Beneficial implications of adjuvant chemotherapy for stage IB lung adenocarcinoma exhibiting elevated SUVmax in FDG-PET/CT: a retrospective study from a single center.

Background: Controversy surrounds the efficacy of adjuvant chemotherapy (ACT) in the treatment of stage I lung adenocarcinoma (LUAD). The objective of this study was to examine the impact of the maximum standardized uptake value (SUVmax) as measured by 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) on the efficacy of ACT in patients diagnosed with stage I LUAD. Methods: We scrutinized the medical records of 928 consecutive patients who underwent complete surgical resection for pathological stage I LUAD at our institution. The ideal cut-off value for primary tumor SUVmax in terms of disease-free survival (DFS) and overall survival (OS) was determined using the X-tile software. The Kaplan-Meier method and Cox regression analysis were used for survival analysis. Results: Based on the SUVmax algorithm, the ideal cutoff values were determined to be 4.9 for DFS and 5.0 for OS. We selected 5.0 as the threshold because OS is the more widely accepted predictive endpoint. In a multivariate Cox regression analysis, SUVmax ≥ 5.0, problematic IB stage, and sublobectomy were identified as independent risk factors for poor DFS and OS. It is noteworthy that patients who were administered ACT had significantly longer DFS and OS than what was observed in the subgroup of patients with pathological stage IB LUAD and SUVmax ≥ 5.0 (p < 0.035 and p ≤ 0.046, respectively). However, there was no observed survival advantage for patients in stages IA or IB who had an SUVmax < 5.0. Conclusion: The preoperative SUVmax of tumors served as an indicator of the impact of ACT in the context of completely resected pathological stage I LUAD. Notably, patients within the Stage IB category exhibiting elevated SUVmax levels emerged as a subgroup experiencing substantial benefits from postoperative ACT.

NFATc2 promotes lactate and M2 macrophage polarization through USP17 in lung adenocarcinoma.

It is well known that immune cells including macrophages within the tumor microenvironment play an essential role in tumor progression. Here, we studied how NFATc2 regulated macrophage properties in lung adenocarcinoma. Higher expression of NFATc2 was observed in the lung adenocarcinoma tissues than in the normal lung tissues. Positive relationships were found between NFATc2 and genes associated with hypoxia and glycolysis in lung adenocarcinoma from the TCGA dataset. According to single-cell sequence data, NFATc2 was closely associated with infiltrating immune cells and was related to macrophage polarization. As a transcription factor, NFATc2 binding to the USP17 promoter region, that enhanced cell migration and lactate level in lung adenocarcinoma cells, and M2 polarization in macrophages. Furthermore, the NFATc2 inhibitor suppressed lactate and M2 macrophage polarization induced by NFATc2 and USP17. In conclusion, NFATc2 promotes lactate level and M2 macrophage polarization by transcriptionally regulating USP17 in lung adenocarcinoma.

Accuracy and efficiency of an artificial intelligence-based pulmonary broncho-vascular three-dimensional reconstruction system supporting thoracic surgery: retrospective and prospective validation study.

BACKGROUND: Anthropomorphic phantoms are used in surgical planning and intervention. Ideal accuracy and high efficiency are prerequisites for its clinical application. We aimed to develop a fully automated artificial intelligence-based three-dimensional (3D) reconstruction system (AI system) to assist thoracic surgery and to determine its accuracy, efficiency, and safety for clinical use. METHODS: This AI system was developed based on a 3D convolutional neural network (CNN) and optimized by gradient descent after training with 500 cases, achieving a Dice coefficient of 89.2%. Accuracy was verified by comparing virtual structures predicted by the AI system with anatomical structures of patients in retrospective (n = 113) and prospective cohorts (n = 139) who underwent lobectomy or segmentectomy at the Peking University Cancer Hospital. Operation time and blood loss were compared between the retrospective cohort (without AI assistance) and prospective cohort (with AI assistance) for safety evaluation. The time consumption for reconstruction and the quality score were compared between the AI system and manual reconstruction software (Mimics®) for efficiency validation. This study was registered at https://www.chictr.org.cn as ChiCTR2100050985. FINDINGS: The AI system reconstructed 13,608 pulmonary segmental branches from retrospective and prospective cohorts, and 1573 branches of interest corresponding to phantoms were detectable during the operation for verification, achieving 100% and 97% accuracy for segmental bronchi, 97.2% and 99.1% for segmental arteries, and 93.2% and 98.8% for segmental veins, respectively. With the assistance of the AI system, the operation time was shortened by 24.5 min for lobectomy (p < 0.001) and 20 min for segmentectomy (p = 0.007). Compared to Mimics®, the AI system reduced the model reconstruction time by 14.2 min (p < 0.001), and it also outperformed Mimics® in model quality scores (p < 0.001). INTERPRETATION: The AI system can accurately predict thoracic anatomical structures with higher efficiency than manual reconstruction software. Constant optimization and larger population validation are required. FUNDING: This study was funded by the Beijing Natural Science Foundation (No. L222020) and other sources.

Aneuploid Circulating Tumor Cells as a Predictor of Response to Neoadjuvant Chemotherapy in Non-Small Cell Lung Cancer.

PURPOSE: This study aimed to explore the potential application of circulating tumor cells (CTCs) in predicting the therapeutic effect of neoadjuvant chemotherapy (NAC) in non-small-cell lung cancer (NSCLC). METHODS: Using integrated subtraction enrichment and immunostaining-fluorescence in situ hybridization, the serial CTCs of patients with NSCLC were detected in 7.5 mL of blood at baseline and after two cycles of cisplatin-based NAC, and all aneuploidies of chromosome 8 were examined in the enriched CTCs. Tumor responses were evaluated radiologically with serial chest computed tomography (CT) using the response evaluation criteria in solid tumors and microscopically using the tumor cell necrosis rate (TCNR) of the resected specimen after NAC. RESULTS: After two cycles of cisplatin-based NAC, 89% (8/9) of the patients with radiological partial response to NAC had reduced CTC numbers, while 73% (8/11) of the patients with stable disease exhibited increased CTC numbers (P = 0.0098). On pathological examination, 90% (9/10) of patients with a TCNR lower than 30% had >1 CTC post-NAC, while 80% (4/5) of patients with a TCNR higher than 30% had ≤1 CTC post-NAC (P = 0.017). In aneuploidy analysis, the positive rate (CTC > 0) of triploid CTCs was found to have increased after NAC, in contrast with the tetraploid and multiploid CTCs. Furthermore, tetraploid and multiploid CTCs were found to be significantly downregulated in the patients with partial response to NAC. CONCLUSION: The correlations of aneuploid CTCs with both radiological and pathological responses in patients with NSCLC who received NAC were summarized, and the findings indicate that enumerating and karyotyping aneuploid CTCs can serve as a surrogate marker for disease monitoring in NSCLC.

The prognostic analysis of lung cancer patients with occult malignant pleural disease at thoracotomy.

BACKGROUND: This study aims to determine the clinicopathological prognostic factors for occult malignant pleural disease (MPD) that were first detected in patients with non-small cell lung cancer (NSCLC) at thoracotomy and to assess the outcome of surgical intervention. METHODS: A total of 120 thoracotomy-patients with MPD were examined. The Kaplan-Meier test estimated survival curves, and Cox regression analysis was performed to validate the risk factors picked. In assessing surgical intervention, clinical and pathological parameters were matched by propensity score matching (PSM). RESULTS: With a median follow-up of 34 months, the 5-year overall survival of 120 patients was 28.0%. Multivariate analyses showed male (P=0.044), advanced T stages (P<0.001), advanced N stages (P=0.02), pleural invasion in image (P=0.005), pleural effusion (P=0.027), surgical intervention (P=0.008) and EGFR status (P=0.003) were independent predictors of survival. The 5-year survival rate and median survival time (MST) for 21 patients with lobectomy and pleurectomy were 71.6% and undefined, compared with 25.6% and 40.0 months in 46 patients with sublobectomy. When 53 patients only subjected to open-close surgery, their 5-year survival rate and MST were 23.4% and 30.2 months. After PSM, both 21 patients were included in lobectomy with the pleurectomy group and sublobectomy /open-close group. The overall survival of lobectomy with the pleurectomy group was better than the control group (P=0.046). CONCLUSIONS: Age, stage, pleural invasion, pleural effusion, surgical intervention, and EGFR status affected the prognosis of the MPD patients first diagnosed at thoracotomy. Selective surgery gives better recovery, and additional studies are needed.

[Correlation between Lymph Node Ratio and Clinicopathological Features and Prognosis of IIIa-N2 Non-small Cell Lung Cancer].

BACKGROUND: IIIa-N2 non-small cell lung cancer was significant different in survival, although N stage of lung cancer based on anatomic location of metastasis lymph node. Lymph node ratio considered of prognostic factor might be the evaluation index for IIIa-N2 non-small cell lung cancer prognosis. Therefore, the aim of the study was to evaluate the correlation between lymph node ratio and clinicopathological features and prognosis of IIIa-N2 non-small cell lung cancer prognosis. METHODS: A total of 288 cases of pathological IIIa-N2 non-small cell lung cancer were enrolled who received radical resection at the Department of Thoracic Surgery II, Peking University Cancer Hospital from January 2006 to December 2016. The univariate analysis between clinicopathological variables and lymph node ratio used Pearson's chi-squared test. Cox regression was conducted to identify the independent prognosis factors for IIIa-N2 non-small cell lung cancer. RESULTS: There were 139 cases in the lower lymph node ratio group, another 149 cases in the higher lymph node ratio group. Adenocarcinoma (χ²=5.924, P=0.015), highest mediastinal lymph node metastasis (χ²=46.136, P<0.001), multiple-number N2 metastasis (χ²=59.347, P<0.001), multiple-station N2 metastasis (χ²=77.387, P<0.001) and skip N2 lymph node metastasis (χ²=61.524, P<0.001) significantly impacted lymph node ratio. The total number of lymph node dissection was not correlated with the lymph node ratio (χ²=0.537, P=0.464). Cox regression analysis confirmed that adenocarcinoma (P=0.008), multiple-number N2 metastasis (P=0.025) and lymph node ratio (P=0.001) were the independent prognosis factors of disease free survival. The 5-year disease free survival was 18.1% in the higher lymph node ratio group, and 44.1% in the lower. Lymph node ratio was the independent prognosis factor of overall survival (P<0.001). The 5-year overall survival was 36.7% in the higher lymph node ratio group, and 64.1% in the lower. CONCLUSIONS: Lymph node ratio was correlative with the pathology, highest mediastinal lymph node metastasis, multiple-number N2 metastasis, multiple-station N2 metastasis and skip N2 lymph node metastasis. Lymph node ratio was the independent prognosis factor for IIIa-N2 non-small cell lung cancer.

Distinct Molecular Mechanisms Analysis of Three Lung Cancer Subtypes Based on Gene Expression Profiles.

The purpose was to explore distinct molecular mechanisms of three lung cancer subtypes. GSE6044 microarray data downloaded from Gene Expression Omnibus (GEO) database were applied for identifying the differentially expressed genes (DEGs). Genetic global network was constructed to analyze the network annotation. The DEGs in the genetic global network related to small-cell lung carcinoma (SCLC), lung squamous cell carcinoma (SCC), and lung adenocarcinoma (AC) were screened. Protein-protein international networks of DEGs were constructed. Pathway enrichment analyses of DEGs in three subtypes were performed, followed by construction of interactional network among pathways. There were more DEGs screened in SCLC than in AC and SCC. The genetic global network with 341 genes and 1569 interaction edges was constructed. After annotating these DEGs into a protein interactional network, a total of 695 protein interactions related to these 36 DEGs were obtained. HSP90AA1 was the hub node with the highest degree of 81 in the annotation network. DEGs in SCLC and SCC were mainly enriched in some pathways, including cell cycle, DNA replication, and histidine metabolism; whereas DEGs in AC were enriched in complement and coagulation cascades, and extracellular matrix (ECM)-receptor interaction. Pathway interactional network was constructed with the hub node of a neuroactive ligand receptor interaction. The identified DEGs such as retinoid X receptor alpha (RXRA), cyclin-dependent kinase 2 (CDK2), histone deacetylase 2 (HDAC2), and KIT might be the target genes of lung cancer by participating in different pathways such as ECM-receptor interaction. Complement and coagulation cascades, and ECM-receptor interaction might be the specific pathways for AC; smoking might have a closer relationship with SCC.

Long-term survival of patients with locally advanced esophageal squamous cell carcinoma receiving esophagectomy following neoadjuvant chemotherapy: a cohort study.

PURPOSE: The role of neoadjuvant chemotherapy and subsequent adjuvant therapy in the treatment of patients with locally advanced esophageal squamous cell carcinomas (ESCC) is not well established. PATIENTS AND METHODS: We retrospectively reviewed 228 patients with locally advanced ESCC receiving esophagectomy following neoadjuvant chemotherapy from January 2007 through December 2016. The probabilities of disease-free survival (DFS) and overall survival (OS) were estimated by means of the Kaplan-Meier method and were compared with the use of the log-rank test. Univariate and multivariate analyses of predictors of DFS and OS were performed using a Cox proportional-hazards model. Propensity score matching analysis was performed for further analysis regarding the benefit of adjuvant therapy. RESULTS: The pathological complete response of neoadjuvant chemotherapy was achieved in 13 of 228 patients (5.7%). With a median follow-up of 59.6 months, the median DFS and OS were 35.4 and 45.4 months, respectively. The multivariate Cox model determined chemotherapy regimens (P=0.003) and ypT category (P=0.006) were significant independent predictors of DFS; and chemotherapy regimens (P=0.001), ypT category (P<0.001), and ypN category (P=0.013) were significant independent predictors of OS. Furthermore, patients who received adjuvant therapy seemed to be associated with poorer survival (both DFS and OS) compared with those who did not in full cohort (P=0.001 and P=0.184, respectively) and matched cohort (P=0.251 and P=0.374, respectively). CONCLUSION: Surgery following neoadjuvant chemotherapy was applicable. Chemotherapy regimens and ypT category were significant independent predictors of both DFS and OS and ypN category was also a significant independent predictor of OS. However, these patients did not seem to benefit from subsequent adjuvant therapy. The necessity of adjuvant therapy requires further investigation.

Left sleeve lobectomy versus left pneumonectomy for the management of patients with non-small cell lung cancer.

BACKGROUND: The study was conducted to compare the outcomes of sleeve lobectomy (SL) and pneumonectomy (PN) for management of the left lung in patients with non-small cell lung cancer (NSCLC). METHODS: One hundred and thirty-five patients who underwent left SL (n = 87) or left PN (n = 48) for NSCLC from January 2006 to December 2011 were enrolled in this retrospective study. Left SL was performed when technically possible. The clinicopathological features and treatment outcomes in both groups were compared. Survival was evaluated using the Kaplan-Meier method, and significant differences were calculated using the log-rank test. Multivariate analysis was conducted using the Cox proportional hazards model to analyze significant variables associated with the outcomes of left SL. RESULTS: There were no significant differences in general clinicopathological features (age, gender, lymph node metastasis, pathological stage, and complications of bronchial fistula) between patients who underwent left SL and left PN. The operation duration was markedly longer and the extent of bleeding was greater for left SL than left PN; however patients who underwent left SL achieved significantly longer overall survival than patients who underwent left PN. The outcomes of left SL were only associated with pathological stage. CONCLUSIONS: Our results indicate that left SL may offer superior survival than left PN in selected patients. If anatomically feasible, left SL may be a preferred alternative to left PN for NSCLC patients. Pathological stage is an important factor to determine the outcome of SL.

Prognostic analysis of node status of 1 851 non-small cell lung cancer patients on the basis of the eighth TNM staging system: A cohort study / 中国胸心血管外科临床杂志

@#Objective    To evaluate the prognosis of different node status on the basis of the eighth TNM classification for lung cancer. Methods    We retrospectively reviewed the clinical data of 1 851 non-small cell lung cancer (NSCLC) patients who underwent radical resection between January 2005 and December 2014. There were 1 078 males and 773 females at age of 16–86 (59.7±9.7) years. Survival probability was estimated by the Kaplan-Meier method and significance was assessed by the log-rank test. Results    This cohort study was consisted of 1 209 patients with N0, 305 with N1 and 337 with N2. N0 patients were divided into a N0a group and a N0b group according to whether the 13 and 14 level of lymph nodes were examined. The survival rate of the N0a group was significantly higher than that of the N0b group, and the 5-year survival rate was 88.9% and 81.3% (P<0.001), respectively. According to the number of lymph node metastasis stations, N1 was divided into a N1a (single) group and a N1b (multiple) group. And no significant difference was observed between the two groups in survival rate (P=0.562). Based on the presence of lymph nodes of 10–12 level, N1 was divided into a negative group and a positive group. And the negative group was found with significantly higher survival rate than the positive group (5-year survival rate of 78.4% vs. 64.3%, P=0.007). The N2 patients were divided into a single station metastasis group (a N2a1 group), a single station with N1 positive group (a N2a2 group) and a multiple station group (a N2b group), and the percentage was accounted for 22.0% (74/337), 37.7% (127/337) and 40.3% (136/337), respectively. There was a statistical difference in 5-year survival rate (62.2% vs. 56.5% vs. 37.3%) among the three groups (P=0.001). Conclusion    Subgroup analysis of N staging in NSCLC patients shows significant survival differences which may be more consistent with multidisciplinary therapy under precise staging patterns.

Management of occult malignant pleural disease firstly detected at thoracotomy for non-small cell lung cancer patients.

BACKGROUND: The current study was to investigate the risk factors of occult malignant pleural disease (MPD) detected at thoracotomy and the outcomes of surgical intervention for these non-small cell lung cancer (NSCLC) patients with or without MPD. METHODS: We reviewed 2,093 consecutive NSCLC patients who underwent thoracotomy from January 2006 to January 2015. We used univariate and multivariate statistics to analyze the associations between clinicopathological variables and occurrence of occult MPD. Survival probability was estimated by the Kaplan-Meier method. RESULTS: 5.26% (110/2,093) MPD was observed for these NSCLC patients with 28% of 5-year estimated survival rate. Age ≤50 (P=0.055), high CEA level (P=0.006), advanced N stage (P=0.005), adenocarcinoma (P=0.001) and pleural invasion (P=0.041) were detected to be independent risk factors for the occult MPD. Combination of these five factors, 0.756 of area under curve (AUC) was shown by the integrated prediction model test. Based on the optimal cut-off value (risk score =2.795), low-risk patients have better prognosis than the high-risk patients (median survival time 61.4 months vs. not reached, P<0.001; 5-year survival 71.8% vs. 51.1%, P<0.001). Significantly, 49.0 months/31.7% and 29.4 months/19.5% of the median survival time/5-year survival rate were found for the occult MPD 110 patients receiving primary lesion resection and open-close surgery, respectively (P=0.037). CONCLUSIONS: We summarized that a new prediction model including 5-risk factors of age, carcinoembryonic antigen (CEA), N stage, adenocarcinoma and pleural invasion was provided to diagnose MPD for the NSCLC patients and primary lesion resection greatly contributed for these MPD patients.

Impact of maximum standardized uptake value of non-small cell lung cancer on detecting lymph node involvement in potential stereotactic body radiotherapy candidates.

BACKGROUND: The retrospective study investigated the association between the maximum standardized uptake value (SUVmax) of primary tumor and lymph node involvement in potential stereotactic body radiotherapy (SBRT) candidates. METHODS: A total of 185 patients with clinical stage I NSCLC were enrolled in the current study. All patients underwent lobectomy with systematic lymph node dissection following preoperative FDG-PET/CT scanning. The association between clinicopathological variables and lymph node involvement was analyzed by univariate and multivariate analysis. Spearman's correlation test was used to evaluate the correlation between them. Receiver operating characteristic (ROC) analysis was performed to calculate the area under the curve. RESULTS: Among these patients, 22.1% had occult lymph node involvement, 15.1% were N1 and 7.0% were N2. Greater tumor size (P=0.007), elevated CEA (P=0.006), central location (P=0.002), higher SUVmax (P<0.001), solid nodule type (P=0.002), visceral pleural invasion (P=0.001) and presence of micropapillary and solid patterns (P=0.002) were significantly associated with lymph node involvement. In multivariate analysis, lymph node involvement was associated with central location (OR 5.784, 95% CI: 1.584-21.114, P=0.008), SUVmax (increase of 1 unite, OR 1.147, 95% CI: 1.035-1.272, P=0.009) and visceral pleural invasion (OR 3.044, 95% CI: 1.369-6.769, P=0.006). ROC area under the curve of SUVmax for lymph node involvement was 0.770 (95% CI: 0.698-0.841), the sensitivity and specificity were 85.4% and 63.2%, respectively. Spearman's correlation test showed that SUVmax of tumor mostly depended on tumor size and nodule type. CONCLUSIONS: SUVmax of primary tumor was a predictor of lymph node involvement for potential SBRT candidates. Centrally located tumor and visceral pleural invasion were related to higher rate of nodal metastasis. Lobectomy and systemic lymph node dissection should be performed in these patients, instead of SBRT.

Upregulation of programmed cell death ligand 1 promotes resistance response in non-small-cell lung cancer patients treated with neo-adjuvant chemotherapy.

To assess the association of the programmed cell death ligand 1 (PD-L1) with cisplatin-based neo-adjuvant chemotherapy (NAC) response, we investigated the level of PD-L1 and found increased PD-L1 expression in chemo-resistant tumors compared with chemo-sensitive tumors according to RNA-Seq analysis. In a cohort of 92 patients with NAC, the positive staining of PD-L1 was correlated with TNM stage, lower sensitive-response rates and shorter overall survival rates. In another 30 paired tumor specimens pre- and post-chemotherapy, the patients with high PD-L1 expression post-chemotherapy had a worse outcome and higher stable disease rate. CD8+ tumor-infiltrating lymphocytes were found to be related to chemosensitive response and better prognosis and negative PD-L1 expression. Furthermore, in two patient-derived xenograft models and cell lines A549 and PC-9, cisplatin upregulated PD-L1 expression, and the enhancement of PD-L1 in cancer cell lines was in a drug dose-dependent manner. Moreover, the depletion of PD-L1 significantly reduced cisplatin resistance. When phosphatidylinositol 3-kinase/protein kinase B signaling was inhibited by corresponding inhibitors, PD-L1 expression was downregulated and apoptosis was upregulated in the cisplatin-treated cancer cells. These results suggest that the upregulation of PD-L1 promotes a resistance response in lung cancer cells that might be through activation of the phosphatidylinositol 3-kinase/protein kinase B pathway and suppression of tumor-infiltrating lymphocytes. The high expression of PD-L1 after NAC could be an indication of therapeutic resistance and poor prognosis in patients with non-small-cell lung cancer.

Identification of lung adenocarcinoma mutation status based on histologic subtype: Retrospective analysis of 269 patients.

BACKGROUND: To evaluate differences in the clinical characteristics and molecular pathology of lung adenocarcinoma subtypes as defined by the new International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society international histological classification. METHODS: We retrospectively reviewed 269 patients with initial primary lung adenocarcinoma who had undergone complete resection at our department from August 2013 to December 2014, focusing on the new histologic subtype classification, clinical characteristics, and molecular pathology. RESULTS: All specimens were invasive adenocarcinoma, and were lepidic (13.0%), papillary (19.7%), acinar (51.7%), solid (8.6%), micropapillary (1.1%) or mucinous predominant (5.9%). Epidermal growth factor receptor (EGFR) mutations were detected in 132 cases (60.3%). Female patients and non-smokers had higher EGFR mutation rates (P = 0.022 and 0.026, respectively). The lepidic, papillary, acinar, solid, micropapillary, and mucinous predominant patterns had EGFR mutation rates of 70.6%, 64.8%, 72.5%, 33.3%, 100%, and 5.9%, respectively. The exon mutation distribution differed according to serum carcinoembryonic antigen (CEA) levels (P = 0.018). v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations were detected in 20 cases (9.2%), and were frequently found in the mucinous and solid predominant subtypes. The serum CEA levels differed among the subtypes. CONCLUSIONS: In China, there are significant differences between lung adenocarcinoma histologic subtypes. The presence of well-differentiated components in lung adenocarcinoma indicates higher EGFR mutation rates; the presence of solid or mucinous components indicates higher KRAS mutation rates. Serum CEA levels are associated with histologic subtype and EGFR exon mutations.