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The adoption of low-dose computed tomography (LDCT) as the standard of care for lung cancer screening results in decreased mortality rates in high-risk population while increasing false-positive rate. Convolutional neural networks provide an ideal opportunity to improve malignant nodule detection; however, due to the lack of large adjudicated medical datasets these networks suffer from poor generalizability and overfitting. Using computed tomography images of the thorax from the National Lung Screening Trial (NLST), we compared discrete wavelet transforms (DWTs) against convolutional layers found in a CNN in order to evaluate their ability to classify suspicious lung nodules as either malignant or benign. We explored the use of the DWT as an alternative to the convolutional operations within CNNs in order to decrease the number of parameters to be estimated during training and reduce the risk of overfitting. We found that multi-level DWT performed better than convolutional layers when multiple kernel resolutions were utilized, yielding areas under the receiver-operating curve (AUC) of 94% and 92%, respectively. Furthermore, we found that multi-level DWT reduced the number of network parameters requiring evaluation when compared to a CNN and had a substantially faster convergence rate. We conclude that utilizing multi-level DWT composition in place of early convolutional layers within a DNN may improve for image classification in data-limited domains.
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Aprendizado Profundo , Neoplasias Pulmonares/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Bases de Dados Factuais , HumanosRESUMO
BACKGROUND AND OBJECTIVE: Late-onset non-allergic asthma in obesity is characterized by an abnormally compliant, collapsible lung periphery; it is not known whether this abnormality exists in proximal airways. We sought to compare collapsibility of central airways between lean and obese individuals with and without asthma. METHODS: A cross-sectional study comparing luminal area and shape (circularity) of the trachea, left mainstem bronchus, right bronchus intermedius and right inferior lobar bronchus at RV and TLC by CT was conducted. RESULTS: In 11 lean controls (BMI: 22.4 (21.5, 23.8) kg/m2 ), 10 lean individuals with asthma (23.6 (22.0, 24.8) kg/m2 ), 10 obese controls (45.5 (40.3, 48.5) kg/m2 ) and 21 obese individuals with asthma (39.2 (35.8, 42.9) kg/m2 ), lumen area and circularity increased significantly with an increase in lung volume from RV to TLC for all four airways (P < 0.05 for all). Changes in area and circularity with lung volume were similar in obese individuals with and without asthma, and both obese groups had severe airway collapse at RV. In multivariate analysis, change in lumen area was related to BMI and change in circularity to waist circumference, but neither was related to asthma diagnosis. CONCLUSION: Excessive collapse of the central airways is related to obesity, and occurs in both obese controls and obese asthma. Increased airway collapse could contribute to ventilation abnormalities in obese individuals particularly at lower lung volumes, and complicate asthma in obese individuals.
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Asma , Asma/complicações , Brônquios/diagnóstico por imagem , Estudos Transversais , Humanos , Pulmão/diagnóstico por imagem , Obesidade/complicações , FenótipoRESUMO
Factors secreted from tumors/tumor cells are hypothesized to cause skeletal muscle wasting in cancer patients. We examined whether cancer cells secrete factors to promote atrophy by evaluating the effects of conditioned media (CM) from murine lung cancer cells and primary cultures of human lung tumor cells on cultured myotubes. We evaluated murine Lewis lung carcinoma (LLC) and KRASG12D cells, and primary cell lines derived from tumor biopsies from patients with lung cancer (hTCM; n = 6). In all experiments, serum content was matched across treatment groups. We hypothesized that CM from murine and human tumor cells would reduce myotube myosin content, decrease mitochondrial content, and increase mitochondrial reactive oxygen species (ROS) production. Treatment of myotubes differentiated for 7 days with CM from LLC and KRASG12D cells did not alter any of these variables. Effects of murine tumor cell CM were observed when myotubes differentiated for 4 days were treated with tumor cell CM and compared with undiluted differentiation media. However, these effects were not apparent if tumor cell CM treatments were compared with control cell CM or dilution controls. Finally, CM from human lung tumor primary cell lines did not modify myosin content or mitochondrial content or ROS production compared with either undiluted differentiated media, control cell CM, or dilution controls. Our results do not support the hypothesis that factors released from cultured lung cancer/tumor cells promote myotube wasting or mitochondrial abnormalities, but we cannot dismiss the possibility that these cells could secrete such factors in vivo within the native tumor microenvironment.
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Caquexia/metabolismo , Carcinoma Pulmonar de Lewis/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Meios de Cultivo Condicionados/farmacologia , Neoplasias Pulmonares/metabolismo , Mitocôndrias Musculares/efeitos dos fármacos , Fibras Musculares Esqueléticas/efeitos dos fármacos , Miosinas/metabolismo , Adenocarcinoma/metabolismo , Idoso , Idoso de 80 Anos ou mais , Animais , Caquexia/etiologia , Carcinoma de Células Escamosas/metabolismo , Linhagem Celular Tumoral , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Mitocôndrias Musculares/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Mioblastos Esqueléticos , Neoplasias/complicações , Neoplasias/metabolismo , Cultura Primária de Células , Espécies Reativas de Oxigênio/metabolismo , Células Tumorais CultivadasRESUMO
Rationale: Less invasive, nonsurgical approaches are needed to treat severe emphysema.Objectives: To evaluate the effectiveness and safety of the Spiration Valve System (SVS) versus optimal medical management.Methods: In this multicenter, open-label, randomized, controlled trial, subjects aged 40 years or older with severe, heterogeneous emphysema were randomized 2:1 to SVS with medical management (treatment) or medical management alone (control).Measurements and Main Results: The primary efficacy outcome was the difference in mean FEV1 from baseline to 6 months. Secondary effectiveness outcomes included: difference in FEV1 responder rates, target lobe volume reduction, hyperinflation, health status, dyspnea, and exercise capacity. The primary safety outcome was the incidence of composite thoracic serious adverse events. All analyses were conducted by determining the 95% Bayesian credible intervals (BCIs) for the difference between treatment and control arms. Between October 2013 and May 2017, 172 participants (53.5% male; mean age, 67.4 yr) were randomized to treatment (n = 113) or control (n = 59). Mean FEV1 showed statistically significant improvements between the treatment and control groups-between-group difference at 6 and 12 months, respectively, of 0.101 L (95% BCI, 0.060-0.141) and 0.099 L (95% BCI, 0.048-0.151). At 6 months, the treatment group had statistically significant improvements in all secondary endpoints except 6-minute-walk distance. Composite thoracic serious adverse event incidence through 6 months was greater in the treatment group (31.0% vs. 11.9%), primarily due to a 12.4% incidence of serious pneumothorax.Conclusions: In patients with severe heterogeneous emphysema, the SVS shows significant improvement in multiple efficacy outcomes, with an acceptable safety profile.Clinical trial registered with www.clinicaltrials.gov (NCT01812447).
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Pulmão/fisiopatologia , Próteses e Implantes , Enfisema Pulmonar/terapia , Idoso , Brônquios/fisiopatologia , Feminino , Volume Expiratório Forçado , Humanos , Inalação , Masculino , Próteses e Implantes/efeitos adversos , Enfisema Pulmonar/fisiopatologia , Resultado do TratamentoRESUMO
The mammalian runt-related factor 1 (RUNX1) is a master transcription factor that regulates lineage specification of hematopoietic stem cells. RUNX1 translocations result in the development of myeloid leukemias. Recently, RUNX1 has been implicated as a tumor suppressor in other cancers. We postulated RUNX1 expression may be associated with lung adenocarcinoma etiology and/or progression. We evaluated the association of RUNX1 mRNA expression with overall survival data from The Cancer Genome Atlas (TCGA), a publically available database. Compared to high expression levels, Low RUNX1 levels from lung adenocarcinomas were associated with a worse overall survival (Hazard Ratio = 2.014 (1.042-3.730 95% confidence interval), log-rank p = 0.035) compared to those that expressed high RUNX1 levels. Further immunohistochemical examination of 85 surgical specimens resected at the University of Vermont Medical Center identified that low RUNX1 protein expression was associated with larger tumors (p = 0.038). Gene expression network analysis was performed on the same subset of TCGA cases that demonstrated differential survival by RUNX1 expression. This analysis, which reveals regulatory relationships, showed that reduced RUNX1 levels were closely linked to upregulation of the transcription factor E2F1. To interrogate this relationship, RUNX1 was depleted in a lung cancer cell line that expresses high levels of RUNX1. Loss of RUNX1 resulted in enhanced proliferation, migration, and invasion. RUNX1 depletion also resulted in increased mRNA expression of E2F1 and multiple E2F1 target genes. Our data implicate loss of RUNX1 as driver of lung adenocarcinoma aggression, potentially through deregulation of the E2F1 pathway.
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Adenocarcinoma/metabolismo , Agressão/fisiologia , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Regulação da Expressão Gênica/fisiologia , Neoplasias Pulmonares/metabolismo , Adenocarcinoma de Pulmão/metabolismo , Proliferação de Células/fisiologia , Perfilação da Expressão Gênica/métodos , Células-Tronco Hematopoéticas/metabolismo , Humanos , Ativação Transcricional/fisiologiaRESUMO
Real-time endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is an established technique for invasive mediastinal staging of non-small cell lung cancer (NSCLC). Needle-based techniques are now recommended as a first-line diagnostic modality for mediastinal staging. Accurate performance of systematic staging with EBUS-TBNA requires a detailed knowledge of mediastinal anatomy. This examination begins at the N3 lymph nodes, progressing through the N2 and N1 lymph node stations, unless a higher station lymph node is positive for malignant cells by rapid on-site cytologic examination. Objective methods of identifying EBUS-TBNA targets include sampling any lymph node station with a visible lymph node or with a lymph node greater than 5 mm in short axis. Three passes per station or the use of rapid on-site cytologic examination with identification of diagnostic material (tumor or lymphocytes) up to five passes are well-established techniques. Obtaining sufficient tissue for molecular profiling may require performing more than three passes. The operating characteristics of EBUS-TBNA are similar to mediastinoscopy. However, mediastinoscopy should be considered in the setting of a negative EBUS-TBNA and a high posterior probability of N2 or N3 involvement.
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Brônquios/patologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , Mediastino/patologia , Ultrassonografia de Intervenção , Biópsia por Agulha Fina/métodos , Brônquios/diagnóstico por imagem , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico , Humanos , Biópsia Guiada por Imagem/métodos , Neoplasias Pulmonares/diagnóstico por imagem , Metástase Linfática , Mediastinoscopia , Mediastino/diagnóstico por imagem , Estadiamento de NeoplasiasRESUMO
BACKGROUND: Continued improvement in deep learning methodologies has increased the rate at which deep neural networks are being evaluated for medical applications, including diagnosis of lung cancer. However, there has been limited exploration of the underlying radiological characteristics that the network relies on to identify lung cancer in computed tomography (CT) images. OBJECTIVE: In this study, we used a combination of image masking and saliency activation maps to systematically explore the contributions of both parenchymal and tumor regions in a CT image to the classification of indeterminate lung nodules. METHODS: We selected individuals from the National Lung Screening Trial (NLST) with solid pulmonary nodules 4-20 mm in diameter. Segmentation masks were used to generate three distinct datasets; 1) an Original Dataset containing the complete low-dose CT scans from the NLST, 2) a Parenchyma-Only Dataset in which the tumor regions were covered by a mask, and 3) a Tumor-Only Dataset in which only the tumor regions were included. RESULTS: The Original Dataset significantly outperformed the Parenchyma-Only Dataset and the Tumor-Only Dataset with an AUC of 80.80 ± 3.77% compared to 76.39 ± 3.16% and 78.11 ± 4.32%, respectively. Gradient-weighted class activation mapping (Grad-CAM) of the Original Dataset showed increased attention was being given to the nodule and the tumor-parenchyma boundary when nodules were classified as malignant. This pattern of attention remained unchanged in the case of the Parenchyma-Only Dataset. Nodule size and first-order statistical features of the nodules were significantly different with the average malignant and benign nodule maximum 3d diameter being 23 mm and 12 mm, respectively. CONCLUSION: We conclude that network performance is linked to textural features of nodules such as kurtosis, entropy and intensity, as well as morphological features such as sphericity and diameter. Furthermore, textural features are more positively associated with malignancy than morphological features.
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Neoadjuvant intratumoral cisplatin has the potential to generate substantial cytotoxicity and immune priming within the tumor environment, while minimizing systemic, off-target, adverse events. We initiated a phase 1A, 3+3 dose-ranging study of neoadjuvant, intratumoral cisplatin, delivered through endobronchial ultrasound bronchoscopy, in the same procedure as the initial diagnosis. There were no dose-limiting toxicity identified at the 20mg level.
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Rationale: Follow-up of patients with emphysema treated with endobronchial valves is limited to 3-12 months after treatment in prior reports. To date, no comparative data exist between treatment and control subjects with a longer follow-up. Objectives: To assess the durability of the Spiration Valve System (SVS) in patients with severe heterogeneous emphysema over a 24-month period. Methods: EMPROVE, a multicenter randomized controlled trial, presents a rigorous comparison between treatment and control groups for up to 24 months. Lung function, respiratory symptoms, and quality-of-life (QOL) measures were assessed. Results: A significant improvement in forced expiratory volume in 1 second was maintained at 24 months in the SVS treatment group versus the control group. Similarly, significant improvements were maintained in several QOL measures, including the St. George's Respiratory Questionnaire and the COPD Assessment Test. Patients in the SVS treatment group experienced significantly less dyspnea than those in the control group, as indicated by the modified Medical Research Council dyspnea scale score. Adverse events at 24 months did not significantly differ between the SVS treatment and control groups. Acute chronic obstructive pulmonary disease exacerbation rates in the SVS treatment and control groups were 13.7% (14 of 102) and 15.6% (7 of 45), respectively. Pneumothorax rates in the SVS treatment and control groups were 1.0% (1 of 102) and 0.0% (0 of 45), respectively. Conclusions: SVS treatment resulted in statistically significant and clinically meaningful durable improvements in lung function, respiratory symptoms, and QOL, as well as a statistically significant reduction in dyspnea, for at least 24 months while maintaining an acceptable safety profile. Clinical trial registered with www.clinicaltrials.gov (NCT01812447).
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Enfisema , Doença Pulmonar Obstrutiva Crônica , Enfisema Pulmonar , Humanos , Qualidade de Vida , Seguimentos , Broncoscopia , Resultado do Tratamento , Volume Expiratório Forçado , Dispneia/etiologia , Doença Pulmonar Obstrutiva Crônica/complicaçõesRESUMO
Real-time endobronchial ultrasound images are crucial for the accurate placement of the needle in peribronchial lung tumors and lymph nodes for diagnostic sampling. Beyond its role as a diagnostic tool, ultrasound-guided bronchoscopy can also aid the delivery of anti-cancer agents intratumorally, enabling diagnosis, staging, and treatment to occur within the same anesthesia, reducing the patient's burden. However, determining drug retention and distribution in situ remains challenging, albeit pivotal in assessing the success or failure of the therapeutic intervention. We hypothesized that ultrasound images acquired by the bronchoscope during the injection can provide qualitative and quantitative real-time information about drug transport. As a proof-of-concept, we retrospectively analyzed 13 videos of intratumoral cisplatin injections in advanced non-small cell lung cancers. We identified the injection and performed quantitative analysis through image processing and segmentation algorithms and mathematical models in 5 of them. We were able to infer the unlikeliness of a laminar flow through interstitial pores in favor of the emergence of tissue fractures. These data imply that the structural integrity of the tumor is a critical determinant of the ultimate distribution of an intratumorally delivered agent.
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BACKGROUND: Radiomics, defined as quantitative features extracted from images, provide a non-invasive means of assessing malignant versus benign pulmonary nodules. In this study, we evaluate the consistency with which perinodular radiomics extracted from low-dose computed tomography images serve to identify malignant pulmonary nodules. MATERIALS AND METHODS: Using the National Lung Screening Trial (NLST), we selected individuals with pulmonary nodules between 4mm to 20mm in diameter. Nodules were segmented to generate four distinct datasets; 1) a Tumor dataset containing tumor-specific features, 2) a 10 mm Band dataset containing parenchymal features between the segmented nodule boundary and 10mm out from the boundary, 3) a 15mm Band dataset, and 4) a Tumor Size dataset containing the maximum nodule diameter. Models to predict malignancy were constructed using support-vector machine (SVM), random forest (RF), and least absolute shrinkage and selection operator (LASSO) approaches. Ten-fold cross validation with 10 repetitions per fold was used to evaluate the performance of each approach applied to each dataset. RESULTS: With respect to the RF, the Tumor, 10mm Band, and 15mm Band datasets achieved areas under the receiver-operator curve (AUC) of 84.44%, 84.09%, and 81.57%, respectively. Significant differences in performance were observed between the Tumor and 15mm Band datasets (adj. p-value <0.001). However, when combining tumor-specific features with perinodular features, the 10mm Band + Tumor and 15mm Band + Tumor datasets (AUC 87.87% and 86.75%, respectively) performed significantly better than the Tumor Size dataset (66.76%) or the Tumor dataset. Similarly, the AUCs from the SVM and LASSO were 84.71% and 88.91%, respectively, for the 10mm Band + Tumor. CONCLUSIONS: The combined 10mm Band + Tumor dataset improved the differentiation between benign and malignant lung nodules compared to the Tumor datasets across all methodologies. This demonstrates that parenchymal features capture novel diagnostic information beyond that present in the nodule itself. (data agreement: NLST-163).
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Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Nódulos Pulmonares Múltiplos , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/patologia , Pulmão/patologia , Adenocarcinoma de Pulmão/patologia , Nódulos Pulmonares Múltiplos/patologia , Tomografia Computadorizada por Raios X/métodos , Estudos RetrospectivosRESUMO
RATIONALE: Direct intratumoral delivery of cisplatin via endobronchial ultrasound guided-transbronchial needle injections (EBUS-TBNI) is a novel approach for salvage treatment of advanced stage non-small cell lung cancer (NSCLC). The goal of this study was to evaluate changes in the tumor immune microenvironment during the course of EBUS-TBNI cisplatin therapy. METHODS: Under an IRB approved protocol, patients with recurrence after radiation therapy who were not receiving other cytotoxic therapy, were prospectively enrolled, and underwent weekly treatments with EBUS-TBNI with additional biopsies obtained for research. Needle aspiration was performed prior to cisplatin delivery at each procedure. Samples were evaluated by flow cytometry for the presence of immune cell types. RESULTS: Three of the six patients responded to the therapy based on RECIST criteria. Compared to the pre-treatment baseline, intratumoral neutrophils increased in 5 of the 6 patients (p = 0.041), with an average increase of 27.1%, but was not associated with response. A lower pre-treatment CD8+/CD4+ ratio at baseline was associated with response (P = 0.01). Responders demonstrated a lower final proportion of PD-1+ CD8+ T cells compared to non-responders (8.6% vs. 62.3%, respectively, P<0.001. Lower doses of intratumoral cisplatin were associated with subsequent increases in CD8+ T cells within the tumor microenvironment (P = 0.008). CONCLUSIONS: EBUS-TBNI cisplatin resulted in significant alterations in the tumor immune microenvironment. Further studies are needed to determine if the changes seen here generalize to larger cohorts.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Cisplatino/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Microambiente Tumoral , Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico/métodosRESUMO
We recently developed a computational model of cisplatin pharmacodynamics in an endobronchial lung tumor following ultrasound-guided transbronchial needle injection (EBUS-TBNI). The model suggests that it is more efficacious to apportion the cisplatin dose between injections at different sites rather than giving it all in a single central injection, but the model was calibrated only on blood cisplatin data from a single patient. Accordingly, we applied a modified version of our original model in a set of 32 patients undergoing EBUS-TBNI for non-small cell lung cancer (NSCLC). We used the model to predict clinical responses and compared them retrospectively to actual patient outcomes. The model correctly predicted the clinical response in 72% of cases, with 80% accuracy for adenocarcinomas and 62.5% accuracy for squamous-cell lung cancer. We also found a power-law relationship between tumor volume and the minimal dose needed to induce a response, with the power-law exponent depending on the number of injections administered. Our results suggest that current injection strategies may be significantly over- or under-dosing the agent depending on tumor size, and that computational modeling can be a useful planning tool for EBUS-TBNI of cisplatin in lung cancer.
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Antineoplásicos/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico/métodos , Neoplasias Pulmonares/tratamento farmacológico , Linhagem Celular Tumoral , Cisplatino/administração & dosagem , Simulação por Computador , Feminino , Previsões , Humanos , Concentração Inibidora 50 , Injeções Intralesionais , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND AND OBJECTIVE: The CISNET models provide predictions for dying of lung cancer in any year of life as a function of age and smoking history, but their predictions are quite variable and the models themselves can be complex to implement. Our goal was to develop a simple empirical model of the risk of dying of lung cancer that is mathematically constrained to produce biologically appropriate probability predictions as a function of current age, smoking start age, quit age, and smoking intensity. METHODS: The six adjustable parameters of the model were evaluated by fitting its predictions of cancer death risk versus age to the mean of published predictions made by the CISNET models for the never smoker and for six different scenarios of lifetime smoking burden. RESULTS: The mean RMS fitting error of the model was 6.16 × 10 -2 (% risk of dying of cancer per year of life) between 55 and 80 years of age. The model predictions increased monotonically with current age, quit age and smoking intensity, and decreased with increasing start age. CONCLUSIONS: Our simple model of the risk of dying of lung cancer in any given year of life as a function of smoking history is easily implemented and thus may serve as a useful tool in situations where the mortality risks of smoking need to be estimated.
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Neoplasias Pulmonares , Abandono do Hábito de Fumar , Humanos , Pulmão , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/etiologia , Risco , Fumar/efeitos adversos , Fumar/epidemiologiaRESUMO
BACKGROUND: CT screening for lung cancer results in a significant mortality reduction but is complicated by invasive procedures performed for evaluation of the many detected benign nodules. The purpose of this study was to evaluate measures of nodule location within the lung as predictors of malignancy. METHODS: We analyzed images and data from 3,483 participants in the National Lung Screening Trial (NLST). All nodules (4-20 mm) were characterized by 3D geospatial location using a Cartesian coordinate system and evaluated in logistic regression analysis. Model development and probability cutpoint selection was performed in the NLST testing set. The Geospatial test was then validated in the NLST testing set, and subsequently replicated in a new cohort of 147 participants from The Detection of Early Lung Cancer Among Military Personnel (DECAMP) Consortium. RESULTS: The Geospatial Test, consisting of the superior-inferior distance (Z distance), nodule diameter, and radial distance (carina to nodule) performed well in both the NLST validation set (AUC 0.85) and the DECAMP replication cohort (AUC 0.75). A negative Geospatial Test resulted in a less than 2% risk of cancer across all nodule diameters. The Geospatial Test correctly reclassified 19.7% of indeterminate nodules with a diameter over 6mm as benign, while only incorrectly classifying 1% of cancerous nodules as benign. In contrast, the parsimonious Brock Model applied to the same group of nodules correctly reclassified 64.5% of indeterminate nodules as benign but resulted in misclassification of a cancer as benign in 18.2% of the cases. Applying the Geospatial test would result in reducing invasive procedures performed for benign lesions by 11.3% with a low rate of misclassification (1.3%). In contrast, the Brock model applied to the same group of patients results in decreasing invasive procedures for benign lesion by 39.0% but misclassifying 21.1% of cancers as benign. CONCLUSIONS: Utilizing information about geospatial location within the lung improves risk assessment for indeterminate lung nodules and may reduce unnecessary procedures. TRIAL REGISTRATION: NCT00047385, NCT01785342.
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BACKGROUND: Endobronchial ultrasound-guided transbronchial needle injection of cisplatin (EBUS-TBNI cisplatin) is a therapeutic option for patients with recurrent lung cancer. However, the tumor characteristics that influence the distribution of the agent following intratumoral delivery remain largely unknown. METHODS: We performed a retrospective evaluation of EBUS-TBNI cisplatin cases performed at two centers. Semi-automated tumor segmentation from CT scans was performed while blinded to the outcome of response. Twenty-four algorithmic radiomics features from two categories, Morphology (i.e., shape, volume) and Intensity (i.e., density), were extracted, and feature selection performed via least absolute shrinkage and selection operator (LASSO) regression. Models were constructed from clinicoepidemiologic variables and selected radiomics features and evaluated using the likelihood ratio chi-square assessment and Akaike's information criterion (AIC). RESULTS: Thirty-eight patients with available imaging data were analyzed. Based on RECIST criteria, 27 of 38 treated sites demonstrated complete or partial remission (71%). The top three features identified by LASSO regression were variance, energy, and kurtosis. All three are measures of intensity, a surrogate for tumor density. Two logistic regression models with the outcome of response were created, each with the top 3 categorical features: (I) an Intensity model including variance, energy, and kurtosis, and (II) a Morphology model including surface-to-volume ratio, spherical disproportion, and maximum 3-dimensional (3D) diameter. Only the Intensity model met criteria for significance (P=0.024), and it resulted in a lower AIC and higher pseudo R square value vs. the Morphology model. CONCLUSIONS: Measures of tumor density are more highly associated with response to EBUS-TBNI cisplatin than measures of morphology.
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RATIONALE AND OBJECTIVES: We have developed a technique to measure ventilation heterogeneity (VH) on low dose chest CT scan that we hypothesize may be associated with the development of lung nodules, and perhaps cancer. If true, such an analysis may improve screening by identifying regional areas of higher risk. MATERIALS AND METHODS: Using the National Lung Screening Trial database, we identified a small subset of those participants who were labeled as having a positive screening test at 1 year (T1) but not at baseline (T0). We isolated the region in which the nodule would form on the T0 scan ("target region") and measured VH as the standard deviation of the linear dimension of a virtual cubic airspace based on measurement of lung attenuation within the region. RESULTS: We analyzed 24 cases, 9 with lung cancer and 15 with a benign nodule. We found that the VH of the target region was nearly statistically greater than that of the corresponding contralateral control region (0.168 [0.110-0.226] vs. 0.112 [0.083-0.203], p = 0.051). The % emphysema within the target region was greater than that of the corresponding contralateral control region (1.339 [0.264-4.367] vs. 1.092 [0.375-4.748], p = 0.037). There was a significant correlation between the % emphysema and the VH of the target region (rhoâ¯=â¯+0.437, pâ¯=â¯0.026). CONCLUSION: Our study provides the first data in support of increased local VH being associated with subsequent lung nodule formation. Further work is necessary to determine whether this technique can enhance screening for lung cancer by low dose chest CT scan.
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Detecção Precoce de Câncer/métodos , Neoplasias Pulmonares/patologia , Pulmão/diagnóstico por imagem , Pulmão/patologia , Tomografia Computadorizada por Raios X/métodos , Adulto , Feminino , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Masculino , Programas de Rastreamento , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
BACKGROUND: Guidelines recommend invasive mediastinal staging for patients with non-small cell lung cancer and a "central" tumor. However, there is no consensus definition for central location. As such, the decision to perform invasive staging largely remains on an empirical foundation. RESEARCH QUESTION: Should patients with peripheral T1 lung tumors undergo invasive mediastinal staging? STUDY DESIGN AND METHODS: All participants with a screen-detected cancer with a solid component between 8 and 30 mm were identified from the National Lung Screening Trial. After translation of CT data, cancer location was identified and the X, Y, Z coordinates were determined as well as distance from the main carina. A multivariable logistic regression model was constructed to evaluate for predictors associated with lymph node metastasis. RESULTS: Three hundred thirty-two participants were identified, of which 69 had lymph node involvement (20.8%). Of those with lymph node metastasis, 39.1% were N2. There was no difference in rate of lymph node metastasis based on tumor size (OR, 1.03; P = .248). There was also no statistical difference in rate of lymph node metastasis based on location, either by distance from the carina (OR, 0.99; P = .156) or tumor coordinates (X: P = .180; Y: P = .311; Z: P = .292). When adjusted for age, sex, histology, and smoking history, there was no change in the magnitude of the risk, and tests of significance were not altered. INTERPRETATION: Our data indicate a high rate of N2 metastasis among T1 tumors and no significant relationship between tumor diameter or location. This suggests that patients with small, peripheral lung cancers may benefit from invasive mediastinal staging.
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Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico/métodos , Neoplasias Pulmonares/diagnóstico , Linfonodos/patologia , Estadiamento de Neoplasias/métodos , Broncoscopia , Carcinoma Pulmonar de Células não Pequenas/secundário , Feminino , Humanos , Metástase Linfática , Masculino , Mediastino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons/métodosRESUMO
Intratumoral delivery of cisplatin by endobronchial ultrasound-guided transbronchial needle injection (EBUS-TBNI) has recently emerged as a therapy for treating peribronchial lung cancers. It remains unclear, however, where best to inject drug into a tumor, and at how many sites, so current cisplatin delivery strategies remain empirical. Motivated by the need to put EBUS-TBNI treatment of lung cancer on a more objective footing, we developed a computational model of cisplatin pharmacodynamics following EBUS-TBNI. The model accounts for diffusion of cisplatin within and between the intracellular and extracellular spaces of a tumor, as well as clearance of cisplatin from the tumor via the vasculature and clearance from the body via the kidneys. We matched the tumor model geometry to that determined from a thoracic CT scan of a patient with lung cancer. The model was calibrated by fitting its predictions of cisplatin blood concentration versus time to measurements made up to 2 hrs following EBUS-TBNI of cisplatin into the patient's lung tumor. This gave a value for the systemic volume of distribution for cisplatin of 12.2 L and a rate constant of clearance from the tumor into the systemic compartment of 1.46 × 10-4 s-1. Our model indicates that the minimal dose required to kill all cancerous cells in a lung tumor can be reduced by roughly 3 orders of magnitude if the cisplatin is apportioned between 5 optimally spaced locations throughout the tumor rather than given as a single bolus to the tumor center. Our findings suggest that optimizing the number and location of EBUS-TBNI sites has a dramatic effect on the dose of cisplatin required for efficacious treatment of lung cancer.
Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Cisplatino/administração & dosagem , Cisplatino/farmacocinética , Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico , Neoplasias Pulmonares/tratamento farmacológico , Algoritmos , Sobrevivência Celular/efeitos dos fármacos , Gerenciamento Clínico , Relação Dose-Resposta a Droga , Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico/métodos , Humanos , Neoplasias Pulmonares/diagnóstico , Modelos TeóricosRESUMO
BACKGROUND: Although endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has an excellent diagnostic yield, there remain cases where the diagnosis is not obtained. We hypothesized that additional sampling with a 19-G EBUS-TBNA needle may increase diagnostic yield in a subset of cases where additional tissue sampling was required. METHODS: Indications for use of the 19-G needle following 22-G sampling with rapid on-site cytologic examination were: (1) diagnostic uncertainty of the on-site cytopathologist (eg, nondiagnostic, probable lymphoma, etc.), (2) non-small cell lung cancer with probable need for molecular genetic and/or PD-L1 testing, or (3) need for a larger tissue sample for consideration of inclusion in a research protocol. RESULTS: A 19-G EBUS-TBNA needle was utilized following standard sampling with a 22-G needle in 48 patients (50 sites) during the same procedure. Although the diagnostic yield between the needles was equivalent, the concordance rate was only 83%. The 19-G determined a diagnosis in 4 additional patients (8%) and provided additional histopathologic information in 6 other cases (12%). Conversely, in 3 cases (6%) diagnostic information was provided only by the 22-G needle. Compared with 22-G EBUS-TBNA alone, sampling with both the 22- and 19-G EBUS needles resulted in an increase in diagnostic yield from 92% to 99% (P=0.045) and a number needed to sample of 13 patients to provide one additional diagnosis. There were no significant complications. CONCLUSION: In select cases where additional tissue may be needed, sampling with a 19-G EBUS needle following standard aspiration with a 22-G needle results in an increase in diagnostic yield.