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Purpose: Focal interstitial fibrosis (FIF) manifesting as a persistent part-solid nodule (PSN) has been mistakenly treated surgically due to similar imaging features to invasive adenocarcinoma (ADC). The purpose of this study was to observe predictive imaging features correlated with FIF through CT morphologic analysis., Materials and Methods: From January 2009 to December 2020, 44 patients with surgically proven FIF in a single institution were enrolled and compared with 88 ADC patients through propensity score matching. Patient characteristics and CT morphologic analysis of persistent PSNs were used to identify predictive imaging features of FIF. Receiver operating characteristic (ROC) curve analysis was used to quantify the performance of imaging features., Results: A total of 132 patients with 132 PSNs (44 FIF, 88 ADC; mean age, 67.7±7.58; 75 females) were involved in our analysis. Multivariable analysis demonstrated that preserved peritumoral vascular margin (preserved vascular margin), preserved secondary pulmonary lobule margin (preserved lobular margin), and lower coronal to axial ratio (C/A ratio; cutoff: 1.005) were significant independent predictors of FIF ( P< 0.05). ROC curve analysis to evaluate the predictive value of the logistic model based on the imaging features of FIF, and the AUC value was 0.881., Conclusion: CT imaging features of preserved vascular margin, preserved lobular margin, and lower C/A ratio (cutoff, <1.005) might be helpful imaging features in discriminating FIF over ADC among persistent PSN in clinical practice., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

ISG15 is an interferon-stimulated ubiquitin-like protein (UBL) with multifaceted roles as a posttranslational modifier in ISG15 conjugation (ISGylation). However, the mechanistic consequences of ISGylation in cancer have not been fully elucidated, largely due to a lack of knowledge on the ISG15 target repertoire. Here, we identified SIRT1, a nicotinamide adenine dinucleotide (NAD + )-dependent protein deacetylase, as a new target for ISGylation. SIRT1 ISGylation impairs the association of SIRT1 with its negative regulator, deleted in breast cancer 1 (DBC1), which unleashes SIRT1 from its inactive state and leads to an increase in its deacetylase activity. Importantly, SIRT1 ISGylation promoted lung cancer progression and limited lung cancer cell sensitivity to DNA damage-based therapeutics in vivo and in vitro models. The levels of ISG15 mRNA and protein were significantly higher in lung cancer tissues than in adjacent normal tissues. Accordingly, elevated expression of SIRT1 and ISG15 was associated with poor prognosis in lung cancer patients, a finding that could be translated for lung cancer patient stratification and disease outcome evaluation. Taken together, our findings provide a mechanistic understanding of the regulatory effect of SIRT1 ISGylation on tumor progression and therapeutic efficacy in lung cancer., (© 2024. The Author(s).)

Background: Interstitial lung abnormalities (ILAs) are associated with the risk of lung cancer and its mortality. However, the impact of ILA on treatment-related complications and survival in patients who underwent curative surgery is still unknown., Research Question: This study aimed to evaluate the significance of the presence of computed tomography-diagnosed ILA and histopathologically matched interstitial abnormalities on postoperative pulmonary complications (PPCs) and the long-term survival of patients who underwent surgical treatment for lung cancer., Study Design and Methods: A matched case-control study was designed to compare PPCs and mortality among 50 patients with ILA, 50 patients with idiopathic pulmonary fibrosis (IPF) and 200 controls. Cases and controls were matched by sex, age, smoking history, tumour location, the extent of surgery, tumour histology and pathological TNM stage., Results: Compared with the control group, the OR of the prevalence of PPCs increased to 9.56 (95% CI 2.85 to 32.1, p<0.001) in the ILA group and 56.50 (95% CI 17.92 to 178.1, p<0.001) in the IPF group. The 5-year overall survival (OS) rates of the control, ILA and IPF groups were 76% (95% CI 71% to 83%), 52% (95% CI 37% to 74%) and 32% (95% CI 19% to 53%), respectively (log-rank p<0.001). Patients with ILA had better 5-year OS than those with IPF (log-rank p=0.046) but had worse 5-year OS than those in the control group (log-rank p=0.002)., Conclusions: The presence of radiological and pathological features of ILA in patients with lung cancer undergoing curative surgery was associated with frequent complications and decreased survival., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Abstract: Basaloid squamous cell carcinoma (SCC) is very rare subtype of SCC of the lung and it is important to distinguish basaloid to other subtypes of SCCs, since the prognosis of basaloid subtype is considered poorer than that of other non-basaloid subtypes of SCCs. Aim of this study was to assess computed tomography (CT) findings of basaloid SCC of the lung in 12 patients.From January 2016 to April 2021, 12 patients with surgically proven basaloid SCC of the lung were identified. CT findings were analyzed, and the imaging features were compared with histopathologic reports. Clinical and demographic features were also analyzed.Axial location of the tumor was central in 5 patients, while 7 was in peripheral. Of the 7 patients whose tumors were located in the peripheral, margin of the tumor were smooth (n  = 2), lobulated (n  = 2), or spiculated (n  = 3). After contrast injection, net enhancement value ranged from 15.8 to 71.8 HU (median, 36.4 HU). Endobronchial growth were seen in 5 patients and these patients accompanied obstructive pneumonia or atelectasis. Internal profuse necrosis, cavitation, or calcifications were not seen.On CT, basaloid squamous cell presents as solitary nodule or mass with moderate enhancement. Tumor was located either peripheral or central compartment of the lung and cavitation was absent., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Mixed squamous and glandular papilloma (mixed papilloma) of the lung has been reported in fewer than 25 cases in the English literature. Although it is known as a benign tumor, malignant transformation has been reported. Papillary cystic carcinoma is characterized by papillary and cystic growth patterns and has been reported as a subtype of adenocarcinoma, mainly in the salivary glands, breast, and pancreas. In this article, we report a case of adenocarcinoma-papillary cystic pattern arising from mixed papilloma of the lung in a 76-year-old male patient. Chest computed tomography scan revealed an endobronchial mass growing at the right medial segmental bronchus. Middle lobe lobectomy was performed, revealing a 4.9 × 1.9 cm-sized mass that protruded into the bronchus. Microscopically, the tumor showed numerous cysts lined by micropapillary projections. The tumor cells had round and vesicular nuclei with prominent nucleoli, and mitosis was frequent. A limited portion of the tumor consisted of benign mixed papilloma. The tumor showed diffuse immunoreactivity for thyroid transcription factor-1 and strong expression of p16. We investigated the mutational status of cancer-related genes using targeted next-generation sequencing and identified a genetic alteration in the BRAF gene. This is the first case report of papillary cystic carcinoma arising in mixed papilloma of the lung.

Background Multicenter studies are required to validate the added benefit of using deep convolutional neural network (DCNN) software for detecting malignant pulmonary nodules on chest radiographs. Purpose To compare the performance of radiologists in detecting malignant pulmonary nodules on chest radiographs when assisted by deep learning-based DCNN software with that of radiologists or DCNN software alone in a multicenter setting. Materials and Methods Investigators at four medical centers retrospectively identified 600 lung cancer-containing chest radiographs and 200 normal chest radiographs. Each radiograph with a lung cancer had at least one malignant nodule confirmed by CT and pathologic examination. Twelve radiologists from the four centers independently analyzed the chest radiographs and marked regions of interest. Commercially available deep learning-based computer-aided detection software separately trained, tested, and validated with 19 330 radiographs was used to find suspicious nodules. The radiologists then reviewed the images with the assistance of DCNN software. The sensitivity and number of false-positive findings per image of DCNN software, radiologists alone, and radiologists with the use of DCNN software were analyzed by using logistic regression and Poisson regression. Results The average sensitivity of radiologists improved (from 65.1% [1375 of 2112; 95% confidence interval {CI}: 62.0%, 68.1%] to 70.3% [1484 of 2112; 95% CI: 67.2%, 73.1%], P < .001) and the number of false-positive findings per radiograph declined (from 0.2 [488 of 2400; 95% CI: 0.18, 0.22] to 0.18 [422 of 2400; 95% CI: 0.16, 0.2], P < .001) when the radiologists re-reviewed radiographs with the DCNN software. For the 12 radiologists in this study, 104 of 2400 radiographs were positively changed (from false-negative to true-positive or from false-positive to true-negative) using the DCNN, while 56 of 2400 radiographs were changed negatively. Conclusion Radiologists had better performance with deep convolutional network software for the detection of malignant pulmonary nodules on chest radiographs than without. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Jacobson in this issue.

Background: Lung cancer is a common comorbidity of idiopathic pulmonary fibrosis (IPF) and has poor outcomes. The incidence and clinical factors related to development of lung cancer in idiopathic pulmonary fibrosis (IPF) are unclear. The aim of this study was to elucidate the cumulative incidence, risk factors, and clinical characteristics of lung cancer in IPF., Methods: In this retrospective study, we analyzed clinical data for 938 patients who were diagnosed with IPF without lung cancer between 1998 and 2013. Demographic, physiologic, radiographic, and histologic characteristics were reviewed. Cumulative incidence of lung cancer and survival were estimated by the Kaplan-Meier method. Risk factors of lung cancer development were determined by Cox proportional hazard analysis., Results: Among 938 IPF patients without lung cancer at initial diagnosis, lung cancer developed in 135 (14.5%) during the follow-up period. The cumulative incidences of lung cancer were 1.1% at 1 year, 8.7% at 3, 15.9% at 5, and 31.1% at 10 years. Risk factors of lung cancer were male gender, current smoking at IPF diagnosis, and rapid annual decline of 10% or more in forced vital capacity (FVC). Patients who developed lung cancer were mostly elderly men with smoking history. Squamous cell carcinoma followed by adenocarcinoma was the most common histologic type. Lung cancer was frequently located in areas abutting or within fibrosis. Survival was significantly worse in patients with lung cancer compared to patients with IPF alone., Conclusion: Lung cancer frequently developed in patients with IPF and was common in current-smoking men with rapid decline of FVC.

Purpose: To determine the outcomes of transthoracic rebiopsy for epidermal growth factor receptor (EGFR) mutation in patients with lung adenocarcinoma and to explore the clinical and procedure-related risk factors for the acquisition of nondiagnostic rebiopsy specimens., Patients and Methods: We retrospectively reviewed 367 patients with lung adenocarcinoma who underwent transthoracic core needle biopsy for mutation analysis from September 2011 to October 2016. Of these, 199 patients underwent rebiopsy. Patient characteristics, treatment history, target lesion characteristics, and procedure-related factors were evaluated. The adequacy rate of specimens for mutation analysis was evaluated. Univariable and multivariable analyses were performed to determine the independent predictors of nondiagnostic specimens., Results: Ninety percent of specimens (179 of 199) were adequate for mutation analysis. The EGFR mutation (exon 18-21) was 65% (117 of 179) and the EGFR T790M mutation 33% (59 of 179) of specimens. In univariable analysis, an internal low-attenuation area in the target lesion (P = .001) and pleural contact (P = .004) on computed tomography were significant risk factors for nondiagnostic specimens. In multivariable analysis, an internal low-attenuation area in the target lesion (odds ratio = 7.333; 95% confidence interval, 1.755-30.633; P = .006) was an independent predictor for acquisition of nondiagnostic specimens., Conclusion: Image-guided transthoracic rebiopsy to obtain specimens for mutation analysis in lung adenocarcinoma provides high diagnostic accuracy, with a low rate of nondiagnostic specimens. The presence of internal low-attenuation area in the target lesion on computed tomography was an independent predictor for acquiring nondiagnostic specimens., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: The objective of our study was to investigate histopathology features, imaging features, and prognoses of surgically resected pure small cell lung carcinomas (SCLCs) and combined SCLCs., Materials and Methods: Forty-one patients with a pure SCLC or a combined SCLC underwent preoperative chest CT and 18 F-FDG PET/CT and subsequent surgical resection. The clinicopathologic findings were noted by reviewing the electronic medical records. The imaging features of individual tumors were analyzed on chest CT and PET/CT scans. Each tumor was classified as being located centrally (at or in the segmental bronchus or proximal to the segmental bronchus) or peripherally (distal to the segmental bronchus). The maximum standardized uptake value (SUV max ) of each tumor was measured at PET. The 7th edition of the TNM staging system was adopted for staging., Results: The study group was composed of 34 men and seven women with a mean age of 62.0 ± 10.2 (SD) years. Sixteen of 41 (39%) patients had pure SCLC, and the remaining patients had combined SCLC. The most common combined SCLC histologic subgroup was combined SCLC and large cell neuroendocrine carcinoma in 17 (41%) patients. The mean SUV max of pure SCLCs was 5.6 ± 2.2 and was significantly lower than that of combined SCLCs (p < 0.01). Thirty-one patients (76%) had a peripheral tumor, and 10 (24%) had a central tumor. The overall survival (OS) of the 10 patients with a central tumor was 44.6 months, significantly shorter than the OS of the 31 patients with a peripheral tumor (179.2 months) (p = 0.017). The OS of 21 patients with stage I disease was significantly longer than the OS of patients with higher-stage cancer (p = 0.004)., Conclusion: In our study group of patients with surgically resected SCLC, patients with a peripheral tumor (including a purely endobronchial tumor) or stage I disease showed a better prognosis than those with a central tumor or higher-stage disease.

Objective: To evaluate the efficacy of the morphologic-metabolic (M-M) dissociation sign based on computed tomography (CT) and fluorine-18-fluorodeoxyglucose positron emission tomography (PET)/CT in discriminating invasive mucinous adenocarcinoma (IMA) from invasive non-mucinous adenocarcinomas (ADCs) of the lung., Materials and Methods: The Institutional Review Board approved this retrospective study. Among surgically resected solitary pulmonary nodule (SPN)-type ADCs (< 3 cm in diameter), 35 patients with IMAs and 329 with invasive non-mucinous ADCs were included. Morphologic malignancy was established if the tumor with lobulated or spiculated margin on CT presented a tumor shadow disappearance rate of < 0.5. The M-M dissociation sign was determined when a malignant-morphologic nodule on CT showed maximum standardized uptake value (SUVmax) < 3.5 on PET/CT., Results: Among 35 IMAs (size: 21 ± 7 mm, SUVmax: 1.8 ± 2.0) and 329 invasive non-mucinous ADCs (size: 21 ± 6 mm, SUVmax: 4.6 ± 4.2), the M-M dissociation sign was observed in 54% of IMAs (19/35) and 10% of invasive non-mucinous ADCs (34/329) ( p < 0.001). The diagnostic performance of the sign in discriminating IMA from invasive non-mucinous ADCs showed a sensitivity of 54.3% (95% confidence interval [CI], 36.7-71.2), specificity 89.7% (95% CI, 85.9-92.7), positive predictive value 35.8% (95% CI, 26.5-46.5), and negative predictive value 94.9% (95% CI, 92.8-96.4). Multivariate analyses revealed metabolic benignity (odds ratio [OR] 2.99; 95% CI, 1.01-8.93; p = 0.047) and M-M dissociation sign (OR 6.35; 95% CI, 2.76-14.62; p < 0.001) to be significant predictors of SPN-type IMAs., Conclusion: Identification of the absence of M-M dissociation sign is an accurate indicator for excluding IMA from SPN-type lung ADCs., Competing Interests: The authors have no financial conflicts of interest., (Copyright © 2019 The Korean Society of Radiology.)

Purpose: The aim of this study was to evaluate the diagnostic performance of a trained deep convolutional neural network (DCNN) model for detecting operable lung cancer with chest radiographs (CXRs)., Materials and Methods: The institutional review board approved this study. A deep learning model (DLM) based on DCNN was trained with 17,211 CXRs (5700 CT-confirmed lung nodules in 3500 CXRs and 13,711 normal CXRs), finally augmented to 600,000 images. For validation, a trained DLM was tested with 1483 CXRs with surgically resected lung cancer, marked and scored by 2 radiologists. Furthermore, diagnostic performances of DLM and 6 human observers were compared with 500 cases (200 visible T1 lung cancer on CXR and 300 normal CXRs) and analyzed using free-response receiver-operating characteristics curve (FROC) analysis., Results: The overall detection rate of DLM for resected lung cancers (27.2±14.6 mm) was a sensitivity of 76.8% (1139/1483) with a false positive per image (FPPI) of 0.3 and area under the FROC curve (AUC) of 0.732. In the comparison with human readers, DLM demonstrated a sensitivity of 86.5% at 0.1 FPPI and a sensitivity of 92% at 0.3 FPPI with AUC of 0.899 at an FPPI range of 0.03 to 0.44 for detecting visible T1 lung cancers, which were superior to the average of 6 human readers [mean sensitivity; 78% (range, 71.6% to 82.6%) at an FPPI of 0.1% and 85% (range, 80.2% to 89.2%) at an FPPI of 0.3, AUC of 0.819 (range, 0.754 to 0.862) at an FPPI of 0.03 to 0.44)., Conclusions: A DLM has high diagnostic performance in detecting operable lung cancer with CXR, demonstrating a potential of playing a pivotal role for lung cancer screening.

Purpose To identify the features at CT that are predictive of spread through air spaces (STAS) in surgically resected lung adenocarcinomas. Materials and Methods For this retrospective study, presence of STAS was evaluated in 948 consecutive patients who underwent surgical resection for lung adenocarcinoma from April 2015 to December 2016. Patients who were positive for STAS and negative for STAS were matched at a ratio of 1:2 by using patient variables (age, sex, and smoking status). CT features (ie, percentage of solid component, maximum diameter of solid component, lesion density, location, margin, shape, pseudocavity, calcification, central low attenuation, ill-defined peripheral opacity, air bronchogram, satellite lesions, and pleural retraction) were analyzed by using multivariable logistic regression and receiver operating characteristic curves. Results The final study population consisted of 276 patients (mean age, 59 years; age range, 32-78 years) including 129 men (mean age, 60 years; age range, 36-78 years) and 147 women (mean age, 59 years; age range, 32-78 years). Ninety-two patients were positive for STAS and 184 patients were negative for STAS. STAS was more common in solid tumors (71 of 92; 77%) than in part-solid (21 of 92; 23%) or ground-glass lesions (0 of 92; 0%) (P < .001). STAS was also associated with central low attenuation, ill-defined opacity, air bronchogram, and percentage of solid component (all P < .001). Percentage of solid component was an independent predictor of STAS (odds ratio, 1.06; 95% confidence interval: 1.03, 1.08) and a cut-off value of 90% showed a discriminatory power with a sensitivity of 89.2% and a specificity of 60.3%. Conclusion Percentage of solid component was independently associated with spread through air spaces in lung adenocarcinomas. © RSNA, 2018 Online supplemental material is available for this article.

Pancreatic cancer has poor prognosis because of its rapid progression and treatment resistance. Based on the results of the Metastatic Pancreatic Adenocarcinoma Clinical Trial (MPACT), a combination regimen of gemcitabine with nab-paclitaxel is currently used as standard therapy for the treatment of metastatic pancreatic cancer. However, because studies in Asian populations are lacking, we investigated the treatment efficacy and safety of this combination therapy in Korean population. Patients with metastatic pancreatic cancer (n=81) treated with gemcitabine and nab-paclitaxel (1,000 and 125 mg/m 2 , respectively) as the first-line chemotherapy from January 2016 were identified using the Severance Hospital Pancreatic Cancer Cohort Registry. Treatment efficacy and treatment-related adverse events (AEs) were analyzed. The median follow-up period was 10.7 months (range, 1.5-23.3 months). Median overall survival, progression-free survival, and objective response rates were 12.1 months (95% confidence interval [CI], 10.7-not estimable), 8.4 months (95% CI, 5.0-11.8), and 46.9%, respectively. The incidence of grade ≥3 neurotoxicity and neutropenia were 18.5% and 46.9%, respectively. Febrile neutropenia and grade ≥3 gastrointestinal AEs occurred in 13 (16.0%) and 16 (19.8%) patients, respectively. Dose reductions because of AEs were required in 60.5% of patients. The combination of gemcitabine with nab-paclitaxel is an effective anti-cancer regimen in Korean population of patients with metastatic pancreatic adenocarcinoma. However, careful monitoring and management are required because of occurrence of treatment-related AEs., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Introduction: The documented incidence of multiple primary lung cancer has increased as a result of the widespread use of early detection tools. We report the successful surgical treatment of a case who had consecutive metachronous adenocarcinoma and squamous cell carcinoma of the lung after successful treatment for small cell carcinoma of the lung.A 73-year-old man underwent a routine health check-up. Computed tomography showed ground-glass opacity in the upper lobe of the right lung, which was diagnosed as small cell carcinoma. Twenty-nine months after concurrent chemoradiotherapy for the carcinoma, which was in complete remission, a nodule was detected in the apical segment of the right upper lobe. Histopathologically, the tumor was diagnosed as poorly differentiated adenocarcinoma. The second metachronous adenocarcinoma was completely removed by right upper lobectomy with lymph node dissection. Seventeen months later, the patient underwent left upper lobectomy with lymph node dissection and received 4 cycles of adjuvant chemotherapy for another moderately differentiated squamous cell carcinoma., Conclusion: This case highlights the need for continuous screening for metachronous lung cancer following the successful treatment of primary lung cancer, even small cell carcinoma, to identify patients who could benefit from curative surgery.

Background: Benign metastatic leiomyoma (BML) is an extremely rare disease. Although uterine leiomyomas are benign histologically, they can metastasize to distant sites. While the incidence is very low, the lung is the organ most frequently affected by BML. Pulmonary BML usually presents as numerous well-defined nodules of various sizes, while the cavitary or cystic features in the nodules are rarely observed on radiologic images., Case Presentation: A 52-year-old woman complained of cough and dyspnea for one month. She had been previously diagnosed with uterine leiomyoma and had undergone total hysterectomy about 14 years prior. High-resolution computed tomography (CT) images showed that there were multiple cystic nodules of various sizes in both lungs. Pathologic examination revealed that the pulmonary nodule had complex branching glandular structures lined by a single layer of simple cuboidal to columnar epithelium that was surrounded by abundant spindle cells. Additional immunohistochemistry data suggested that pulmonary nodule diagnosis was BML-associated uterine leiomyoma., Conclusion: In this report, we introduce an interesting case of pulmonary BML that presented as a combination of various kinds of nodules including simple round nodules, simple cysts, and cysts with a solid portion, which are very rare radiologic features of BML in lung. In addition, when the patient is a woman of reproductive age, physicians should meticulously review the gynecological history and suspect BML when there are various cystic pulmonary lesions.

The histological subtypes by peripheral tumor location remain uncharacterized in COPD patients with emphysema. We investigated histologic subtypes of peripheral lung cancers based on the context of heterogeneous emphysema distribution in patients with airflow limitation and CT-determined emphysema. A retrospective, cross-sectional study was conducted using data from 754 patients with airflow limitation and newly-diagnosed primary lung cancers from February 2013 to February 2015. Of these, 230 patients had emphysema, as determined by computed tomography software designed to quantify emphysema. Among the 230 patients, the most common subtype in central lesions (n=84) was squamous cell carcinoma (SCC) (n=64/84, 76%). Adenocarcinoma (ADC) was more frequently observed in peripheral lesions (n=146) than central lesions (58/146 [40%] vs. 4/84 [5%], p<0.001). In peripheral lesions, ADC was more frequently seen in areas without emphysema than emphysema areas (43/74 [58%] vs. 15/72 [21%], p<0.001), while SCC was more frequently found in emphysema areas than areas without emphysema (44/72 [61%] vs. 13/74 [18%], p<0.001). These associations persisted with adjustments for age, sex, smoking status and forced expiratory volume in 1s. In patients with both airflow limitation and CT-determined emphysema, the main histological subtype of peripheral lung cancer was SCC in emphysema areas and ADC in areas without emphysema., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

This study aims to evaluate the joint effect of severity of airflow limitation and emphysema on postoperative pulmonary complications (PPCs) and overall survival after complete resection in patients with early-stage nonsmall cell lung cancer (NSCLC).We retrospectively studied 413 male patients with pathologic stage I or II NSCLC between 2007 and 2009. Severity of airflow limitation was defined based on forced expiratory volume in 1 s. Emphysema was defined by ≥5% low attenuation area at -950 HU.In multivariable-adjusted analyses, the adjusted odds ratio (aOR) for any PPC, comparing patients with moderate-to-severe airflow limitation to those without airflow limitation, was 2.23, and the aOR comparing patients with emphysema to those without emphysema was 1.77. However, the joint effect of airflow limitation and emphysema was much higher than expected from the independent effects of both factors (aOR 8.90). Moreover, patients with coexisting moderate-to-severe airflow limitation and emphysema had significantly poorer overall survival than any other group.Patients with moderate-to-severe airflow limitation and emphysema had almost nine times the risk of PPCs and poorer survival than patients with neither of these conditions. Integrated assessment of airflow limitation severity and emphysema is necessary for the optimal selection of candidates for lung resection surgery of early-stage NSCLC., (Copyright ©ERS 2016.)

Objectives: SR-splicing factors (SRSFs) play important roles in oncogenesis. However, the expression of SRSF 5-7 proteins in lung cancer (LC) is unclear, and their use in the diagnosis of pleural diseases has never been assessed. We evaluated SRSF 5-7 protein levels in LC and their diagnostic potential for cancer cells in lung and pleural effusion (PE) and, for the dysregulated SRSFs, investigated their neutralization effect on LC., Materials and Methods: SRSF 5-7 levels in lung tissue and PE cell lysate samples (n=453) were compared with the results of conventional tumor markers. Knockdown of SRSF gene expression was performed using small interfering RNAs on small-cell LC (SCLC) cell lines., Results: In lung tissue analysis, SRSF 5-7 levels were up-regulated in LC samples compared with non-tumoral lung tissue samples; they were markedly higher in SCLC than in adenocarcinoma or squamous cell carcinoma. SRSF5 showed the highest detection accuracy (89%) for total LC, and it was superior to that (74%) of carcinoembryonic antigen [CEA, a commonly used non-SCLC (NSCLC) marker]. Notably, the detection accuracies of the three SRSFs for SCLC were all 100% and higher than that (69%) of a pro-gastrin-releasing peptide (a well-known SCLC marker). In PE cell analysis, the detection accuracy (86%) of SRSF5 for malignant cells was highest among SRSFs and comparable to that (83%) of CEA. SRSF5 additionally detected 70% of CEA-missed non-NSCLC cases. Down-regulation of the SRSFs induced mild (SRSF5 and SRSF7) to remarkably (SRSF6) reduced cell proliferation., Conclusions: Our results demonstrated the up-regulated expression of SRSF 5-7 proteins in LC with much more profound up-regulation in SCLC than in NSCLC and suggest that up-regulation of the SRSFs is related to SCLC proliferation. Moreover, we identified SRSF5 as a novel detection marker for SCLC and pleural metastatic cancer cells., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: To compare the capability of lung nodule detection and characterization between dual-energy radiography with color-representation (DCR) and conventional gray scale chest radiography (GSR)., Methods: A total of 130 paired chest radiographs (DCR and GSR) obtained from 65 patients (14 with normal scans and 51 with pulmonary nodules) were evaluated. After analysis, 45 non-calcified and 21 calcified nodules were identified. DCR was obtained by adding color space within material-decomposed data (blue for high attenuation and red for low attenuation) and by compounding the manipulated data to one color image. Three radiologists marked suggested nodules on radiographic images and assessed the level of confidence of lesion presence and probability of nodule calcification by using a nine-point rating scale. The jackknife active free-response receiver operating characteristics (JAFROC) analysis was used to evaluate lesion detectability, and multi-reader multi-case receiver operating characteristics (MRMC ROC) analysis was used for the evaluation of the accuracy of nodule calcification prediction., Results: Figures of merit (FOM) from JAFROC was 0.807 for DCR and 0.811 for GSR, respectively; nodule detectability was not significantly different between DCR and GSR (p = 0.93). Areas under curve (AUC) from MRMC ROC were 0.944 for DCR and 0.828 for GSR, respectively; performance of DCR in predicting lung nodule calcification was significantly higher than that of GSR (p = 0.04)., Conclusions: DCR showed similar performance in terms of lung nodule detection compared with GSR. However, DCR does provide a significant benefit in predicting the presence of nodule calcification.

No study has been published on aortic valve calcification (AVC) extent at lung cancer screening low-dose CT (LDCT) and its relationship with aortic stenosis (AS). The purpose of this study was to estimate the cutoff value of AVC on LDCT for detecting AS in asymptomatic Asian subjects. Six thousand three hundred thirty-eight subjects (mean age, 55.9 years ± 8.6) self-referred to health-promotion center underwent LDCT, coronary calcium scoring CT (CSCT), and echocardiography. AVC was quantified using Agatston methods on CT. AVC extent on LDCT was compared with that on CSCT, and AVC threshold for diagnosing AS was calculated. Clinical factors associated with AS and AVC were sought.AVC was observed in 403 subjects (64.9 years ± 8.7) on LDCT (6.4%), and AVC score measured from LDCT showed strong positive correlation with that from CSCT (r = 0.83, P < 0.0001). Of 403 subjects, 40 (10%) were identified to have AS on echocardiography. Cutoff value of AVC score for detecting AS was 138.37 with sensitivity of 90.0% and specificity 83.2%. On multivariate analysis, age (odds ratio [OR] = 1.10, 95% CI: 1.09-1.12) and hypertension (OR = 1.39, 95% CI: 1.10-1.76) were associated with the presence of AVC, whereas AVC extent at LDCT (OR = 104.32, 95% CI: 16.16-673.70) was the only significant clinical factor associated with AS; AVC extent on LDCT (OR = 104.32, 95% CI: 16.16-673.70) was the significant clinical factor associated with AS.The AVC extent on LDCT is significantly related to the presence of AS, and we recommend echocardiography for screening AS based on quantified AVC values on LDCT.

This study aimed to evaluate the clinical correlations between serum lactate dehydrogenase (LDH) levels and tumor characteristics and to investigate the prognostic impact of serum LDH levels in advanced non-small cell lung cancer (NSCLC). A total of 394 patients were included in the present study between June 2007 and January 2013. All eligible patients had serum LDH levels available before treatment, and whole-body metastatic extent was measured using whole-body metastatic scores, as determined by 18(F)-fludeoxyglucose positron emission tomography scans from 1 to 7 as the sum of each metastatic region. The diagnostic cutoff value for an abnormal serum LDH level was 450 IU/L. The median serum LDH level was 477 IU/L (range, 113-2850), and 224 (56.9 %) patients had abnormal serum LDH levels. The serum LDH levels showed no significant associations with age, gender, histology, tumor differentiation, and smoking history. However, the proportion of patients with abnormal serum LDH levels was statistically significantly higher in the high total metastatic score group (scores 3-7) than in the low total metastatic score group (scores 1-2) (65.3 vs 50.4 %, p = 0.001). In a multivariate survival analysis, age (p = 0.001), gender (p = 0.001), histology (p = 0.003), tumor differentiation (p = 0.001), Eastern Cooperative Oncology Group (ECOG) performance status (p = 0.001), LDH levels (p = 0.046), and treatment factors (p = 0.001) proved to be independent prognostic factors for survival outcomes. The results of this study suggest that the serum LDH levels at presentation may be significantly correlated with whole-body tumor extent and might independently but modestly prognosticate OS in stage IV NSCLC.

Objective: To assess the performance of adaptive statistical iterative reconstruction (ASIR)-applied ultra-low-dose CT (ULDCT) in detecting small lung nodules., Materials and Methods: Thirty patients underwent both ULDCT and standard dose CT (SCT). After determining the reference standard nodules, five observers, blinded to the reference standard reading results, independently evaluated SCT and both subsets of ASIR- and filtered back projection (FBP)-driven ULDCT images. Data assessed by observers were compared statistically., Results: Converted effective doses in SCT and ULDCT were 2.81 ± 0.92 and 0.17 ± 0.02 mSv, respectively. A total of 114 lung nodules were detected on SCT as a standard reference. There was no statistically significant difference in sensitivity between ASIR-driven ULDCT and SCT for three out of the five observers (p = 0.678, 0.735, < 0.01, 0.038, and < 0.868 for observers 1, 2, 3, 4, and 5, respectively). The sensitivity of FBP-driven ULDCT was significantly lower than that of ASIR-driven ULDCT in three out of the five observers (p < 0.01 for three observers, and p = 0.064 and 0.146 for two observers). In jackknife alternative free-response receiver operating characteristic analysis, the mean values of figure-of-merit (FOM) for FBP, ASIR-driven ULDCT, and SCT were 0.682, 0.772, and 0.821, respectively, and there were no significant differences in FOM values between ASIR-driven ULDCT and SCT (p = 0.11), but the FOM value of FBP-driven ULDCT was significantly lower than that of ASIR-driven ULDCT and SCT (p = 0.01 and 0.00)., Conclusion: Adaptive statistical iterative reconstruction-driven ULDCT delivering a radiation dose of only 0.17 mSv offers acceptable sensitivity in nodule detection compared with SCT and has better performance than FBP-driven ULDCT.

Multiple or second primary lung cancers can develop at any sites in the lung with same or different histologic types, synchronously and/or metachronously. In case of metachronous occurrence of the second primary lung cancer, it is easy to confuse with the primary lung cancer as a recurrence of precedent lung malignancy treated successfully or metastasis. Previous reports have demonstrated that majority of the second primary lung malignancies have same histologic types regardless of their developing time and location. However, the repeated occurrence of the second primary lung malignancy, in particular with the different histologic features, is a very rare condition.A 62-year-old male who had past history of squamous cell carcinoma treated with surgery and adjuvant chemotherapy and the recurrence of lung malignancy on the trachea, which was also resected successfully visited our hospital due to blood tinged sputum. Evaluation using bronchoscopy and chest computed tomography revealed the tracheal mass looked similar grossly to the previous recurred tracheal mass that was resected surgically. Unexpectedly, the newly developed tracheal mass was confirmed as small cell lung cancer, the different histologic type from previous ones.In this report, we describe an interesting case of subsequent occurrence of second primary lung cancers showing histologic shifting at different sites in trachea, suggesting that it is important for physician to make an effort to identify the histologic characteristics of second primary lung cancers for the correct and adequate treatment no matter what they exhibit similar gross morphology.

Background and Objective: Subcentimeter nodules without change in size during long-term follow-up period (for minimum 2 years) are assumed as benign lesions. However, the 2-year stability rule has not been fully verified so far and is still questionable. Thus, we aimed to retrospectively investigate long-term follow-up results for 2-year stable subcentimeter nodules at screening low-dose computed tomography (LDCT)., Methods: A total of 635 subjects having had follow-up LDCTs for the initial 2-year screening period and additional 3 years thereafter and having had non-calcified subcentimeter nodules were included. By using computed tomography (CT) nodule volumetry software, we measured interval changes in nodule volume., Results: A total of 1107 subcentimeter nodules (1037 solid, 70 ground-glass opacity nodules (GGNs)) were detected at baseline CT. Of 1037 solid nodules, 1032 showed no growth during the initial 2-year and 5-year follow-up period. Fifty-nine GGNs were stable for initial 2 years, but two (3.4%) were later proved as adenocarcinomas. Among five solid nodules that showed growth during the initial 2-year follow-up period, one (20%) proved to be an adenocarcinoma, whereas four (36.4%) of 11 GGNs that demonstrated growth were diagnosed as lung cancers., Conclusions: All solid subcentimeter nodules having initial 2-year stability at screening LDCT can be considered benign because none shows growth at further follow-up CT. On the other hand, subcentimeter GGNs have more chance of growth than solid nodules and need further follow-up CT for more than 2 years., (© 2014 Asian Pacific Society of Respirology.)

Objective: To compare the diagnostic performance of light emitting diode (LED) backlight monitors and cold cathode fluorescent lamp (CCFL) monitors for the interpretation of digital chest radiographs., Materials and Methods: We selected 130 chest radiographs from health screening patients. The soft copy image data were randomly sorted and displayed on a 3.5 M LED (2560 × 1440 pixels) monitor and a 3 M CCFL (2048 × 1536 pixels) monitor. Eight radiologists rated their confidence in detecting nodules and abnormal interstitial lung markings (ILD). Low dose chest CT images were used as a reference standard. The performance of the monitor systems was assessed by analyzing 2080 observations and comparing them by multi-reader, multi-case receiver operating characteristic analysis. The observers reported visual fatigue and a sense of heat. Radiant heat and brightness of the monitors were measured., Results: Measured brightness was 291 cd/m(2) for the LED and 354 cd/m(2) for the CCFL monitor. Area under curves for nodule detection were 0.721 ± 0.072 and 0.764 ± 0.098 for LED and CCFL (p = 0.173), whereas those for ILD were 0.871 ± 0.073 and 0.844 ± 0.068 (p = 0.145), respectively. There were no significant differences in interpretation time (p = 0.446) or fatigue score (p = 0.102) between the two monitors. Sense of heat was lower for the LED monitor (p = 0.024). The temperature elevation was 6.7℃ for LED and 12.4℃ for the CCFL monitor., Conclusion: Although the LED monitor had lower maximum brightness compared with the CCFL monitor, soft copy reading of the digital chest radiographs on LED and CCFL showed no difference in terms of diagnostic performance. In addition, LED emitted less heat.

Background: Digital tomosynthesis considerably reduces problems created by overlapping anatomy compared with chest X-ray (CXR). However, digital tomosynthesis requires a longer scan time compared with CXR, and thus may be vulnerable to motion artifacts., Purpose: To compare the diagnostic performance of digital tomosynthesis in subjects with and without respiratory motion artifacts., Material and Methods: The institutional review board approved this retrospective study, and the requirement for written informed consent was waived. A total of 46 subjects with imaging containing respiratory motion artifacts were enrolled in this study, 18 of whom were positive and 28 of whom were negative for lung nodules on computed tomography (CT). The control group was comprised of 92 age-matched subjects with imaging devoid of motion artifacts. Of these, 36 were positive and 56 were negative for lung nodules on subsequent CT scan. The size criteria of nodules were 4-10 mm. Three chest radiologists independently evaluated the radiographs and digital tomosynthesis images for the presence of pulmonary nodules. Multireader multicase receiver-operating characteristic (ROC) analyses was used for statistical comparisons., Results: Within the control group, the areas under curve (AUC) for observer performances in detecting lung nodules on digital tomosynthesis was higher than that on CXR (P = 0.017). Within the study group, there were no significant differences in AUCs for observer performances (P = 0.576)., Conclusion: When no motion artifacts are present, the detection performance of nodules (4-10 mm) on digital tomosynthesis is significantly better than that on CXR, whereas there is not a significant difference in cases with motion artifacts.

Cortactin is an F-actin binding protein involved in cell migration and tumor metastasis. Recent reports suggest that silent mating-type information regulation 2 homologue 1 (sirtuin1; SIRT1) enhances the function of cortactin and promotes cell migration. We investigated SIRT1 and cortactin expression in 144 invasive non-small cell lung cancers (NSCLC) and 19 adenocarcinomas in situ (AIS) by immunohistochemistry and evaluated their clinicopathological significance in NSCLC. Positive SIRT1 and cortactin expression was observed in 67% (96 of 144) and 58% (84 of 144) of patients with invasive NSCLC, respectively. SIRT1 and cortactin expression was significantly associated with unfavorable clinicopathological factors, including high pathological T stage, lymph node metastasis, and advanced tumor invasion (AIS vs. invasive adenocarcinoma). Cortactin was significantly associated with high pathological T stage and lymph node metastasis in SIRT1-positive tumors. Cytoplasmic SIRT1 was significantly associated with high pathological T stage and large tumor size compared to that of nuclear SIRT1. Large tumor size, high pathological T stage, lymph node metastasis, and cytoplasmic SIRT1 expression were significantly associated with shorter overall survival in a univariate analysis. Our findings suggest that SIRT1 and cortactin may play a role in the progression of NSCLC and may cooperate during tumor progression in NSCLC., (Copyright © 2013 Elsevier GmbH. All rights reserved.)

Purpose: To evaluate the feasibility and safety of repeat biopsy for mutational analysis in patients with non-small cell lung cancer (NSCLC) who have a resistance history to previous chemotherapy., Materials and Methods: This prospective study was institutional review board approved, and written informed consent was obtained from all patients. Of 126 patients referred for repeat biopsy (hereafter, rebiopsy) with NSCLC that was resistant to conventional chemotherapy or epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors, 94 patients (31 men, 63 women; mean age ± standard deviation, 57 years ± 10.3) were selected for rebiopsy. Thirty-two patients were excluded for several reasons after strict review of the chest computed tomography (CT) images. Percutaneous transthoracic lung biopsy was performed with C-arm cone-beam CT guidance. The technical success rates for the rebiopsy and the adequacy rates of specimens for mutational analysis were evaluated. Any biopsy-related complications were recorded., Results: The technical success rate for biopsy was 100%. In 75 (80%) of 94 patients, specimens were adequate for mutational analysis. Of 75 specimens, 35 were tested for EGFR mutation, 34 for anaplastic lymphoma kinase gene (ALK) rearrangement, and six for both. The results were positive for EGFR-sensitizing mutation (exon 19 or 21) in 20, for EGFR T790M mutation in five, and for ALK rearrangement in 11. Postprocedural complications occurred in 13 (14%) of 94 patients., Conclusion: When performed by employing rigorous CT criteria, rebiopsies for the mutational analysis of NSCLCs treated previously with chemotherapy are feasible in all patients and are adequate in approximately four-fifths of patients referred for gene analysis, with acceptable rates of complications., (© RSNA, 2012.)

Objective: To evaluate tumor responses in patients treated with anti-angiogenic agents for non-small cell lung cancer (NSCLC) by assessing intratumoral changes using a dual-energy CT (DECT) (based on Choi's criteria) and to compare it to traditional Response Evaluation Criteria in Solid Tumors (RECIST) criteria., Materials and Methods: Ten NSCLC patients treated with bevacizumab underwent DECT. Tumor responses to anti-angiogenic therapy were assessed and compared with the baseline CT results using both RECIST (size changes only) and Choi's criteria (reflecting net tumor enhancement). Kappa statistics was used to evaluate agreements between tumor responses assessed by RECIST and Choi's criteria., Results: The weighted κ value for the comparison of tumor responses between the RECIST and Choi's criteria was 0.72. Of 31 target lesions (21 solid nodules, 8 lymph nodes, and two ground-glass opacity nodules [GGNs]), five lesions (16%) showed discordant responses between RECIST and Choi's criteria. Iodine-enhanced images allowed for a distinction between tumor enhancement and hemorrhagic response (detected in 14% [4 of 29, excluding GGNs] of target lesions on virtual nonenhanced images)., Conclusion: DECT may serve as a useful tool for response evaluation after anti-angiogenic treatment in NSCLC patients by providing information on the net enhancement of target lesions without obtaining non-enhanced images.

Stress that impairs endoplasmic reticulum (ER) function leads to an accumulation of unfolded or misfolded proteins in the ER (ER stress). Autophagy is a lysosomal pathway involved in the turnover of cellular macromolecules and organelles, which emerging data indicate that ER stress is also a potent inducer of autophagy. ER stress and autophagy are involved in human cancer. We examined the expression of ER stress-related proteins [GRP78 and C/EBP homologous protein (CHOP)] and autophagic proteins (Beclin-1 and LC3) in non-small cell lung carcinomas (NSCLCs), bronchioloalveolar carcinomas (BACs) and atypical adenomatous hyperplasias (AAHs) to understand their role in the NSCLC pathogenesis. The expression of GRP78 and CHOP, Beclin-1 and LC3 were analyzed using immunohistochemistry on tissue sections from 133 NSCLC (69 squamous cell carcinomas, 56 adenocarcinomas (AC) and eight other NSCLCs), 21 BAC and 9 AAH. Expression of GRP78 and Beclin-1 was correlated with low tumor stage (p < 0.001 and p = 0.019, respectively) and longer survival (p = 0.007 and p <0.001, respectively) by Kaplan-Meier analysis. However, CHOP was correlated with high tumor stage (p = 0.038) and shorter survival (p = 0.012). Expression of GRP78 and Beclin-1 was positively correlated (p = 0.006). Our study showed that the expression of GRP78, CHOP, Beclin-1 and LC3 in lung cancer and its relation with clinicopathologic factors and patients survival. These results suggest that GRP78, CHOP and Beclin-1 may play an important role in tumorigenesis of lung AC and may serve as new prognostic indicators for outcome of the patients with NSCLC., (Copyright © 2011 UICC.)

Objectives: To determine the positive reading criteria for malignant nodes when interpreting combined MRI and PET/CT images for preoperative nodal staging in non-small-cell lung cancer (NSCLC)., Methods: Forty-nine patients with biopsy-proven NSCLC underwent both PET/CT and thoracic MRI [diffusion weighted imaging (DWI)]. Each nodal station was evaluated for the presence of metastasis by applying either inclusive (positive if either one read positive) or exclusive (positive if both read positive) criteria in the combined interpretation of PET/CT and MRI. Nodal stage was confirmed pathologically. The combined diagnostic accuracy of PET/CT and MRI was determined on per-nodal station and per-patient bases and compared with that of PET/CT alone., Results: In 49 patients, 39 (19%) of 206 nodal stations harboured malignant cells. Out of 206 nodal stations, 186 (90%) had concordant readings, while the rest (10%) had discordant readings. Inclusive criteria of combined PET/CT and MRI helped increase sensitivity for detecting nodal metastasis (69%) compared with PET/CT alone (46%; P = 0.003), while specificity was not significantly decreased., Conclusion: Inclusive criteria in combined MRI and PET/CT readings help improve significantly the sensitivity for detecting nodal metastasis compared with PET/CT alone and may decrease unnecessary open thoracotomy. Key Points • Combined interpretation of MRI and PET/CT enhances the detection of nodal metastasis. • Inclusive criteria of combined MRI/PET/CT improved the sensitivity for detecting nodal metastasis. • Combined interpretation of MRI and PET/CT may reduce unnecessary open thoracotomies.

Aim: To evaluate the performance of digital tomosynthesis (DT) of the chest for detection of lung nodules in patients with colorectal cancer (CRC)., Materials and Methods: The institutional review board approved this study, and all patients provided informed consent. A commercial caesium iodide/amorphous silicon (CsI/a-Si) flat-panel detector system was used to verify the performance of the DT and chest radiography (XR) methods. DT was performed in 142 patients with CRC. All 142 patients underwent chest computed tomography (CT) within a week of DT. As a reference standard, two radiologists reviewed the chest CT in consensus and recorded the presence of pulmonary nodules. Another two radiologists independently observed the DT images and recorded the presence of pulmonary nodules. The status of all lung nodules was assessed either histologically or by follow-up over a period of 1 year. The nodules were classified into metastasis, benign, and uncertain. Statistical analysis of the results was performed., Results: Two hundred and thirty-seven nodules from 142 patients were found at CT. These included 71 proven metastases and 126 benign nodules; 40 nodules were uncertain. Observers detected 83% of all lung nodules and 93% of proven metastases using DT. Among 237 nodules, 147 nodules were larger than 4mm in diameter on the CT images. Observers detected 87% of lung nodules that were larger than 4mm., Conclusion: Despite a reasonably low radiation dose, DT is a sensitive method, and is comparable to chest CT for the detection of lung nodules, particularly metastatic lung nodules in patients with CRC., (Copyright © 2011 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Giant cell tumor (GCT) of bone has been described as the most challenging benign bone tumors. The majority of these tumors, classically, are involved in the epiphysis of long bones; however, on rare occasions, the tumors occur in the small bones of hands and feet. Although this disorder is benign, GCTs show a tendency of significant bone destruction, local recurrence and, occasionally, pulmonary metastasis. Approximately 3% of GCTs is known to metastasize to the lung. Herein, the authors describe an extremely rare case of multiple pulmonary metastatic GCTs in a 54-year-old man who presented asymptomatic pulmonary nodular lesions detected incidentally on chest x-ray of routine health checkup. He underwent chemotherapy with adriamycin and cisplatin and achieved nearly complete remission.

Inflammatory myofibroblastic tumor (IMT) is a rare tumorous lesion that presents as a solitary nodule. Complete surgical resection is the standard treatment. However, due to its rarity, the optimal therapeutic strategy for multiple IMTs has not been defined. A 32-year-old man was referred to our hospital for evaluation of multiple pulmonary nodules. On computed tomography (CT) scan of the chest, there were a 3.0 × 1.7 cm mass with heterogeneous enhancement in the left upper lobe and multiple small nodules bilaterally. We performed wedge resection of the mass, and histopathology revealed IMT. He was treated with oral corticosteroids. The clinical and radiologic responses were so excellent that a CT scan showed complete resolution 1 month after the initiation of corticosteroid therapy. These observations suggest that corticosteroids may be the way to treat bilateral multiple IMT of the lung.

We aimed to devise new CT response criteria (new response criteria, NRC) in patients with non-small cell lung cancer (NSCLC) and to evaluate the efficacy of the criteria for stratifying patient responses and predicting patient survival compared to that of the traditional size-based criteria RECIST version 1.1. Our institutional review board approved this study with a waiver of informed consent. We enrolled 80 NSCLC patients as an experimental arm and treated them with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs). Two blinded, independent radiologists assessed CT images for tumor response using the NRC, which were also validated in a separate arm (75 NSCLC patients). Tumor responses evaluated by RECIST 1.1 and the new criteria were compared from each other and correlated with patient survival. For statistical analyses, Kaplan-Meier method and kappa statistics were used. In the experimental arm (n=80), interobserver agreements for the assessment of patient response were excellent for both RECIST and NRC. Sixteen RECIST nonresponding patients achieved a designation of partial response according to NRC. In the validation arm (n=75), patients of optimal response (partial response) with the new criteria had median overall survival of 18.4 months compared with 8.5 months in patients with poor response (P=.04). However, RECIST failed to show survival difference between the two response groups. In NSCLC patients treated with EGFR-TKIs, new CT criteria reflecting additional morphological characteristics of target lesions are reproducible and have statistically significant association with overall survival., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Objective: We wanted to evaluate the usefulness of the computer-aided detection (CAD) system for detecting pulmonary nodules in real clinical practice by using the CT images., Materials and Methods: Our Institutional Review Board approved our retrospective study with a waiver of informed consent. This study included 166 CT examinations that were performed for the evaluation of pulmonary metastasis in 166 patients with colorectal cancer. All the CT examinations were interpreted by radiologists and they were also evaluated by the CAD system. All the nodules detected by the CAD system were evaluated with regard to whether or not they were true nodules, and they were classified into micronodules (MN, diameter < 4 mm) and significant nodules (SN, 4 ≤ diameter ≤ 10 mm). The radiologic reports and CAD results were compared., Results: The CAD system helped detect 426 nodules; 115 (27%) of the 426 nodules were classified as true nodules and 35 (30%) of the 115 nodules were SNs, and 83 (72%) of the 115 were not mentioned in the radiologists' reports and three (4%) of the 83 nodules were non-calcified SNs. One of three non-calcified SNs was confirmed as a metastatic nodule. According to the radiologists' reports, 60 true nodules were detected, and 28 of the 60 were not detected by the CAD system., Conclusion: Although the CAD system missed many SNs that are detected by radiologists, it helps detect additional nodules that are missed by the radiologists in real clinical practice. Therefore, the CAD system can be useful to support a radiologist's detection performance.

D2-40 is a recently developed monoclonal antibody that reacts with a 40 kDa O-linked sialoglycoprotein and has been used for the assessment of lymphatic invasion in tumor specimens. We have evaluated the diagnostic usefulness of D2-40 and association of its immunopositivity with clinicopathological parameters in adenocarcinoma and squamous cell carcinoma of the lung. We investigated 97 cases of surgically resected adenocarcinoma or squamous cell carcinoma of the lung for the determination of D2-40 positivity in tumor cells and peritumoral lymphatic vessel density (LVD) using an immunostaining method. D2-40 immunoreactivity in tumor cells was invariably negative in adenocarcinoma but 47% of squamous cell carcinomas were positive. D2-40 positivity in the tumor was significantly associated with high LVD in squamous cell carcinoma (P < 0.006). There was no significant association between peritumoral LVD and clinicopathologic parameters, including lymphatic vessel invasion, lymph node metastasis, and survival in adenocarcinoma and squamous cell carcinoma. These results suggest that D2-40 immunoreactivity in tumor cells can be used for distinguishing between adenocarcinoma and squamous cell carcinoma and that the reactivity of tumor cells with D2-40 is positively correlated with LVD in squamous cell carcinoma but not with lymph node metastasis in adenocarcinoma and squamous cell carcinoma.

Objective: The purpose of this study was to evaluate the usefulness of C-arm conebeam CT-guided percutaneous transthoracic lung biopsy of small (≤ 2 cm) lung nodules., Materials and Methods: Twenty-seven patients who underwent C-arm cone-beam CT-guided percutaneous transthoracic lung biopsy of small (≤ 2 cm) lung nodules were enrolled in the study. The mean nodule size was 13 ± 4 mm in diameter. These lesions were divided into two groups according to size: 10 lesions 1 cm or smaller and 17 lesions larger than 1 cm. The diagnostic accuracy, sensitivity, and specificity in the two groups were compared by use of Fisher's exact test. Radiation dose in a female humanoid phantom was measured with radiophotoluminescent glass dosimeters. The average patient dose was calculated., Results: Eighteen malignant (67%) and eight benign (30%) nodules and one (3%) indeterminate nodule were found. The overall sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 94%, 89%, 94%, 89%, and 92%. The sensitivity, specificity, and accuracy were 100%, 75%, and 90% for the lesions 1 cm or smaller and 91%, 100%, and 94% for the lesions larger than 1 cm. The accuracy, sensitivity, and specificity did not differ significantly between the groups (all p > 0.05, Fisher's exact test). The average radiation dose among 27 patients was 4.6 mSv (range, 2.19-9.37)., Conclusion: C-arm cone-beam CT-guided percutaneous transthoracic lung biopsy is a useful diagnostic technique in the evaluation of small lung nodules.

Objective: We wanted to compare the efficacy of the new CT response evaluation criteria for predicting the tumor progression-free survival (PFS) with that of RECIST 1.1 in non-small cell lung cancer (NSCLC) patients who were treated with bevacizumab., Materials and Methods: Sixteen patients (M:F = 11:5; median age, 57 years) treated with bevacizumab and combined cytotoxic chemotherapeutic agents were selected for a retrospective analysis. The tumor response was assessed by four different methods, namely, by using RECIST 1.1 (RECIST), RECIST but measuring only the solid component of tumor (RECISTsolid), the alternative method reflecting tumor cavitation (the alternative method) and the combined criteria (the combined criteria) that evaluated both the changes of tumor size and attenuation. To evaluate the capabilities of the different measurement methods to predict the patient prognosis, the PFS were compared, using the log rank test, among the responder groups (complete response [CR], partial response [PR], stable disease [SD] and progressive disease [PD]) in terms of the four different methods., Results: The overall (CR, PR or SD) response rates according to RECIST, RECISTsolid, the alternative method and the combined criteria were 81%, 88%, 81% and 85%, respectively. The confirmed response rates (CR or PR) were 19%, 19%, 50% and 54%, respectively. Although statistically not significant, the alternative method showed the biggest difference for predicting PFS among the three response groups (PR, SD and PD) (p = 0.07). RECIST and the alternative method showed a significant difference for predicting the prognosis between the good (PR or SD) and poor overall responders (p = 0.02)., Conclusion: The response outcome evaluations using the three different CT response criteria that reflect tumor cavitation, the ground-glass opacity component and the attenuation changes in NSCLC patients treated with bevacizumab showed different results from that with using the traditional RECIST method.

Discoidin domain receptors (DDRs) are a novel class of receptor tyrosine kinases that bind to several collagens and facilitate cell adhesion. DDR1 is involved in cancer invasion. However, very limited data are available on the aspect of clinical significance of DDR1 expression in cancer. The aim of this study was to investigate prognostic impact of DDR1 expression in non-small cell lung carcinoma (NSCLC). Tumor tissues from 171 NSCLC, including 86 squamous cell carcinomas, 69 adenocarcinomas, and 16 pure bronchioloalveolar carcinomas (BAC), were analyzed for expression of DDR1 using immunohistochemical staining. In addition, two lung adenocarcinoma cell lines (A549, H358) were transfected with two isoforms of DDR1, DDR1a and DDR1b, and then migration and invasion assays were carried out. DDR1 was expressed in 6 of 16 BAC (38%) and 95 of 155 invasive NSCLC (61%, p=0.065). DDR1 up-regulation tend to be more frequently observed in invasive adenocarcinoma (64%) compared to DDR1 expression in BAC (38%) (p=0.056). In invasive NSCLC, DDR1 expression was significantly correlated with lymph node metastasis (p=0.001). Overexpression of DDR1 in lung cancer cells resulted in a significant increase of cell motility and invasiveness (p<0.001) and the interaction of DDR1 with collagen facilitates the invasiveness of NSCLC cells. DDR1 overexpression produced an activation of MMP-9 in H358 cells. In conclusion, these findings indicate that up-regulation of DDR1 may contribute to the progression and poor prognosis of NSCLC and this effect may be associated with increased invasiveness.

Background: The Response Evaluation Criteria in Solid Tumors (RECIST) has been revised (RECIST 1.1) since initial publication of RECIST 1.0 in 2000. Major changes in RECIST 1.1 involve lymph node measurement, the maximum number of target lesions, and the definition of disease progression (PD). The purpose of this study was to evaluate the accuracy of RECIST 1.1 for non-small cell lung cancer (NSCLC) patients being treated with epidermal growth factor receptor tyrosine kinase inhibitors (TKIs)., Patients and Methods: We compared responses of 104 NSCLC patients treated with TKIs from eight prospective studies using RECIST 1.0 and 1.1., Results: The short axis measurement for lymph nodes was the most influential change in RECIST 1.1 for the evaluation of response. Overall response rates (ORRs) using RECIST 1.0 and 1.1 were 35.6% and 38.5%, respectively. Under RECIST 1.1, six best responses were reclassified: two partial responses (PR) were re-categorized as complete responses, three cases of stable disease (SD) were reclassified as PR, and one case of SD was reclassified as PD. The progression-free survivals of three patients were extended. RECIST 1.1 showed a slightly increased ORR compared with RECIST 1.0., Conclusion: RECIST 1.1 may reflect tumor burden more accurately than RECIST 1.0 in NSCLC patients treated with TKIs., (Copyright 2009 Elsevier Ireland Ltd. All rights reserved.)

Objective: To evaluate the relationship between a computed tomographic reconstruction kernel and the sensitivity of a computer-aided detection (CAD) system for lung nodule detection., Methods: We retrospectively studied 36 consecutive patients with no known pulmonary nodules who underwent low-dose computed tomography for lung cancer screening with 3 different reconstruction kernels (B, C, and L). All series were reviewed with a commercial CAD system for lung nodule detection., Results: The 36 scans showed 231 uncalcified nodules (170 micronodules and 61 nodules). There was little variation of sensitivities for each series (82%, 88%, and 82% for the nodules of B, C, and L, respectively). When the results of 2 series were combined, sensitivities were boosted (B + C, 89%; B + L, 95%; and C + L, 96% for the nodules)., Conclusions: Sensitivity of the CAD system was influenced by the selection of the reconstruction kernel. By combining data from 2 different kernels, CAD sensitivity can be elevated without further patient radiation exposure.