a reliable model to investigate the role of mitochondria. In a gas inhalation chamber, ρ- and ρ+ cells were exposed to radon gas produced by a radium source. Results showed that apoptosis was significantly increased both in ρ- and ρ+ cells irradiated by radon. Moreover, apoptosis in ρ- cells showed a lower level than in ρ+ cells. Radon was further found to depress mitochondrial membrane potential (MMP) of HBE cells with knockdown mtDNA. Production of reactive oxygen species (ROS) was markedly elevated both in ρ- and ρ+ cells exposed to radon. The distribution of phases of cell cycle was different in ρ- compared to ρ+ cells. Radon irradiation induced a rise in G2/M and decrease in S phase in ρ+ cells. In ρ- cells, G1, G2/M, and S populations remained similar to cells exposed to radon. In conclusion, radon-induced changes in ROS generation, MMP and cell cycle are all attributed to reduction of apoptosis, which may trigger and promote cell transformation, leading to carcinogenesis. Our study indicates that the use of the ρ- knockdown mtDNA HBE cells may serve as a reliable model to study the role played by mitochondria in carcinogenic diseases.

Direct and bystander effects induced by scattered radiation generated during penetration of radiation inside a water-phantom.

In this study, the dose distribution of photon (6 MV) and electron (22 MeV) radiation in a water-phantom was compared with the frequency of apoptotic and micronucleated cells of two human cell lines (BEAS-2B normal bronchial epithelial cells and A549 lung cancer epithelial cells). Formation of micronuclei and apoptotic-like bodies was evaluated by the cytokinesis-block micronucleus test. Measurements were performed for five different phantom depths (3-20 cm). Irradiated cells were placed in a water-phantom in three variants: directly on the axis in the beam, under shielding (only in photon radiation) and outside the beam field. The results reveal a discrepancy between the distribution of physical dose at different depths of the water-phantom and biological effects. This discrepancy is of special significance in case of cells irradiated at a greater depth or placed outside the field and under shield during the exposure to radiation. The frequency of cytogenetic damage was higher than the expected value based on the physical dose received at different depths. Cells placed outside the beam axis were exposed to scattered radiation at very low doses, so we tested if bystander effects could have had a role in the observed discrepancy between physical radiation dose and biological response. We explored this question by use of a medium-transfer technique in which medium (ICM-irradiation conditioned medium) from irradiated cells was transferred to non-irradiated (bystander) cells. The results indicate that when cells were incubated in ICM transferred from cells irradiated at bigger depths or from cells exposed outside the radiation field, the number of apoptotic and micronucleated cells was similar to that after direct irradiation. This suggests that these damages are caused by factors released by irradiated cells into the medium rather than being induced directly in DNA by X-rays. Evaluation of biological effects of scattered radiation appears useful for clinical practice.

Effect of site-specific bronchial radon progeny deposition on the spatial and temporal distributions of cellular responses.

Inhaled short-lived radon progenies may deposit in bronchial airways and interact with the epithelium by the emission of alpha particles. Simulation of the related radiobiological effects requires the knowledge of space and time distributions of alpha particle hits and biological endpoints. Present modelling efforts include simulation of radioaerosol deposition patterns in a central bronchial airway bifurcation, modelling of human bronchial epithelium, generation of alpha particle tracks, and computation of spatio-temporal distributions of cell nucleus hits, cell killing and cell transformation events. Simulation results indicate that the preferential radionuclide deposition at carinal ridges plays an important role in the space and time evolution of the biological events. While multiple hits are generally rare for low cumulative exposures, their probability may be quite high at the carinal ridges of the airway bifurcations. Likewise, cell killing and transformation events also occur with higher probability in this area. In the case of uniform surface activities, successive hits as well as cell killing and transformation events within a restricted area (say 0.5 mm(2)) are well separated in time. However, in the case of realistic inhomogeneous deposition, they occur more frequently within the mean cycle time of cells located at the carinal ridge even at low cumulative doses. The site-specificity of radionuclide deposition impacts not only on direct, but also on non-targeted radiobiological effects due to intercellular communication. Incorporation of present results into mechanistic models of carcinogenesis may provide useful information concerning the dose-effect relationship in the low-dose range.

Multi-scaled Monte Carlo calculation for radon-induced cellular damage in the bronchial airway epithelium.

Radon is a leading cause of lung cancer in indoor public and mining workers. Inhaled radon progeny releases alpha particles, which can damage cells in the airway epithelium. The extent and complexity of cellular damage vary depending on the alpha particle's kinetic energy and cell characteristics. We developed a framework to quantitate the cellular damage on the nanometer and micrometer scales at different intensities of exposure to radon progenies Po-218 and Po-214. Energy depositions along the tracks of alpha particles that were slowing down were simulated on a nanometer scale using the Monte Carlo code Geant4-DNA. The nano-scaled track histories in a 5 µm radius and 1 µm-thick cylindrical volume were integrated into the tracking scheme of alpha trajectories in a micron-scale bronchial epithelium segment in the user-written SNU-CDS program. Damage distribution in cellular DNA was estimated for six cell types in the epithelium. Deep-sited cell nuclei in the epithelium would have less chance of being hit, but DNA damage from a single hit would be more serious, because low-energy alpha particles of high LET would hit the nuclei. The greater damage in deep-sited nuclei was due to the 7.69 MeV alpha particles emitted from Po-214. From daily work under 1 WL of radon concentration, basal cells would respond with the highest portion of complex DSBs among the suspected progenitor cells in the most exposed regions of the lung epithelium.

Deformable image registration of heterogeneous human lung incorporating the bronchial tree.

PURPOSE: To investigate the effect of the bronchial tree on the accuracy of biomechanical-based deformable image registration of human lungs. METHODS: Three dimensional finite element models have been developed using four dimensional computed tomography image data of ten lung cancer patients. Each model is built of a body, left and right lungs, tumor, and bronchial trees. Triangular shell elements are used for the bronchial trees while tetrahedral elements are used for other components. Hyperelastic material properties based on experimental investigation on human lungs are used for the lung parenchyma. Different material properties are assigned for the bronchial tree using five values for the modulus of elasticity of 0.01, 0.12, 0.5, 10, and 18 MPa. Lungs are modeled to slide inside chest cavities by applying frictionless contact surfaces between each lung and corresponding chest cavity. The accuracy of the models is examined using an average of 40 bronchial bifurcation points identified on inhale and exhale images. Relative accuracy is evaluated by comparing the displacement of all nodes within the lungs as well as the dosimetric difference at the exhale position predicted by the model. RESULTS: There is no significant effect of bronchial tree on the model accuracy based on the bifurcation points analysis. However, on the local level, using an average of 38 000 nodes, there is a maximum difference of 8.5 mm in the deformation of the bronchial trees, as the modulus of elasticity of the bronchial trees increases from 0.01 to 18 MPa; however, more than 96% of nodes are within a 2.5 mm difference in each direction. The average dose difference at the predicted exhale position is less than 35 cGy between the models. CONCLUSIONS: The bronchial tree has little effect on the global deformation and the accuracy of deformable image registration of lungs. Hence, the homogenous model is a reasonable assumption. Since there are some local deformation differences between nodes as the material properties of the bronchial tree change that may affect the accuracy of dosimetric results, heterogeneity may be required for a smaller scale modeling of lungs.