Bronchial Research Articles

Serum Allergen-Specific Immunoglobulin E in Cats with Inflammatory Bronchial Disease.

The etiology of feline inflammatory bronchial disease is poorly understood. This study compares the degree of allergen-specific serum IgE responses between cats with feline asthma, chronic bronchitis, mixed inflammation, and clinically healthy cats (HCs). The retrospective case-control study used serum from eighteen cats with eosinophilic inflammation (EI), ten with neutrophilic inflammation (NI), six with mixed inflammation (MI), and fourteen HCs. Affected cats were categorized into groups based on bronchoalveolar lavage cytology. The measurement of IgE for 34 different allergens including fungal organisms, weeds, grasses, trees, mites, and insects was performed using an indirect ELISA. Positive reactions to allergens were detected in the serum of 17/18 cats with EI, 8/10 with NI, 6/6 with MI, and 11/14 HCs (p = 0.364). When overall positive reactions were compared between groups, cats with MI (p = <0.01) had significantly more positive reactions against mite allergens than HCs. Blood eosinophils inversely correlated with the absolute amount of allergen-specific serum IgE expressed in ELISA absorbance units (EAs) (p = 0.014). Sensitization against dust mites seems to be more prevalent in cats with MI. However, positive IgE reactions can be observed in healthy and diseased cats, and, therefore, need to be interpreted in the light of clinical findings and environmental conditions of individual patients.

A preliminary study of dynamic interactive simulation and computational CT scan of the ideal alveolus model.

While the development of CT imaging technique has brought cognition of in vivo organs, the resolution of CT images and their static characteristics have gradually become barriers of microscopic tissue research. Previous research used the finite element method to study the airflow and gas exchange in the alveolus and acinar to show the fate of inhaled aerosols and studied the diffusive, convective, and sedimentation mechanisms. Our study combines these techniques with CT scan simulation to study the mechanisms of respiratory movement and its imaging appearance. We use 3D fluid-structure interaction simulation to study the movement of an ideal alveolus under regular and forced breathing situations and ill alveoli with different tissue elasticities. Additionally, we use the Monte Carlo algorithm within the OpenGATE platform to simulate the computational CT images of the dynamic process with different designated resolutions. The resolutions show the relationship between the kinematic model of the human alveolus and its imaging appearance. The results show that the alveolus and the wall thickness can be seen with an image resolution smaller than 15.6μm. With ordinary CT resolution, the alveolus is expressed with four voxels. This is a preliminary study concerning the imaging appearance of the dynamic alveolus model. This technique will be used to study the imaging appearance of the dynamic bronchial tree and the lung lobe models in the future.

GENERAL REGULATIONS OF MACRO-AND MICROMORPHOLOGY OF THE LUNGS OF A MATURE HORSE (EQUUS FERUSCABALLUS L., 1758)

The rapidly changing ecological situation implies a high level of adaptation capabilities of the animal organism to the realities of the environment. In the conditions of animal husbandry, this is possible only with regular monitoring of the morphological state of organs and systems, especially the respiratory system, which is actively influenced by the features of housing, atmospheric air, feeding, as well as the medical and preventive measures that are carried out. Therefore, the functioning of the lungs as an open morphofunctional system directly depends on the nature of their dynamic interaction with a complex complex of physical and chemical environmental factors. In this regard, there is an obvious need for a detailed study of the macro- and micromorphology of the respiratory organs, since such organs are a system by which the body "builds itself from environmental conditions". It is also necessary to take into account that this system occupies one of the leading positions in ensuring the optimal level of functioning of the body, since the animal's development, metabolic processes, and its state of health largely depend on its work. Establishing the macro- and micromorphological features of the respiratory system is the foundation for preventive and therapeutic measures. The respiratory system ensures the intake of oxygen into the body and the excretion of carbon dioxide from it, and the gas exchange between blood and air.&#x0D; The scientific article is devoted to the study of the macro- and micromorphological features of the lungs of a sexually mature horse - Equus Feruscaballus L., 1758. With the help of anatomical preparation and macroscopic, histological, morphometric and statistical methods of research, the morphology of the lungs was investigated and their belonging to a certain anatomical type was determined. As a result of the research, the partial structure of the lungs was determined, their topography, shape, dimensions, branching of the bronchi of the bronchial tree, results of organometry (absolute and relative lung mass), morphometric assessment of their morphological structures, asymmetry coefficient, etc. were determined.&#x0D; According to the results of morphological studies, the characteristic morphological features of the macro- and microscopic structure of the lungs of a mature horse were revealed according to the class, age and species of animals. The presence of individual morphological features in the lobular structure of the lungs of horses was revealed. In particular, there are only two lobes in the left lung (cranial and caudal), and three lobes in the right lung (cranial, caudal and additional). The alveolar tree of the lungs of horses is shortened, wide and has a vesicular structure.&#x0D; The conducted research to a certain extent expands and supplements information about the species, breed and morphological features of the anatomical and histological structure of the lungs in domestic animals and is important for assessing the clinical and morphological state of animals in normal conditions and for identifying the pathogenesis of animal diseases related to the respiratory organs.

Lung Microbiota in Idiopathic Pulmonary Fibrosis, Hypersensitivity Pneumonitis, and Unclassified Interstitial Lung Diseases: A Preliminary Pilot Study.

(1) Introduction: Although historically, the lung has been considered a sterile organ, recent studies through 16S rRNA gene sequencing have identified a substantial number of microorganisms. The human microbiome has been considered an "essential organ," carrying about 150 times more information (genes) than are found in the entire human genome. The purpose of the present study is to characterize and compare the microbiome in three different interstitial lung diseases: idiopathic pulmonary fibrosis (IPF), hypersensitivity pneumonitis, and nondifferential interstitial lung disease. (2) Material and methods: This was a prospective cohort study where the DNA of 28 patients with ILD was extracted from the lavage and then processed using the standard technique of 16S RNA gene sequencing. In a tertiary teaching hospital in the northern, western part of Romania, samples were collected through bronchoscopy and then processed. (3) Results: The same four species were found in all the patients but in different quantities and compositions: Firmicutes, Actinobacteria, Proteobacteria and Bacteroides. Streptococcus was the most prevalent genus, followed by Staphylococcus and Prevotella. Statistically significant differences in the OUT count for the ten most abundant taxa were found for the genus: Gemella, Actinobacteria, Prevotella, Neisseria, Haemophilus, and Bifidobacterium. The comparative analysis showed a richer microbiota in patients with IPF, as shown by the alpha diversity index. (4) Conclusions: In interstitial lung diseases, the microorganisms normally found in the lung are reduced to a restricted flora dominated by the Firmicutes family. These changes significantly disrupt the continuity of the observed bacterial pattern from the oropharynx to the bronchial tree and lung, possibly impacting the evolution and severity of interstitial lung diseases.

A clinical case of primary ciliary dyskinesia in a child under one year old with a pathogenic genetic variant of the DNAH5 gene described for the first time

Relevance: primary ciliary dyskinesia (PCD) is a rare hereditary autosomal recessive disease from the group of ciliopathies, which is based on a defect in the ultrastructure of the cilia of the epithelium of the respiratory tract and similar structures, leading to a violation of their motor function. It is characterized by the defeat of all parts of the respiratory tract with the formation of a chronic inflammatory process and bronchiectasis. About half of patients with PCD have a complete or incomplete reverse arrangement of internal organs with various variants of heterotaxy (situs inversus). Primary ciliary dyskinesia should be differentiated from cystic fibrosis, primary immunodeficiency conditions, congenital anomalies of the structure of the bronchial tree, bronchiectasis of other origin, bronchial asthma, congenital anomalies of the cardiovascular system. Objective: describe the clinical case of a PCD patient with the first-described pathogenic variant of the nucleotide sequence (chr5:13700862CCATAGA&gt;C) of the DNAH5 gene to familiarize doctors with the clinical features of the disease and modern diagnostic capabilities. Materials and methods: the data from the patient’s medical history, transmission electron microscopy to detect anomalies in the structure of cilia in the biopsy of the nasal mucosa and the results of molecular genetic diagnostics were used. Results. The patient was admitted for 8 months for examination and treatment in June 2022. A child from the 1st pregnancy, the first birth at 43 weeks. From anamnesis: suffered intrauterine pneumonia, otitis media without hearing loss, obstructive bronchitis, episodes of apnea. Neonatal screening for cystic fibrosis is negative. According to the PICADOR scale, 12 points were obtained. On high-speed video microscopy of cilia, there is a violation of the movements of the cilia. On computed tomography of the chest organs, the reverse location of the internal organs was noted, there were no pathological changes in the lungs. The total absence of external and internal dynein handles on transmission electron microscopy was revealed. Exome sequencing revealed the previously described variant of the nucleotide sequence in exon 68 of the DNAH5 gene (chr5:13735348G&gt; A) in a heterozygous state. Also, a previously undescribed variant of the nucleotide sequence (chr5:13700862CCATAGA&gt; C) in a heterozygous state was detected in exon 78 of the DNAH5 gene. Conclusion: modern possibilities of PCD diagnostics are demonstrated by the example of clinical observation. It is noted that patients with suspected PCD need a comprehensive examination. A pathogenic variant of the nucleotide sequence (chr5:13700862CCATAGA&gt;C) of the DNAH5 gene in a heterozygous state has been described for the first time, leading to the deletion of two amino acids without shifting the reading frame (c.13604_13609del p. (Val4535_Tyr4536del); NM_001369.3), which will help for the diagnosis of PCD in the future.

Small airways dysfunction: The importance of utilising Z-scores to define MMEF abnormalities in clinical practice

BackgroundThe small airways comprise the largest cross-sectional area of the lungs, however, assessing and reporting abnormalities for this region of the bronchial tree has been practically and scientifically uncertain. MethodsUsing routinely collected spirometry data for patients with either asthma or COPD, the accuracy of % predicted values for defining small airways dysfunction was assessed. A z-score of ≤ −1.645 of the maximal-mid expiratory flow (MMEF) was used as the gold standard for defining abnormality in the small airways. ResultsRecords of 3396 patients were included in the analysis. The false positive (FP) rates were 24.6 %, 16.1 %, 11.5 %, or 7.9 % when the % predicted value of 80 %, 70 %, 65 %, or 60 % were used, respectively. Sex, age, and BMI were associated with FP rates. Males were more likely to be categorised as FP with odds ratio (OR) between 1.10 and 1.49 across % predicted groups. Age was associated with FP rates with an OR between 1.01 and 1.08. The BMI was also associated with FP rates with an OR of 1.03 across all % predicted groups. Assessing the association of age groups with FP rate showed that those above 60 years old were more likely to be categorised as FP with an OR between 1.23 and 73.2 compared to those less than 30 years old. ConclusionWhen assessing the small airways in clinical practice or for scientific purposes, the % predicted values overestimate the actual impairment leading to FP interpretation. Utilising z-score values are recommended to assess the small airways using the spirometric index, MMEF.

A rare case of endobronchial tuberculosis with left main bronchial stenosis in a patient with pulmonary tuberculosis

Endobronchial tuberculosis (EBTB) is a condition that occurs as a result of pulmonary tuberculosis (TB), where the infection spreads to the inner walls of the bronchial tubes or the trachea. This causes the inner lining and the layer underneath to become inflamed, swollen, ulcerated, or to develop granulated tissue or scar. We discuss a 19-year-old lady with active pulmonary TB who was receiving anti-TB drug treatment. Despite being on anti-TB medications, she had persistent cough, loss of weight and increasing dyspnea. She was diagnosed with EBTB with left main bronchus (LMB) stenosis, based upon a strong clinical suspicion, followed by using a variety of techniques, including lung function testing, a chest and neck CT scan, and a bronchoscopy. Given that EBTB is a rare consequence of TB, it is crucial for clinicians to take it into account when patients present with symptoms that are comparable. This will enable prompt and effective treatment.

A family case Williams – Campbell syndrome in clinical practice

Currently, among all pathologies of the respiratory system, bronchiectasis receives special attention. This is due to its increasing incidence and the improvement of diagnostic methods. Williams – Campbell syndrome is a congenital form of bronchiectasis characterized by a defect or complete absence of bronchial wall cartilage in the subsegmental bronchi. In view of this, medical personnel should be familiar with the basics of differential diagnosis and treatment, as well as the prognosis of this disease. The aim of this paper is to present a clinical family case of Williams – Campbell syndrome. The father of the family was diagnosed with WCS at the age of 3 years by bronchography, and his daughter has all clinical signs of this disease today. To date, the question remains as how to diagnose WCS and monitor the patient’s health in the future. Conclusion. Physicians of all specialties should be informed about rare diseases.

Toxicity of Patients with Ultra-Central Thoracic Tumors Treated with Stereotactic Body Radiotherapy (SBRT) with Dose of 50 Gy in 5 Fractions

The ideal regimen for stereotactic body radiotherapy (SBRT) in ultra-central lung tumors is still to be defined, mostly due to the risk of unacceptable or fatal toxicity. There is not much information on outcomes after SBRT for this group of patients. We summarize here our experience with ultra-central lung cancer patients treated with the dose of 50 Gy delivered in 5 fractions. This study is a retrospective review of all cases of ultra-central thoracic tumors treated with SBRT with the dose of 50 Gy in 5 fractions, delivered every other day, at our institution. In all cases, as we defined ultra-central lung tumor, the PTV overlapped or touched one or more of the following structures: bronchial tree, trachea, great vessels, heart, and esophagus. Metastatic and primary lung lesions were included. The volumes of treatment were defined by 4D-CT to consider breathing motion. Normal organs constraints followed the recommendations of the RTO 0813 trial as follows: Spinal cord: max 30 Gy. Lung right or lung left: V13 Gy[cc] < 1500. Esophagus: max 52 Gy and nonadjacent esophagus: V27.5 Gy[cc] < 5. Heart: V32 Gy[cc] < 15; max 52 Gy. Great vessels: max 52 Gy and non-adjacent great vessels V47 Gy[cc] < 10. Trachea plus bronchus: max 52 Gy and non-adjacent V18 Gy[cc] < 4. Follow-up, at the discretion of the treating MD, included periodic CT scans of the thorax after SBRT and assessment of radiation-induced toxicity scored with CTCv3.0. Between December 2015 and February 2022, 86 patients were eligible for this review. Median follow-up was 17 months (range: 1-76 months); the median age was 74 years (range: 37-98 years). Histology was as follows: 50 patients had biopsy proved NSCLC, 16 had no biopsy, and 20 had metastatic non-lung primaries. Overlapped structures were as follows: with great vessels in 46 cases, heart in 20 cases, trachea/branchial tree in 18 cases, and esophagus in 2 cases. In 16 patients the overlap was present in more than one structure. Overall, 68.6% did not report acute toxicity. The most common acute side effects were fatigue (15.1%), coughing (8.1%), shortness of breath (6.9%), esophagitis (2.3%), and dysphagia (1.1%). No grade 3 or more significant toxicity was described. As acute side effects, many patients had exacerbations of the previous condition, such as shortness of breath (16 pts) or coughing (4 pts) during follow-up. Pneumonitis was found as a late side effect in four cases. One patient had empyema associated with a fistula in the non-irradiated lung, where the patient had previous surgery, but in the irradiated lung no severe complication was detected. There were no deaths attributed to the SBRT treatment. 67.5% of 86 patients were alive at the time of the review; 87.2% had local control, and 65.1% had metastases-free survival. In this cohort of patients, no death or even severe acute or chronic toxicity was attributed to SBRT. SBRT seems safe for ultra-central lesions using the regimen of 50 Gy in 5 fractions with the constraints of the RTOG 0813 trial.

Escalating SBRT Dose to Hypoxic Centers of Large Pulmonary Tumors via Simultaneous Integrated Boost Confers Effective Local Control with Minimal Toxicity

Hypoxia confers radio-resistance to tumor cells and drives malignant disease progression. SBRT treatment of large (>5.0 cm) pulmonary tumors pose significant dosimetric challenges in minimizing dose to adjacent organs at risk (OARs). Here, we detail the use of SBRT with simultaneous integrated boost (SIB) to the hypoxic centers of large pulmonary masses with effective local control and minimal normal tissue toxicity. Highly conformal treatment plans utilized 3-4 non-coplanar VMAT arcs with 6MV-FFF (1400 MU/min) and 4D-CT on TrueBeam to deliver 50 Gy in 5 fractions to the planning target volume (PTV). SIB dose of 60 Gy was delivered to a 1-cm internal margin from the gross tumor volume (GTV). Dose was calculated using Acuros-based engine. Pre-treatment Conebeam CT imaging was used for patient setup and verification. Treatments were delivered in < 15 minutes. Patients underwent post-treatment clinical evaluation and CT imaging in 3-month intervals to assess changes in tumor size and post-radiation sequelae. Clinical outcomes reported include treatment response and toxicity. Twenty-six patients with large, centrally (n = 13) or peripherally (n = 13) located tumors were evaluated; this included 16 NSCLC patients with T2-T3N0 disease and 5 with pulmonary metastases from distant sites. One patient had declined surgery, while 25/26 (96.1%) were deemed medically inoperable. All plans met RTOG-0813 requirements for target coverage and dose to OARs. Median follow-up interval was 11 months (0 to 23 months). Twenty-one of 26 (80.7%) patients received post-treatment CT imaging within 6 months of SBRT. Local control was achieved in 20/21 (95.2%) patients; one patient with a peripherally located tumor progressed outside the treatment field. Acute toxicity profile amongst the 25 patients assessed included grade 1 fatigue (n = 2), grade 1 rib pain (n = 1), and grade 2 pulmonary fibrosis (n = 1). Otherwise, 22/25 (88%) patients reported no radiation induced toxicities. Subgroup analysis was performed on patients with centrally located tumors, defined as located <2 cm from the hilum, heart, or bronchial trees. One of 13 (7.6%) patients with central tumors reported grade 1 rib pain; otherwise, no radiation induced adverse effects were observed. All patients with centrally located lung tumors experienced local control on surveillance imaging. SBRT with SIB to the hypoxic centers of large pulmonary masses is a safe, efficacious treatment that confers improved local control while maintaining dose to adjacent OARs. This study demonstrates the feasibility of delivering doses up to 60 Gy to the hypoxic centers of large lung tumors, while decreasing local tumor burden, minimizing treatment mobility, and improving clinic workflow. SBRT with SIB shortens treatment course to 5 fractions (in contrast to the traditional daily 30 fractions), thus improving patient comfort and compliance.

Conversion of the bronchial tree into a conforming electrode to ablate the lung nodule in a porcine model

BackgroundRadiofrequency ablation (RFA) is one of the treatment options for lung nodules. However, the need for exact delivery of the rigid metal electrode into the center of the target mass often leads to complications or suboptimal results. To overcome these limitations, a concept of conforming electrodes using a flexible material has been tested in this study.MethodsA bronchoscopy-guided RFA (CAROL) under a temperature-controlled mode was tested in in-vivo and ex-vivo porcine lungs. Gallium-based liquid metal was used for turning the bronchial tree into temporary RF electrodes. A customized bronchoscopy-guided balloon-tipped guiding catheter (CAROL catheter) was used to make the procedure feasible under fluoroscopy imaging guidance. The computer simulation was also performed to gain further insight into the ablation results. Safety was also assessed including the liquid metal remaining in the body.ResultsThe bronchial electrode injected from the CAROL catheter was able to turn the target site bronchial air pipe into a temporally multi-tined RF electrode. The mean volume of Gallium for each effective CAROL was 0.46 ± 0.47 ml. The ablation results showed highly efficacious and consistent results, especially in the peripheral lung. Most bronchial electrodes were also retrieved by either bronchoscopic suction immediately after the procedure or by natural expectoration thereafter. The liquid metal used in these experiments did not have any significant safety issues. Computer simulation also supports these results.ConclusionThe CAROL ablation was very effective and safe in porcine lungs showing encouraging potential to overcome the conventional approaches.

The Interplay Effect and Mitigations with Cyclotron and Linac Proton Beam Scanning for Lung SBRT

To evaluate the impact of different types of pencil beam scanning proton accelerators and spot sizes on interplay effects, mitigations, and plan quality for lung cancer patients treated with SBRT. Twenty lung cancer patients (ten peripheral and ten central tumors) treated in our institution with photon SBRT were selected to represent varying tumor volumes and respiratory motion amplitudes for this retrospective study. The respiratory motion amplitude ranged from 0.1 to 1.0 cm with compression. For each patient, plans were created using: 1) cyclotron-generated proton beams (CPB) (σ: 2.7-7.0 mm); 2) linear accelerator proton beams (LPB) (σ: 2.9-5.5 mm); and 3) linear accelerator proton minibeams (LPMB) (σ: 0.9-3.9 mm). Plans were robustly optimized on the GTV using each individual 4DCT phase. Single-filed optimization (SFO) plans were the first attempt, and if the plan quality did not meet the dosimetric requirement, multi-field optimization (MFO) was used. MFO plans were created for all patients for comparison. For each patient, all plans were normalized to have the same dose to 99% of the GTV. Interplay effects were evaluated for ten scenarios of treatment delivery starting in ten breathing phases using machine generic time models and a constant breathing period of 4 seconds. Volumetric repainting (VR) was performed 2-6 times for each plan. To assess plan quality in the nominal scenario, we compared the conformity index (CI), R50, and the percentage of lung volume receiving 20 Gy (RBE) (V20Gy). CI is defined as the ratio of the 100% isodose volume to the GTV. R50 is defined as the 50% isodose volume divided by the GTV. Dmax and V18Gy of the proximal bronchial tree (PBT) were evaluated for central tumors. Twelve of 20 plans can be optimized sufficiently with SFO. In interplay effect evaluation, the mean V100%RX values of the GTV were 99.42±0.6%, 97.52±3.9%, and 94.49±7.3%for CPB, LPB, and LPMB plans respectively. After VR 2/3/5 times, the V100%RX values were improved (on average) by 0.13%/1.84%/4.63% for CPB/LPB/LPMB plans. The delivery time for VR plans was the lowest for LPB plans, while delivery time for LPMB was on average 1 minute longer than CPB plans. VR showed no effect on lung V20Gy, Dmax and V18Gy of the PBT. SFO plans were more robust against the interplay effect compared with MFO plans for LPB and LPMB. Average CIs of 1.88±0.4, 1.79±0.4, and 1.75±0.4; average R50s of 7.99±4.0, 6.68±3.0, and 5.70±2.6; and average lung V20Gy values of 2.81±1.5, 2.26±1.3, and 1.85±1.1 were obtained for CPB, LPB, and LPMB plans, respectively. Dmax and V18Gy of the PBT decreased with decreasing spot sizes. LPMB, with the smallest spot size, produced superior plan quality. In the absence of VR, proton machines with large spot sizes generated more robust plans against interplay effects. VR improved the plan robustness against interplay effects for modalities with small spot sizes and fast energy changes, preserving the low dose sparing aspect of the LPMB, even when motion is included.

Safety and Efficacy of Stereotactic Body Radiotherapy for Ultra-Central Thoracic Tumors

Stereotactic body radiotherapy (SBRT) is increasingly utilized in the management of ultra-central thoracic tumors, although concerns regarding significant toxicity remain. We sought to evaluate the toxicity and efficacy of SBRT to these tumors at our institution. Patients with ultra-central lung tumors or nodes treated at our institution with SBRT between 2009 and 2019 were retrospectively reviewed. Ultra-central was defined as having the planning target volume (PTV) overlapping or abutting the central bronchial tree and/or esophagus. All SBRT plans were generated with homogenous dose distributions using target coverage objectives of ITV V100% >99%, PTV V95% >99%, and an ideal PTV Dmax <105% (strict <120%). All plans were reviewed in quality assurance rounds by a team of dosimetrists, physicists, and radiation oncologists. The primary endpoint was incidence of severe toxicity (ST), defined as SBRT-related grade ≥3 toxicities, graded using the Common Terminology Criteria for Adverse Events V5.0. Secondary endpoints included local failure (LF), progression-free survival (PFS) and overall survival (OS). Competing risk analysis was used to estimate incidence and predictors of ST and LF, with death as a competing risk. Kaplan-Meier method was used to estimate PFS and OS. A total of 154 patients who received 162 ultra-central courses of SBRT were included, with a median follow-up of 21.5 months. Treatment intent was most commonly for oligoprogression (46%), oligometastasis (30%), followed by curative (20%). The most frequent tumor histologies were NSCLC (41%) and RCC (26%). SBRT prescription doses ranged from 30-55 Gy in 5 fractions (BED10 range 48-115 Gy). The most common prescription was 50 Gy in 5 fractions (42%). The cumulative incidence of ST was 8.9% at 3-years. The most common ST was pneumonitis (n = 4). Notable toxicities included bronchopleural fistula (n = 2, grade 3 and 4), bronchial stricture (n = 1, grade 3), and esophagitis leading to bleeding (n = 1, grade 4). There were no esophageal strictures or perforations, and no bronchial bleeds. There was 1 possible treatment related death from pneumonitis/pneumonia. Predictors of any ST included increased lung V5 Gy, decreased PTV V95%, and not having prior radiation therapy to the chest. The cumulative incidence of LF was 4.8%, 11% and 14% at 1-, 2-, and 3-years respectively. Predictors of LF included younger age, and greater volume of overlap between the PTV and esophagus. Median PFS was 8.4 months, while median OS was 3.7 years. In one of the largest case series of ultra-central thoracic SBRT reported to date, homogenously prescribed SBRT plans were associated with relatively low rates of ST and LF across a variety of treatment indications. Predictors of ST should be interpreted recognizing the heterogeneity in toxicities observed. Identified predictors of both ST and LF can contribute to future work to optimize the therapeutic ratio in treatment of ultra-central thoracic tumors.

Central Lung Tumors Eligible for Stereotactic Ablative Radiotherapy (SABR) Trials: Analysis of a Cohort Treated Using MR-Guided SABR

SABR for central and ultracentral lung tumors results in increased toxicity. We implemented MR-guided SABR in patients meeting the IASLC classification for central tumors, namely a Gross Tumor Volume (GTV) ≤2cm from trachea, main bronchi, esophagus, heart, brachial plexus, main mediastinal vessels, phrenic or laryngeal nerves and spinal cord. As patient inclusion criteria for ongoing clinical trials varies, we studied the eligibility of MR-SABR patients for inclusion into 3 clinical trials for central tumors. An Ethics approved institutional database was accessed for details of patients treated using multifractionated lung MR-SABR between 2016 and 2022. GTV and Planning Target Volumes (PTV) had been delineated on a breath-hold planning MRI and CT scans. For each tumor meeting the IASLC classification, patient eligibility for HILUS (NCT04917224), STRICT/STARLUNG (NCT05354596) and SUNSET (NCT03306680) trials were examined. Multifraction MR-SABR was performed in 97 central lung lesions meeting IASLC criteria. Of these, 73 patients (75.3%) fulfilled inclusion criteria for at least 1 trial, but inclusion in all 3 trials was possible in just 18.6% of treated lesions. Inclusion in the HILUS, STRICT/STARLUNG and SUNSET trials were possible in 33.0%, 73.2% and 25.8% of MR-SABR patients, respectively. For HILUS-eligible patients, 11 met the HILUS group A classification (GTV ≤1cm from the trachea and main bronchi), and 21 in group B (GTV >1cm from the trachea and main bronchi but ≤1cm from the intermediate and lobar bronchi). Use of STRICT/STARLUNG trial criteria would have defined 13 tumors as ultracentral (GTV ≤0.5cm from the trachea, main bronchi or intermediary bronchus or esophagus), and 58 as central (GTV 0.5cm-2.5cm from previously described structures or ≤0.5cm from the heart, aorta, spinal cord or lobar bronchi). For the SUNSET study, 25 tumors fulfilled criteria for ultracentral location (PTV touching or overlapping the central bronchial tree, esophagus, pulmonary vein or pulmonary artery). Ongoing clinical trials in central or ultracentral lung SABR enroll considerably different patient populations than those selected using the IASLC definition of central tumors. Due to steep dose-fall off in SABR plans, detailed descriptions of the location of tumor and organs-at-risk, as well as dose-distributions achieved, are necessary in order to allow study results to be uniformly extrapolated to clinical practice.

Predictive Factors for Response to Adaptive Therapy in Thoracic Stereotactic Ablative Radiotherapy

Online adaptive radiotherapy (ART) has been increasingly adopted for clinical use. However, ART for thoracic malignancies has lagged beyond its implementation for other primary cancers. Efforts are needed to identify optimal patients for ART by finding trends for changes in tumor position, shape, or proximity to OARs are needed. We hypothesized tumor size, histology, pre-RT SUV value, and intrathoracic location could influence how tumors change during cone beam computed tomography (CBCT)-based ART Stereotactic Ablative Radiotherapy (SAbR) for thoracic disease. Data was collected from a prospective registry of patients who received CBCT-ART and SAbR for primary and secondary lung tumors. Dosimetry data was obtained from the simulation planning and the daily adaptive workflow. Central lung tumors were defined as those located within 2 cm of the bronchial tree. Plans were either delivered as per simulation or through the online adaptive workflow delivery (AD). Change in planning tumor volumes (PTV) were calculated between initial and final fractions (ΔPTV). A total of 42 patients with a median age of 67 (range 17-90) and median 8.3 months follow up, treated between June 2021 and December 2022 were included. Most patients had NSCLC or presumed NSCLC (73.85%, 31/42), and most lesions were peripheral (61.9%, 26/42) versus central (31%, 13/42) or apical (7.1%, 3/42). Mean dose and median fractions were 52.5 Gy (SD 8.07) and 5 (range 3-5) while median initial (i) PTV was 31.75 cm3 (IQR 42.3 cm3). On average, ΔPTV decreased by 4.9% (SD 21) and volume shrunk by 5 cm3 (SD 14.5). AD improved per fraction PTV coverage and conformality while esophageal, cardiac, and spinal cord dose were significantly decreased (all p < 0.05), and most fractions were delivered with AD (73.4%, 138/188). AD was aborted most often for small iPTVs. ΔPTV grew >10% for two lesions though their iPTV were < 10 cm3. 12/42 ΔPTV were >10% smaller by the end of RT and corresponded to larger iPTVs. Age, lung primary, metastatic disease, smoking status, and tumor location were not predictive for >10% decrease in ΔPTV. Among 24 biopsy-proven NSCLC ΔPTV was >10% smaller in 6/12 patients (50%) with adenocarcinoma and only in 2/12 (16.7%) with SCC, although this was not significant on χ2 testing (p = 0.08). There were no differences in local, regional, distant failure or death comparing those with a ΔPTV of >10% vs <10% (all p > 0.1). Comparing pre-treatment PET SUV and tumor response, lower SUVs appear to be associated with more PTV shrinkage, with no significant PTV change plateauing at SUV 20. However, this analysis was limited by the number of patients with high SUV values. CBCT-ART SAbR is associated with improved PTV coverage, target conformality, and reduced OAR dose. Large iPTV and adenocarcinomas were more likely to decrease >10%. High metabolic activity appeared predictive for a lack of significant ΔPTV. Further clinical and radiographic features should be explored to predict response to ART.

Determining the Dosimetric Accuracy of Deep Learning-Based Fully Automated Registration-Segmentation Approach for Thoracic Cancer Organs-at-Risk Contouring

For adaptive radiation therapy (ART), the contours on the planning CT (pCT) are frequently propagated to cone-beam CT (CBCT) via deformable image registration and manually edited, which is observer-dependent and time-consuming. To automate this process, we created a fully automated workflow by combining a deep learning (DL)-based pCT segmentation model with a CT-to-CBCT registration-segmentation DL model. The purpose of our research is to determine how using the proposed workflow's automatically generated contours affects thoracic organs-at-risk sparing (OAR). Seven patients with locally advanced non-small cell lung cancer who underwent treatment with intensity modulated radiation therapy were included in this study. Each patient's pCT was segmented using a published DL model that has been used for generating thoracic OAR segmentation and radiotherapy planning in the clinic since July of 2020. Next, pCT was deformably registered using a published recurrent deep registration-segmentation method. Whereas the original method's segmentation sub-network was only trained to segment esophagus, the registration sub-network was used to propagate contours for heart, esophagus, and the proximal bronchial tree (PBT). Geometric segmentation accuracy using the Dice Similarity Coefficient (DSC) and the 95th percentile Hausdorff Distance (HD) and dose metrics including the mean esophageal dose (MED) and D90% of the heart (D90) were computed from the total accumulated dose for the first two weeks of treatment. The esophagus had a high DSC and a low HD (0.93 and 2.85mm) and conversely, the heart had lower accuracy (DSC = 0.85, HD = 22.06mm). PBT showed relatively high performance as well, with DSC of 0.91 and HD of 2.28mm, owing to its proximity to the esophagus. The accumulated MED for manual contour was slightly lower than AI-contours (11.34 vs 11.83 Gy), suggesting reliability of the proposed workflow. The reverse is seen for the D90 of the heart (manual = 1.74 and AI-contour = 1.56 Gy), likely due to the heart not being included in the original DL framework. This study reported preliminary results on the feasibility of using a fully automated and patient-specific workflow for CBCT auto-segmentation in ART, confirming its role as a geometrically and dosimetrically accurate solution for thoracic OARs. However, because it is currently limited to the esophagus, we believe that re-training the algorithm will increase confidence in other OARs such as the heart and lungs.

Temporospatial Feathering of Hot Spots for Computed Tomography-Guided Stereotactic Adaptive Radiotherapy (CT-STAR) for the Ultra-Central Thorax

SBRT to the ultra-central thorax is limited by potential toxicity. It has been demonstrated that exposing proximal bronchial tree or pulmonary arteries to high dose per fraction (fx) treatment may induce bronchopulmonary hemorrhage, amongst other serious complications. Online adaptive radiotherapy is a technique that adjusts a treatment plan to the anatomy-of-the-day and benefits have been demonstrated in ultra-central thoracic disease. In addition, feathering is a treatment planning technique that generates several plans to avoid consistent organ-at-risk (OAR) doses throughout treatment. With daily adaptation, it may be possible to adjust the position of a hot spot (>120% prescription (Rx)) within the tumor each fx (temporospatial feathering) while respecting hard OAR constraints. We investigated the feasibility and plan quality of using CBCT-guided stereotactic adaptive radiotherapy (CT-STAR) for ultra-central lung tumors with hotspot temporospatial feathering. Seven patients with ultra-central thoracic disease (6 patients with parenchymal tumors in contact with the trachea, proximal bronchial tree, great vessels, esophagus, or heart; 1 patient with a subcarinal lymph node) receiving standard of care radiotherapy were enrolled on an imaging study. An in-silico planning study first generated an SBRT plan (in silico Rx: 55 Gy in 5fx) that used a GTV_OPT (GTV minus OAR plus a safety margin) to optimize the location of the plan hotspot. Five spherical boost structures were manually created inside of the GTV_OPT structure. The same planning template was used except the boost structures were iteratively used in plan optimization instead of the GTV_OPT structure, to simulate the five CT-STAR fx hotspot temporospatially feathering. The five-plan composite was compared to the initial plan. All plans generated met strict OAR constraints. Table 1 shows the mean difference in PTV, GTV, and OARs percent coverage by various isodose levels. Feathering the hotspot had negligible impact on target coverage by 50 Gy and 55 Gy isodose lines as well as OAR doses compared to the base SBRT plan. The feathered plan sum resulted in 14.7% increase in V66 Gy of the GTV. One patient saw a decrease in V66 Gy coverage to all target structures, though V50 Gy and V55 Gy were not affected. We demonstrated the feasibility and utility of temporospatially adapting the hotspot for central lung SBRT, which safely increases the amount of tumor receiving more than 120% Rx.

Risk-Adapted SABR for Ultra-Central Lung Tumors Attaining High BED10 to Targets in a Steep Dose-Response Window of 72-105 Gy under Tumor Tracking: A Planning Study

Higher rate of durable local control in stereotactic ablative radiotherapy (SABR) for ultra-central lung tumors (UCLTs) strongly correlates to a BED10 ≥ 100 Gy to the tumors. However, higher rates of grade 5 toxicities are reported to be directly associated with higher dose to the organs at risk (OARs) abutting or in close distance to the UCLTs, including trachea, proximal bronchial tree (PBT) and esophagus. This study evaluated two risk-adapted SABR schemes in a steep dose-response window of BED10 at 72 -105 Gy with isotoxic optimization and dynamic tumor tracking to safely attain high BED10 to the tumors while keeping dose to the OARs within evidence-based tolerances. A total of 12-16 patients are included for planning under two risk-adapted-SABR schemes of 60 Gy in 8 (scheme A) and15 (scheme B) fractions to attain high BED10 of ≥100 Gy to the distal sections of the PTV and yet potent BED10 at 72-84 Gy to the proximal sections of the PTV. Such inhomogeneous dose plans use a 3-5 mm GTV to PTV margins under a scenario that patients have at least one fiducial marker placed in or near the GTV for real-time tumor tracking on a robotic SRS-SABR system. All plans used fixed cone collimators and a planning tool's dose calculation to reach highest BED10 dose coverage achievable to the target volumes while respecting the OAR dose tolerances, including V105 Gy, V100 Gy, V84 Gy and V72 Gy in BED10 for target volumes and the maximum EQD2 dose tolerances (α/β = 3 Gy) in D0.03cc for the trachea/PBT ≤80.5-82.5 Gy and esophagus ≤64.0-77.6 Gy in scheme-A; and trachea/PBT≤97.7 Gy and esophagus ≤64.3 Gy in scheme-B. Median and range of plan dosimetry metrics are compared between the two schemes. For scheme-A, mean BED10 to PTV are 118.0 Gy (median) in105.5-133.5 Gy (range), and mean BED10 dose to GTV are 132.2 (118.3-149.4 Gy). EQD2 dose to trachea are 80.5 Gy (68.0-81.7 Gy), PBT 80.5 Gy (49.1-82.2 Gy), esophagus 67.2 Gy (51.6-77.3 Gy). PTV coverage by BED10 of 72 Gy, 84 Gy, 100 Gy and 105 Gy are 98.9% (87.5-100%), 97.1% (81.8-99.8%), 91.9% (72.5-98.6%) and 85.3% (68.5-97.9%). For scheme-B, mean BED10 to PTV are 102.2 Gy (93.4-106.0 Gy), and mean BED10 dose to GTV are 115.4 (103.4-117.3 Gy). EQD2 dose to trachea are 73.3 Gy (67.5-96.3 Gy), PBT 90.9 Gy (74.4-97.2 Gy), esophagus 61.4 Gy (41.9-64.1 Gy). PTV coverage by BED10 of 72 Gy, 84 Gy, 100 Gy and 105 Gy are 100% (94.9-100%), 95.5% (83.9-99.0%), 54.8% (31.2-65.4%) and 42.8% (17.9-53.2%). Two risk-adapted SABR of 7.5 Gyx8 and 4 Gyx15 are implemented for treating ultra-central lung tumors with BED10 ≥100 Gy to the distal sections of PTV and yet attain potent BED10 ≥72-84 Gy to the proximal sections of PTV that abut or overlap with trachea, proximal bronchial tree or esophagus. Accurate dose calculation by a planning tool and real-time tumor tracking are essential for safe and accurate delivery of such high-risk SABR treatments.

Long-Term Toxicity in Patients Receiving Radiotherapy for Ultracentral Stage I Non-Small Cell Lung Cancer – A Secondary Analysis of the LUSTRE Randomized Trial

Hypofractionated and stereotactic body radiotherapy (SBRT) are increasingly used in the treatment of centrally located, early-stage non-small cell lung cancer (NSCLC), though there are concerns of increased morbidity and mortality in patients with ultracentral tumors (UC). We report on the long-term toxicity of patients with UC lung cancer treated on a prospective randomized clinical trial of SBRT versus conventionally hypofractionated radiotherapy (CRT) for stage I NSCLC (NCT01968941). Patients with UC tumors, defined as those where the planning target volume directly overlaps with the proximal bronchial tree (PBT), were identified from the larger cohort of patients treated on the trial. These patients received either SBRT with 60 Gy in 8 fractions or CRT with 60 Gy in 15 fractions. The primary endpoint of this secondary analysis was development of any grade 3 or higher toxicity defined using CTCAE version 3.0. Secondary endpoints included local control, as well as dosimetric analysis of the PBT, using EQD2 with α/β ratio of 3 to assess the relationship between dose to the PBT and toxicity. Twenty-nine patients were identified with UC tumors; 21 received SBRT and 8 received CRT. Median age was 72 years (range 55-88 years) and 59% were female. Median FEV1 was 1.46L (range 0.64-2.37L). Patients had either T1 (59%) or T2 (41%) lesions, with median tumor size 2.5cm (range 1.1-4.9cm). Most patients had histologically confirmed disease (squamous cell, n = 10; adenocarcinoma, n = 8; radiographically suspicious, n = 11). The median follow-up was 2.9 years (range 0.7-5.2 years). The 3-year local control rate of all patients was 88.3% (95% confidence interval: 75.7-100%). There were 3 patients with late (>3 months) grade 3 toxicity (bronchial stricture, chest pain, and atelectasis) and 1 patient with late grade 5 toxicity (bleeding/hemorrhage), all treated in the SBRT arm. Median EQD2 dose to PBT in patients with grade ≥3 late toxicity compared to the rest of the cohort was: Dmax, 132 vs 129 Gy; D0.1cc, 129 vs 119 Gy; D1cc, 124 vs 80 Gy; and D5cc, 83 vs 41 Gy. Median EQD2 volumetric doses in grade ≥3 patients (compared to the rest) to PBT were: V65 Gy, 9.7 vs 2.2cc; V80 Gy, 7.9 vs 1.1cc; V90 Gy, 6.2 vs 0.4cc; and V100 Gy, 4.8 vs 0.3cc. The single patient with grade 5 toxicity had the highest D5cc (116 Gy) and V100 Gy (7cc) among all patients. Stereotactic radiation with 60 Gy in 8 fractions for UC lung cancer provides good local control but carries an approximately 15-20% rate of late grade ≥3 toxicity. There appears to be a dosimetric association between toxicity and dose to the PBT. It may be more important to minimize volumetric PBT dose rather than maximum point dose to reduce risk of severe late toxicity.

Primary pulmonary myxoid sarcoma: A case report and review of the literature

Background: Primary pulmonary myxoid sarcoma is a very rare tumor, with less than 25 cases being described in the literature. When found in the bronchial tree, an R0 resection with post-operative follow-up is sufficient for curative treatment. We present a case of primary pulmonary myxoid sarcoma in a middle-aged man with an associated review of the literature to highlight this rare tumor. Case presentation: A 62-year-old man with a 40-pack-year smoking history presented to the thoracic surgery clinic for evaluation of a suspicious lung nodule. Pre-operative testing revealed a spiculated mass in the left upper lobe and the biopsy was non-diagnostic. The patient was taken for left upper lobectomy tri-segmentectomy with mediastinal lymph node dissection. Final pathology of the nodule revealed primary pulmonary myxoid sarcoma with an Ewing sarcoma breakpoint region 1 on chromosome 22 with activating transcription factor 1 (EWSR-ATF1) fusion transcript consistent with the diagnosis. Conclusion: Primary pulmonary myxoid sarcoma is an exceedingly rare sarcoma of the lung with less than 25 reported cases in the literature. This case report highlights our experience treating primary pulmonary myxoid sarcoma in a middle-aged man, and a review of current treatment recommendations in the available published literature.