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.

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.

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.

The solvent and treatment regimen of sodium selenite cause its effects to vary on the radiation response of human bronchial cells from tumour and normal tissues.

Sodium selenite is often given to moderate the side effects of cancer therapy to enhance the cellular defence of non-cancerous cells. To determine whether sodium selenite during radiotherapy protects not only normal cells but also cancer cells, which would imply a reduction of the desired effect of irradiation on tumour during radiotherapy, the effect of the combined treatment of irradiation and sodium selenite was investigated. Human bronchial cells from carcinoma (A549) and normal tissue (BEAS-2B) were treated with sodium selenite and effects on growth and in combination with radiation on metabolic activity and cell cycle distribution were studied. The influence on radiosensitivity was determined via colony forming assays using different solvents of sodium selenite and treatment schedules. It was shown that sodium selenite inhibits growth and influences cell cycle distribution of both normal and tumour cells. Metabolic activity of normal cells decreased more rapidly compared to that of cancer cells. The influence of sodium selenite on radiation response depended on the different treatment schedules and was strongly affected by the solvent of the agent. It could be shown that the effect of sodium selenite on radiation response is strongly dependent on the respective experimental in vitro conditions and ranges from lead to an initially suspected but ultimately no real radioprotection to radiosensitizing up to no effect in one and the same cell line. This might be a reason for controversially described cell responses to radiation under the influence of sodium selenite in studies so far.

Central Airway Toxicity After High Dose Radiation: A Combined Analysis of Prospective Clinical Trials for Non-Small Cell Lung Cancer.

PURPOSE: To study the dosimetric risk factors for radiation-induced proximal bronchial tree (PBT) toxicity in patients treated with radiation therapy for non-small cell lung cancer (NSCLC). METHODS AND MATERIALS: Patients with medically inoperable or unresectable NSCLC treated with conventionally fractionated 3-dimensional conformal radiation therapy (3DCRT) in prospective clinical trials were eligible for this study. Proximal bronchial tree (PBT) and PBT wall were contoured consistently per RTOG 1106 OAR-Atlas. The dose-volume histograms (DVHs) of physical prescription dose (DVHp) and biological effective dose (α/ß = 2.5; DVH2.5) were generated, respectively. The primary endpoint was PBT toxicities, defined by CTCAE 4.0 under the terminology of bronchial stricture/atelectasis. RESULTS: Of 100 patients enrolled, with a median follow-up of 64 months (95% confidence interval [CI], 50-78), 73% received 70 Gy or greater and 17% developed PBT toxicity (grade 1, 8%; grade 2, 6%; grade 3, 0%; and grade 4, 3%). The median time interval between RT initiation and onset of PBT toxicity was 8.4 months (95% CI, 4.7-44.1). The combined DVHs showed that no patient with a PBT maximum physical dose <65 Gy developed any PBT toxicity. Cox proportional hazards analysis and receiver operating characteristic analysis demonstrated that V75 of PBT was the most significant dosimetric parameter for both grade 1+ (P = .035) and grade 2+ (P = .037) PBT toxicities. The dosimetric thresholds for V75 of PBT were 6.8% and 11.9% for grade 1+ and grade 2+ PBT toxicity, respectively. CONCLUSIONS: V75 of PBT appeared be the most significant dosimetric parameter for PBT toxicity after conventionally fractionated thoracic 3DCRT. Constraining V75 of PBT can limit clinically significant PBT toxicity.

Thermoablative Techniques for Excessive Central Airway Collapse: An Ex Vivo Pilot Study on Sheep Tracheal Tissue.

BACKGROUND: Tracheobronchoplasty is the definitive treatment for patients with symptomatic excessive central airway collapse. This procedure is associated with high morbidity and mortality rates. Bronchoscopic techniques are an appealing alternative with less morbidity and the ability to apply it in nonsurgical patients. Although thermoablative methods have been proposed as treatment options to induce fibrosis of the posterior tracheobronchial wall, no studies have compared direct histologic effects of such methods. This study compared the effects of electrocautery, radiofrequency ablation, potassium titanyl phosphate laser, and argon plasma coagulation (APC) in the tracheobronchial tree in an ex vivo animal model. METHODS: Four adult sheep cadavers were used for this study. Under flexible bronchoscopy, the posterior tracheal membrane was treated using different power settings on 4 devices. The airways were assessed for the presence of treatment-related histopathologic changes. RESULTS: Histologic changes observed were that of acute thermal injury including: surface epithelium ablation, collagen fiber condensation, smooth muscle cytoplasm condensation, and chondrocyte pyknosis. No distinct histologic differences in the treated areas among different modalities and treatment effects were observed. APC at higher power settings was the only modality that produced consistent and homogenous thermal injury effects across all tissue layers with no evidence of complete erosion. CONCLUSION: Although electrocautery, radiofrequency ablation, potassium titanyl phosphate laser, and APC all induce thermal injury of the airway wall, only APC at high power settings achieves this effect without complete tissue erosion, favoring potential regeneration and fibrosis. Live animal studies are now plausible.

Validation of RTOG 0813 Proximal Bronchial Tree Constraints for Pulmonary Toxicity With Stereotactic Body Radiation Therapy for Central Non-small Cell Lung Cancer.

PURPOSE: Clinical validation of protocol-specified dosimetric constraints for the proximal bronchial tree (PBT) is limited for central non-small cell lung cancer treated with stereotactic body radiation therapy. We sought to validate Radiation Therapy Oncology Group (RTOG) PBT constraints with a large institutional data set. METHODS AND MATERIALS: Lesions ≤2 cm from the PBT treated with definitive stereotactic body radiation therapy from 2009 to 2016 were identified from a prospective registry of 1462 patients. Every PBT dose and volume combination, ranging from 0 cGy to 8000 cGy in increments of 10 cGy and volumes ranging from 0.03 cm3 to 50 cm3 in increments of 0.03 cm3, was analyzed. The sensitivity and specificity of these endpoints for identifying pulmonary toxicity were calculated. Pulmonary toxicity was classified as pneumonitis or nonpneumonitis toxicity (NPT) (fistula, stenosis, necrosis, hemoptysis, clinically significant pleural effusion). The optimal dosimetric predictor was chosen by calculation of F-score (highest sensitivity and specificity). RESULTS: The study included 132 patients, with 26.0-month median follow-up. Eight grade ≥2 NPT (2 grade 5) and 8 grade 2 pneumonitis toxicities were observed. The PBT dosimetric endpoint with the highest F-score for identification of grade 2 to 5 NPT was D0.03cc ≤5000 cGy and that for grade 3 to 5 NPT was D0.33cc ≤4710 cGy, with sensitivity and specificity of 87.5% and 76.6% and 100.0% and 85.7%, respectively. Applying the RTOG 0813 PBT constraints to our data set achieved a sensitivity and specificity of 33.3% and 92.1% for D4cc ≤1800 cGy and 37.5% and 92.7% for D0.03cc ≤5250 cGy for identification of grade 2 to 5 NPT. A PBT dosimetric correlation for pneumonitis toxicity could not be identified. CONCLUSIONS: This novel dosimetric analysis validates current RTOG constraints and emphasizes high-dose, small-volume constraints as better predictors for NPT. We demonstrated that a slightly lower maximum point dose PBT constraint may be optimal for identification of NPT. Validation of these findings in a larger cohort of patients with longer follow-up is necessary.

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.

Effects of mucus thickness and goblet cell hyperplasia on microdosimetric quantities characterizing the bronchial epithelium upon radon exposure.

PURPOSE: The most exposed tissue upon radon exposure is the bronchial epithelium where goblet cells serve as responsive and adaptable front-line defenders. They can rapidly produce a vast amount of mucus, and can change in number, in response to airway insults. The objective of the present study is to quantify the effects of mucus discharge and goblet cell hyperplasia on the microscopic dose consequences of macroscopic radon exposures. METHODS: For this purpose, computational models of the bronchial epithelium and alpha-particle transport have been prepared and applied to quantify the hits received and doses absorbed by cell nuclei in case of different mucus thicknesses and goblet cell number. RESULTS AND CONCLUSIONS: Both mucus discharge and induction of goblet cell hyperplasia reduce radiation burden at the cellular level, and as such they both can be considered as radioadaptive responses to radon exposure. As compared to basal cell hyperplasia, goblet cell hyperplasia is more effective in reducing the microscopic dose consequences of a given macroscopic exposure. Such changes in exposure geometry highlight the need for improvements in the application of biokinetic and dosimetry models for incorporated radionuclides as well as the dose and dose rate effectiveness factor.

Non-thermal plasma treated solution with potential as a novel therapeutic agent for nasal mucosa regeneration.

Adequate and rapid mucosal regeneration is one of the most important factors in the healing process of nasal mucosa after surgery or trauma. In particular, delayed mucosal regeneration after surgery is an important cause of surgical failure. However, no effective treatment is available yet. Non-thermal plasma (NTP) has several medical effects, but the existing probe type is limited to local direct treatment. Therefore, we investigated the various effects using liquid type plasma to overcome this limitation. In addition, the therapeutic effects of non-thermal plasma treated solution (NTS) on nasal mucosa have yet to be determined. Experiments were carried out using BEAS-2B, a human bronchial epithelial cell line similar to nasal mucosa epithelium. NTS had no cytotoxicity to the BEAS-2B cells and enhanced cell proliferation. NTS also promoted migration of BEAS-2B cells. NTS increased cell proliferation and migration via epidermal growth factor receptor (EGFR) activities and epithelial-to-mesenchymal transition (EMT) signaling. Furthermore, NTS enhanced wound healing of nasal mucosa in an animal model. Accordingly, NTS promotes nasal mucosa wound healing by increasing cell proliferation and migration. These findings suggest the therapeutic potential of NTS in nasal mucosa wound healing.

Automated Instead of Manual Treatment Planning? A Plan Comparison Based on Dose-Volume Statistics and Clinical Preference.

PURPOSE: Automated planning aims to speed up treatment planning and improve plan quality. We compared manual planning with automated planning for lung stereotactic body radiation therapy based on dose-volume histogram statistics and clinical preference. METHODS AND MATERIALS: Manual and automated intensity modulated radiation therapy plans were generated for 56 patients by use of software developed in-house and Pinnacle 9.10 Auto-Planning, respectively. Optimization times were measured in 10 patients, and the impact of the automated plan (AP) on the total treatment cost was estimated. For the remaining 46 patients, each plan was checked against our clinical objectives, and a pair-wise dose-volume histogram comparison was performed. Three experienced radiation oncologists evaluated each plan and indicated their preference. RESULTS: APs reduced the average optimization time by 77.3% but only affected the total treatment cost by 3.6%. Three APs and 0 manual plans failed our clinical objectives, and 13 APs and 9 manual plans showed a minor deviation. APs significantly reduced D2% (2% of the volume receives a dose of at least D2%) for the spinal cord, esophagus, heart, aorta, and main stem bronchus (P < .05) while preserving target coverage. The radiation oncologists found >75% of the APs clinically acceptable without any further fine-tuning. CONCLUSIONS: APs may help to create satisfactory treatment plans quickly and effectively. Because critical appraisal by qualified professionals remains necessary, there is no such thing as "fully automated" planning yet.

BRONCHUS AND LUNG CANCER INCIDENCE IN POPULATION LIVING AROUND THE FORMER URANIUM MAINING AND MILING SITES.

The indoor radon concentrations and lung cancer incidence in Eleshnitza village and Blagoevgrad district of Bulgaria were examined in the study reported here. The Eleshnitza was the second largest uranium mining and milling region of the country. The geometric mean of indoor radon concentration in Eleshnitza (465 Bq/m3) was higher than the geometric mean of Blagoevgrad district (78 Bq/m3). Retrospective analyses on lung cancer incidence, covering the period 1995-2012 have been shown the same trend. The results were suggestive of an existing relationship between the two variables. Possible effects attributable to age and gender on lung cancer incidence were examined and found to be significant.

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.

Galactic Cosmic Radiation Induces Persistent Epigenome Alterations Relevant to Human Lung Cancer.

Human deep space and planetary travel is limited by uncertainties regarding the health risks associated with exposure to galactic cosmic radiation (GCR), and in particular the high linear energy transfer (LET), heavy ion component. Here we assessed the impact of two high-LET ions 56Fe and 28Si, and low-LET X rays on genome-wide methylation patterns in human bronchial epithelial cells. We found that all three radiation types induced rapid and stable changes in DNA methylation but at distinct subsets of CpG sites affecting different chromatin compartments. The 56Fe ions induced mostly hypermethylation, and primarily affected sites in open chromatin regions including enhancers, promoters and the edges ("shores") of CpG islands. The 28Si ion-exposure had mixed effects, inducing both hyper and hypomethylation and affecting sites in more repressed heterochromatic environments, whereas X rays induced mostly hypomethylation, primarily at sites in gene bodies and intergenic regions. Significantly, the methylation status of 56Fe ion sensitive sites, but not those affected by X ray or 28Si ions, discriminated tumor from normal tissue for human lung adenocarcinomas and squamous cell carcinomas. Thus, high-LET radiation exposure leaves a lasting imprint on the epigenome, and affects sites relevant to human lung cancer. These methylation signatures may prove useful in monitoring the cumulative biological impact and associated cancer risks encountered by astronauts in deep space.

Normal Tissue Complication Probability Modeling of Pulmonary Toxicity After Stereotactic and Hypofractionated Radiation Therapy for Central Lung Tumors.

PURPOSE: To evaluate clinical pulmonary and radiographic bronchial toxicity after stereotactic ablative radiation therapy and hypofractionated radiation therapy for central lung tumors, and perform normal tissue complication probability modeling and multivariable analyses to identify predictors for toxicity. METHODS AND MATERIALS: A pooled analysis was performed of patients with a central lung tumor treated using ≤12 fractions at 2 centers between 2006 and 2015. Airways were manually contoured on planning computed tomography scans, and doses were recalculated to an equivalent dose of 2 Gy per fraction with an α/ß ratio of 3. Grade ≥3 (≥G3) clinical pulmonary toxicity was evaluated by 2 or more physicians. Radiographic toxicity was defined as a stenosis or an occlusion with or without atelectasis using follow-up computed tomography scans. Logistic regression analyses were used for statistical analyses. RESULTS: A total of 585 bronchial structures were studied in 195 patients who were mainly treated using 5 or 8 fractions (60%). Median patient survival was 27.9 months (95% confidence interval 22.3-33.6 months). Clinical ≥G3 toxicity was observed in 24 patients (12%) and radiographic bronchial toxicity in 55 patients (28%), both mainly manifesting ≤12 months after treatment. All analyzed dosimetric parameters correlated with clinical and lobar bronchial radiographic toxicity, with V130Gy,EQD having the highest odds ratio. Normal tissue complication probability modeling showed a volume dependency for the development of both clinical and radiographic toxicity. On multivariate analyses, significant predictors for ≥G3 toxicity were a planning target volume overlapping the trachea or main stem bronchus (P = .005), chronic obstructive pulmonary disease (P = .034), and the total V130Gy,EQD (P = .012). Radiographic bronchial toxicity did not significantly correlate with clinical toxicity (P = .663). CONCLUSIONS: We identified patient and dosimetric factors associated with clinical and radiographic toxicity after high-dose radiation therapy for central lung tumors. Additional data from prospective studies are needed to validate these findings.

Endobronchial brachytherapy with curative intent: the impact of reference points setting according to the bronchial diameter.

Endobronchial brachytherapy (EBB) is an effective treatment for endobronchial tumors. However, bronchial toxicity caused by over-irradiation remains problematic. To decrease bronchial toxicity, we developed a source-centralizing applicator for EBB. The purpose of the present study was to assess the efficacy and safety of EBB with varying reference dose points according to the bronchial diameter, using a source-centralizing applicator. We reviewed 15 patients with endobronchial carcinoma who were treated with curative intent using a combination of external beam radiotherapy (EBRT) and high-dose-rate EBB between 2005 and 2014. During each EBB session, we used a source-centralizing applicator that maintained the source-delivering catheter in the center of the bronchial lumen. Reference dose points were 5-7 mm from the source axis, depending on the bronchial diameter. The median radiation doses of EBRT and EBB were 40 Gy in 20 fractions and 18 Gy in 3 fractions, respectively. The median observation period was 36 months. The 3-year overall survival, progression-free survival and local control rates were 79%, 77% and 100%, respectively. Grade 2 radiation pneumonitis was observed in two cases. Bronchial toxicities, such as hemoptysis or the symptoms of chronic bronchitis, were not observed. EBB with varying reference dose points according to bronchial diameter, using a source-centralizing applicator, is a promising procedure that may be effective for tumor elimination and reducing toxicity to the bronchial wall.

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.

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.

Dosimetric impact of an air passage on intraluminal brachytherapy for bronchus cancer.

The brachytherapy dose calculations used in treatment planning systems (TPSs) have conventionally been performed assuming homogeneous water. Using measurements and a Monte Carlo simulation, we evaluated the dosimetric impact of an air passage on brachytherapy for bronchus cancer. To obtain the geometrical characteristics of an air passage, we analyzed the anatomical information from CT images of patients who underwent intraluminal brachytherapy using a high-dose-rate 192Ir source (MicroSelectron V2r®, Nucletron). Using an ionization chamber, we developed a measurement system capable of measuring the peripheral dose with or without an air cavity surrounding the catheter. Air cavities of five different radii (0.3, 0.5, 0.75, 1.25 and 1.5 cm) were modeled by cylindrical tubes surrounding the catheter. A Monte Carlo code (GEANT4) was also used to evaluate the dosimetric impact of the air cavity. Compared with dose calculations in homogeneous water, the measurements and GEANT4 indicated a maximum overdose of 5-8% near the surface of the air cavity (with the maximum radius of 1.5 cm). Conversely, they indicated a minimum overdose of ~1% in the region 3-5 cm from the cavity surface for the smallest radius of 0.3 cm. The dosimetric impact depended on the size and the distance of the air passage, as well as the length of the treatment region. Based on dose calculations in water, the TPS for intraluminal brachytherapy for bronchus cancer had an unexpected overdose of 3-5% for a mean radius of 0.75 cm. This study indicates the need for improvement in dose calculation accuracy with respect to intraluminal brachytherapy for bronchus cancer.