Visible blue light inhibits infection and replication of SARS-CoV-2 at doses that are well-tolerated by human respiratory tissue.

The delivery of safe, visible wavelengths of light can be an effective, pathogen-agnostic, countermeasure that would expand the current portfolio of SARS-CoV-2 intervention strategies beyond the conventional approaches of vaccine, antibody, and antiviral therapeutics. Employing custom biological light units, that incorporate optically engineered light-emitting diode (LED) arrays, we harnessed monochromatic wavelengths of light for uniform delivery across biological surfaces. We demonstrated that primary 3D human tracheal/bronchial-derived epithelial tissues tolerated high doses of a narrow spectral band of visible light centered at a peak wavelength of 425 nm. We extended these studies to Vero E6 cells to understand how light may influence the viability of a mammalian cell line conventionally used for assaying SARS-CoV-2. The exposure of single-cell monolayers of Vero E6 cells to similar doses of 425 nm blue light resulted in viabilities that were dependent on dose and cell density. Doses of 425 nm blue light that are well-tolerated by Vero E6 cells also inhibited infection and replication of cell-associated SARS-CoV-2 by > 99% 24 h post-infection after a single five-minute light exposure. Moreover, the 425 nm blue light inactivated cell-free betacoronaviruses including SARS-CoV-1, MERS-CoV, and SARS-CoV-2 up to 99.99% in a dose-dependent manner. Importantly, clinically applicable doses of 425 nm blue light dramatically inhibited SARS-CoV-2 infection and replication in primary human 3D tracheal/bronchial tissue. Safe doses of visible light should be considered part of the strategic portfolio for the development of SARS-CoV-2 therapeutic countermeasures to mitigate coronavirus disease 2019 (COVID-19).

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.

Acoustic tracheal rupture provides insights into larval mosquito respiration.

Acoustic larviciding (AL) occurs by exposing mosquito larvae to acoustic energy that ruptures their dorsal tracheal trunks (DTTs) by the expulsion of gas bubbles into the body. In studying this technique, we serendipitously identified undescribed anatomical and physiological respiratory features. The classical theory of respiration is that the siphon and DTTs play obligate roles in respiration. Our results contradict the accepted theory that culicine larvae respire via atmospheric gas exchange. We identified an undescribed tracheal occlusion (TO) at the posterior extremities the DTTs. The TOs appear necessary for the acoustic rupture of DTTs; this constriction prevents the escape of energized gas from the siphon and allows the tracheal system to be pressurized. With a pressurized isolated tracheal system, metabolic gas exchange directly with the atmosphere is unlikely and could mostly occur through the chitin and setae. Future studies are needed to explore respiration and elucidate the mechanisms of oxygen absorption and carbon dioxide elimination.

Combined surgery and radiotherapy as curative treatment for tracheal adenoid cystic carcinoma: a case report.

BACKGROUND: Adenoid cystic carcinoma of the trachea is a rare tumor, characterized by slow growth and low rate of local and distant metastasis. When achievable, complete surgical resection represents the optimal treatment approach, with the highest results in terms of overall survival. Radiation therapy is a reasonable alternative in cases of inoperable disease. CASE PRESENTATION: We report a case of an 82-year-old white man affected by primary adenoid cystic carcinoma of the trachea, treated with debulking surgery and radiotherapy on the residual disease. A three-dimensional conformal radiation therapy was conducted. The total dose amounted to 70 Gy, administered in 35 fractions of 2 Gy. The medium doses given to the esophagus and lungs were 23 Gy and 4.2 Gy respectively. The maximum dose delivered to the spinal cord was 31 Gy with satisfactory results in terms of local control of the disease. CONCLUSION: A combined approach of surgical resection followed by radiotherapy on the residual disease provided an excellent result in terms of disease control, quality of life, and overall survival in a patient with locally advanced tracheal adenoid cystic carcinoma.

The feasibility of gamma radiation sterilization for decellularized tracheal grafts.

OBJECTIVES/HYPOTHESIS: The most promising stem cell-derived tracheal transplantation approach is dependent upon the use of decellularized tracheal grafts. It has been assumed that a sterilization step, such as gamma radiation, would damage the delicate extracellular matrix of the graft, thus rendering it less viable for cellular repopulation, although this has not been thoroughly investigated. STUDY DESIGN: Laboratory-based comparative analysis. METHODS: Fifteen murine tracheas of strain C57/B-6 mice were obtained. Thirteen were subjected to a detergent-enzymatic decellularization process. Of these decellularized tracheas (DT), eight were irradiated, exposing five tracheas to a radiation level of 25 kGy (DT25) and three to 5 kGy (DT5). Two were left untreated. The two untreated tracheas, two DTs, and two DT25s were prepared and examined using both scanning and transmission electron microscopy. Bioburden calculations were obtained from three DTs, three DT25s, and three DT5s by homogenization, serial dilution, and streak plating. RESULTS: Electron microscopy of untreated fresh tracheas and DTs showed a slight qualitative degradation of cartilage ultrastructure due to the decellularization process. In contrast, examination of DT25 shows significant degradation including poor overall preservation of cartilage architecture with disorganized collagen fibers. The nonirradiated DTs had a calculated bacterial bioburden of 7.8 × 107 to 3.4 × 108 colony-forming units per gram. Both the DT25 and DT5 specimens were found to have a bioburden of zero. CONCLUSIONS: Gamma radiation at 25 kGy degrades the architecture of decellularized tracheal grafts. These ultrastructural changes may prove detrimental to graft viability; however, bioburden calculations suggest that a 5 kGy radiation dose may be sufficient for sterilization. LEVEL OF EVIDENCE: NA Laryngoscope, 127:E258-E264, 2017.

Light-Emitting Diode treatment ameliorates allergic lung inflammation in experimental model of asthma induced by ovalbumin.

Since asthma is a multifactorial disease where treatment sometimes is not effective, new therapies that improve the respiratory discomfort of patients are of great importance. Phototherapy as Light-emitting diode (LED) has emerged as a treatment that presents good results for diseases that are characterized by inflammation. Thus, our objective was to investigate the effects of LED on lung inflammation, by an evaluation of lung cell infiltration, mucus secretion, oedema, and the production of cytokines. Male Balb/c mice were or not sensitized and challenged with ovalbumin (OVA) and treated or not with LED therapy (1 h and 4 h after each OVA challenge). Twenty-four hours after the last OVA challenge, analyzes were performed. Our results showed that LED treatment in asthmatic mice reduced the lung cell infiltration, the mucus production, the oedema, and the tracheal's contractile response. It also increased the IL-10 and the IFN-gamma levels. The effects of LED treatment on lung inflammation may be modulated by IL-10, IFN-gamma, and by mast cells. This study may provide important information about the effects of LED, and in addition, it may open the possibility of a new approach for the treatment of asthma.

A Novel Self-Expandable, Radioactive Airway Stent Loaded with 125I Seeds: A Feasibility and Safety Study in Healthy Beagle Dog.

PURPOSE: Airway stent placement is an effective treatment for the immediate palliation of malignant airway obstruction. However, restenosis caused by tumor ingrowth and/or overgrowth after stenting is common. The purpose of this study was to investigate the feasibility and safety of a novel self-expandable stent loaded with 125I seeds in healthy beagle dog. MATERIALS AND METHODS: Under fluoroscopic guidance, forty-eight self-expandable airway stents loaded with 125I seeds were perorally placed in the main trachea of 48 healthy beagle dogs, who were randomly divided into four groups (Group A: 0.3 mCi; Group B: 0.6 mCi; Group C: 0.9 mCi; Control group: 0 mCi). The estimated radiation dose was calculated using the isotropic point source approximation. Radiological follow-up examinations and histopathological examinations of stented tracheal segments and their adjacent organs and tissues were performed at 2, 4, 8, and 16 weeks following the stenting. RESULTS: All stents were successfully deployed in the targeted tracheal segment in the beagle dogs without procedure-related complications. Tracheal stenosis became severe gradually in all the four groups, which was not associated with the radioactivity of 125I seeds (p > 0.05). The tracheal injury scores increased along with the higher dose of radioactive seeds which reached peak at 8 weeks and then turned back slightly at 16 weeks. The adjacent tissue did not show pathohistological changes under microscope, while mild and reversible ultrastructure changes were showed under electronic microscope. CONCLUSIONS: This study demonstrates that it is feasible and safe to insert this novel self-expandable airway stent loaded with 125I seeds in healthy beagle dog.

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.

Rabbit model of tracheal stenosis using cylindrical diffuser.

BACKGROUND AND OBJECTIVE: Variable methods of animal model have been introduced to develop tracheal stenosis. However, none of the prior models allow for predictable determination of the grade of stenosis. This study sought to establish an animal model of tracheal stenosis by using a cylindrical diffuser and to evaluate the feasibility of a reproducible model. STUDY DESIGN/MATERIALS AND METHODS: A cylindrical diffuser was developed to have a 5 mm active segment to emit laser light circumferentially. Twenty one New Zealand white rabbits were enrolled in this study. The cylindrical diffuser was inserted transorally under bronchoscopic view and the diffused light was delivered to tracheal mucosa 2 cm below the level of vocal cord. Input power of irradiation was 10 W, 5 seconds in group A (n = 7), 10 W, 7 seconds in group B (n = 7), and 8 W, 5 seconds in group C (n = 7). The degree of tracheal stenosis was observed weekly and the rabbits were euthanized 4 weeks after the laser irradiation. RESULTS: The degree of stenosis in group B (90-98%) was significantly larger than that of group A (75-92%) (P = 0.004), while degree in group C (24-35%) was significantly smaller than that of group A (P < 0.001). Two rabbits of group A were euthanized at 3 weeks due to costal retraction. In group B, six rabbits died within 3 weeks after laser irradiation due to severe tracheal stenosis and tracheal malacia, while one rabbit was euthanized 16 days after the irradiation. All rabbits in group C survived up to 4 weeks. Survival between three groups showed significant difference (P = 0.001). CONCLUSION: The degree of stenosis was significantly different according to the delivered optical energy to tracheal mucosa. Therefore, the proposed model may be used in animal studies to emulate variable grades of tracheal stenosis. Lasers Surg. Med. 49:372-379, 2017. © 2016 Wiley Periodicals, Inc.

Re-irradiation for locoregionally recurrent tumors of the thorax: a single-institution, retrospective study.

BACKGROUND: Re-irradiation (re-RT) of the thorax is challenging due to the impact of prior therapies on normal tissues, and there are few reports of definitive re-RT. The treatment toxicities and efficacy of re-RT are not well known. The aim of the present study was to assess the safety and efficacy of definitive re-RT of the thorax. METHODS: Patients who were treated with thoracic re-RT between March 2007 and December 2014 were retrospectively analyzed. Primary and re-irradiation plans were required to have an overlap of dose distributions for the 80 % isodose level. All doses were recalculated to an equivalent dose of 2 Gy per fraction (EQD2). When possible, analysis of dose accumulation was carried out using the medical image merge (MIM) (®) software program (version 6.5, MIM Software Inc., Cleveland, OH). Administration dosages for organs at risk were defined. RESULTS: Fourteen (67 %) and seven (33 %) patients with non-small cell carcinoma (NSCLC) and small cell carcinoma (SCLC), respectively, were identified. The patients' median age was 72 (range 53-85) years. Fifteen patients (71 %) had "proximal" tumors, defined as tumors at the distal 2 cm of the trachea, carina, and main bronchi. The median interval from initial RT to re-RT was 26.8 (range 11.4-92.3) months. Re-RT was delivered by X-ray beam and proton beam therapy in 20 (95 %) patients and 1 (5 %) patient, respectively. The median radiation dose of re-RT was 60 (range 54-87.5) Gy10 and 50 (range 50.0-87.5) Gy10 for patients with NSCLC and SCLC, respectively. Grade 3 acute radiation pneumonitis occurred in only one patient. There were no other serious complications. The median follow-up time was 22.1 (range 2.3-56.4) months. The median local progression-free survival time (LPFS) and overall survival time (OS) were 12.9 (95 % confidence interval (CI): 8.9-27.9) months and 31.4 (95 % CI: 16.9-45.9) months, respectively. Patients receiving ≥ 60 Gy10 at re-RT had longer LPFS (p = 0.04). CONCLUSIONS: Good safety with longer OS than in previous reports was demonstrated. Re-RT seems to be a promising treatment option. Further study to define the risk-benefit ratios is necessary.

Dosimetric Factors and Toxicity in Highly Conformal Thoracic Reirradiation.

PURPOSE: We determined cumulative dose to critical structures, rates of toxicity, and outcomes following thoracic reirradiation. METHODS AND MATERIALS: We retrospectively reviewed our institutional database for patients treated between 2008 and 2014, who received thoracic reirradiation with overlap of 25% prescribed isodose lines. Patients received courses of hyperfractionated (n=5), hypofractionated (n=5), conventionally fractionated (n=21), or stereotactic ablative radiation therapy (n=51). Doses to critical structures were converted to biologically effective dose, expressed as 2 Gy per fraction equivalent dose (EQD2; α/ß = 2 for spinal cord; α/ß = 3 for other critical structures). RESULTS: We identified 82 courses (44 for retreatment) in 38 patients reirradiated at a median 16 months (range: 1-71 months) following initial RT. Median follow-up was 17 months (range: 3-57 months). Twelve- and 24-month overall survival rates were 79.6% and 57.3%, respectively. Eighteen patients received reirradiation for locoregionally recurrent non-small cell lung cancer with 12-month rates of local failure and regional recurrence and distant metastases rates of 13.5%, 8.1%, and 15.6%, respectively. Critical structures receiving ≥75 Gy EQD2 included spinal cord (1 cm(3); n=1), esophagus (1 cm(3); n=10), trachea (1 cm(3); n=11), heart (1 cm(3); n=9), aorta (1 cm(3); n=16), superior vena cava (1 cm(3); n=12), brachial plexus (0.2 cm(3); n=2), vagus nerve (0.2 cm(3); n=7), sympathetic trunk (0.2 cm(3); n=4), chest wall (30 cm(3); n=12), and proximal bronchial tree (1 cm(3); n=17). Cumulative dose-volume (D cm(3)) toxicity following reirradiation data included esophagitis grade ≥2 (n=3, D1 cm(3) range: 41.0-100.6 Gy), chest wall grade ≥2 (n=4; D30 cm(3) range: 35.0-117.2 Gy), lung grade 2 (n=7; V20combined-lung range: 4.7%-21.7%), vocal cord paralysis (n=2; vagus nerve D0.2 cm(3) range: 207.5-302.2 Gy), brachial plexopathy (n=1; D0.2 cm(3) = 242.5 Gy), and Horner's syndrome (n=1; sympathetic trunk D0.2 cm(3) = 130.8 Gy). No grade ≥4 toxicity was observed. CONCLUSIONS: Overlapping courses of reirradiation can be safely delivered with acceptable toxicity. Some toxicities occurred acutely at doses considered safe for a single course of therapy (esophagus). We observed rib fracture, brachial plexopathy, and Horner's syndrome for patients receiving high cumulative doses to corresponding critical structures.

[The surrounding radiation dose of iodine-125 seeds on normal larynx tissue in rabbits].

Objective:To monitor the change of the radiation dose of the rabbits which were implanted rasioactive 125I seed into the normal laryngeal tiseue at different time,and to evaluate the safety of radiation protection. Method:Sixty New Zwaland rabbits, weighing 2.15-2.30 kg，were randomly divided into 5 groups:7 d,1month,2 month,4 month group and the control group, 12 rabbits in each group Iodine-125 of 0.8 mCi were implanted into the right side of the first trachea ring. At the different time and different distance, the surrounding radiation dose was measured after 4 months of implanting. The results were analyzed in statistics. Result:With the increase of the distance and the prolong of the time, the radiation dose was decreasing，and with the increase of distance,the radiation dose decreased slowly. At the site of 1 meter from the seeds, the detected dose is close to the natural background radiation dose. Conclusion:The clinical application of radioactive 125I seed interstitial implant is easy to protected,the surrounding close contacts is satety.

Intermediate Megavoltage Photon Beams for Improved Lung Cancer Treatments.

The goal of this study is to evaluate the effects of intermediate megavoltage (3-MV) photon beams on SBRT lung cancer treatments. To start with, a 3-MV virtual beam was commissioned on a commercial treatment planning system based on Monte Carlo simulations. Three optimized plans (6-MV, 3-MV and dual energy of 3- and 6-MV) were generated for 31 lung cancer patients with identical beam configuration and optimization constraints for each patient. Dosimetric metrics were evaluated and compared among the three plans. Overall, planned dose conformity was comparable among three plans for all 31 patients. For 21 thin patients with average short effective path length (< 10 cm), the 3-MV plans showed better target coverage and homogeneity with dose spillage index R50% = 4.68±0.83 and homogeneity index = 1.26±0.06, as compared to 4.95±1.01 and 1.31±0.08 in the 6-MV plans (p < 0.001). Correspondingly, the average/maximum reductions of lung volumes receiving 20 Gy (V20Gy), 5 Gy (V5Gy), and mean lung dose (MLD) were 7%/20%, 9%/30% and 5%/10%, respectively in the 3-MV plans (p < 0.05). The doses to 5% volumes of the cord, esophagus, trachea and heart were reduced by 9.0%, 10.6%, 11.4% and 7.4%, respectively (p < 0.05). For 10 thick patients, dual energy plans can bring dosimetric benefits with comparable target coverage, integral dose and reduced dose to the critical structures, as compared to the 6-MV plans. In conclusion, our study indicated that 3-MV photon beams have potential dosimetric benefits in treating lung tumors in terms of improved tumor coverage and reduced doses to the adjacent critical structures, in comparison to 6-MV photon beams. Intermediate megavoltage photon beams (< 6-MV) may be considered and added into current treatment approaches to reduce the adjacent normal tissue doses while maintaining sufficient tumor dose coverage in lung cancer radiotherapy.

[Radiation injury of interstitial implantation 125I seeds on normal trachea tissue of rabbits].

OBJECTIVE: To study the radition injury of tracheal mucous membrane tissue after interstitial implanted radioactive 125I in normal rabbit,improve the safety of clinical application. METHOD: Sixty New Zealand rabbits, weighing 2.15-2.30 kg, were randomly divided into 1 w, 1 m, 2 m, 4 m and the control group, the control group was further divided into four subgroups. The 0.8mCi 125I seeds were implanted into the tissue by the first tracheal ring in the treatment groups and nonradioactive seeds were implanted in the control group. Taking the tracheal mucous membrane tissue for pathological examination by HE staining to observe the mucosal injury and VEGF, Pan-Cadherin immunohistochemical staining to observe the expression in differernt time. RESULT: Immunohistochemical staining: VEGF and Pan-Cadherin have statistically significant differences in the expression on different time, the expression is dynamic. CONCLUSION: The expression of VEGF and Pan-Cadherin reflect the radioactive 125I seed has little influence on normal trachea tissue and the damage can be repaired by the regeneration of the basal cell.

Toxicities of organs at risk in the mediastinal and hilar regions following stereotactic body radiotherapy for centrally located lung tumors.

INTRODUCTION: We investigated tolerable doses to organs at risk (OARs) in the mediastinum and pulmonary hilum following stereotactic body radiotherapy for centrally located lung tumors. METHODS: Between 2005 and 2012, 381 patients with lung tumors were treated with stereotactic body radiotherapy of 40 to 60 Gy in five fractions. From among these patients, we extracted those who received greater than 25 Gy irradiation to OARs and analyzed dosimetric factors in relation to grade 3 to 5 toxicities. RESULTS: In total, 398 OARs in 133 patients were analyzed, with a median follow-up of 33 (range, 3-87) months. The numbers receiving greater than 25 Gy irradiation to the aorta, vena cava, pulmonary artery, pulmonary vein, bronchus, trachea, heart, and esophagus were 72, 33, 73, 60, 55, 13, 69, and 23, respectively. The corresponding median Dmax 0.5 ml were 43.8, 32.0, 32.2, 29.1, 28.4, 28.7, 41.1, and 21.7 Gy. Of these patients, two developed grade 5 and one grade 3 hemoptysis, and two had grade 3 obstructive pneumonia. Two patients with grade 5 hemoptysis received high doses at the pulmonary artery and bronchus (59.2 and 54.4 Gy, and 61.3 and 59.6 Gy, respectively). No other grade 3 to 5 toxicities occurred. CONCLUSION: Therapeutic indications and dose-intensity should be carefully determined for patients with central tumors, especially when doses to the pulmonary artery and bronchus in the pulmonary hilum exceed 50 Gy. Tolerable doses for other OARs might, however, be higher than in this study, though longer follow-up is necessary to assess this possibility.

[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.

Primary radiotherapy with endobronchial high-dose-rate brachytherapy boost for inoperable lung cancer: long-term results.

BACKGROUND: To retrospectively evaluate the outcome of patients with inoperable non-small-cell lung cancer treated with primary external beam radiotherapy combined with high-dose-rate endobronchial brachytherapy boost. PATIENTS AND METHODS: Between 1988 and 2005, 35 patients with non-small-cell lung cancer (stage I-III) ineligible for surgical resection and/or chemotherapy, were primarily treated with external beam radiotherapy with a median total dose of 50 Gy (range, 46-60). A median of 3 fractions high-dose-rate endobronchial brachytherapy was applied as a boost after external beam radiotherapy, the median total dose was 15 Gy (range, 8-20). High-dose-rate endobronchial brachytherapy was carried out with iridium-192 sources (370 GBq) and prescribed to 1 cm distance from the source axis. RESULTS: With a median follow-up of 26 months from the first fraction of high-dose-rate endobronchial brachytherapy, the 1-, 2- and 5-year overall (local progression-free) survival rates were 76% (76%), 61% (57%) and 28% (42%), respectively. Complete or partial remission rates 6 to 8 weeks after treatment were 57% and 17%, respectively. Significant prognostic favorable factors were a complete remission 6-8 weeks after treatment and a negative nodal status. In patients without mediastinal node involvement, a long-term local control could be achieved with 56% 5-year local progression-free survival. Common Toxicity Criteria grade 3 toxicities were hemoptysis (n = 2) and necrosis (n = 1). One fatal hemoptysis occurred in combination with a local tumor recurrence. CONCLUSIONS: The combination of external beam radiotherapy with high-dose-rate endobronchial brachytherapy boost is an effective primary treatment with acceptable toxicity in patients with non-small-cell lung cancer ineligible for surgical resection and/or chemotherapy.

4π noncoplanar stereotactic body radiation therapy for centrally located or larger lung tumors.

PURPOSE: To investigate the dosimetric improvements in stereotactic body radiation therapy for patients with larger or central lung tumors using a highly noncoplanar 4π planning system. METHODS AND MATERIALS: This study involved 12 patients with centrally located or larger lung tumors previously treated with 7- to 9-field static beam intensity modulated radiation therapy to 50 Gy. They were replanned using volumetric modulated arc therapy and 4π plans, in which a column generation method was used to optimize the beam orientation and the fluence map. Maximum doses to the heart, esophagus, trachea/bronchus, and spinal cord, as well as the 50% isodose volume, the lung volumes receiving 20, 10, and 5 Gy were minimized and compared against the clinical plans. A dose escalation study was performed to determine whether a higher prescription dose to the tumor would be achievable using 4π without violating dose limits set by the clinical plans. The deliverability of 4π plans was preliminarily tested. RESULTS: Using 4π plans, the maximum heart, esophagus, trachea, bronchus and spinal cord doses were reduced by 32%, 72%, 37%, 44%, and 53% (P≤.001), respectively, and R50 was reduced by more than 50%. Lung V20, V10, and V5 were reduced by 64%, 53%, and 32% (P≤.001), respectively. The improved sparing of organs at risk was achieved while also improving planning target volume (PTV) coverage. The minimal PTV doses were increased by the 4π plans by 12% (P=.002). Consequently, escalated PTV doses of 68 to 70 Gy were achieved in all patients. CONCLUSIONS: We have shown that there is a large potential for plan quality improvement and dose escalation for patients with larger or centrally located lung tumors using noncoplanar beams with sufficient quality and quantity. Compared against the clinical volumetric modulated arc therapy and static intensity modulated radiation therapy plans, the 4π plans yielded significantly and consistently improved tumor coverage and critical organ sparing. Given the known challenges in central structure dose constraints in stereotactic body radiation therapy to the lung, 4π planning may increase efficacy and reduce toxicity.