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Background The eighth edition of nodal classification for non-small cell lung cancer (NSCLC) is defined only by the anatomical location of metastatic lymph nodes. Research Question We sought to evaluate the prognostic significance and discriminatory capability of the number of involved nodal stations (nS) in a large Chinese cohort. Study Design and Methods A total of 4,011 patients with NSCLC undergoing surgical resection between 2009 and 2013 were identified. The optimal cutoff values for nS classification were determined with X-tile software. Kaplan-Meier and multivariate Cox analysis were used to examine the prognostic performance of nS classification in comparison with location-based N classification. A decision curve analysis was performed to evaluate the standardized net benefit of nS classification in predicting prognosis. Results All the patients were classified into four prognostically different subgroups according to the number of involved nodal stations: (1) nS0 (none positive), (2) nS1 (one involved station), (3) nS2 (two involved stations), and (4) nS ≥ 3 (three or more involved stations). The prognoses among all the neighboring categories of nS classification were statistically significantly different in terms of disease-free survival and overall survival. The multivariate Cox analysis demonstrated that nS was an independent prognostic factor of disease-free survival and overall survival. Patients with N1 or N2 stage disease could be divided into three prognostically different subgroups according to nS classification. However, the prognosis was similar between the N1 and N2 subgroups when patients were staged in the same nS category. The decision curve analysis showed that nS classification tended to have a higher predictive capability than location-based N classification. Interpretation The nS classification could be used to provide a more accurate prognosis for patients with resected NSCLC. The nS is worth taking into consideration when defining nodal category in the forthcoming ninth edition of the staging system.

Our study aimed to validate the clinicopathological characteristics and prognosis of lung adenocarcinoma (ADC) with a filigree pattern and to further investigate the relationship between the filigree pattern and the classical micropapillary (MP) pattern. We retrospectively reviewed the clinical and pathologic characteristics of 461 Chinese patients with completely resected ADC (stage I, 310; stage II, 44; stage III, 107). The filigree pattern was more likely to be observed in ADC with a higher stage (p = 0.003) and the classical MP pattern (p < 0.001). Patients with filigree-predominant ADC showed poor survival, similar to those with classical MP-predominant ADC. Multivariate analysis confirmed that the presence of the filigree pattern was an independent prognostic factor for recurrence-free survival (hazard ratio (HR), 2.01; 95% confidence interval (CI), 1.50-2.68; p < 0.001) and overall survival (OS; HR, 1.83; 95% CI, 1.34-2.50; p < 0.001). Patients with both classical MP-positive and filigree-positive ADC had the worst survival compared with those with the filigree pattern or classical MP pattern alone. In stage I, ADC with both the filigree and classical MP patterns had a higher incidence of micrometastasis than ADC with the filigree pattern or classical MP pattern alone. Lymph node micrometastasis indicated poor survival in patients with ADC with the filigree pattern or classical MP pattern. Similar clinicopathologic features between patients with the filigree pattern and the classical MP pattern support the inclusion of the filigree pattern in the MP category. Recognition of the filigree pattern could provide helpful prognostic information, especially for stage I ADC.

Background Invasive adenocarcinoma intraoperatively underestimated as adenocarcinoma in situ (AIS) or minimally invasive adenocarcinoma (MIA) based on frozen section (FS) is more likely to undergo insufficient resection. We aimed to investigate the predictors of upstage and treatment strategies for stage IA invasive adenocarcinoma after sublobar resection for AIS and MIA. Methods We identified 2,006 patients from January 2012 to December 2016 with early-stage lung adenocarcinoma who underwent sublobar resection based on FS diagnosis to guide surgical decision-making. All FS were categorized into three groups in real-time: (I) atypical adenomatous hyperplasia (AAH), (II) AIS, and (III) MIA. Results A total of 272 (13.5%, 272/2,006) cases were upstaged in the final pathology (FP) diagnosis (82 AAH to AIS, 127 AIS to MIA, and nine AIS and 54 MIA to invasive adenocarcinoma), and most upstage cases (64.3%, 175/272) were attributed to sampling error. Multivariate logistic regression showed that tumor size ≥1 cm was the only independent predictor of upstage. The upstage of 209 cases to AIS or MIA had no influence on the therapy because the extent of their resection was enough. Of the 63 cases upstaged to invasive adenocarcinoma, only 13 cases agreed to receive complementary treatment: five patients underwent complementary lobectomy, and seven patients received chemotherapy. Two invasive adenocarcinoma cases without complementary treatment experienced a local recurrence after surgery. No recurrence was observed in AAH, AIS and MIA. No patient died until December 01, 2019. Conclusions Timely complementary treatment is encouraged in AIS/MIA upstaged to invasive adenocarcinoma based on the FP after sublobar resection to avoid local recurrence. Pathologists should be more cautious about AIS and MIA with tumor size ≥1 cm to avoid underestimation and potentially insufficient resection.

Objectives There is still some dispute regarding the performance of limited mediastinal lymphadenectomy (LML) even for lung adenocarcinoma ≤ 2 cm. We aimed to recognize the potential candidates who can benefit from LML based on the percentage of histological components (PHC). Methods We analyzed 1160 surgical patients with invasive lung adenocarcinoma ≤ 2 cm from seven institutions between January 2012 and December 2015. All histological subtypes were listed in 5% increments by pathological slices. To test the accuracy of frozen section in judging PHC, frozen section slides from 140 cases were reviewed by three pathologists. Results There were 882 patients with systematic mediastinal lymphadenectomy (SML) and 278 with LML. Multivariable analysis indicated that, the total percentage of micropapillary and solid components (PHCMIP+S) > 5 % was the independent predictor of N2 metastasis (P 5 % (RFS, HR = 2.143, P Conclusions PHCMIP+S showed the predictive value for N2 metastasis and procedure-specific outcome (LML vs. SML). It may serve as a feasible indicator for identifying proper candidates of LML by using intraoperative frozen section.

OBJECTIVES The aim of the study was to investigate the relationship between ground-glass opacity (GGO) and tumour spread through air space (STAS), as well as their joint influence on the prognosis of stage I lung adenocarcinoma. METHODS A total of 620 consecutive patients with surgically resected lung adenocarcinoma between January 2011 and December 2012 were reviewed retrospectively. The relevance of STAS and GGO was analysed by logistic regression, and their prognostic significance was investigated via the Kaplan–Meier method and Cox regression models. Furthermore, to determine the magnitude of the prognostic impact of GGO and STAS, we respectively performed survival analysis in subgroups according to the presence of STAS and GGO. RESULTS Of all 620 cases, 26.7% were positive for STAS, and 32.9% had a GGO component. STAS was present in 10.8% of part-solid lesions and 34.9% of pure solid nodules (P CONCLUSIONS STAS is associated with a GGO component, and each factor was a significant predictor for the prognosis of stage I lung adenocarcinoma. Moreover, the favourable prognostic impact of a GGO component was greater than the adverse prognostic influence of STAS, indicating that GGO is a more reliable prognostic predictor in stage I lung adenocarcinoma.

OBJECTIVES As evidence has proven that sublobar resection is oncologically contraindicated by tumour spread through air spaces (STAS), its preoperative recognition is vital in customizing surgical strategies. We aimed to assess the value of radiomics in predicting STAS in stage I lung adenocarcinoma. METHODS We retrospectively reviewed the patients with stage I lung adenocarcinoma, who accepted curative resection in our institution between January 2011 and December 2013. Using ‘PyRadiomics’ package, 88 radiomics features were extracted from computed tomography (CT) images and a prediction model was consequently constructed using Naïve Bayes machine-learning approach. The accuracy of the model was assessed through receiver operating curve analysis, and the performance of the model was validated both internally and externally. RESULTS A total of 233 patients were included as the training cohort with 69 (29.6%) patients being STAS (+). Patients with STAS had worse recurrence-free survival and overall survival (P CONCLUSIONS CT-based radiomics is valuable in preoperatively predicting STAS in stage I lung adenocarcinoma, which may aid surgeons in determining the optimal surgical approach.

Background The long noncoding RNA cancer susceptibility 9 (CASC9) has been recognized as an important modulator of cell growth and metastasis in many cancers. However, its detailed roles in lung cancer remain unclear. In this study, we aimed to investigate its functions and molecular mechanism in lung cancer progression. Methods Expression of CASC9 was determined in lung cancer tissues and cell lines by real-time PCR. CCK-8, colony formation, wound healing and transwell assays were done to evaluate the cell proliferation, migration and invasion capacities in vitro. Real-time PCR, Western blot and RNA immunoprecipitation (RIP) assays were performed to dissect the mechanisms. Results CASC9 was overexpressed in lung cancer specimens and cell lines. Knockdown of CASC9 inhibited cell proliferation, migration, invasion and EMT in lung cancer cells. While overexpression of CASC9 in normal lung epithelial cells did the opposite. CASC9 interacted with HIF-1α and enhanced its protein stability. They formed a positive feedback loop by reciprocally inducing each other expression and regulated cell proliferation and metastasis. Conclusion Our findings demonstrated a novel regulatory signaling pathway, namely the CASC9/HIF-1α axis, which was involved in lung cancer progression. These findings can provide valuable insights on the potential therapy application for lung cancer.

This study aimed to clarify differences in the prognostic impact of tumor spread through air spaces (STAS) in lobectomy versus sublobar resection (SR). The study also investigated the frequency and significance of STAS in residual lung segments. This study identified 752 patients with p-stage 1A non-small cell lung cancer (NSCLC) from 2010 to 2012. Recurrence-free survival (RFS) and overall survival (OS) were compared. For proactive simulation of SR, 100 consecutive lobectomy specimens of p-stage 1A NSCLC were selected. The study found STAS in 182 (28.7%) of 634 lobectomy cases and 43 (36.4%) of 118 SR cases. Multivariable analysis showed that STAS was not a prognostic factor in the lobectomy group, but showed a significantly worse prognostic effect for the SR group (RFS, P

The behavior of the pathological subtypes of tracheal glomus tumor (benign, uncertain malignant potential UMP, malignant) is vague. In a 51-year-old gentleman, suffering from cough for 4 months, computed tomography scan showed a mass at lower third of the trachea and the bronchoscope revealed exophytic mass at the tracheal lumen. Segmental tracheal resection was done using special modified endotracheal tube for the distal lung ventilation. The tracheal glomus tumor was also diagnosed based on the immunohistochemical staining. The tumor was 2 cm in diameter, deeply located, mitotic phase was difficult to identify, and a diagnosis of UMP subtype was made. There was no recurrence after 2 years follow-up. This is the first reported case of UMP subtype in lower trachea and we studied the treatment options with the clinic-pathological behavior of this tumor and its sequel by regular follow-up.

BackgroundTumor spread through air spaces (STAS) has three morphologic subtypes: single cells, micropapillary clusters, and solid nests. However, whether their respective clinical significance is similar remains unclear.MethodsWe retrospectively reviewed 803 patients with resected non-small cell lung cancer (NSCLC) from January to December 2009. Recurrence-free survival (RFS) and overall survival (OS) were compared among patients stratified by STAS subtypes. We also performed a prospective study of NSCLC resection specimens to evaluate the influence of a prosecting knife on the presence of STAS subtypes during specimen handling (83 cases).ResultsSTAS was found in 370 NSCLCs (46%), including 47 single cell STAS (13%), 187 micropapillary cluster STAS (50%), and 136 solid nest STAS (37%). STAS-negative patients had significantly better survival than patients with micropapillary cluster STAS (RFS: P < 0.001; OS: P < 0.001) and solid nest STAS (RFS: P < 0.001; OS: P < 0.001), but similar survival compared with those with single cell STAS (RFS: P = 0.995; OS: P = 0.71). Multivariate analysis revealed micropapillary cluster (RFS: P < 0.001; OS: P < 0.001) and solid nest STAS (RFS: P = 0.001; OS: P = 0.003) to be an independent prognostic indicator, but not for single cell STAS (RFS: P = 0.989; OS: P = 0.68). Similar results were obtained in subgroup analysis of patients with adenocarcinoma. The prospective study of NSCLC specimens suggested that 18 cases were considered as STAS false-positive, and most were singe cell pattern (13/18, 72%).ConclusionsSingle cell STAS was the common morphologic type of artifacts produced by a prosecting knife. A precise protocol of surgical specimen handling is required to minimize artifacts as much as possible.

Objective To compare the baseline clinical characteristics between patients with ROS1-positive and ALK-positive advanced non-small cell lung cancer (NSCLC), and the correlations of these subtypes with the distribution of metastases. Methods We compared the clinical characteristics and imaging features of patients with ROS1-positive and ALK-positive NSCLC using statistical methods. Results Data for 232 patients were analyzed. Compared with ALK-positive NSCLC, ROS1-positive NSCLC was more likely to occur in women (71% vs 53%), and primary lesions ≤3 cm were more common in patients with ROS1-positive compared with ALK-positive NSCLC (58% vs 37%). There was no significant difference in the distribution of metastases between the two groups. Subgroup analysis within the ROS1-positive group showed that, compared with primary lesions >3 cm, primary lesions ≤3 cm were more likely to present as peripheral tumors (72% vs 43%) and more likely to exhibit non-solid density (44% vs 4%). Conclusions Although ROS1-positive and ALK-positive NSCLCs show similar clinical features, the differences may help clinicians to identify patients requiring further genotyping at initial diagnosis.

Radiation resistance is linked to immune escaping and radiation sensitivity. In this study, we found that the PD-L1 expressions of non-killed tumor cells in NSCLC were enhanced after radiotherapy, and dihydroartemisinin (DHA) could synergistically enhance the antitumor effect of radiotherapy in NSCLC. A total of 48 NSCLC patients with sufficient tumor tissues for further analyses were enrolled. The PD-L1 expressions of NSCLC were evaluated by immunohistochemistry. Cell apoptosis was measured by flow cytometry, and the relationship between the PD-L1 expression and radiation resistance was investigated in patient specimens, xenograft model, and cell lines. First, the results indicate that the PD-L1 expression of NSCLC was positively related with the radiation resistance. Second, we found that DHA could eliminate the radiation resistance and synergistically enhance the antitumor effect of radiotherapy in the NSCLC cells lines and xenograft model. Finally, mechanistically, DHA could inhibit the PD-L1 expression to avoid immune escaping by inhibiting TGF-β, PI3K/Akt, and STAT3 signaling pathways. In addition, DHA could activate TRIM21 and regulate the EMT-related proteins by inhibiting the PD-L1 so as to enhance the radiation sensitivity and eliminate radiation resistance to NSCLC. Collectively, this study established a basis for the rational design of integrated radiotherapy and DHA for the treatment of NSCLC.

Background In this study, we investigated the prognostic significance of a micropapillary (MP) component in patients with subcentimeter lung adenocarcinoma. Methods A total of 311 patients with subcentimeter lung adenocarcinoma who underwent surgical resection between January 2009 to December 2012 from seven medical centers were included. Recurrence‐free survival (RFS) and overall survival (OS) were analyzed. Results The five‐year RFS was 79.8% in 97 (97/311, 31%) cases of adenocarcinoma with a MP component and 93.5% in the 214 (214/311, 69%) cases without. In multivariate analysis, MP was an independent risk factor for worse RFS (hazard ratio [HR], 3.73; 95% confidence interval [CI]: 1.87–7.42; P, Presence of a micropapillary component in subcentimeter lung cancer indicated that anatomical resection should be performed instead of wedge resection.

Background Light chain deposition disease (LCDD) is a systemic disorder typically characterized by non-amyloid monoclonal immunoglobulin light chain deposition in tissues. LCDD is recognized as a multisystem disease, in which the kidneys and liver are often affected. However, it is rarely encountered as a localized pulmonary disease. This study set out to characterize the clinical manifestations and features of pulmonary light-chain deposition disease (PLCDD) by conducting a retrospective analysis of clinical data obtained from patients, with the aim of improving clinical understanding of PLCDD. Methods Data from inpatients diagnosed with PLCDD at Shanghai Pulmonary Hospital (Shanghai, China) between January 2010 and December 2018 were retrospectively collected and analyzed. Results A total of 4 PLCDD patients confirmed with PLCDD by pulmonary tissue biopsy were analyzed. All of the patients were female and were found by physical examination. Chest images of each patient's lungs showed multiple cystic cavities with nodules. A history of Sjogren's syndrome was present with 1 patient, 2 patients were diagnosed with Sjogren's syndrome after surgery (including 1 diagnosed with Sjogren's syndrome in the 8th year of follow up), and 3 patients had leukopenia. The longest follow-up period was 8 years. During the follow-up period, 2 patients developed pulmonary lesions (1 patient had an enlarged original cystic lesion in basal segment of right lower lobe 2 years after surgery, while the other developed new nodules 7 years after surgery). Conclusions PLCDD is characterized by multiple cystic changes with nodules in both lungs and can be easily complicated by lymphoid diseases such as Sjogren's syndrome. The clinical symptoms cannot be characterized, and the diagnosis depends on lung biopsy.

Objective Whether TEAD4 itself plays a vital role in the tumorigenesis and development of lung adenocarcinoma remains unclear. In our study, we aim to investigate the expression pattern and biological functions of TEAD4 and further investigate the potential mechanisms. Methods Clinical tumor and paired normal samples were collected for preparing tissue microarray. Western blot and immunohistochemical (IHC) staining of TEAD4 expression in these tissues were conducted to explore the expression pattern. Moreover, A549 cell line was select for investigating the function of TEAD4 for lung adenocarcinoma in vitro and in vivo. RNA sequencing was finally performed to further detect the potential downstream genes. Results The elevated TEAD4 expression level was observed in tumor tissues and the patients with higher TEAD4 expression tended to have worse overall survival. The knockdown of TEAD4 inhibits A549 cells proliferation ability and migration ability. A total of 431 differentially expressed genes (DEGs), including 239 down-regulated genes and 191 up-regulated genes, were finally identified and some of DEGs were validated. Moreover, knockdown of TEAD4 led to the down-regulation of pERK, which maybe the potential TEAD4-targeted signaling pathway to play the pro-tumorigenic function. Conclusions The expression level of TEAD4 is high in lung adenocarcinoma tumor tissues and positively associated with worse prognosis. Up-regulation of TEAD4 may lead to excessive transcription and phosphorylation of ERK proteins and therefore accelerates the process of tumor development. Our results demonstrate that overexpression of TEAD4 is a new mechanism of dysregulation of Hippo pathway.

The clinical activity and favorable toxicity profile of osimertinib has led it to be approved not only for advanced non-small cell lung cancer (NSCLC) patients with T790M-positive tumors when first, or second-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) treatment fails, but also for untreated advanced NSCLC patients with EGFR sensitizing mutation, so how to manage patients who get acquired resistance to osimertinib has becoming an emerging clinical challenge. This presentation would report a case of an advanced NSCLC patient with EGFR 19DEL who received combination therapy of toripalimab and chemotherapy after resistance to first line osimertinib therapy and achieved a PFS benefit of over 8 months. This case highlighted that immune checkpoint blockade combined chemotherapy might be a new possibility for advanced NSCLC patients with acquired resistance to osimertinib.

Invasive adenocarcinoma intraoperatively misdiagnosed as adenocarcinoma in situ or minimally invasive adenocarcinoma is more likely to undergo potentially insufficient resection. The purpose of our study was to evaluate the diagnostic accuracy of frozen section. We retrospectively reviewed 1,111 lung adenocarcinomas from January to March 2016 to evaluate the diagnostic performance of frozen section. A derivation cohort consisting of 436 cases of adenocarcinoma in situ or minimally invasive adenocarcinoma diagnosed by frozen section in the same period were analyzed to find predictive factors for invasive adenocarcinoma as the final diagnosis. Validation cohorts (first: April to June 2016, second: January to March 2015) were included to confirm the results. The overall concordance rate between frozen section and final diagnosis was 92%. Most frozen section errors were underestimation. The sensitivity of frozen section diagnosis for minimally invasive adenocarcinoma (74%) was significantly lower than others. Intraoperatively measured tumor size was the only independent factor for invasive adenocarcinoma as the final diagnosis (1 cm: 2%, reference; 1-1.4 cm: 15%, odds ratio, 5.678; 1.5 cm: 18%, odds ratio, 5.878; P = 0.001) in the derivation cohort, and was confirmed by validation cohorts. Fifty-nine misdiagnosed invasive adenocarcinomas in the three cohorts consisted of 54 lepidic predominant type, 1 papillary and 4 acinar predominant type. There were no positive N1, N2 node, pleural, lymphatic and vascular invasion cases found. Thirty-seven (37/59, 63%) cases of misdiagnosis were attributed to sampling error, which was the main reason. Our study suggests that adenocarcinoma in situ or minimally invasive adenocarcinoma ≥1 cm by frozen section were more likely to be invasive adenocarcinoma because of sampling error. Frozen section diagnosis of adenocarcinoma in situ or minimally invasive adenocarcinoma should be considered cautiously for tumors ≥1 cm to avoid potentially insufficient resection.

Objectives T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) is a promising checkpoint. However, its features and prognostic value in lung adenocarcinoma remain undetermined. In this study, we aimed to characterize TIM-3 expression and its prognostic significance in patients with surgically resected lung adenocarcinoma. Materials and methods Expression of TIM-3 and programmed cell death 1 (PD-1), and density of CD8+ tumor infiltrating lymphocytes (TILs) were evaluated by immunohistochemistry in resected lung adenocarcinoma. The association between clinicopathological features or clinical outcomes and TIM-3 expression was analyzed. Results A total of 223 patients were enrolled. TIM-3 expression was observed in 107 (48.0%) samples. Positive TIM-3 expression significantly correlated with positive PD-1 expression (p Conclusion TIM-3 had a relatively high positive expression rate and special clinicopathological features in patients with lung adenocarcinoma. A combination of TIM-3 and/or PD-1 expression or CD8+ TILs density could further stratify patients into different groups with distinct prognosis.

Objectives We aimed to assess the predictive value of different T descriptors, including the whole tumour size (Dwhole) and solid component size (Dsolid), in patients with clinical Stage IA adenocarcinoma who underwent sublobar resection. Methods According to computed tomography images in the lung window, T descriptors, Dwhole and Dsolid, were applied. To evaluate the predictive value of these 2 different descriptors in predicting tumour recurrence and pathological malignant behaviours, Cox hazard regression and a receiver-operating characteristic curve analysis, respectively, were used. Results In total, 247 patients were included. Of these patients, 109 and 138 had ground glass and solid nodules, respectively. When the T descriptor was changed from Dwhole to Dsolid, 37 tumours (15%) were downgraded to T1a status from T1b/T1c status. Multivariable Cox analysis showed that Dsolid was an independent risk factor of worse recurrence-free survival [hazard ratio (HR) 2.36, 95% confidence interval (CI) 1.24-4.47; P = 0.009], while Dwhole was not (HR 1.51, 95% CI 0.79-2.89; P = 0.215). In the receiver-operating characteristic analysis, the areas under the curves for Dwhole and Dsolid used to identify pathological malignant behaviours were 0.598 and 0.739, respectively. Conclusions The T descriptor, which is represented by Dsolid, rather than Dwhole, is a better predictor of tumour recurrence after sublobar resection in clinical Stage IA lung adenocarcinoma. Furthermore, our results provide some clues indicating that sublobar resection should be performed cautiously in patients with lung adenocarcinoma manifesting as ground glass nodule with Dsolid >2 cm.

Adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) are assumed to be indolent lung adenocarcinoma with excellent prognosis. We aim to identify these lesions from invasive adenocarcinoma (IA) by a radiomics approach. This retrospective study was approved by institutional review board with a waiver of informed consent. Pathologically confirmed lung adenocarcinomas manifested as lung nodules less than 3 cm were retrospectively identified. In-house software was used to quantitatively extract 60 CT-based radiomics features quantifying nodule’s volume, intensity and texture property through manual segmentation. In order to differentiate AIS/MIA from IA, least absolute shrinkage and selection operator (LASSO) logistic regression was used for feature selection and developing radiomics signatures. The predictive performance of the signature was evaluated via receiver operating curve (ROC) and calibration curve, and validated using an independent cohort. 402 eligible patients were included and divided into the primary cohort (n = 207) and the validation cohort (n = 195). Using the primary cohort, we developed a radiomics signature based on five radiomics features. The signature showed good discrimination between MIA/AIS and IA in both the primary and validation cohort, with AUCs of 0.95 (95% CI, 0.91–0.98) and 0.89 (95% CI, 0.84–0.93), respectively. Multivariate logistic analysis revealed that the signature (OR, 13.3; 95% CI, 6.2–28.5; p < 0.001) and gender (OR, 3.5; 95% CI, 1.2–10.9; p = 0.03) were independent predictors of indolent lung adenocarcinoma. The signature based on radiomics features helps to differentiate indolent from invasive lung adenocarcinoma, which might be useful in guiding the intervention choice for patients with pulmonary nodules. • Based on radiomics features, a signature is established to differentiate adenocarcinoma in situ and minimally invasive adenocarcinoma from invasive lung adenocarcinoma.

This study aimed to investigate the relationship between lymph node micrometastasis and histologic patterns of adenocarcinoma, with a particular focus on their joint effect on prognosis. We retrospectively reviewed 235 patients with stage I adenocarcinoma from January 2009 to December 2009. Lymph node micrometastasis was evaluated by immunohistochemical staining for cytokeratin (AE1/AE3) and thyroid transcription factor-1. A logistic regression model was applied to confirm the predictive factors of micrometastasis. Survival analysis was performed to evaluate the effect of micrometastasis on prognosis. Lymph node micrometastasis was observed in 35 patients (15%). Patients with micrometastasis had significantly worse recurrence-free survival (P

Introduction Immune escape frequently occurs and restricts the durability of the antitumor immune response to radiotherapy. Programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1) are important immune checkpoint molecules that could cause tumor cells to escape the host immune response. The aim of the study was to explore the role of PD-L1 in radioresistance and the antitumor effect of combined radiotherapy and anti–PD-L1 therapy in NSCLC. Methods The role of the phosphoinositide 3-kinase/protein kinase B signal transducer and activator of transcription 3, epithelial-mesenchymal transition, and tripartite motif containing 21 in regulating PD-L1 expression after radiotherapy was investigated by small interfering-PD-L1-RNA transfection, immunohistochemistry, Western blot, and immunoprecipitation. The synergistic effect of radiotherapy and anti–PD-L1 antibody was evaluated in a mouse model. PD-L1 expression on tumor specimens was examined in a retrospective cohort of patients who received concurrent chemoradiotherapy. Results PD-L1 expression was increased in vivo and in vitro after conventionally fractionated radiation. Radiotherapy in combination with anti–PD-L1 antibody synergistically enhanced antitumor immunity by promoting CD8-positive T-cell infiltration and reducing the accumulation of myeloid-derived suppressor cells and tumor-infiltrating regulatory T cells in a mouse model. Radiotherapy may up-regulate PD-L1 expression through the phosphoinositide 3-kinase / AKT and signal transducer and activator of transcription 3 pathways. PD-L1 may also stimulate cell migration and facilitate the epithelial-mesenchymal transition process to induce radioresistance. Moreover, down-regulating PD-L1 could alleviate radioresistance by promoting apoptosis. Intriguingly, patients with negative PD-L1 expression had a significantly higher objective response rate (88% versus 43.1% [ p p = 0.026]) than those with positive PD-L1 expression after delivery of radiotherapy. Conclusions Conventionally fractionated radiotherapy in combination with anti–PD-L1 antibody shows a synergistic antitumor immunity in NSCLC. Furthermore, PD-L1 expression may be a significant clinical predictive factor for treatment response to radiotherapy in NSCLC.

The present study aimed to investigate the clinical and radiological characteristics in addition to the bronchoscopic appearance in patients with endobronchial aspergilloma (EBA). Clinical and radiological characteristics were analyzed alongside the bronchoscopic appearance in 17 patients with EBA diagnosed by bronchoscopy with histological examination. The present study assessed the relevant literature and 13 males and 4 females were included in the comparison, with a median age of 59. Associated diseases included 8 previous diagnoses of pulmonary tuberculosis (47.6%), 4 previous diagnoses lung cancer (23.5%), 1 pulmonary resection (5.9%) and 1 bronchial foreign body (5.9%). The primary symptom was hemoptysis (9/17, 53%). Chest computed tomography (CT) indicated a markedly higher incidence of aspergillosis lesion in the left lung (13/17; 76.5%) compared with the right lung (4/17; 23.5%). CT manifestation included space occupying disease in 10 patients (58.8%), aspergilloma in 3 patients (17.6%), pneumonic consolidation in 2 patients (11.8%) and ground glass opacity in 1 patient (5.9%). Bronchoscopy examination identified masses in all 17 patients' bronchial lumen and 15 patients had endobronchial obstruction by necrotic material. The case presented in the current study demonstrated the merits of combining bronchosopic intervention with voriconazole. The dominant symptom of EBA was hemoptysis. Chest CT demonstrated that aspergillosis lesions were more frequently identified in the left lung compared with the right. EBA often occurs in individuals with underlying lung diseases, which cause lumen structural change or bronchial obstruction. EBA may be clearly diagnosed by bronchoscopy biopsy, although the potential for a co-exististing tumor requires consideration. Bronchoscopic intervention and anti-fungal therapy may have an advantage in the effective treatment of patients with EBA.

Objectives We prospectively investigate the accuracy of frozen sections for diagnosing visceral pleural invasion (VPI) by autofluorescence and evaluated its usefulness in sublobar resection. Methods We included patients with lung adenocarcinoma 2 cm or less to evaluate the diagnostic performance of autofluorescence for VPI in frozen sections via a fluorescence microscope. Furthermore, the impact of VPI on patients treated with sublobar resection was assessed in another cohort. Results A total of 112 patients were enrolled. The accuracy, sensitivity, and specificity of autofluorescence for VPI diagnosis was 95.5%, 86.8%, and 100%, respectively. Sublobar resection was an independent risk factor for recurrence in patients with lung adenocarcinomas 2 cm or less with VPI positivity (hazard ratio, 3.30; P = .023), whereas it was not in those with VPI negativity. Conclusions Using autofluorescence in frozen sections appears to be an accurate method for diagnosing VPI, which is helpful for surgical decision making.

Backgroud Early diagnosis of gastric tuberculosis is often challenging because the disease is very rare and its clinical manifestation is nonspecific and misleading. To raise the awareness and emphasize early diagnosis of gastric tuberculosis, we present a case of gastric tuberculosis secondary to pleural and pulmonary tuberculosis. Case presentation A 26-year-old woman complained gastric pain for 1 month but showed no other symptoms, who had no previous exposure to tuberculosis.Gastric stromal tumor was originally suspected. However, the pathology of her gastroscopic biopsy of the gastric lesion showed granulomatous lesions and caseating necrosis. Gene sequencing of the biopsy specimen identified deoxyribonucleic acid fragment of Mycobacterium tuberculosis. Chest computed tomography scan revealed nodular shadows in the lesser curvature soft tissue of the stomach, patchy densities and calcified nodular shadows in the upper right lung, bilateral pleural thickening, and calcified pleural nodules. Thus, the diagnosis was gastric tuberculosis secondary to pulmonary and pleural tuberculosis. The patient was hospitalized and treated with the antituberculosis therapy for 1 week. After discharged from the hospital, the patient continued routine antituberculosis therapy for 18 months and was follow-up was normal.Literature search found 22 cases of gastric tuberculosis reported from 2000 to 2016. Review of the 22 cases suggested that polymerase chain reaction has been increasingly used in the recent years in addition to the conventional histopathological and bacteriological approaches. Conclusion Clinical presentation of gastric tuberculosis is not specific.When granuloma or caseation is detected on biopsy in patients who are suspected of having gastric malignancy or acid peptic diseases, polymerase chain reaction for Mycobacterium tuberculosis could be used as an available and sensitive diagnostic test in addition to pathology, acid-fast bacilli smear staining and culture.

Objective: Synchronous multiple ground-glass nodules (SM-GGNs) are a distinct entity of lung cancer which has been emerging increasingly in recent years in China. The oncogenesis molecular mechanisms of SM-GGNs remain elusive. Methods: We investigated single nucleotide variations (SNV), insertions and deletions (INDEL), somatic copy number variations (CNV), and germline mutations of 69 SM-GGN samples collected from 31 patients, using target sequencing (TRS) and whole exome sequencing (WES). Results: In the entire cohort, many known driver mutations were found, including EGFR (21.7%), BRAF (14.5%), and KRAS (6%). However, only one out of the 31 patients had the same somatic missense or truncated events within SM-GGNs, indicating the independent origins for almost all of these SM-GGNs. Many germline mutations with a low frequency in the Chinese population, and genes harboring both germline and somatic variations, were discovered in these pre-stage GGNs. These GGNs also bore large segments of copy number gains and/or losses. The CNV segment number tended to be positively correlated with the germline mutations (r = 0.57). The CNV sizes were correlated with the somatic mutations (r = 0.55). A moderate correlation (r = 0.54) was also shown between the somatic and germline mutations. Conclusion: Our data suggests that the precancerous unstable CNVs with potentially predisposing genetic backgrounds may foster the onset of driver mutations and the development of independent SM-GGNs during the local stimulation of mutagens.

Background Approximately 30-70% percent of patients with non-small cell lung cancer (NSCLC) still relapse after receiving complete resection and even suffer distant metastasis. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have gradually replaced chemotherapy to become the first-line postoperative NSCLC treatment because they can effectively inhibit the postoperative recurrence of lung cancer. However, the clinical efficacy of neoadjuvant EGFR-TKIs in EGFR mutant NSCLC patients is still unclear. The purpose of this study was to evaluate their clinical efficacy and to further explore factors affecting recurrence in such patients. Methods EGFR-mutated patients receiving neoadjuvant EGFR-TKI treatment in our hospital from July 2016 to September 2020 were retrospectively included. These patients underwent radical tumor resection after treatment. The primary endpoint was the objective response rate (ORR). The secondary endpoints were the major pathological response (MPR), disease-free survival (DFS), and overall survival (OS). Results A total of 42 patients who met the inclusion criteria were included in this study. The ORR was 47.6% (20/42), and the MPR was 23.8% (10/42). The average follow-up time was 23.7 months. As of the final follow-up date, 18 (42.9%, 18/42) patients had experienced tumor recurrence. Of these, there were 11 (61.1%) cases of local recurrence and 7 (38.9%) cases of distant metastasis, including 5 bone metastases and 2 brain metastases. Multivariate Cox regression results showed that the high-risk subtype [P=0.012, hazard ratio (HR) =24.560; 95% confidence interval (CI), 2.016-299.227] was a risk factor for postoperative recurrence. Patients with a high-risk subtype (solid or micropapillary subtype) had significantly worse recurrence-free survival (RFS, log-rank P=0.032). Although patients with pathological remission had a similar RFS as patients who did not achieve pathological remission (log-rank P=0.069), the patients without pathological remission showed a tendency toward a worse prognosis. Conclusions Neoadjuvant EGFR-TKIs had good effects on EGFR-mutant NSCLC patients at different stages, especially those with MPR. Patients with high-risk subtypes (solid or micropapillary) should be closely followed up after surgery because of the high risk of recurrence.

// Yunlang She 1,* , Lilan Zhao 1,* , Chenyang Dai 1 , Yijiu Ren 1 , Junyan Zha 1 , Huikang Xie 2 , Sen Jiang 3 , Jingyun Shi 3 , Shunbin Shi 4 , Weirong Shi 5 , Bing Yu 6 , Gening Jiang 1 , Ke Fei 1 , Yongbing Chen 7 and Chang Chen 1 1 Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, P.R. China 2 Department of Pathology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, P.R. China 3 Department of Radiology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, P.R. China 4 Department of Thoracic Surgery, The Affiliated Wujiang Hospital of Nantong University, Jiangsu, P.R. China 5 Department of Thoracic Surgery, Nantong Sixth People’s Hospital, Jiangsu, P.R. China 6 Department of Thoracic Surgery, Fenghua People’s Hospital, Zhejiang, P.R. China 7 Department of Thoracic Surgery, The Second Affiliated Hospital of Soochow University, Jiangsu, P.R. China * These authors have contributed equally to this work Correspondence to: Chang Chen, email: // Yongbing Chen, email: // Keywords : ground-glass nodule, lung adenocarcinoma, nomogram Received : December 15, 2015 Accepted : June 04, 2016 Published : August 11, 2016 Abstract Purpose: To construct a preoperative nomogram to differentiate invasive pulmonary adenocarcinomas (IPAs) from preinvasive lesions in patients with solitary pure ground-glass nodules (GGN). Methods: A primary cohort of patients with pathologically confirmed pulmonary solitary pure GGN after surgery were retrospectively studied at five institutions from January 2009 to September 2015. Half of the patients were randomly selected and assigned to a model-development cohort, and the remaining patients were assigned to a validation cohort. A nomogram predicting the invasive extent of the solitary GGNs was constructed based on the independent risk factors. Predictive performance was evaluated by concordance index (C-index) and calibration curve. Results: Out of 898 cases included in the study, 501 (55.8%) were preinvasive lesions and 397 (44.2%) were IPAs. In the univariate analysis, lesion size ( p < 0.001), lesion margin ( p = 0.041), lesion shape ( p < 0.001), mean computed tomography (CT) value ( p = 0.018), presence of pleural indentation ( p = 0.017), and smoking status ( p = 0.014) were significantly associated with invasive extent. In multivariate analysis, lesion size ( p < 0.001), lesion margin ( p = 0.042), lesion shape ( p < 0.001), mean CT value ( p = 0.014), presence of pleural indentation ( p = 0.026), and smoking status ( p = 0.004) remained the predictive factors of invasive extent. A nomogram was developed and validation results showed a C-index of 0.94, demonstrating excellent concordance between predicted and observed results. Conclusions: We established and validated a novel nomogram that can identify IPAs from preinvasive lesions in patients with solitary pure GGN.

Background: Radiologically characteristic ground-glass opacity (GGO) represents a special cohort of pulmonary adenocarcinomas that has been unanimously defined as biologically inert. Lymph node metastasis, however, occurs occasionally in these biologically “indolent” cancers. The incidence and underlying risk factors of nodal metastasis remain unknown. Methods: All surgically removed GGO lesions between January 2008 and December 2014 were retrospectively reviewed from a single treatment institution. Pathologically-confirmed adenocarcinomas with systemic lymph node dissection or sampling were enrolled into the present study. All the lesions were classified into three groups according to the proportion of solid densities: group I, pure GGO; group II, 1% to 50%; and group III, 50% to 79%. Risk factor analysis of lymph node involvement was performed by multivariate logistic regression. Results: Of the 867 patients eligible for this study, 553 (63.7%) presented as pure GGOs (Group I) and 314 (36.2%) were mixed GGOs, of which 160 (18.5%) were in group II and 154 (17.8%) in group III. Lymph node metastasis was confirmed in 25 patients, among these 25 cases, 11 (11/160) were group II and 14 (14/154) were group III; two of the 25 patients died from lung cancer metastases at their postoperative 23rd and 36th month, respectively. Statistical analysis revealed three predictors for lymph nodal metastasis: tumor size, preoperative serum carcinoembryonic antigen level and proportion of the mix density. Conclusions: A larger size, mixed GGOs with a higher proportion of solid component, and elevated serum CEA level were associated with a higher preference for nodal metastasis.

Visceral pleural invasion (VPI) had been demonstrated as an aggressive sign in non-small cell lung cancers (NSCLC). However, its incidence and clinical relevance in early lung cancer showing ground glass nodules (GGNs) has not been clarified.All consecutive surgically treated patients with solitary GGNs between 2009 and 2013 were reviewed retrospectively. Inclusion criteria were defined as lesions ≤3 cm with pleura abutting on computed tomography (CT) scan and pathologically confirmed NSCLC.Out of 156 enrolled patients, 38 had pathologically confirmed VPI. The incidence of VPI was 41.5% (27/65) if the tumor diameter was larger than 2.0 cm and 14.3% (13/91) if diameter was smaller than 2.0 cm (P0.001). Further, the incidence was 17.4% (12/69) in pure GGNs and 32.2% (28/87) in part-solid GGNs (P=0.040). The tumor size and the nodule nodule-pleural relationship were significant predictors of positive VPI. In cases with pleural indentation, attachment, and closeness, the incidence was 38.1%, 25.5%, and 5.3%, respectively (P=0.001). All cases were PL0 and PL1, with no PL2 cases observed.Although VPI was visible in both pure/mix GGNs, it was more common in larger (2 cm) GGNs. The radiographic findings of nodule abutment or a pleural tag did not reliably predict or exclude VPI. In patients with GGNs, a low rate of PL2 invasion may be observed.

Background It is common to observe synchronous pure ground-glass nodules (PGN) along with operable primary tumor on initial CT scans while clinical and radiological features of these PGNs remain unclear. Methods We included patients with primary tumor and PGNs detected between June 2010 and December 2013 retrospectively. The radiographic manifestations of all PGNs, pathologic findings of resected PGNs, and follow-up outcomes of unresected PGNs were analyzed to determine the predictors of malignant PGNs. Results Overall, 84 PGNs in 71 patients were included, of which 41 were resected at primary surgery and 43 were followed up. In resected group, there were 17 carcinomatous PGNs, 11 atypical adenomatous hyperplasia, and 13 benign lesions. In a follow-up group, 7 out of 43 PGNs grew, out of which four PGNs were diagnosed as adenocarcinoma and the remaining three PGNs were still followed up. In univariate analysis, size (P

Background Invasive lung adenocarcinoma (IAC) occurs in 22.8% to 40.4% of pure ground-glass opacity (GGO) cases. This study assessed the malignancy and survival outcomes of IAC manifesting as pure GGO with the aim of providing suggestions on T staging of these tumors. Methods From January 2010 to December 2012, the study focused on 109 cases of IAC that radiologically manifested as pure GGO. For comparison, 305 clinical stage IA part-solid IACs were also included. Clinicopathological characteristics, managements, and prognoses were evaluated. Results As compared with part-solid nodules, pure GGOs showed lower T stage, lower N stage, smaller invasive size, less invasive predominant components, and better survival. Long-term outcomes were independently influenced by whether the tumors presented as pure GGO. For the pure GGO group, the 5-year overall and disease-free survival rates were 100% and 99.1%, respectively. The pT stage, invasive size, and predominant component type did not influence survival. Conclusions IAC radiologically manifesting as pure GGO is a group of tumors with low-grade malignancies and excellent prognosis. External validation is needed to assess whether it should be restaged in the TNM classification of non-small lung cancers.

This study aimed to investigate the significance of lymph node micrometastasis (LNMM) in the lung cancer nodal categories. Between 1 January 2009 and 31 December 2013, 589 patients with suspected c-stage 1 and p-T1-2aN0-1M0 lung adenocarcinoma were enrolled in this study. The study evaluated LNMM with cytokeratin (AE1/AE3) and transcription factor-1 (TTF1) (8G7G3/1) expression by immunohistochemistry. Recurrence-free survival (RFS) and overall survival (OS) were compared among the T1-2aN0-1M0 patients stratified by the new N categories. From 589 patients, 7892 removed lymph nodes were examined, and LNMM was observed in 55 (9.3%) of the patients. The patients without LNMM or N1 had the best RFS (5-year rate: 80% vs 25%; P

Some clinical N0 lung adenocarcinomas have been pathologically diagnosed as N1 or N2. To improve the preoperative diagnostic accuracy of lymph node disease, we developed a prediction model for lymph node metastasis in cT1 N0 M0 lung adenocarcinoma based on computed tomography texture analysis and clinical characteristics to estimate the probability of lymph node metastasis.The records of 501 consecutive patients with cT1 N0 M0 lung adenocarcinoma who underwent computed tomography scan and pulmonary resection with systematic lymph nodes dissection or lymph nodes sampling were reviewed. Each nodule was manually segmented, and its computerized texture features were extracted. Multivariate logistic regression with fivefold validation was used to estimate independent predictors and build the prediction model. The prediction model was then externally validated. A nomogram was developed based on logistic regression results.Among 501 patients, 41 were diagnosed with positive lymph nodes (8.18%). Four independent predictors were identified: the skewness and 90th percentile of computed tomography number, nodule compactness, and carcinoembryonic antigen level. This model showed good calibration (Hosmer-Lemeshow test, p = 0.337), with an area under the curve of 0.883 (95% confidence interval, 0.842 to 0.924; p0.001). The area under the curve was 0.808 (95% confidence interval, 0.735 to 0.880) when validated with independent data.A model based on computerized textures and carcinoembryonic antigen level can assess the lymph node status of patients with cT1 N0 M0 lung adenocarcinoma preoperatively, which could assist surgeons in making subsequent clinical decisions.

We would like to thank Dr. Chen and his colleagues for their interest and positive comments concerning our work (1). The tumor spread through air spaces (STAS), which has been defined as tumor cells (single cells, micropapillary clusters, or solid nests) within air spaces in the surrounding lung parenchyma beyond the edges of the main tumor, was first introduced in the 2015 World Health Organization (WHO) classification for lung cancer and formally proposed as a new invasive pattern of adenocarcinoma (ADC) (2). After that, STAS attracted tremendous interest and has been studied more intensely (3).

In this study we aimed to identify the risk factors of recurrence in patients with clinical stage IA adenocarcinoma presented as ground glass nodule (GGN) on computed tomography scans.The study included 245 patients with clinical stage IA adenocarcinoma presented as GGN who underwent surgery during 2010 to 2013. All patients were divided into 2 subgroups on the basis of consolidation diameter to tumor diameter (C/T) ratio on lung window: (1) ground-glass opacity (GGO)-dominant subgroup (C/T ≤ 0.5; n = 179); (2) solid-dominant subgroup (C/T0.5; n = 66). Recurrence-free survival (RFS) was analyzed to identify independent risk factors of recurrence using the Kaplan-Meier approach and multivariable Cox models.Patients in the GGO-dominant subgroup had a better prognosis than those in the solid-dominant subgroup (5-year RFS: 98% vs. 87%; P .001). Multivariate analysis confirmed that C/T ratio was an independent risk factor for RFS in patients with clinical stage IA adenocarcinoma presented as GGN (hazard ratio [HR], 9.47; 95% confidence interval [CI], 1.75-51.1; P = .009). In the analysis of the solid-dominant group, multivariate analysis showed that limited resection was an independent risk factor of recurrence in this subgroup (HR, 6.86; 95% CI, 1.50-31.42; P = .013). Regarding the GGO-dominant subgroup, surgical type was not a risk factor of recurrence.Patients with clinical stage IA solid-dominant adenocarcinoma (C/T ratio0.5) had a higher rate of recurrence after limited resection than lobectomy. Thus, limited resection should be performed cautiously in these patients (C/T ratio0.5).

Objectives To develop and validate a nomogram to estimate the pretest probability of malignancy in Chinese patients with solid solitary pulmonary nodule (SPN). Materials and Methods A primary cohort of 1798 patients with pathologically confirmed solid SPNs after surgery was retrospectively studied at five institutions from January 2014 to December 2015. A nomogram based on independent prediction factors of malignant solid SPN was developed. Predictive performance also was evaluated using the calibration curve and the area under the receiver operating characteristic curve (AUC). Results The mean age of the cohort was 58.9 ± 10.7 years. In univariate and multivariate analysis, age; history of cancer; the log base 10 transformations of serum carcinoembryonic antigen value; nodule diameter; the presence of spiculation, pleural indentation, and calcification remained the predictive factors of malignancy. A nomogram was developed, and the AUC value (0.85; 95%CI, 0.83-0.88) was significantly higher than other three models. The calibration cure showed optimal agreement between the malignant probability as predicted by nomogram and the actual probability. Conclusions We developed and validated a nomogram that can estimate the pretest probability of malignant solid SPNs, which can assist clinical physicians to select and interpret the results of subsequent diagnostic tests.

Objectives Tumor spread through air spaces (STAS) is a novel invasive pattern in lung adenocarcinoma (ADC). The effects of the combination of STAS and tumor size on survival have not been well studied. Methods A total of 383 patients with ADC 3 cm or smaller (stage IA) and 161 patients with stage IB ADC were identified from 2009 to 2010. Recurrence-free survival (RFS) and overall survival (OS) were compared between patients as stratified by STAS and tumor size. A validation cohort was included in this study. Results STAS was observed in 116 ADCs 3 cm or smaller (30.3%). In cases involving ADCs 3 cm or smaller, patients with STAS had worse RFS ( p = 0.006) and OS rates ( p p = 0.091) and OS ( p = 0.443) rates were observed in patients with ADCs 3 cm or smaller with STAS present and those with stage IB ADC. Multivariate analysis revealed STAS to be an independent prognostic factor in ADCs 3 cm or smaller (RFS, p = 0.043; OS, p = 0.009). Among patients with ADCs larger than 2 to 3 cm, STAS still stratified the prognosis. Moreover, the unfavorable prognosis of patients with ADCs larger than 2 to 3 cm with STAS present was similar to that of patients with stage IB ADC. Among patients with ADCs 2 cm or smaller, STAS failed to stratify the prognosis significantly. Similar results were obtained in the validation cohort. Conclusions These results provide preliminary evidence that STAS could be considered as a factor in a staging system to predict prognosis more precisely, especially in ADCs larger than 2 to 3 cm.

Yifeng Sun,1,* Likun Hou,2,* Yu Yang,1 Huikang Xie,2 Yang Yang,1 Zhigang Li,1 Heng Zhao,1 Wen Gao,3 Bo Su4 1Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiaotong University, 2Department of Pathology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, 3Department of Thoracic Surgery, Shanghai Huadong Hospital, Fudan University School of Medicine, Shanghai, 4Central Lab, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China *These authors contributed equally to this work Background: In this study, we investigated the contribution of a gene expression–based signature (composed of BAG1, BRCA1, CDC6, CDK2AP1, ERBB3, FUT3, IL11, LCK, RND3, SH3BGR) to survival prediction for early-stage lung adenocarcinoma categorized by the new International Association for the Study of Lung Cancer (IASLC)/the American Thoracic Society (ATS)/the European Respiratory Society (ERS) classification. We also aimed to verify whether gene signature improves the risk discrimination of IASLC/ATS/ERS classification in early-stage lung adenocarcinoma. Patients and methods: Total RNA was extracted from 93 patients with pathologically confirmed TNM stage Ia and Ib lung adenocarcinoma. The mRNA expression levels of ten genes in the signature (BAG1, BRCA1, CDC6, CDK2AP1, ERBB3, FUT3, IL11, LCK, RND3, and SH3BGR) were detected using real-time polymerase chain reaction. Each patient was categorized according to the new IASLC/ATS/ERS classification by accessing hematoxylin–eosin-stained slides. The corresponding Kaplan–Meier survival analysis by the log-rank statistic, multivariate Cox proportional hazards modeling, and c-index calculation were conducted using the programming language R (Version 2.15.1) with the “risksetROC” package. Results: The multivariate analysis demonstrated that the risk factor of the ten-gene expression signature can significantly improve the discriminatory value of TNM staging in survival prediction, but not the value of the IASLC/ATS/ERS classification. Further analysis suggested that only BRCA1 and ERBB3 in the signature were independent risk factors after adjusting for the IASLC/ATS/ERS classification by Cox regression. A new algorithm of the two-gene expression signature containing BRCA1 and ERBB3 was generated. Adding the two-gene signature into the IASLC/ATS/ERS classification model further improved the discriminatory c-statistic from 0.728 to 0.756. Conclusion: The two-gene signature composed of BRCA1 and ERBB3 was an independent risk factor of the IASLC/ATS/ERS classification, which can be used to improve the discriminatory power of prognosis prediction of the IASLC/ATS/ERS classification in early-stage lung adenocarcinoma. The two-gene signature combination with the IASLC/ATS/ERS classification might contribute to better patient stratification for adjuvant chemoradiotherapy or targeted therapy after the surgery. Keywords: molecular biomarker, prognosis, lung, adenocarcinoma