Joung-Ho Han

Prediction of Recurrence-Free Survival in Postoperative Non–Small Cell Lung Cancer Patients by Using an Integrated Model of Clinical Information and Gene Expression

Purpose: One of the main challenges of lung cancer research is identifying patients at high risk for recurrence after surgical resection. Simple, accurate, and reproducible methods of evaluating individual risks of recurrence are needed. Experimental Design: Based on a combined analysis of time-to-recurrence data, censoring information, and microarray data from a set of 138 patients, we selected statistically significant genes thought to be predictive of disease recurrence. The number of genes was further reduced by eliminating those whose expression levels were not reproducible by real-time quantitative PCR. Within these variables, a recurrence prediction model was constructed using Cox proportional hazard regression and validated via two independent cohorts (n = 56 and n = 59). Results: After performing a log-rank test of the microarray data and successively selecting genes based on real-time quantitative PCR analysis, the most significant 18 genes had P values of <0.05. After subsequent stepwise variable selection based on gene expression information and clinical variables, the recurrence prediction model consisted of six genes (CALB1, MMP7, SLC1A7, GSTA1, CCL19, and IFI44). Two pathologic variables, pStage and cellular differentiation, were developed. Validation by two independent cohorts confirmed that the proposed model is significantly accurate (P = 0.0314 and 0.0305, respectively). The predicted median recurrence-free survival times for each patient correlated well with the actual data. Conclusions: We have developed an accurate, technically simple, and reproducible method for predicting individual recurrence risks. This model would potentially be useful in developing customized strategies for managing lung cancer.

Persistent pure ground-glass opacity lung nodules ≥ 10 mm in diameter at CT scan: histopathologic comparisons and prognostic implications.

BACKGROUND Little is known about the histopathology and prognosis of persistent pure ground-glass opacity nodules (GGNs) of ≥ 10 mm in diameter. We aimed to compare the morphologic features of persistent pure GGNs of ≥ 10 mm in diameter at thin-section CT (TSCT) scan with histopathology and patient prognosis. METHODS A total of 46 resected GGNs that were evaluated with TSCT scan and followed up for ≥ 3 years were included in this study. Correlations between histopathology (adenocarcinoma in situ [AIS], minimally invasive adenocarcinoma [MIA], and invasive adenocarcinoma) and CT scan characteristics were examined. CT scan and clinicodemographic data were investigated by univariate and multivariate analyses to identify features that helped distinguish invasive adenocarcinoma from AIS or MIA. Disease recurrence was also evaluated. RESULTS The nodules included 19 AISs (41%), nine MIAs (20%), and 18 invasive adenocarcinomas (39%). On univariate analysis, the presence of air bronchogram (P = .012), size of nodule (P = .032, cutoff = 16.4 mm in diameter), and mass of nodule (P = .040, cutoff = 0.472 g) were significant factors that differentiated invasive adenocarcinoma from AIS or MIA. On multivariate analysis, size (P = .010) and mass of nodule (P = .016) were significant determinants for invasive adenocarcinoma. There were no cases of recurrence during a follow-up period of ≥ 3 years after surgical resection. CONCLUSIONS In persistent pure GGNs of ≥ 10 mm in diameter, the size and mass of the nodule are determinants of invasive adenocarcinoma, for which surgical resection leads to excellent prognosis.

Pure Ground-Glass Opacity Neoplastic Lung Nodules: Histopathology, Imaging, and Management

OBJECTIVE The purpose of this article is to discuss histologic diagnosis of pure pulmonary ground-glass opacity nodules (GGNs), high-resolution CT (HRCT) findings and pathologic correlation, and management. CONCLUSION When pure GGNs are greater than 15 mm in diameter with nodularity or have high pixel attenuation (>-472 HU), the nodules are more likely to be invasive adenocarcinomas. Sublobar resection with a secured safety margin and without nodal dissection is performed for HRCT-suggested pure-GGN invasive adenocarcinomas and has a 100% 5-year survival rate.

Repeated derecruitments accentuate lung injury during mechanical ventilation.

OBJECTIVES The aim of our study was to assess whether repeated derecruitments induced by the repetitive withdrawal of high positive end-expiratory pressure could induce lung injury in a swine model. DESIGN Prospective, randomized, experimental animal study. SETTING University laboratory. SUBJECTS Specific pathogen-free pigs (Choong-Ang Laboratory Animals, Seoul, Korea) weighing around 30 kg. INTERVENTIONS After lung injury was induced by repeated saline lavage, pigs were ventilated in pressure-limited mode with the highest possible positive end-expiratory pressure with a tidal volume of 8 mL/kg and maximum inspiratory pressure of 30 cm H2O. With this initial ventilator setting, the control group (n = 5) received ventilation without derecruitments for 4 hours, and in the derecruitment group (n = 5), derecruitments were repeatedly induced by intentional disconnection of the ventilatory circuit for 30 seconds every 5 minutes for 4 hours. MEASUREMENTS AND MAIN RESULTS After the initial increase in positive end-expiratory pressure, the PaO2 increased to greater than 450 mm Hg in both groups. The PaO2 remained at greater than 450 mm Hg in the control group persistently, but in the derecruitment group, PaO2 significantly decreased to 427.7 mm Hg (adjusted p = 0.03) after 2 hours and remained significant for the rest of the study. PaCO2, oxygenation index, and alveolar-arterial oxygen gradient also significantly increased after 2 hours compared with the control group. However, the variables of respiratory mechanics except for minute volume at 2-hour point showed no difference between the two groups for the duration of the study. Histologically, significant bronchiolar injury was observed in the dependent portion of the derecruitment group compared with the controls (p = 0.03), but not in the nondependent area of the lung. CONCLUSIONS Repeated derecruitments exacerbated lung injury, particularly at the bronchiolar level in the dependent portion. Strategies to minimize this type of injury should be incorporated when designing optimal ventilator strategies in acute respiratory distress syndrome patients.Objectives:The aim of our study was to assess whether repeated derecruitments induced by the repetitive withdrawal of high positive end-expiratory pressure could induce lung injury in a swine model. Design:Prospective, randomized, experimental animal study. Setting:University laboratory. Subjects:Specific pathogen-free pigs (Choong–Ang Laboratory Animals, Seoul, Korea) weighing around 30 kg. Interventions:After lung injury was induced by repeated saline lavage, pigs were ventilated in pressure-limited mode with the highest possible positive end-expiratory pressure with a tidal volume of 8 mL/kg and maximum inspiratory pressure of 30 cm H2O. With this initial ventilator setting, the control group (n = 5) received ventilation without derecruitments for 4 hours, and in the derecruitment group (n = 5), derecruitments were repeatedly induced by intentional disconnection of the ventilatory circuit for 30 seconds every 5 minutes for 4 hours. Measurements and Main Results:After the initial increase in positive end-expiratory pressure, the PaO2 increased to greater than 450 mm Hg in both groups. The PaO2 remained at greater than 450 mm Hg in the control group persistently, but in the derecruitment group, PaO2 significantly decreased to 427.7 mm Hg (adjusted p = 0.03) after 2 hours and remained significant for the rest of the study. PaCO2, oxygenation index, and alveolar-arterial oxygen gradient also significantly increased after 2 hours compared with the control group. However, the variables of respiratory mechanics except for minute volume at 2-hour point showed no difference between the two groups for the duration of the study. Histologically, significant bronchiolar injury was observed in the dependent portion of the derecruitment group compared with the controls (p = 0.03), but not in the nondependent area of the lung. Conclusions:Repeated derecruitments exacerbated lung injury, particularly at the bronchiolar level in the dependent portion. Strategies to minimize this type of injury should be incorporated when designing optimal ventilator strategies in acute respiratory distress syndrome patients.

Imaging of Pulmonary Vasculitis

The presence of pulmonary vasculitis can be suggested by a clinical presentation that includes diffuse pulmonary hemorrhage, acute glomerulonephritis, chronic refractory sinusitis or rhinorrhea, imaging findings of nodules or cavities, mononeuritis multiplex, multisystemic disease, and palpable purpura. Serologic tests, including the use of cytoplasmic antineutrophil cytoplasmic antibody (ANCA) and perinuclear ANCA, are performed for the differential diagnosis of the diseases. A positive cytoplasmic ANCA test result is specific enough to make a diagnosis of ANCA-associated granulomatous vasculitis if the clinical features are typical. Perinuclear ANCA positivity raises the possibility of Churg-Strauss syndrome or microscopic polyangiitis. Imaging findings of pulmonary vasculitis are diverse and often poorly specific. The use of a pattern-based approach to the imaging findings may help narrow the differential diagnosis of various pulmonary vasculitides. Integration of clinical, laboratory, and imaging findings is mandatory for making a reasonably specific diagnosis.

Comprehensive analysis of RET and ROS1 rearrangement in lung adenocarcinoma

The success of crizotinib in ALK-positive patients has elicited efforts to find new oncogenic fusions in lung cancer. These efforts have led to the discovery of novel oncogenic fusion genes such as ROS1 and RET. However, the molecular and clinicopathologic characteristics associated with RET or ROS1 fusion, compared with ALK fusion-positive lung cancer, remain unclear. We accordingly analyzed the clinicopathologic characteristics of RET- and ROS1-fusion-positive lung adenocarcinomas. We further performed immunohistochemistry and fluorescence in situ hybridization analysis (FISH) in 15 cases of RET and 9 cases of ROS1 fusion tumors by identified NanoString’s nCounter screening. RET fusion-positive patients were younger in age, never-smokers, and in early T stage; ROS1 fusion-positive patients had a higher number of never-smokers compared with patients with quintuple-negative (EGFR−/KRAS−/ALK−/ROS1−/RET−) lung adenocarcinoma. Histologically, RET and ROS1 fusion tumors share the solid signet-ring cell and mucinous cribriform pattern, as previously mentioned in the histology of ALK fusion tumors. Therefore, it can be presumed that fusion gene-associated lung adenocarcinomas share similar histologic features. In immunohistochemistry, the majority of 15 RET and 9 ROS1 fusion-positive cases showed positivity of more than moderate intensity and cytoplasmic staining for RET and ROS1 proteins, respectively. In FISH, the majority of RET and ROS1 rearrangement showed two signal patterns such as one fusion signal and two separated green and orange signals (1F1G1O) and an isolated 3′ green signal pattern (1F1G). Our study has provided not only characteristics of fusion gene-associated histologic features but also a proposal for a future screening strategy that will enable clinicians to select cases needed to be checked for ROS1 and RET rearrangements based on clinicohistologic features.

Downregulation of cell-free miR-198 as a diagnostic biomarker for lung adenocarcinoma-associated malignant pleural effusion.

Circulating cell‐free microRNAs (miRNAs) are potential cancer biomarkers. The aim of this study was to identify miRNAs that are differentially expressed between benign pleural effusion (BPE) and lung adenocarcinoma‐associated malignant pleural effusion (LA‐MPE). The expression level of cell‐free miRNA was investigated in 107 patients with pleural effusion. Microarrays were used to screen 160 miRNAs in a discovery set comprising 20 effusion samples (ten BPEs and ten LA‐MPEs). Real‐time quantitative reverse transcription polymerase chain reaction (qRT‐PCR) was used to validate the profiling results obtained for the discovery set and those obtained for a validation set comprising 42 BPEs and 45 LA‐MPEs. The area under the receiver operating characteristic curve (AUC) was used to evaluate the diagnostic performance of the identified miRNAs and other common tumor markers, such as carcinoembryonic antigen (CEA) and cytokeratin fragment (CYFRA) 21‐1. Microarray profiling showed that miR‐198 was significantly downregulated in LA‐MPE compared with BPE (p = 0.002). The miRNA microarray analysis results were confirmed by qRT‐PCR (p < 0.001) using the validation set. The AUCs for miR‐198, CEA and CYFRA 21‐1 in the validation set were 0.887, 0.898 and 0.836, respectively. The diagnostic performance of miR‐198 was comparable with that of CEA, but better than that of CYFRA 21‐1. The AUC for all three markers combined was 0.926 (95% confidence interval, 0.843–0.973) with a sensitivity of 89.2% and a specificity of 85.0%. The present study suggests that cell‐free miR‐198 from patients with pleural effusion might have diagnostic potential for differentiating LA‐MPE from BPE.

Is the addition of choleretic agents in multiple double-pigtail biliary stents effective for difficult common bile duct stones in elderly patients? A prospective, multicenter study

BACKGROUND Temporary biliary stenting is both technically easy and feasible, and choleretic agents such as ursodeoxycholic acid (UDCA) and a terpene preparation may promote a reduction in stone size. However, there are few comparative data on the effectiveness of choleretic agents available. OBJECTIVE To investigate the efficacy of multiple double-pigtail stents with or without UDCA and terpene on difficult common bile duct (CBD) stones. DESIGN A prospective, multicenter study. SETTING Four tertiary-care referral centers. PATIENTS This study involved 51 patients. INTERVENTION In total, 51 elderly patients with comorbidities who had difficult CBD stones refractory to conventional methods were randomized to receive either multiple 7F double-pigtail stents (group A) or stents in combination with UDCA and terpene (group B) for a period of 6 months. MAIN OUTCOME MEASUREMENTS Stone size reduction, successful duct clearance, and complications. RESULTS Complete endoscopic duct clearance was achieved in 14 patients (73.7%) in group A and 19 patients (86.4%) in group B (P = .826). The mean size of CBD stones (transverse/longitudinal diameter, mean ± SD) was 19.12 ± 4.48 mm/20.47 ± 3.86 mm in group A and 21.30 ± 7.08 mm/22.58 ± 7.61 mm in group B. Stone size decreased significantly to 12.04 ± 3.26 mm/13.31 ± 5.12 mm and 13.67 ± 5.40 mm/14.04 ± 6.12 mm, respectively (P < .01). However, there was no statistical difference in stone size reduction between the two groups (P = .685, P = .289). No serious complications related to the stent or endoscopic procedures were observed, except for cholangitis (n = 1, group A) and distal stent migration (n = 2, group B). LIMITATIONS Small number of patients in East Asia. CONCLUSION Temporary multiple double-pigtail biliary stenting was a safe and feasible method of treating difficult and large CBD stones in elderly patients and contributed to a reduction in stone size and successful duct clearance. However, the addition of choleretic agents did not result in a statistical difference in stone size or rate of successful duct clearance.

Solitary Pulmonary Nodular Lung Adenocarcinoma: Correlation of Histopathologic Scoring and Patient Survival with Imaging Biomarkers

PURPOSE To evaluate the usefulness of histopathologic scoring for survival prediction in patients with solitary pulmonary nodular (SPN) lung adenocarcinomas and to correlate the histopathologic scoring with the results of computed tomography (CT) and fluorine 18 fluorodeoxyglucose positron emission tomography (PET)/CT. MATERIALS AND METHODS This retrospective study was institutional review board approved and the requirement for informed consent was waived. A total of 148 patients with SPN lung adenocarcinoma underwent PET/CT and CT. Correlations between histopathologic scores estimated by using two predominant histologic subtypes from each surgically resected specimen and the mass of the nodule at CT or maximum standardized uptake value (SUV(max)) at PET/CT were assessed. Disease-free survival (DFS) was estimated by using the Kaplan-Meier method, and the log-rank test was used to evaluate differences in each histopathologic subtype. RESULTS In 135 (91%) patients, tumors had a mixed subtype. The most frequently observed histologic subtypes, in decreasing order, were acinar (51%), lepidic (18%), solid (10%), and papillary (9%). DFS rates at 5 years were higher than 90% for the group of patients with nodules that showed the lepidic growth pattern, and 50% for patients with nodules that showed the micropapillary pattern. The pathologic score proved to be a significant predictor of DFS (P < .001). Both SUV(max) and the mass of the nodule were closely correlated with pathologic score. CONCLUSION Pathologic scoring appears to help predict DFS in patients with SPN lung adenocarcinoma and shows close correlation with imaging biomarkers including the mass of the nodule at CT and SUV(max) at PET/CT.

High-Resolution CT Findings in Fibrotic Idiopathic Interstitial Pneumonias With Little Honeycombing: Serial Changes and Prognostic Implications

OBJECTIVE This retrospective study evaluates serial changes of lung abnormalities on high-resolution CT (HRCT) and clarifies prognostic determinants among CT findings in fibrotic idiopathic interstitial pneumonias (IIPs) with little honeycombing. MATERIALS AND METHODS We enrolled 154 patients with a histologic diagnosis of a fibrotic IIP (< 5% honeycombing on CT) who were followed clinically for at least 2 years. One hundred one patients had usual interstitial pneumonia (UIP) and 53 had fibrotic nonspecific interstitial pneumonia (NSIP). On baseline CT, the extent and distribution of lung abnormalities were visually assessed, and serial CT scans were evaluated with a follow-up period of at least 6 months (n = 132). RESULTS Significant differences were noted in the extent of reticulation and ground-glass opacification (GGO) between the UIP and fibrotic NSIP groups (p < 0.001). On serial scans, honeycombing (5% in UIP and 3% in fibrotic NSIP; p = 0.08) and reticulation (3% in UIP and 8% in fibrotic NSIP; p = 0.03) progressed in extent and GGO (-2% in UIP and -10% in fibrotic NSIP; p = 0.009) decreased in extent. Overall extent of lesions increased in UIP (6%) and decreased in NSIP (-4%) (p = 0.04). On univariate and multivariate Cox proportional hazards analysis, the overall extent of parenchymal abnormalities was a prognostic factor predictive of poor survival duration. CONCLUSION Even in cases of fibrotic IIP with little honeycombing, serial CT reveals an increase in the extent of honeycombing and reticulation and a decrease in extent of GGO. Overall extent of lung fibrosis on the baseline CT examination appears predictive of survival in fibrotic IIP with little honeycombing.