MAZ promotes tumor proliferation and immune evasion in lung adenocarcinoma.

Lung adenocarcinoma (LUAD) is the most dominant histological subtype of lung cancer and one of the most lethal malignancies. The identification of novel therapeutic targets is required for the treatment of LUAD. Here, we showed that MYC-associated zinc-finger protein (MAZ) is upregulated in LUAD tissues. MAZ expression levels are inversely correlated with patient survival. Silencing of MAZ decreased tumor proliferation and the expression of pro-tumorigenic chemokines and Galectin-9 (Gal-9), an immune checkpoint molecule. The pro-tumorigenic chemokines and Gal-9 induce immune suppression by recruitment of myeloid cells and inhibition of T cell activation, respectively. Mechanistically, MAZ transcriptionally regulates KRAS expression and activates its downstream AKT-NF-κB signaling pathway, which is crucial for tumor progression and immune evasion. Additionally, in vivo animal models and bioinformatic analyses indicated that MAZ suppression could enhance the efficacy of immune checkpoint blockade (ICB) therapy for LUAD. Overall, our results suggest that MAZ plays an important role in regulating cell proliferation and immune evasion via KRAS/AKT/NF-κB signaling in LUAD. Our findings offer a candidate molecular target for LUAD therapy, with implications for improving the efficacy of ICB therapy.

Disulfiram/copper complex improves the effectiveness of the WEE1 inhibitor Adavosertib in p53 deficient non-small cell lung cancer via ferroptosis.

Cancer cells lacking functional p53 exhibit poor prognosis, necessitating effective treatment strategies. Inhibiting WEE1, the G2/M cell cycle checkpoint gatekeeper, represents a promising approach for treating p53-deficient NSCLC. Here, we investigate the connection between p53 and WEE1, as well as explore a synergistic therapeutic approach for managing p53-deficient NSCLC. Our study reveals that p53 deficiency upregulates both protein levels and kinase activity of WEE1 by inhibiting its SUMOylation process, thereby enhancing the susceptibility of p53-deficient NSCLC to WEE1 inhibitors. Furthermore, we demonstrate that the WEE1 inhibitor Adavosertib induces intracellular lipid peroxidation, specifically in p53-deficient NSCLC cells, suggesting potential synergy with pro-oxidant reagents. Repurposing Disulfiram (DSF), an alcoholism medication used in combination with copper (Cu), exhibits pro-oxidant properties against NSCLC. The levels of WEE1 protein in p53-deficient NSCLC cells treated with DSF-Cu exhibit a time-dependent increase. Subsequent evaluation of the combination therapy involving Adavosertib and DSF-Cu reveals reduced cell viability along with smaller tumor volumes and lighter tumor weights observed in both p53-deficient cells and xenograft models while correlating with solute carrier family 7-member 11 (SLC7A11)/glutathione-regulated ferroptosis pathway activation. In conclusion, our findings elucidate the molecular interplay between p53 and WEE1 and unveil a novel synergistic therapeutic strategy for treating p53-deficient NSCLC.

Research on the local path planning of an orchard mowing robot based on an elliptic repulsion scope boundary constraint potential field method.

In orchard scenes, the complex terrain environment will affect the operational safety of mowing robots. For this reason, this paper proposes an improved local path planning algorithm for an artificial potential field, which introduces the scope of an elliptic repulsion potential field as the boundary potential field. The potential field function adopts an improved variable polynomial and adds a distance factor, which effectively solves the problems of unreachable targets and local minima. In addition, the scope of the repulsion potential field is changed to an ellipse, and a fruit tree boundary potential field is added, which effectively reduces the environmental potential field complexity, enables the robot to avoid obstacles in advance without crossing the fruit tree boundary, and improves the safety of the robot when working independently. The path length planned by the improved algorithm is 6.78% shorter than that of the traditional artificial potential method, The experimental results show that the path planned using the improved algorithm is shorter, smoother and has good obstacle avoidance ability.

Disinfection effect of hexadecyl pyridinium chloride on SARS-CoV-2 in vitro.

The novel coronavirus (COVID-19 or 2019-nCoV) is a respiratory virus that can exist in the mouth and saliva of patients and spreads through aerosol dispersion. Therefore, stomatological hospitals and departments have become high-infection-risk environments. Accordingly, oral disinfectants that can effectively inactivate the virus have become a highly active area of research. Hexadecyl pyridinium chloride, povidone-iodine, and other common oral disinfectants are the natural primary choices for stomatological hospitals. Therefore, this study investigated the inhibitory effect of hexadecyl pyridinium chloride on SARS-CoV-2 in vitro. Vero cells infected with SARS-CoV-2 were used to determine the disinfection effect; the CCK-8 method was used to determine cytotoxicity, and viral load was determined by real-time PCR. The results showed that hexadecyl pyridinium chloride has no obvious cytotoxic effect on Vero cells in the concentration range 0.0125-0.05 mg/mL. The in vitro experiments showed that hexadecyl pyridinium chloride significantly inhibits the virus at concentrations of 0.1 mg/mL or above at 2 min of action. Thus, the results provide experimental support for the use of hexadecyl pyridinium chloride in stomatological hospitals.

A Comprehensive Study to Identify Major Metabolites of an Amoxicillin-Sulbactam Hybrid Molecule in Rats and Its Metabolic Pathway Using UPLC-Q-TOF-MS/MS.

Amoxicillin and sulbactam are widely used compound drugs in animal food. The amoxicillin-sulbactam hybrid molecule can achieve better curative effects through the combination of the two drugs. However, its pharmacokinetic behavior needs to be explored. In this study, a randomized crossover experiment was performed to investigate the metabolism of the novel amoxicillin-sulbactam hybrid molecule in rats after gastric administration. Ultrahigh performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry (UPLC-Q-TOF-MS/MS) was used to isolate and to identify the metabolites in rats. Amoxicillin, amoxicilloic acid, amoxicillin diketopiperazine, and sulbactam were eventually detected in the plasma, liver, urine, and kidneys; no hybrid molecules and their metabolites were detected in feces. The in vivo metabolism results showed that the hybrid molecule was absorbed into the body in the intestine, producing amoxicillin and sulbactam, then amoxicillin was partially metabolized to amoxicilloic acid and amoxicillin diketopiperazine, which are eventually excreted in the urine by the kidneys. In this study, four major metabolites of the amoxicillin-sulbactam hybrid molecule were identified and their metabolic pathways were speculated, which provided scientific data for understanding the metabolism of the hybrid molecule and for its clinical rational use.

Tertiary lymphoid structure and decreased CD8+ T cell infiltration in minimally invasive adenocarcinoma.

Knowledge of the tumor microenvironment (TME) in patients with early lung cancer, especially in comparison with the matched adjacent tissues, remains lacking. To characterize TME of early-stage lung adenocarcinoma, we performed RNA-seq profiling on 58 pairs of minimally invasive adenocarcinoma (MIA) tumors and matched adjacent normal tissues. MIA tumors exhibited an adaptive TME characterized by high CD4+ T cell infiltration, high B-cell activation, and low CD8+ T cell infiltration. The high expression of markers for B cells, activated CD4+ T cells, and follicular helper T (Tfh) cells in bulk MIA samples and three independent single-cell RNA-seq datasets implied tertiary lymphoid structures (TLS) formation. Multiplex immunohistochemistry staining validated TLS formation and revealed an enrichment of follicular regulatory T cells (Tfr) in TLS follicles, which may explain the lower CD8+ T cell infiltration and attenuated anti-tumor immunity in MIA. Our study demonstrates how integrating transcriptome and pathology characterize TME and elucidate potential mechanisms of tumor immune evasion.

Seven interferon gamma response genes serve as a prognostic risk signature that correlates with immune infiltration in lung adenocarcinoma.

Interferon-gamma (IFN-γ) plays a complex role in modulating tumor microenvironment during lung adenocarcinoma (LUAD) development. In order to define the role of IFN-γ response genes in LUAD progression, we characterized the gene expression, mutation profile, protein-protein interaction of 24 IFN-γ response genes, which exhibited significant hazard ratio in overall survival. Two subgroups of LUAD from the TCGA cohort, which showed significant difference in the survival rate, were identified based on the expression of these genes. Furthermore, LASSO penalized cox regression model was used to derive a risk signature comprising seven IFN-γ response genes, including CD74, CSF2RB, PTPN6, MT2A, NMI, LATS2, and PFKP, which can serve as an independent prognostic predictor of LUAD. The risk signature was validated in an independent LUAD cohort. The high risk group is enriched with genes regulating cell cycle and DNA replication, as well as a high level of pro-tumor immune cells. In addition, the risk score is negatively correlated with the expression of immune metagenes, but positively correlated with DNA damage repair genes. Our findings reveal that seven-gene risk signature can be a valuable prognostic predictor for LUAD, and they are crucial participants in tumor microenvironment of LUAD.

The number of lymph nodes examined is associated with survival outcomes and nodal upstaging in patients with stage I small cell lung cancer.

OBJECTIVE(S): Lymph node status is vital for patients with small cell lung cancer (SCLC). We sought to evaluate the association between the number of lymph nodes examined (NLNE) and prognosis and nodal upstaging in stage I SCLC patients. METHODS: We queried the Surveillance, Epidemiology and End Results (SEER) database and our department for surgically treated patients with pathologic stage I SCLC to evaluate the correlation between NLNE and overall survival (OS). We further investigated the association between the NLNE and nodal upstaging in clinical stage I SCLC. RESULTS: A total of 878 patients with pathologic stage I SCLC were enrolled from the SEER database. Univariate and multivariate Cox regression analysis revealed that removing more than 6 lymph nodes was associated with significantly improved OS. We validated the prognostic impact from examining more than 6 nodes in pathologic stage I SCLC patients from our department. Logistic regression analysis found that removing more than 6 nodes increased the odds of nodal upstaging for clinical stage I SCLC. CONCLUSIONS: Adequate nodal examination leads to survival benefits and accurate nodal staging. Our analysis indicated that examining more than 6 lymph nodes could confer better OS and predict nodal upstaging for stage I SCLC patients.

Lymph Node Examination for Stage I Second Primary Lung Cancer Patients Who Received Second Surgical Treatment.

PURPOSE: This study aims to investigate the effect of lymph node examination on overall survival (OS) and lung cancer-specific survival (LCSS) in stage I second primary lung cancer (SPLC) patients who underwent second pulmonary resection. PATIENTS AND METHODS: We conducted a retrospective study with the Surveillance, Epidemiology, and End Results (SEER) database to identify stage I SPLC patients who received surgery from 1998 to 2015. The Kaplan-Meier method with landmark analysis and multivariable Cox regression analysis were performed to evaluate the prognostic value of lymph node examination. RESULTS: A total of 842 patients from the SEER database with stage I SPLC who underwent a second surgical treatment were included. The 5-year survival rate was 54.8% for the whole cohort. Multivariable analysis revealed that the number of lymph nodes examined (LNE) was associated with better OS and LCSS in SPLC patients after 12 months postoperatively. Patients with contralateral SPLC had significantly more nodes removed than those with ipsilateral SPLC. For contralateral SPLC, more than 10 LNE was correlated with improved long-term survival outcomes. Ipsilateral SPLC patients benefited from 4 or more LNE. However, the current analysis did not show a significant survival benefit from lymph node examination within 12 months after surgery. CONCLUSIONS: For stage I SPLC patients who received surgical treatment after initial resection, an adequate number of LNE would improve both OS and LCSS. We recommend more than 10 LNE for contralateral SPLC and at least 4 LNE for ipsilateral SPLC.

Clinicopathological and prognostic analyses of 86 resected pulmonary lymphoepithelioma-like carcinomas.

BACKGROUND: Pulmonary lymphoepithelioma-like carcinoma (LELC) is a rare subtype of primary lung cancer. The present study aims at investigating clinicopathological features and prognostic characteristics of the resected pulmonary LELC. METHODS: Patients with resected pulmonary LELC were identified in our hospital from December 2008 to December 2018. Data of these patients were retrospectively reviewed, clinicopathological features and prognostic characteristics were analyzed subsequently. RESULTS: In total, 86 patients were enrolled in the study, including 39 (45.3%) males and 47 (54.7%) females. Most of the serum tumor markers were normal. Immunohistochemical staining result showed frequent differentiation traits of epithelial tissue such. Positive PD-L1 (15 of 19, 78.9%) and PD-1 (13 of 17, 76.5%) were also common, but cancer-related genetic mutation was scarce (1 of 47, 2.1%). Survival analyses demonstrated that the N stage (p = .011) and extent of resection (p = .023) were identified as independent predictive factors for overall survival. CONCLUSIONS: Pulmonary LELC is a distinctive subtype of lung cancer with several exclusive traits, such as the trend to happen among nonsmoking young people, epithelial origin of tumor differentiation, frequent expression of the immune checkpoint, and scarce presence of driver mutation. In addition, pulmonary LELC was apt to get a favorable outcome, especially in cases diagnosed and treated in the early stage.

Quality of life with adjuvant gefitinib versus vinorelbine plus cisplatin in patients with completely resected stage II-IIIA (N1-N2) EGFR-mutant non-small-cell lung cancer: Results from the ADJUVANT (CTONG1104) study.

OBJECTIVES: Health-related quality of life (HRQoL) data complement conventional clinical endpoints when comparing adjuvant gefitinib with chemotherapy in patients with early-stage non-small-cell lung cancer (NSCLC) and epidermal growth factor receptor (EGFR) mutations. This study aimed to assess changes in HRQoL with adjuvant gefitinib vs chemotherapy in this patient group. MATERIALS AND METHODS: In the phase III ADJUVANT trial, patients with completely resected, stage II-IIIA (N1-N2), EGFR-mutant NSCLC were randomized (1:1) to receive either gefitinib for 24 months or vinorelbine plus cisplatin (VP) every 3 weeks for four cycles. HRQoL was assessed as a secondary endpoint using the Functional Assessment of Cancer Therapy-Lung Cancer (FACT-L), Lung Cancer Symptom Scale (LCSS) questionnaires, and Trial Outcome Index (TOI) composite score. HRQoL dynamics, improvements, and time to deterioration were compared between groups. RESULTS: At baseline, 104 of 106, and 80 of 87 patients receiving gefitinib and VP, respectively, completed two questionnaires (FACT-L and LCSS). Baseline scores were balanced between groups. Although HRQoL fluctuated and gradually improved in both groups, longitudinally higher scores were reported with gefitinib than VP (FACT-L, odds ratio 418.16, 95 % confidence interval [CI] 2.75-63509.05, p =  0.019; LCSS, 1.13, 1.04-1.22, p =  0.003; TOI, 88.39, 4.40-1775.05, p =  0.003). Time to deterioration in HRQoL was delayed with gefitinib compared with VP (FACT-L, median 69 vs 6 weeks, hazard ratio 0.62, 95 % CI 0.42-0.90, p =  0.013; LCSS, median 45 vs 6 weeks, 0.63, 0.43-0.93, p =  0.020; TOI, median 164 vs 9 weeks, 0.51, 0.33-0.77, p =  0.001). CONCLUSION: Adjuvant gefitinib is associated with improved HRQoL over VP, supporting its use in patients with stage II-IIIA (N1-N2), EGFR-mutant NSCLC.

Radiomics nomogram for prediction disease-free survival and adjuvant chemotherapy benefits in patients with resected stage I lung adenocarcinoma.

BACKGROUND: Robust imaging biomarkers are needed for risk stratification in stage I lung adenocarcinoma patients in order to select optimal treatment regimen. We aimed to construct and validate a radiomics nomogram for predicting the disease-free survival (DFS) of patients with resected stage I lung adenocarcinoma, and further identifying candidates benefit from adjuvant chemotherapy (ACT). METHODS: Using radiomics approach, we analyzed 554 patients' computed tomography (CT) images from three multicenter cohorts. Prognostic radiomics features were extracted from computed tomography (CT) images and selected using least absolute shrinkage and selection operator (LASSO) Cox regression model to build a radiomics signature for DFS stratification. The biological basis of radiomics was explored in the Radiogenomics dataset (n=79) by gene set enrichment analysis (GSEA). Then a nomogram that integrated the signature with these significant clinicopathologic factors in the multivariate analysis were constructed in the training cohort (n=238), and its prognostic accuracy was evaluated in the validation cohort (n=237). Finally, the predictive value of nomogram for ACT benefits was assessed. RESULTS: The radiomics signature with higher score was significantly associated with worse DFS in both the training and validation cohorts (P<0.001). The GSEA presented that the signature was highly correlated to characteristic metabolic process and immune system during cancer progression. Multivariable analysis revealed that age (P=0.031), pathologic TNM stage (P=0.043), histologic subtype (P=0.010) and the signature (P<0.001) were independently associated with patients' DFS. The integrated radiomics nomogram showed good discrimination performance, as well as good calibration and clinical utility, for DFS prediction in the validation cohort. We further found that the patients with high points (point ≥8.788) defined by the radiomics nomogram obtained a significant favorable response to ACT (P=0.04) while patients with low points (point <8.788) showed no survival difference (P=0.7). CONCLUSIONS: The radiomics nomogram could be used for prognostic prediction and ACT benefits identification for patient with resected stage I lung adenocarcinoma.

Clinical characteristics of hyperprogressive disease in NSCLC after treatment with immune checkpoint inhibitor: a systematic review and meta-analysis.

BACKGROUND: A number of studies have reported hyperprogressive disease (HPD) in non-small cell lung cancer (NSCLC) after treatment with immune checkpoint inhibitor (ICI). This study aimed to summarize the incidence and survival outcome of HPD in NSCLC and identify the clinicopathological features associated with HPD based on available eligible studies. METHODS: Four databases (Medline/PubMed, Embase, Web of Science, and Cochrane Library) were searched for eligible studies on HPD published before January 23, 2020, to evaluate the incidence, outcome, and clinical features of HPD. Statistical analyses were performed using STATA 15.0. All meta-analyses were performed based on the random-effects model. RESULTS: This study included 6 studies involving 1389 patients. The incidence of HPD ranged from 8.02 to 30.43%. Compared with patients with non-HPD, those with HPD were associated with worse overall survival. We identified that Eastern Cooperative Oncology Group > 1, Royal Marsden Hospital score ≥ 2, serum lactate dehydrogenase > upper limit of normal, the number of metastasis sites > 2, and liver metastasis were associated with the risk of HPD. CONCLUSIONS: This study summarized the clinical features of HPD in NSCLC patients. The meta-analysis showed that five pre-treatment clinicopathological features might be associated with HPD, which may help in selecting patients for ICIs.

Germline Predisposition and Copy Number Alteration in Pre-stage Lung Adenocarcinomas Presenting as Ground-Glass Nodules.

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.

Broncholithiasis: retrospect of 15 surgical treatment patients.

BACKGROUND: Broncholithiasis is a rare disease with life-threatening event. The purpose of this study was to describe our experience in patients with broncholithiasis managed by surgical treatment. METHODS: From May 2008 to November 2014, 15 patients were diagnosed with broncholithiasis in Shanghai Pulmonary Hospital. They all received surgical treatment. RESULTS: A total of 15 patients, including 2 males and 13 females, were identified with a median age of 54 years (range, 36 to 70 years). The indication for operation was the patients who had single symptom or several symptoms, such as persistent or recurrent cough, hemoptysis, chest pain etc. Furthermore, asymptomatic patients who were suspected of malignant were also surgically treated. Postoperative complications occurred in 4 patients (26.7%). Four patients (26.7%) had cough and/or hemoptysis after surgeries. Moreover, 1 patient recurrent (6.7%) with broncholithiasis appearing in a new location and 2 patients had the postoperative infection (13.3%). Thoracotomy was performed on 13 patients. In this group, 2 of them infected within 1 month after the surgery. The other 2 patients accepted video-assisted thoracic surgery (VATS) and 1 of them occurred recurrence 9 months after surgery. CONCLUSIONS: Surgical resection is a crucial and conventional treatment for broncholithiasis with low risk of mortality and morbidity. However, VATS is a new technique that makes patients have the potential of recurrence. Therefore, this paper suggests that thoracotomy is the best surgical treatment for patients of broncholithiasis who need to accept surgical treatment.

The secondary surgery provides significant benefits to recurrent thymoma: a retrospective analysis based on Surveillance, Epidemiology and End Results database.

BACKGROUND: Recurrent thymoma (RT) with appropriate therapies has acceptable survival. The role of secondary surgery for RT remains controversial. METHODS: Surgical treated thymoma patients were reviewed from Surveillance, Epidemiology and End Results database (SEER). Propensity score matching (PSM) was utilized to match baseline factors to balance secondary surgical treated RT and thymoma without recurrence (NRT). Univariate and multivariate analyses were performed to evaluate the role of secondary surgery for RT. RESULTS: According to analysis, 815 patients were NRT, and 185 were RT. Surgical treated RT had significantly better overall survival (OS) than conservative treated RT (P<0.001). Survival between surgical treated RT and NRT had no significant difference. Focused on surgical treated RT and NRT, after PSM, elder diagnostic age, advanced clinical stage, upgraded pathologic grade predicted worse OS (P<0.01, for all), whereas, secondary surgery for RT provided comparable outcomes to NRT. CONCLUSIONS: Masaoka stage I-III RT with secondary surgery causes acceptable outcomes compared to NRT. In addition, elder patients, advanced Masaoka stage, upgraded pathologic grade, and without PORT indicate significantly worse OS in thymoma.

CT-based radiomics signature for the stratification of N2 disease risk in clinical stage I lung adenocarcinoma.

BACKGROUND: Risk stratification of N2 disease is vital for selecting candidates to receive invasive mediastinal staging modalities. In this study, we aimed to stratify the risk of N2 metastasis in clinical stage I lung adenocarcinoma using radiomics analysis. METHODS: Two datasets of patients with clinical stage I lung adenocarcinoma who underwent lung resection were included (training dataset, 880; validation dataset, 322). Using PyRadiomics, 1,078 computed tomography (CT)-based radiomics features were extracted after semi-automated lung nodule segmentation. In order to predict N2 status, a radiomics signature was constructed after selecting the optimal radiomics feature subset by sequentially applying minimum-redundancy-maximum-relevance and least absolute shrinkage and selection operator (LASSO) techniques. Its performance was validated in the validation dataset. RESULTS: The incidences of N2 metastasis were 8.4% and 7.1% in the training and validation datasets, respectively. Unsupervised cluster analysis revealed that radiomics features significantly correlated with lymph node status and pathological subtypes. For N2 disease prediction, five radiomics features were selected to establish the radiomics signature, which showed a significantly better predictive performance than clinical factors (P<0.001). The area under the receiver operating characteristic curve was 0.81 (0.77-0.86) and 0.69 (0.63-0.75) for radiomics signature and clinical factors, respectively, in the training dataset, and 0.82 (0.71-0.92) and 0.64 (0.52-0.75), respectively, in the validation dataset. CONCLUSIONS: The established CT-based radiomics signature could stratify the risk of N2 metastasis in clinical stage I lung adenocarcinoma, thus assisting clinicians in making patient-specific mediastinal staging strategy.

The Unique Spatial-Temporal Treatment Failure Patterns of Adjuvant Gefitinib Therapy: A Post Hoc Analysis of the ADJUVANT Trial (CTONG 1104).

INTRODUCTION: Adjuvant gefitinib therapy prolonged disease-free survival in patients with resected early-stage EGFR-mutation positive NSCLC in the ADJUVANT study (CTONG 1104). However, treatment failure patterns after gefitinib therapy are less well characterized. METHODS: Overall, 222 stage N1-N2, EGFR-mutant NSCLC patients received gefitinib or vinorelbine plus cisplatin (VP) treatment. Tumor recurrences or metastases occurring during follow-up were defined as treatment failure; sites and data of first treatment failure were recorded. A post hoc analysis of treatment failure patterns which was estimated by Kaplan-Meier and hazard rate curves in modified intention-to-treat patients was conducted. RESULTS: There were 114 recurrences and 10 deaths before recurrence across 124 progression events. Spatial distribution analysis showed that the first metastasis site was most frequently the central nervous system in the gefitinib group (29 of 106 [27.4%]), extracranial metastases were most frequent in the VP group (32 of 87 [36.8%]). Temporal distribution analysis showed lower tumor recurrence with gefitinib than with VP 0 to 21 months post-surgery. However, recurrence with gefitinib showed a constant rate of increase 12 months post-surgery. The first peak of extracranial metastasis appeared during 9 to 15 months with VP and 24 to 30 months with gefitinib. The highest peak for central nervous system metastases post-surgery occurred after 12 to 18 months with VP and 24 to 36 months with gefitinib. CONCLUSIONS: Adjuvant gefitinib showed advantages over VP chemotherapy in treatment failure patterns especially in extracranial metastasis. Adjuvant tyrosine kinas inhibitors may be considered as a treatment option in resected stage N1-N2 EGFR-mutant NSCLC but longer duration should be explored.

A Proposal for Restaging of Invasive Lung Adenocarcinoma Manifesting as Pure Ground Glass Opacity.

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.

The predictive value of CT-based radiomics in differentiating indolent from invasive lung adenocarcinoma in patients with pulmonary nodules.

OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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. KEY POINTS: • Based on radiomics features, a signature is established to differentiate adenocarcinoma in situ and minimally invasive adenocarcinoma from invasive lung adenocarcinoma.