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Introduction: Radiology scoring systems are critical to the success of lung cancer screening (LCS) programs, impacting patient care, adherence to follow-up, data management and reporting, and program evaluation. LungCT ScreeningReporting and Data System (Lung-RADS) is a structured radiology scoring system that provides recommendations for LCS follow-up that are utilized (a) in clinical care and (b) by LCS programs monitoring rates of adherence to follow-up. Thus, accurate reporting and reliable collection of Lung-RADS scores are fundamental components of LCS program evaluation and improvement. Unfortunately, due to variability in radiology reports, extraction of Lung-RADS scores is non-trivial, and best practices do not exist. The purpose of this project is to compare mechanisms to extract Lung-RADS scores from free-text radiology reports., Methods: We retrospectively analyzed reports of LCS low-dose computed tomography (LDCT) examinations performed at a multihospital integrated healthcare network in New York State between January 2016 and July 2023. We compared three methods of Lung-RADS score extraction: manual physician entry at time of report creation, manual LCS specialist entry after report creation, and an internally developed, rule-based natural language processing (NLP) algorithm. Accuracy, recall, precision, and completeness (i.e., the proportion of LCS exams to which a Lung-RADS score has been assigned) were compared between the three methods., Results: The dataset includes 24,060 LCS examinations on 14,243 unique patients. The mean patient age was 65 years, and most patients were male (54 %) and white (75 %). Completeness rate was 65 %, 68 %, and 99 % for radiologists' manual entry, LCS specialists' entry, and NLP algorithm, respectively. Accuracy, recall, and precision were high across all extraction methods (>94 %), though the NLP-based approach was consistently higher than both manual entries in all metrics., Discussion: An NLP-based method of LCS score determination is an efficient and more accurate means of extracting Lung-RADS scores than manual review and data entry. NLP-based methods should be considered best practice for extracting structured Lung-RADS scores from free-text radiology reports., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The authors have no conflicts of interest related to the submission of this manuscript. Dr. Bade is a site PI on industry-sponsored trials for Nucleix, Delfi Diagnostics, and Biodesix., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The diagnosis of brain metastases (BMs) in patients with lung cancer (LC) predominantly relies on magnetic resonance imaging (MRI), a method that is constrained by high costs and limited accessibility. This study explores the potential of serum neurofilament light chain (sNfL) and serum glial fibrillary acidic protein (sGFAP) as screening biomarkers for BMs in LC patients. We conducted a retrospective analysis of 700 LC cases at the National Cancer Center, Korea, from July 2020 to June 2022, measuring sNfL and sGFAP levels at initial LC diagnosis. The likelihood of BM was evaluated using multivariate analysis and a predictive nomogram. Additionally, we prospectively monitored 177 samples from 46 LC patients initially without BM. Patients with BMs ( n = 135) had significantly higher median sNfL (52.5 pg/mL) and sGFAP (239.2 pg/mL) levels compared to those without BMs (n = 565), with medians of 17.8 pg/mL and 141.1 pg/mL, respectively ( p < 0.001 for both). The nomogram, incorporating age, sNfL, and sGFAP, predicted BM with an area under the curve (AUC) of 0.877 (95% CI 0.84-0.914), showing 74.8% sensitivity and 83.5% specificity. Over nine months, 93% of samples from patients without BM remained below the cutoff, while all patients developing BMs showed increased levels at detection. A nomogram incorporating age, sNfL, and sGFAP provides a valuable tool for identifying LC patients at high risk for BM, thereby enabling targeted MRI screenings and enhancing diagnostic efficiency.

Polo-like kinase 1 (PLK1), which is crucial in cell cycle regulation, is considered a promising anticancer drug target. Herein, we present the N-degron pathway-based proteolysis targeting chimera (PROTAC) for PLK1 degradation, targeting the Polo-box domain (PBD). We identified DD-2 as the most potent PROTAC that selectively induces PLK1 degradation in cancer cells, including HeLa and nonsmall cell lung cancer (NSCLC), through the N-degron pathway. DD-2 exhibited significant in vitro anticancer effects, inducing G2/M arrest and apoptosis in HeLa and NSCLC cell lines. DD-2 showed significant tumor growth inhibition in a xenograft mouse model using HeLa and NSCLC cell lines, highlighting its potential in cancer treatment. Furthermore, the combination of DD-2 with tyrosine kinase inhibitor (TKI), osimertinib, effectively suppressed tumor growth in double-mutated H1975 cell lines, emphasizing DD-2's potential in combination cancer therapies. Collectively, this study demonstrates the potential of the N-degron pathway, especially using DD-2, for targeted cancer therapies.

Background: Cancer patients with preexisting autoimmune diseases (AID) have been traditionally excluded from clinical trials of immune checkpoint inhibitors (ICI) due to concerns for toxicity. As indications for ICI expand, more data are needed on the safety and efficacy of ICI treatment in cancer patients with AID., Methods: We systematically searched for studies consisting of NSCLC, AID, ICI, treatment response, and adverse events. Outcomes of interest include incidence of autoimmune flare, irAE, response rate, and ICI discontinuation. Study data were pooled using random-effects meta-analysis., Results: Data were extracted from 24 cohort studies, consisting of 11,567 cancer patients (3774 NSCLC patients and 1157 with AID). Pooled analysis revealed an AID flare incidence of 36% (95% CI, 27%-46%) in all cancers and 23% (95% CI, 9%-40%) in NSCLC. Preexisting AID was associated with an increased risk of de novo irAE in all cancer patients (RR 1.38, 95% CI, 1.16-1.65) and NSCLC patients (RR 1.51, 95% CI, 1.12-2.03). There was no difference in de novo grade 3 to 4 irAE and tumor response between cancer patients with and without AID. However, in NSCLC patients, preexisting AID was associated with a 2-fold increased risk of de novo grade 3 to 4 irAE (RR 1.95, 95% CI, 1.01-3.75) but also better tumor response in achieving a complete or partial response (RR 1.56, 95% CI, 1.19-2.04)., Conclusions: NSCLC patients with AID are at a higher risk of grade 3 to 4 irAE but are more likely to achieve treatment response. Prospective studies focused on optimizing immunotherapeutic strategies are needed to improve outcomes for NSCLC patients with AID., Competing Interests: Disclosure The authors have no conflict of interests to disclose., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Thymic carcinomas are rare aggressive mediastinal tumors with a median survival of 2 years., Observation: We present a pediatric patient who was diagnosed with metastatic thymic carcinoma and showed continuous improvement of his primary mass and lung metastases with a regimen of cisplatin/docetaxel followed by long-term maintenance therapy with sunitinib for over 5 years., Conclusions: This report demonstrates a long-term positive treatment effect using chemotherapy followed by sunitinib in an advanced thymic carcinoma. We are not aware of other reports of pediatric patients with metastatic thymic carcinoma treated with sunitinib maintenance who maintained a durable response for this prolonged period of time., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To describe utilization and long-term outcomes of pneumonectomy in children and adolescents with cancer., Summary Background Data: Pneumonectomy in adults is associated with significant morbidity and mortality. Little is known about the indications and outcomes of pneumonectomy for pediatric tumors., Methods: The Pediatric Surgical Oncology Research Collaborative (PSORC) identified pediatric patients <21 years of age who underwent pneumonectomy from 1990 to 2017 for primary or metastatic tumors at 12 institutions. Clinical information was collected; outcomes included operative complications, long-term function, recurrence, and survival. Univariate log rank, and multivariable Cox analyses determined factors associated with survival., Results: Thirty-eight patients (mean 12 ± 6 yrs) were identified; median (IQR) follow-up was 19 (5-38) months. Twenty-six patients (68%) underwent pneumonectomy for primary tumors and 12 (32%) for metastases. The most frequent histologies were osteosarcoma (n = 6), inflammatory myofibroblastic tumors (IMT; n = 6), and pleuropulmonary blastoma (n = 5). Median postoperative ventilator days were 0 (0-1), intensive care 2 (1-3), and hospital 8 (5-16). Early postoperative complications occurred in 10 patients including 1 death. Of 25 (66%) patients alive at 1 year, 15 reported return to preoperative pulmonary status. All IMT patients survived while all osteosarcoma patients died during follow-up. On multivariable analysis, metastatic indications were associated with nonsurvival (HR = 3.37, P = 0.045)., Conclusion: This is the largest review of children who underwent pneumonectomy for cancer. There is decreased procedure-related morbidity and mortality than reported for adults. Survival is worse with preoperative metastatic disease, especially osteosarcoma., Competing Interests: The authors report no conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Interventional pulmonology is a rapidly evolving subspecialty of pulmonary medicine that offers advanced consultative and procedural services to patients with airway diseases, pleural diseases, as well as in the diagnosis and management of patients with thoracic malignancy., Areas of Uncertainty: The institution of lung cancer screening modalities as well as the search of additional minimally invasive diagnostic and treatment modalities for lung cancer and other chronic lung diseases has led to an increased focus on the field of interventional pulmonology. Rapid advancements in the field over the last 2 decades has led to development of various new minimally invasive bronchoscopic approaches and techniques for patients with cancer as well as for patients with chronic lung diseases., Data Sources: A review of literature was performed using PubMed database to identify all articles published up till October 2020 relevant to the field of interventional pulmonology and bronchoscopy. The reference list of each article was searched to look for additional articles, and all relevant articles were included in the article., Therapeutic Advances: Newer technologies are now available such navigation platforms to diagnose and possibly treat peripheral pulmonary nodules, endobronchial ultrasound in diagnosis of mediastinal and hilar adenopathy as well as cryobiopsy in the diagnosis of diffuse lung diseases. In addition, flexible and rigid bronchoscopy continues to provide new and expanding ability to manage patients with benign and malignant central airway obstruction. Interventions are also available for diseases such as asthma, chronic bronchitis, chronic obstructive pulmonary disease, and emphysema that were traditionally treated with medical management alone., Conclusions: With continued high quality research and an increasing body of evidence, interventional bronchoscopy has enormous potential to provide both safe and effective options for patients with a variety of lung diseases., Competing Interests: The author has no conflicts of interest to declare., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

We learned many unanticipated and valuable lessons since we started planning our study of low-dose computed tomography (CT) screening for lung cancer in 1991. The publication of the baseline results of the Early Lung Cancer Action Project (ELCAP) in Lancet 1999 showed that CT screening could identify a high proportion of early, curable lung cancers. This stimulated large national screening studies to be quickly started. The ELCAP design, which provided evidence about screening in the context of a clinical program, was able to rapidly expand to a 12-institution study in New York State (NY-ELCAP) and to many international institutions (International-ELCAP), ultimately working with 82 institutions, all using the common I-ELCAP protocol. This expansion was possible because the investigators had developed the ELCAP Management System for screening, capturing data and CT images, and providing for quality assurance. This advanced registry and its rapid accumulation of data and images allowed continual assessment and updating of the regimen of screening as advances in knowledge and new technology emerged. For example, in the initial ELCAP study, introduction of helical CT scanners had allowed imaging of the entire lungs in a single breath, but the images were obtained in 10 mm increments resulting in about 30 images per person. Today, images are obtained in submillimeter slice thickness, resulting in around 700 images per person, which are viewed on high-resolution monitors. The regimen provides the imaging acquisition parameters, imaging interpretation, definition of positive result, and the recommendations for further workup, which now include identification of emphysema and coronary artery calcifications. Continual updating is critical to maximize the benefit of screening and to minimize potential harms. Insights were gained about the natural history of lung cancers, identification and management of nodule subtypes, increased understanding of nodule imaging and pathologic features, and measurement variability inherent in CT scanners. The registry also provides the foundation for assessment of new statistical techniques, including artificial intelligence, and integration of effective genomic and blood-based biomarkers, as they are developed.

Young women represent a target of E-cigarette (E-cig) companies, raising concern for potential connections with breast cancer (BC) that have not yet been elucidated. We hypothesized that E-cig promotes BC development and lung metastasis possibly through BC-monocyte/tumor-associated macrophage (TAM) crosstalk via CCL5 and V-CAM-1 axes. We demonstrated that E-cig promoted the infiltration of circulating monocytes in mammary fat pad (MFP) model. Furthermore, E-cig exposure significantly enhanced BC cell growth in MFP tumor and metastatic lung colonization; immunohistochemical stains illustrated the increase of TAMs infiltration, reduced BC cell apoptosis and increased proliferation index after E-cig exposure. In vitro studies show E-cig vapor condensate (EVC) treatment upregulated protein expressions of CCL5, V-CAM-1, and other pro-tumorigenic factors in BC cells. Mechanistically, co-culture system demonstrated both EVC and macrophages independently stimulated BC cell growth and the migration via CCL5/CCR1/CCR5 axis. During metastasis, E-Cig exposure stimulated BC cell survival via direct interaction with infiltrated macrophages, regulated by VCAM-1 and integrin α 4 β1. Our findings, for the first time, showed that E-cig promotes BC growth and metastasis. This study highlights the critical role of TAMs via CCL5 and VCAM-1 pathways in E-cig promoted BC tumor development., (Published by Elsevier B.V.)

Background: Osteosarcoma is a highly metastatic primary bone tumor that predominantly affects adolescents and young adults. A mainstay of treatment in osteosarcoma is removal of the primary tumor. However, surgical excision itself has been implicated in promoting tumor growth and metastasis, an effect known as surgery-accelerated metastasis. The underlying mechanisms contributing to surgery-accelerated metastasis remain poorly understood, but pro-tumorigenic alterations in macrophage function have been implicated., Methods: The K7M2-BALB/c syngeneic murine model of osteosarcoma was used to study the effect of surgery on metastasis, macrophage phenotype, and overall survival. Pharmacological prevention of surgery-accelerated metastasis was examined utilizing gefitinib, a receptor interacting protein kinase 2 inhibitor previously shown to promote anti-tumor macrophage phenotype., Results: Surgical excision of the primary tumor resulted in increases in lung metastatic surface nodules, overall metastatic burden and number of micrometastatic foci. This post-surgical metastatic enhancement was associated with a shift in macrophage phenotype within the lung to a more pro-tumor state. Treatment with gefitinib prevented tumor-supportive alterations in macrophage phenotype and resulted in reduced metastasis. Removal of the primary tumor coupled with gefitinib treatment resulted in enhanced median and overall survival., Conclusions: Surgery-accelerated metastasis is mediated in part through tumor supportive alterations in macrophage phenotype. Targeted pharmacologic therapies that prevent pro-tumor changes in macrophage phenotype could be utilized perioperatively to mitigate surgery-accelerated metastasis and improve the therapeutic benefits of surgery.

Purpose: To improve outcomes for lung cancer through low-dose computed tomography (LDCT) early lung cancer detection. The International Association for the Study of Lung Cancer is developing the Early Lung Imaging Confederation (ELIC) to serve as an open-source, international, universally accessible environment to analyze large collections of quality-controlled LDCT images and associated biomedical data for research and routine screening care., Methods: ELIC is an international confederation that allows access to efficiently analyze large numbers of high-quality computed tomography (CT) images with associated de-identified clinical information without moving primary imaging/clinical or imaging data from its local or regional site of origin. Rather, ELIC uses a cloud-based infrastructure to distribute analysis tools to the local site of the stored imaging and clinical data, thereby allowing for research and quality studies to proceed in a vendor-neutral, collaborative environment. ELIC's hub-and-spoke architecture will be deployed to permit analysis of CT images and associated data in a secure environment, without any requirement to reveal the data itself (ie, privacy protecting). Identifiable data remain under local control, so the resulting environment complies with national regulations and mitigates against privacy or data disclosure risk., Results: The goal of pilot experiments is to connect image collections of LDCT scans that can be accurately analyzed in a fashion to support a global network using methodologies that can be readily scaled to accrued databases of sufficient size to develop and validate robust quantitative imaging tools., Conclusion: This initiative can rapidly accelerate improvements to the multidisciplinary management of early, curable lung cancer and other major thoracic diseases (eg, coronary artery disease and chronic obstructive pulmonary disease) visualized on a screening LDCT scan. The addition of a facile, quantitative CT scanner image quality conformance process is a unique step toward improving the reliability of clinical decision support with CT screening worldwide.

Objective: This study was conducted in order to describe the computed tomography (CT) features of local pleural recurrence in patients with malignant pleural mesothelioma undergoing intensity-modulated pleural radiation therapy (IMPRINT) as part of multimodality treatment., Methods: In this observational study, 58 patients treated with IMPRINT between September 21, 2004, and December 1, 2014 were included. Baseline and follow-up CT scans were qualitatively assessed. On follow-up scans, pleural thickening was categorized as unchanged, decreased, or new/increased. New/increased pleural abnormality was subcategorized as diffuse smooth pleural thickening, diffuse nodular pleural thickening, focal pleural nodule, or multiple pleural nodules. To identify features more frequently present at the time of local recurrence, follow-up scans with local recurrence were matched to four control scans; exact conditional logistic regression was performed., Results: Twenty-one (36%) patients had local pleural recurrence and 20 (34%) patients had nonpleural recurrence; 3 patients had both types of recurrence. The 1-year cumulative incidence rate of local recurrence was 27% (95% confidence interval 15, 39). On follow-up scans, three patterns of pleural abnormality were significantly associated with local recurrence: new/increased multiple pleural nodules (10 (48%) positive scans vs 0 control scans), new/increased diffuse nodular pleural thickening (7 (33%) positive scans vs 1 (1%) control scans), and new/increased focal pleural nodule (3 (14%) positive scans vs 1 (1%) control scan) (p < 0.001 for all)., Conclusions: Multiple new/increased pleural nodules are the feature most commonly present at local recurrence following IMPRINT; however, any pattern of increased nodular pleural thickening is suspicious., Key Points: • In patients with mesothelioma receiving intensity-modulated pleural radiation as part of multimodality therapy, increasing multiple pleural nodules is the computed tomography feature most commonly present at local recurrence. • In these patients, any CT pattern of increased nodular pleural thickening should be considered suspicious for local recurrence. • The most common sites of nonpleural recurrence were lung parenchyma, thoracic lymph nodes, and peritoneum.

Background: Stereotactic body radiotherapy (SBRT) had become a therapeutic modality in patients with primary tumors, locally recurrent as well as oligometastasis involving the lung. Some modalities of SBRT require fiducial marker (FM) for dynamic tumor tracking. Previous studies have focused on evaluating bronchoscopic-guided FM placement for peripheral lung nodules. We describe the safety and feasibility of placing FM using real-time convex probe endobronchial ultrasound (CP-EBUS) for SBRT in patients with centrally located hilar/mediastinal masses or lymph nodes., Methods: This is a retrospective review of patients who were referred to Beth Israel Deaconess Medical Center's multidisciplinary thoracic oncology program for FM placement to pursue SBRT., Results: Thirty-seven patients who underwent real-time CP-EBUS were included. Patients had a median age of 71 years [interquartile range (IQR), 59.5 to 80.5]. The median size of the lesion was 2.2 cm (IQR, 1.4 to 3.3 cm). The median distance from the central airway was 2.4 cm (IQR, 0 to 3.4 cm). A total of 51 FMs (median of 1 per patient) were deployed in 37 patients. At the time of SBRT planning, 46 (90.2%) were confirmed radiologically in 32 patients. Patients with unsuccessful fiducial deployment (n=5) underwent a second procedure using the same technique. Of those, 3 patients had a successful fiducial placement via bronchoscopy, 1 patient required FM placement by percutaneous computed tomography-guided approach and 1 patient required FM placement through EUS by gastroenterology., Conclusion: CP-EBUS-guided FM placement for patients with malignant lymph nodes and central parenchymal lung lesions appears to be safe and feasible.

After years of assessment through controlled clinical trials, low-dose CT screening for lung cancer is becoming part of clinical practice. As with any cancer screening test, those undergoing lung cancer screening are not being evaluated for concerning signs or symptoms, but are generally in good health and proactively trying to prevent premature death. Given the resultant obligation to achieve the screening aim of early diagnosis while also minimizing the potential for morbidity from workup of indeterminate but ultimately benign screening abnormalities, careful implementation of screening with conformance to currently recognized best practices and a focus on quality assurance is essential. In this review, we address the importance of each component of the screening process to optimize the effectiveness of CT screening, discussing options for quality assurance at each step. We also discuss the potential added advantages, quality assurance requirements and current status of quantitative imaging biomarkers related to lung cancer screening. Finally, we highlight suggestions for improvements and needs for further evidence in evaluating the performance of CT screening as it transitions from the research trial setting into daily clinical practice.

Tobacco smoke (TS) contains numerous cancer-causing agents, with polycyclic aromatic hydrocarbons (PAHs) and nitrosamines being most frequently cited as the major TS human cancer agents. Many lines of evidence seriously question this conclusion. To resolve this issue, we determined DNA adducts induced by the three major TS carcinogens: benzo( a )pyrene (BP), 4-(methylnitrosamine)-1-(3-pyridyl)-1-butanoe (NNK), and aldehydes in humans and mice. In mice, TS induces abundant aldehyde-induced γ-hydroxy-propano-deoxyguanosine (γ-OH-PdG) and α-methyl-γ-OH-PdG adducts in the lung and bladder, but not in the heart and liver. TS does not induce the BP- and NNK-DNA adducts in lung, heart, liver, and bladder. TS also reduces DNA repair activity and the abundance of repair proteins, XPC and OGG1/2, in lung tissues. These TS effects were greatly reduced by diet with polyphenols. We found that γ-OH-PdG and α-methyl-γ-OH-PdG are the major adducts formed in tobacco smokers' buccal cells as well as the normal lung tissues of tobacco-smoking lung cancer patients, but not in lung tissues of nonsmokers. However, the levels of BP- and NNK-DNA adducts are the same in lung tissues of smokers and nonsmokers. We found that while BP and NNK can induce BPDE-dG and O 6 -methyl-dG adducts in human lung and bladder epithelial cells, these inductions can be inhibited by acrolein. Acrolein also can reduce DNA repair activity and repair proteins. We propose a TS carcinogenesis paradigm. Aldehydes are major TS carcinogens exerting dominant effect: Aldehydes induce mutagenic PdG adducts, impair DNA repair functions, and inhibit many procarcinogens in TS from becoming DNA-damaging agents., Competing Interests: The authors declare no conflict of interest., (Copyright © 2018 the Author(s). Published by PNAS.)

Background: Although metastasis is the major cause of mortality in patients with osteosarcoma, little is known about how micrometastases progress to gross metastatic disease. Clinically relevant animal models are necessary to facilitate development of new therapies to target indolent pulmonary metastases. Intratibial injection of human and murine osteosarcoma cell lines have been described as orthotopic models that develop spontaneous pulmonary metastasis over time. However, there is variability in reported injection techniques and metastatic efficiency., Questions/purposes: We aimed to characterize a widely used murine model of metastatic osteosarcoma, determine whether it is appropriate to study spontaneous pulmonary metastasis by establishing a reliable volume for intratibial injection, determine the incidence of primary tumor and metastatic formation, determine the kinetics of pulmonary metastatic seeding and outgrowth, and the contribution of the primary tumor to subsequent development of metastasis., Methods: The metastatic mouse osteosarcoma cell line K7M2 was injected into the tibia of mice. The maximum volume that could be injected without leakage was determined using Evan's blue dye (n = 8 mice). Primary tumor formation and metastatic efficiency were determined by measuring the incidence of primary tumor and metastatic formation 4 weeks after intratibial injection (n = 30). The kinetics of metastatic development were determined by performing serial euthanasia at 1, 2, 3, and 4 weeks after injection (n = 24; five to six mice per group). Number of metastatic foci/histologic lung section and metastatic burden/lung section (average surface area of metastatic lesions divided by the total surface area of the lung) was calculated in a blinded fashion. To test the contribution of the primary tumor to subsequent metastases, amputations were performed 30 minutes, 4 hours, or 24 hours after injection (n = 21; five to six mice per group). Mice were euthanized after 4 weeks and metastatic burden calculated as described previously, comparing mice that had undergone amputation with control, nonamputated mice. Differences between groups were calculated using Kruskal-Wallis and one-way analysis of variance., Results: The maximum volume of cell suspension that could be injected without leakage was 10 μL. Intratibial injection of tumor cells led to intramedullary tumor formation in 93% of mice by 4 weeks and resulted in detectable pulmonary metastases in 100% of these mice as early as 1 week post-injection. Metastatic burden increased over time (0.88% ± 0.58, week 1; 6.6% ± 5.3, week 2; 16.1% ± 12.5, week 3; and 40.3% ± 14.83, week 4) with a mean difference from week 1 to week 4 of -39.38 (p < 0.001; 95% confidence interval [CI], -57.39 to -21.37), showing pulmonary metastatic growth over time. In contrast, the mean number of metastatic foci did not increase from week 1 to week 4 (36.4 ± 33.6 versus 49.3 ± 26.3, p = 0.18). Amputation of the injected limb at 30 minutes, 4 hours, and 24 hours after injection did not affect pulmonary metastatic burden at 4 weeks, with amputation as early as 30 minutes post-injection resulting in a metastatic burden equivalent to tumor-bearing controls (48.9% ± 6.1% versus 40.9% ± 15.3%, mean difference 7.96, p = 0.819; 95% CI, -33.9 to 18.0)., Conclusions: There is immediate seeding of the metastatic site after intratibial injection of the K7M2 osteosarcoma cell line, independent of a primary tumor. This is therefore not a model of spontaneous metastasis., Clinical Relevance: This model should not be used to study the early components of the metastatic cascade, but rather used as an experimental model of metastasis. Improved understanding of this commonly used model will allow for proper interpretation of existing data and inform the design of future studies exploring the biology of metastasis in osteosarcoma.

Acrolein (Acr) is a potent cytotoxic and DNA damaging agent which is ubiquitous in the environment and abundant in tobacco smoke. Acr is also an active cytotoxic metabolite of the anti-cancer drugs cyclophosphamide and ifosfamide. The mechanisms via which Acr exerts its anti-cancer activity and cytotoxicity are not clear. In this study, we found that Acr induces cytotoxicity and cell death in human cancer cells with different activities of p53. Acr preferentially binds nucleolar ribosomal DNA (rDNA) to form Acr-deoxyguanosine adducts, and induces oxidative damage to both rDNA and ribosomal RNA (rRNA). Acr triggers ribosomal stress responses, inhibits rRNA synthesis, reduces RNA polymerase I binding to the promoter of rRNA gene, disrupts nucleolar integrity, and impairs ribosome biogenesis and polysome formation. Acr causes an increase in MDM2 levels and phosphorylation of MDM2 in A549 and HeLa cells which are p53 active and p53 inactive, respectively. It enhances the binding of ribosomal protein RPL11 to MDM2 and reduces the binding of p53 and E2F-1 to MDM2 resulting in stabilization/activation of p53 in A549 cells and degradation of E2F-1 in A549 and HeLa cells. We propose that Acr induces ribosomal stress which leads to activation of MDM2 and RPL11-MDM2 binding, consequently, activates p53 and enhances E2F-1 degradation, and that taken together these two processes induce apoptosis and cell death.

Renal cell carcinoma (RCC) accounts for majority of all primary renal neoplasms. Classic manifestations of RCC include the triad of flank pain, hematuria and a palpable renal mass. Patients with RCC can develop various extra renal manifestations including involvements of the lungs, inferior vena cava, liver and the bones. The pulmonary manifestations of renal cell carcinoma include metastatic disease including endobronchial, pleural, parenchymal or lymph node metastasis, pleural effusion or hemothorax. Pulmonary embolism and tumor embolism is another common manifestation of renal cell carcinoma. RCC is a highly vascular tumor and can cause pulmonary arterio-venous fistulas leading to high output failure. Rarely, RCC can also present with paraneoplastic presentations including cough or bilateral diaphragm paralysis. Drugs used to treat RCC have been associated with drug related pneumonitis and form an important differential diagnosis in patients with RCC on therapy presenting with shortness of breath. In this review we discuss the various pulmonary manifestations of RCC. A high index of suspicion with these presentations can lead to an early diagnosis and assist in instituting an appropriate intervention., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

The epithelium is part of an integrated immune system where cytokines, toll-like receptors and their ligands, and extracellular vesicles play a crucial role in initiating an innate immune response. IL-36γ is a pro-inflammatory member of the IL-1 family that is mainly expressed by epithelial cells, but regulation of its expression and release are only beginning to be understood. Previous studies reported that IL-36γ is abundant in recurrent respiratory papillomatosis, a rare but devastating disease caused by human papillomaviruses (HPV) types 6 and 11, in which papillomas recurrently grow in and block the airway. Despite the overexpression of IL-36γ, papilloma tissues show no evidence of inflammation, possibly due to suppression of its release by HPVs. We have used primary human foreskin keratinocytes as a model to study IL-36γ regulation in normal epithelial cells. Low doses of poly(I:C) mediate expression and release of IL-36γ without inducing the cell death reported by those using high doses. PKR, an enzyme required for inflammasome activation, does not contribute to controlled release of IL36γ. The keratinocytes secrete IL-36γ in two forms, soluble and in extracellular vesicles. We conclude that there are two separately regulated pathways for the controlled secretion of IL-36γ from keratinocytes, which could contribute to the modulation of both local and systemic immune responses to viruses and other pathogens.

Chromium (VI) [Cr(VI)], a ubiquitous environmental carcinogen, is generally believed to induce mainly mutagenic binary and ternary Cr(III)-deoxyguanosine (dG)-DNA adducts in human cells. However, both adenine (A) and guanine (G) mutations are found in the p53 gene in Cr exposure-related lung cancer. Using UvrABC nuclease and formamidopyrimidine glycosylase (Fpg), and ligation-mediated PCR methods, we mapped the distribution of bulky DNA adducts (BDA) and oxidative DNA damage (ODD) in the p53 gene in Cr(VI)-treated human lung cells. We found that both BDA and ODD formed at 2'-deoxyadenosine (dA) and dG bases. To understand the causes for these Cr-induced DNA damages, we mapped the distribution of BDA adducts and ODD in the p53 gene DNA fragments induced by Cr(III), Cr(VI) and Cr(V), the three major cellular Cr forms. We found that (i) dA at -CA- is a major Cr(VI) binding site followed by -GG- and -G-. Cr(VI) does not bind to -GGG-, (ii) Cr(VI)-DNA binding specificity is distinctly different from the Cr(III)-DNA binding in which -GGG- and -GG- are preferential sites, (iii) Cr(V) binding sites include all of Cr(VI) and Cr(III)-DNA binding sites and (iv) Cr(VI) and Cr(V) induce Fpg-sensitive sites at -G-. Together, these results suggest that Cr(VI) induction of BDA and ODD at dA and dG residues is through Cr(V) intermediate. We propose that these Cr(VI)-induced BDA and ODD contribute to mutagenesis of the p53 gene that leads to lung carcinogenesis.

Background/purpose: Mammalian target of rapamycin suppression by rapamycin inhibits tumor growth and neovascularization via cyclooxygenase-2 (COX-2) downregulation with no effect on lung metastases. We hypothesize that combining a selective COX-2 antagonist (celecoxib) with rapamycin would decrease lung metastases., Methods: Ewing sarcoma cells (SK-NEP-1) were surgically implanted into the left kidney of athymic mice (n = 40). The mice were divided into 4 treatment groups (control, rapamycin only, celecoxib only, and combination) and then killed at 6 weeks. Primary tumors were weighed. Vasculature was examined using lectin angiography and immunohistochemistry, and lung metastases were examined using H&E and CD99 immunostaining. Tumor weight and lung metastases were analyzed., Results: Mean primary tumor weights were significantly reduced in the rapamycin-treated groups but not in the celecoxib-only group. Lectin angiography and endothelial markers immunostaining showed markedly decreased vascularity in the rapamycin-treated groups but not in the celecoxib-only group. Celecoxib-treated groups showed significantly fewer mice with lung metastases than non-celecoxib-treated groups., Conclusion: Celecoxib prevents lung metastasis in a murine model of Ewing sarcoma with no effect on tumor size or neovascularization. Cyclooxygenase-2 may represent a future potential target for metastatic disease prevention., (Copyright © 2011 Elsevier Inc. All rights reserved.)

An open source lesion sizing toolkit has been developed with a general architecture for implementing lesion segmentation algorithms and a reference algorithm for segmenting solid and part-solid lesions from lung CT scans. The CT lung lesion segmentation algorithm detects four three-dimensional features corresponding to the lung wall, vasculature, lesion boundary edges, and low density background lung parenchyma. These features form boundaries and propagation zones that guide the evolution of a subsequent level set algorithm. User input is used to determine an initial seed point for the level set and users may also define a region of interest around the lesion. The methods are validated against 18 nodules using CT scans of an anthropomorphic thorax phantom simulating lung anatomy. The scans were acquired under differing scanner parameters to characterize algorithm behavior under varying acquisition protocols. We also validated repeatability using six clinical cases in which the patient was rescanned on the same day (zero volume change). The source code, data sets, and a running application are all provided under an unrestrictive license to encourage reproducibility and foster scientific exchange.

Rationale and Objectives: Lung cancer is caused primarily by repeated exposure to carcinogenic particulate matter and noxious gasses with high particulate deposition localized to airway bifurcations and the lung periphery. The quantitative measurement and analysis of these sites has the potential to stratify lung cancer risk. The aim of this preliminary study was to assess the performance of a new method for estimating individual lung cancer risk based on the analysis of airway bifurcations on high-resolution (HR) computed tomographic (CT) scanning and spirometry., Materials and Methods: One hundred eight subjects with spirometry and thin-slice CT data were selected from a CT screening study including 15 patients with early lung cancer and 93 age-matched and pack-year-matched controls. A subset of seven patients with cancer and 72 controls were scanned with 1-mm CT slice thickness, representing an HR case subset. A quantitative lung cancer risk index method was developed on the basis of airway bifurcation x-ray attenuation combined with the ratio of forced expiratory volume in 1 second to forced vital capacity. Cochran-Mantel-Haenszel and conditional logistic regression tests were used to analyze performance., Results: Cochran-Mantel-Haenszel crude analysis revealed a cancer detection sensitivity and specificity of 67% and 72% for all cases and 100% and 73% for the HR case subset, respectively. Conditional logistic regression showed that a 0.0328 increase in lung cancer risk index was associated with odds ratios of 1.84 (95% confidence interval, 1.18-2.85) for the full data set (P = .0067) and 2.89 (95% confidence interval, 1.02-8.19) for the HR subset (P = .0467)., Conclusions: A preliminary evaluation of a new lung cancer risk estimation method based on thin slice CT and spirometry showed a statistically significant association with lung cancer., (2010 AUR. Published by Elsevier Inc. All rights reserved.)

This paper describes a neuroendocrine (NE) tumor of the lung that was observed during the necropsy of a 14-year-old female black spider monkey (Ateles paniscus) with sudden death. Grossly, multifocal firm and coalescing nodular masses were observed in the lung. The histological examination showed the tumor to be an typical NE tumor with polygonal cells grouped in small solid aggregates, with regularly sized, spherical, centrally placed nuclei with modest, lightly granular cytoplasm suspended in a fibrovascular stroma. The immunohistochemical examination revealed the tumor to be positive for cytokeratin, chromogranin A and synaptophysin, and negative for CD56. To the best of our knowledge, this is the first report of NE tumor in the lung of the black spider monkey.

The solitary pulmonary nodule is traditionally defined as a relatively spherical opacity 3 cm or less in diameter surrounded by lung parenchyma. The choice of imaging test to evaluate solitary nodules is extensive. However, only 2 findings are considered to be sufficient to preclude further evaluation: calcification in a benign pattern and stability in size for more than 2 years.

Background: Patients with metastatic endometrial carcinoma may respond to hormonal therapy with progestins. There is a need for new therapies for hormone-responsive disease., Case: We report a patient with metastatic endometrial carcinoma to the lungs, who after progressing on progestin therapy, had a lengthy remission with anastrozole; upon further progression, fulvestrant (Faslodex) was instituted, with a resultant partial remission, which has been sustained for almost 3 years., Conclusion: In this case, fulvestrant therapy was successful even in the face of prior anastrozole and megestrol. The activity of fulvestrant in patients with metastatic endometrial carcinoma should be further explored, especially in situations in which the tumor is well differentiated and/or expresses hormone receptors.

Crystal-storing histiocytosis (CSH) is a rare disorder occurring in patients with lymphoproliferative diseases, predominantly in cases of multiple myeloma and low-grade B-cell lymphoma. To the best of our knowledge, only three cases of pulmonary CSH have been reported in the English literature and one of them was associated with a low-grade B-cell lymphoma (immunocytoma). We document a case of a 59-year-old man with bilateral lung masses in which a right middle lobe pulmonary lobectomy specimen showed CSH associated with an extranodal marginal-zone B-cell lymphoma. A single nodule showing features of fibroleiomyomatous hamartoma was present in a wedge biopsy specimen from the left lung. Two nodules within the right middle lobe were composed of sheets of histiocytic cells with abundant eosinophilic cytoplasm resembling striated muscle cells. In addition, there were nodular aggregates and a more diffuse infiltrate of small slightly atypical centrocyte-like lymphocytes, as well as bronchial lymphoepithelial lesions. Immunohistochemistry performed on paraffin-embedded sections demonstrated that the histiocytic cells were immunoreactive with the KP-1 (CD68) antibody while the lymphocytic infiltrate was CD20 positive, co-expressed for CD43, and was negative for CD3, CD5, and CD10. Genotypic analysis demonstrated the presence of an immunoglobulin heavy-chain gene rearrangement, indicating the presence of a monoclonal B-cell population. These features were consistent with pulmonary CSH associated with extranodal marginal-zone lymphoma of baltoma type., (Copyright 2003, Elsevier Science (USA). All rights reserved.)

Human papillomaviruses types 6 or 11 are aetiological agents of recurrent respiratory papillomatosis, a disease characterized by benign exophytic tumours usually on the vocal cords. Surgery debulks the tumours, but these growths generally recur at regular intervals. Adjunct medical treatments, aimed at containing the virus and growth of tumours, include indole-3-carbinol or its dimer diindolylmethane, interferon, photodynamic therapy and others. Preventive and therapeutic vaccines hold promise for eliminating the virus.

We report an unusual case of Epstein-Barr virus (EBV)-associated mucosal-associated lymphoid tissue (MALT) lymphoma involving the lungs, kidneys, and axillary lymph nodes in a child with congenital hypoadrenalism and panhypopituitarism. The patient presented with an aggressive clinical course and histologic evolution. Initial biopsies (1994) of the lung and kidney revealed histologic features of low-grade B-cell MALT lymphoma with lymphoepithelial lesions within the renal tubules and bronchial epithelium. Subsequent biopsies (1996, 1997, and 1999) revealed progressively greater cytologic atypia, polymorphism, and necrosis; an increased mitotic rate; and a preponderance of large cells, indicative of progression from a low-grade to a high-grade MALT lymphoma. Immunophenotyping of the lung and lymph node lesions revealed identical surface marker profiles: cells were CD19(+), CD20(+), immunoglobulin (Ig) G(+), kappa(+), lambda(-), CD5(-), CD10(-), CD23(-), and IgM(-), and also negative for T-cell markers. Genotypic analysis demonstrated the presence of immunoglobulin heavy chain rearrangement and monoclonality of EBV in the lung lesion by Southern blot hybridization and polymerase chain re()action (PCR). The clinicopathologic features suggest that these lesions might represent an immunosupression-related continuum of low-grade to high-grade MALT lymphomas. Infection with EBV may have contributed to this tumor's aggressive clinical and histologic evolution.

An unprecedented presentation of multicentric paraganglioma in a 48-year-old man is described. One of the paragangliomas, originally diagnosed as a carcinoid tumor, presented as a lung mass and was removed. Four years later, an intravagal paraganglioma was discovered. The lung and intravagal tumors had identical morphologic and immunoreactive characteristics. Both tumors consisted of chief cells (type 1) and sustentacular cells (type 2). The chief cells were immunoreactive with neuroendocrine markers (synaptophysin and chromogranin), but nonreactive with epithelial markers (CAM 5.2, high- and low-molecular-weight keratins, epithelial membrane antigen, and carcinoembryonic antigen). The sustentacular cells were positive for S100 protein. Although pulmonary carcinoids may mimic paragangliomas and occasionally contain sustentacular cells, the diagnosis was rejected because the tumor cells did not demonstrate reactivity with epithelial markers.

Mucoepidermoid tumor of the lung is a rare endobronchial neoplasm with a wide spectrum of appearance. We present a case report and describe the plain film and computed tomography (CT) findings.

Standard, thin-section, and reference phantom computed tomography (CT) were performed to evaluate 75 consecutive patients with solitary pulmonary nodules. Follow-up was available for 62 nodules in 59 patients; 53 of the nodules were benign and nine were malignant. Twenty-one of the 62 nodules were assessed as benign with thin-section CT, while 33 of the 62 nodules were assessed as benign with reference phantom CT. Two of the nodules classified as benign with both thin-section and reference phantom CT proved to be malignant (a peripheral, ossified carcinoid and a 3.5-cm-diameter calcified carcinoma). The sensitivity of reference phantom CT (58%) for classification of benign nodules was higher than the sensitivity of thin-section CT (36%). The sensitivity of standard CT was lowest (12%). The presence of fat at thin-section CT was a reliable criterion for benignancy in six hamartomas. While both thin-section and reference phantom CT were useful in the identification of benign pulmonary nodules, reference phantom CT increased sensitivity by 22% compared with thin-section CT.

The onset of a rapidly progressive abducens and trigeminal neuropathy, third-order neuron Horner's syndrome, and decreased lacrimation clinically suggest a malignant lesion at the base of the middle cranial fossa, commonly a metastatic process. A case is reported in which computed tomography and magnetic resonance imaging failed to image the lesion but a bone scan clearly depicted the abnormal area. A malignant meningioma (en plaque) was evident on biopsy, and pulmonary metastases later ensued. Common histological patterns of meningioma (often thought of as a benign tumor) include meningothelial, fibrous, and transitional types. The association of cellular atypia, nuclear pleomorphism, marked mitoses, and brain invasion warrants the designation of malignant meningioma. The incidence of malignancy in meningioma ranges from 2 to 10% with reported metastases occurring in 0.1%.

Usefulness of high-resolution computed tomography (HRCT) in locating pulmonary parenchymal disease in relation to the pulmonary lobule was evaluated in 71 patients, including 30 with normal pulmonary parenchyma and 41 with various pulmonary diseases. Both 10-mm-thick sections and 1.5- or 3.0-mm-thick HRCT scans were obtained. Distribution of pulmonary parenchymal disease was classified as centrilobular, panlobular, perilobular, bronchovascular, or nonlobular. Intralobular classification of disease distribution was more feasible in less severely diseased regions. HRCT revealed thickened intralobular bronchovascular bundles in patients with bronchiolitis obliterans, mycoplasma pneumonia, and pulmonary tuberculosis and thickening of both bronchovascular bundles and perilobular structures in patients with sarcoidosis, lymphangitis carcinomatosa, and malignant lymphoma. Centrilobular areas of increased attenuation were seen in patients with bronchopneumonia and pulmonary cryptococcosis. Centrilobular emphysema and bronchiolectasis were recognized only on HRCT images. The improved clarity and sharpness of parenchymal abnormalities on HRCT images, even in severely involved areas, provide additional information about disease distribution.