Search

Supplementary Figure S1-S16: Figure S1: landscape of variants in all samples; Figure S2: cancer cell fraction of each mutation; Figure S3: patient screen; Figure S4: high frequency CNV in each sample; Figure S5: SNV disparity between PT and MT; Figure S6: SV features; Figure S7: gene enrichment of each gene category; Figure S8: Jaccard similarity in each patient; Figure S9: clonal status of potential driver genes; Figure S10: mutation signature enrichment in trunk, PTun and MTun; Figure S11: mutation signature enrichment in PT and MT; Figure S12: mutation spectrum in PT and MT; Figure S13: immunohistochemistry of PD-L1 and CD8 in PT and MT; Figure S14: CNV of immune regulatory genes in all samples; Figure S15: response to immune checkpoint inhibitor in patient OS06. Figure S16: The genomic microsatellite stability state in all tumor samples.

Osteosarcoma is the most common primary bone malignancy, and the lung is the most frequent site of metastasis. The limited understanding of the tumoral heterogeneity and evolutionary process of genomic alterations in pulmonary metastatic osteosarcoma impedes development of novel therapeutic strategies. Here we systematically illustrate the genomic disparities between primary tumors and corresponding pulmonary metastatic tumors by multiregional whole-exome and whole-genome sequencing in 86 tumor regions from 10 patients with osteosarcoma. Metastatic tumors exhibited a significantly higher mutational burden and genomic instability compared with primary tumors, possibly due to accumulation of mutations caused by a greater number of alterations in DNA damage response genes in metastatic tumors. Integrated analysis of the architecture and relationships of subclones revealed a dynamic mutational process and diverse dissemination patterns of osteosarcoma during pulmonary metastasis (6/10 with linear and 4/10 with parallel evolutionary patterns). All patients demonstrated more significant intertumoral rather than intratumoral heterogeneity between primary tumors and metastatic tumors. Mutated genes were enriched in the PI3K–Akt pathway at both the early and late stages of tumor evolution and in the MAPK pathway at the metastatic stage. Conversely, metastatic tumors showed improved immunogenicity, including higher neoantigen load, elevated PD-L1 expression, and tumor-infiltrating lymphocytes than the corresponding primary tumors. Our study is the first to report the dynamic evolutionary process and temporospatial tumor heterogeneity of pulmonary metastatic osteosarcoma, providing new insights for diagnosis and potential therapeutic strategies for pulmonary metastasis.Significance:High-throughput sequencing of primary and metastatic osteosarcoma provides new insights into the diagnosis of and potential clinical therapeutic strategies for pulmonary metastasis.

The presence of lymph node metastasis puts patients with resectable esophageal squamous cell carcinoma (ESCC) at a high risk of disease recurrence, and these patients would benefit from neoadjuvant treatment. However, current clinical staging is not enough to capture all patients with high-risk disease, and novel diagnostic tools are required to improve the accuracy of treatment planning. We tried to explore a better prediction using genomic features from large-scale gene mutation data. The major public data repositories of whole-exome sequencing for ESCC were involved in this study. The absolute differences in gene mutation frequency were calculated using Fisher’s exact test in nodal negative versus nodal positive patients. The classification of gene mutation status was dichotomized as wild-type and mutant type. To find a reliable gene panel that could provide sufficient population coverage, we set the cut-off level above 85% in both nodal phenotypes. The genomic classifier for nodal metastasis risk prediction was further generated by LASSO logistic regression analysis with 10-fold cross-validation based on the topmost significantly different genes. Above the threshold values, a total of 120 differentially mutated genes were identified in the 561 ESCC genomic sequencing data. The population coverage rates were 85.97% in the nodal positive group (n = 335) and 88.05% in the nodal negative group (n = 226), respectively. According to the LASSO logistic regression approach, a panel of 112 topmost relevant genes (termed LNM112) was selected. The receiver operating characteristic curve of the LNM112 predictive model was plotted with an area under the curve value of 0.95 (95% CI: 0.93–0.96). The sensitivity and specificity of the LNM112 model were 96.72% (324/335) and 71.24% (161/226), respectively. We identified a genomic signature (112 genes) from the large-scale genomic repertoires capable of predicting lymph node metastasis in ESCC. It can be incorporated into the current staging modalities to help inform treatment decisions, and external validation is warranted in different populations.

To depict the genomic and immune landscapes of lung adenocarcinomas (ADCs) in ever and never-smokers and guide the design of immunotherapy strategies, we applied multiple deconvolution methods that allow the identification of immune cell infiltration and immune pathway enrichment using a whole exome and transcriptome sequencing-based approach in 145 patient-matched lung ADC and non-malignant lung parenchymal tissue pairs from ever and never smokers in our in-house cohort. Results were subsequently validated by an external lung ADC cohort, including 108 never-smokers and 61 ever-smokers. Firstly, we showed that ever-smokers had an increased abundance of neutrophils and macrophage infiltration, an elevated antigen processing and presentation capacity, and activated T-cell-mediated immunity. Secondly, ever-smokers revealed elevated macrophages in acinar ADCs, decreased mast cells in lepidic ADCs, and increased neutrophils in papillary ADCs, suggesting the tumor-driven immune characteristic discrepancies among various pathologic subtypes of ADC. Thirdly, we identified mutational disparities in tumor mutation burdens, subclonal single nucleotide variants, and the predicted and expressed neoantigens between ever and never-smokers. The mutant gene KRAS preferably occurred in ever-smokers, further contributing to the infiltration of macrophages and expression of cytokines. The copy number variations of immune-related genes (NFIB, TNFAIP3) were identified as conferring to the dysregulated immune environment in ever-smokers. Moreover, a higher genomic instability index was observed in ever-smokers (p = 0.008). Fourthly, the neoantigen was significantly increased in ever-smoker lung ADCs without nodal disease. While DNA immunoediting preferably occurred in never-smokers. Notably, in lung ADC patients with nodal disease, ever-smokers exhibited slightly more homogenous mutations (p = 0.094), consistent with the evolutionary bottleneck during cancer progression. Finally, the lower immunoediting and higher microenvironment scores significantly determined the more prolonged progression-free survival in never-smokers (p < 0.050). Our multiscale genomic and immune profiling analyses thus offer valuable knowledge of tumor-driven immune disparity arising from smoking and provide a robust solution to the rational design of immune therapies. Citation Format: Xiaozheng Kang, Xin Wang, Liyan Ji, Bingfa Yan, Xuan Gao, Xuefeng Xia, Xingsheng Hu. Heterogeneous tumor-driven immune landscapes between lung adenocarcinomas in ever and never-smokers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2494.

Background Multimodal opioid‐sparing analgesia is a key component of an enhanced recovery pathway after surgery that aims to improve postoperative recovery. Transcutaneous electrical acupoint stimulation (TEAS) is assumed to alleviate pain and anxiety and to modify the autonomic nervous system. This study aimed to determine the efficacy of TEAS for sedation and postoperative analgesia in lung cancer patients undergoing thoracoscopic pulmonary resection. Methods A total of 80 patients were randomized into two groups: the TEAS group and the sham TEAS combined with general anesthesia group. Postoperative pain levels at six, 24, 48 hours, and one month after surgery were measured using the visual analogue scale (VAS). Bispectral index (BIS) score during the TEAS prior to anesthetic induction, Observer's Assessment of Alertness/Sedation (OAAS) score, sufentanil consumption during postoperative patient‐controlled intravenous analgesia (PCIA), number of total and effective attempts of PCIA pump use, and incidence of postoperative nausea and vomiting were recorded and analyzed statistically. Results Patients in the TEAS group had significantly lower VAS scores at six, 24, and 48 hours after surgery (P

There are few prospective studies of brain metastasis from esophageal squamous cell cancer (ESCC). The aim of this study was to investigate the necessity of the brain MRI/CT in the preoperative workup for patients with potentially resectable (cT1-4aN0-3) esophageal squamous cell cancer. Methods This was a prospective cross-section clinical trial (ChiCTR1800020304). There were a total of 468 patients who were diagnosed ESCC from October 2018 to August 2020. Of these 468 patients, 385 patients with cT1-4aN0-3 who were potentially candidates for surgical resection were consecutively enrolled into the study. Preoperative brain MRI/CT was performed preoperatively. The treatment regimen could be changed if the brain metastasis was confirmed. The primary endpoint was the incidence rate of the treatment regimen being changed because of brain metastasis. Results In all 385 patients, there are only 4 (1%) patients changed their treatment regimen because of brain metastasis proved by MRI/CT. The rate of positive brain MRI/CT findings is 1%. The MRI/CT diagnostic performance for brain metastasis was as follows: sensitivity, 100%; specificity, 100%; positive predictive value, 100%; negative predictive value, 100% and accuracy, 100%. There were no significant difference of bone metastasis among the Age, Sex, Tumor location and clinical stage. Conclusion Preoperative brain MRI/CT might help identify brain metastases in patients with esophageal cancer, but we do not recommend the brain MRI/CT in the preoperative workup for patients with potentially resectable esophageal squamous cell cancer.

PURPOSE To assess the benefits of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors as neoadjuvant/adjuvant therapies in locally advanced EGFR mutation-positive non–small-cell lung cancer. PATIENTS AND METHODS This was a multicenter (17 centers in China), open-label, phase II, randomized controlled trial of erlotinib versus gemcitabine plus cisplatin (GC chemotherapy) as neoadjuvant/adjuvant therapy in patients with stage IIIA-N2 non–small-cell lung cancer with EGFR mutations in exon 19 or 21 (EMERGING). Patients received erlotinib 150 mg/d (neoadjuvant therapy, 42 days; adjuvant therapy, up to 12 months) or gemcitabine 1,250 mg/m2 plus cisplatin 75 mg/m2 (neoadjuvant therapy, two cycles; adjuvant therapy, up to two cycles). Assessments were performed at 6 weeks and every 3 months postsurgery. The primary end point was objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1; secondary end points were pathologic complete response, progression-free survival (PFS), overall survival, safety, and tolerability. RESULTS Of 386 patients screened, 72 were randomly assigned to treatment (intention-to-treat population), and 71 were included in the safety analysis (one patient withdrew before treatment). The ORR for neoadjuvant erlotinib versus GC chemotherapy was 54.1% versus 34.3% (odds ratio, 2.26; 95% CI, 0.87 to 5.84; P = .092). No pathologic complete response was identified in either arm. Three (9.7%) of 31 patients and zero of 23 patients in the erlotinib and GC chemotherapy arms, respectively, had a major pathologic response. Median PFS was significantly longer with erlotinib (21.5 months) versus GC chemotherapy (11.4 months; hazard ratio, 0.39; 95% CI, 0.23 to 0.67; P < .001). Observed adverse events reflected those most commonly seen with the two treatments. CONCLUSION The primary end point of ORR with 42 days of neoadjuvant erlotinib was not met, but the secondary end point PFS was significantly improved.

In routine practice, one lung ventilation (OLV) is initiated upon pleural opening. We conducted a randomized controlled trial to compare lung collapse after preemptive OLV versus conventional OLV in thoracoscopic surgery. A total of 67 patients were enrolled (34 with conventional OLV; 33 with preemptive OLV). Preemptive OLV was conducted by closing the DLT lumen to the non‐ventilated lung immediately upon assuming the lateral position with the distal port closed to the atmosphere until pleural opening (>6 minutes in all cases). Lung collapse was assessed at 1, 5, 10, 20, 30 and 40 minutes after pleural opening using a 10‐point rating scale (10: complete collapse). The primary end point was the duration from pleural opening to satisfactory lung collapse (score of 8). Secondary end points included PaO2 and hypoxemia. The duration from pleural opening to satisfactory lung collapse was shorter in the preemptive OLV group (9.1 ± 1.2 vs. 14.1 ± 4.7 minutes, P

Background The development of minimally invasive surgical approaches has revolutionized surgical care and greatly improved surgical outcomes. This study aimed to evaluate the clinical effectiveness of a powered vascular stapler (PVS) during video-assisted thoracoscopic surgery (VATS) lobectomy. Methods This prospective, multi-center, post-market clinical study in China enrolled 50 patients with either a suspected or formal diagnosis of clinical stage IA to IIB non-small cell lung cancer (NSCLC) scheduled for VATS lobectomy. The clinical effectiveness of the PVS for successful pulmonary artery (PA)/pulmonary vein (PV) transection was evaluated. In addition, the surgeon's stress, device usability, and surgeon satisfaction were measured using multiple questionnaires. Results A total of 167 PAs/PVs were transected with 3 (1.8%) requiring intra-operative intervention. Fourteen of the 50 patients (28.0%) experienced at least one adverse event (AE), among whom 5 (10.0%) suffered from serious AEs. There were no postoperative hemorrhagic complications related to transection of the PA/PV with PVS. Surgeon satisfaction was surveyed by questionnaire after each of the 50 procedures resulting in a 96% reported satisfaction with device usability, specifically related to a low stress load and an increase in work efficiency. Conclusions For VATS lobectomy, the PVS demonstrated a positive surgical effectiveness and value in cognitive and physical distress reduction. Complications following VATS lobectomy to treat NSCLC were generally low and as expected. Intraoperative complications were few and there were no postoperative complications related to the transection of the PA and PV during VATS lobectomy. Favorable results were reported on the surgeon satisfaction questionnaire regarding usability and surgeon stress.

Osteosarcoma is the most common primary bone malignancy, and the lung is the most frequent site of metastasis. The limited understanding of the tumoral heterogeneity and evolutionary process of genomic alterations in pulmonary metastatic osteosarcoma impedes development of novel therapeutic strategies. Here we systematically illustrate the genomic disparities between primary tumors and corresponding pulmonary metastatic tumors by multiregional whole-exome and whole-genome sequencing in 86 tumor regions from 10 patients with osteosarcoma. Metastatic tumors exhibited a significantly higher mutational burden and genomic instability compared with primary tumors, possibly due to accumulation of mutations caused by a greater number of alterations in DNA damage response genes in metastatic tumors. Integrated analysis of the architecture and relationships of subclones revealed a dynamic mutational process and diverse dissemination patterns of osteosarcoma during pulmonary metastasis (6/10 with linear and 4/10 with parallel evolutionary patterns). All patients demonstrated more significant intertumoral rather than intratumoral heterogeneity between primary tumors and metastatic tumors. Mutated genes were enriched in the PI3K–Akt pathway at both the early and late stages of tumor evolution and in the MAPK pathway at the metastatic stage. Conversely, metastatic tumors showed improved immunogenicity, including higher neoantigen load, elevated PD-L1 expression, and tumor-infiltrating lymphocytes than the corresponding primary tumors. Our study is the first to report the dynamic evolutionary process and temporospatial tumor heterogeneity of pulmonary metastatic osteosarcoma, providing new insights for diagnosis and potential therapeutic strategies for pulmonary metastasis. Significance: High-throughput sequencing of primary and metastatic osteosarcoma provides new insights into the diagnosis of and potential clinical therapeutic strategies for pulmonary metastasis.

Background The current study aimed to determine the oncological efficacy and surgical safety of multiple pulmonary resections (MPRs) after prior curative surgery for local regional recurrent or second primary lung cancers. Methods All cases of lung cancer included in our prospective database between January 2000 and July 2015 were retrospectively reviewed. The oncological efficacy endpoints for synchronous and metachronous MPR were five-year overall survival (OS), disease-free survival (DFS), and progression-free survival (PFS) rates after the second surgery. The surgical safety endpoints were postoperative mortality and complications (Clavien-Dindo classification) within 30 days. Results In total, 67 MPR cases were identified. There were no significant differences in the five-year OS and DFS between the synchronous MPR group (n = 50) and the propensity score-matched solitary major pulmonary resection group (n = 250) (5-year OS 84.5% vs. 69.0%, log rank P = 0.112; DFS 64.4% vs. 58.0%, log rank P = 0.278). The five-year OS and PFS of the metachronous MPR group (n = 17) were significantly better than those in the non-surgical control group (n = 19) (5-year OS 94.1% vs. 50.7%, log rank P = 0.005; 5-year PFS 53.9% vs. 10.5%, log rank P = 0.020). No postoperative mortality or severe complications occurred in the MPR group. Conclusion The oncological efficacy of MPR is superior to the non-surgical approach for the management of local regional recurrent or second primary lung cancer, with comparable postoperative mortality and complications.

BACKGROUND: Body weight loss (BWL) following esophagectomy is a common complication in esophageal cancer (EC) which represents a deterioration in quality of life (QoL) and poor long-term prognosis. A pilot randomized controlled study was initiated to evaluate the feasibility, safety, and efficacy of a short‐term oral nutritional supplementation (ONS) on postoperative BWL and QoL in patients undergoing esophagectomy. METHODS: Patients enrolled in this study were randomly divided into two different groups: the intervention group which received oral nutritional intervention (300 mL/day for 4 weeks) and the control group which received standard diet alone. Participants were assessed at discharge and 1, 3, and 6 months following discharge for BWL and QoL. At the same time, the data of clinical baseline characteristics, nutrition-related complications, and feasibility were prospectively collected and analyzed. RESULTS: A total of 77 patients were enrolled in this study. However, owing to severe postoperative complications and discontinuation of the program, 33 participants in the ONS group and 31 participants in the control group were eligible for final analysis of body weight change and QoL. Significant differences in percentage of BWL (%BWL) between the two groups were discovered at 3 and 6 months follow-up: participants in the ONS group had lower %BWL than those in the control group (P=0.024; P=0.025, respectively). There were significant differences in body mass index (BMI) loss between the two groups. At 1 month, QoL was significantly improved in the ONS group (P=0.031); however, no differences of QoL were noticed at 3 and 6 months. Compared with the control group, ONS improved the physical function and role function and eased the symptom of fatigue (P=0.014, P=0.030, and P=0.008, respectively). It was also noted that ONS increased the nutrition-related complications compared to the standard diet (50% vs. 42.9%), although the difference was not statistically significant (P=0.647). CONCLUSIONS: This pilot study indicated that addition of ONS was feasible, safe, and might prevent the loss of body weight and BMI and have a positive impact on the QoL in esophagectomy patients. The effectiveness of ONS requires further confirmation in an appropriately powered study. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2100045303.

Analysis of circulating tumor DNA (ctDNA) is emerging as a powerful tool for guiding targeted therapy and monitoring tumor evolution in patients with non-small cell lung cancer (NSCLC), especially when representative tissue biopsies are not available. Here, we have compared the ability of four leading technology platforms to detect epidermal growth factor receptor (EGFR) mutations (L858R, exon 19 deletion, T790M and G719X) in ctDNA from NSCLC patients. Two amplification refractory mutation systems (cobas-ARMS and ADx-ARMS), a droplet digital polymerase chain reaction (ddPCR) and a next-generation sequencing (Firefly NGS) platform were included in the comparison. Fifteen EGFR mutations across twenty NSCLC patients were identified. Firefly NGS, cobas-ARMS and ddPCR all displayed superior sensitivity while ADx-ARMS was better suited for the qualitative detection of EGFR mutations with allele frequency higher than 1% in plasma and tissue samples. We observed high coincidence between the plasma and tissue EGFR mutational profiles for three driver mutations (L858R, exon 19 deletion and G719X) that are known targets of first generation EGFR-TKI therapies among patients who relapsed. Discrepancies between tissue and plasma EGFR mutational profiles were mainly attributable to spatial and temporal tumor heterogeneity, mutation inhibition due to therapy response and drug resistance (T790M). This study illustrates the challenges associated with selection of a technology platform for EGFR ctDNA analysis in the context of treatment evaluation and drug resistance detection.

To assess the benefits of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors as neoadjuvant/adjuvant therapies in locally advancedThis was a multicenter (17 centers in China), open-label, phase II, randomized controlled trial of erlotinib versus gemcitabine plus cisplatin (GC chemotherapy) as neoadjuvant/adjuvant therapy in patients with stage IIIA-N2 non-small-cell lung cancer withOf 386 patients screened, 72 were randomly assigned to treatment (intention-to-treat population), and 71 were included in the safety analysis (one patient withdrew before treatment). The ORR for neoadjuvant erlotinib versus GC chemotherapy was 54.1% versus 34.3% (odds ratio, 2.26; 95% CI, 0.87 to 5.84;The primary end point of ORR with 42 days of neoadjuvant erlotinib was not met, but the secondary end point PFS was significantly improved.

Background To determine oncologic and surgical outcomes after multiple pulmonary resections (MPR) for synchronous or metachronous lung cancer with multiple pulmonary sites of involvement and to identify prognostic factors for these patients. Methods We retrospectively analyzed data from two Chinese high-volume institutions. Eligible patients underwent MPR for synchronous or metachronous lung cancer with multiple pulmonary sites of involvement. Overall survival and disease-free survival after MPR were analyzed, and prognostic factors were explored using multivariable Cox analysis. Postoperative mortality and major morbidities within 30 days were evaluated. Results In total, 142 patients were included: 36 (25%) underwent MPR for the metachronous disease, and 106 (75%) underwent MPR for the synchronous disease. Five-year disease-free survival was 85.4% for the metachronous group and 69.1% for the synchronous group; 5-year overall survival was 86.1% and 84.8%, respectively. Five-year accumulated local and distant recurrence rates were 11.9% and 3.0% for the metachronous group and 26.6% and 5.9% for the synchronous group, respectively. In the synchronous MPR group, a larger sum of tumor size (hazard ratio [HR] 1.04; 95% confidence interval [CI], 1.00 to 1.08) and regional nodal involvement (HR 6.17; 95% CI, 1.42 to 35.46) were both independently associated with worse overall survival. In the metachronous MPR group, the longer disease-free interval was independently associated with favorable overall survival (HR 0.94; 95% CI, 0.88 to 0.98) and disease-free survival (HR 0.96; 95% CI, 0.93 to 0.99). There was no 30-day mortality. The overall rate of major morbidities was 12%. Conclusions Multiple pulmonary resection is valid for patients with synchronous and metachronous lung cancer with multiple pulmonary sites of involvement.

The Notch signaling pathway has been shown to have biological significance and therapeutic application in non-small cell lung cancer (NSCLC). We hypothesize that genetic variants of genes in the Notch signaling pathway are associated with overall survival (OS) of NSCLC patients. To test this hypothesis, we performed multivariate Cox proportional hazards regression analysis to evaluate associations of 19,571 single nucleotide polymorphisms (SNPs) in 132 Notch pathway genes with OS of 1,185 NSCLC patients available from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. We found that five potentially functional tagSNPs in four genes (i.e., ADAM12 rs10794069 A > G, DTX1 rs1732793 G > A, TLE1 rs199731120 C > CA, TLE1 rs35970494 T > TC and E2F3 rs3806116 G > T) were associated with a poor OS, with a variant-allele attributed hazards ratio (HR) of 1.27 [95% confidence interval (95% CI) = 1.13-1.42, P = 3.62E-05], 1.30 (1.14-1.49, 8.16E-05), 1.40 (1.16-1.68, 3.47E-04), 1.27 (1.11-1.44, 3.38E-04), and 1.21 (1.09-1.33, 2.56E-04), respectively. Combined analysis of these five risk genotypes revealed that the genetic score 0-5 was associated with the adjusted HR in a dose-response manner (Ptrend = 3.44E-13); individuals with 2-5 risk genotypes had an adjusted HR of 1.56 (1.34-1.82, 1.46E-08), compared with those with 0-1 risk genotypes. Larger studies are needed to validate our findings.

Background: The incidence of synchronous and metachronous multiple primary lung cancers (MPLCs) has been increasing recently. The new multidisciplinary classification of lung adenocarcinoma and TNM Classification of Lung Cancer (7 th edition, 2009), have improved the understanding of MPLC. Most researchers recommend that surgical therapy should be actively pursued if the patient’s physical condition and lung function permit it and if a complete cure can be achieved. However, few studies have reported the long-term efficacy of surgical treatment for MPLC, which we explored in this study. Methods: A total of 1,290 Lung cancer patients from a prospectively maintained database, treated by a single surgeon group between January 2000 and July 2013, at Beijing Cancer Hospital, Peking University, were reviewed. We retrospectively analyzed the clinical data of 31 patients diagnosed with MPLC out of 1290 lung cancer patients, focusing on long-term survival. Results: MPLC patients accounted for 2.4% (31/1,290) of the patient cohort: 27 had synchronous MPLC (87.1%) and 4 had metachronous MPLC (12.9%). The 1-, 3- and 5-year postoperative survival rates were 100%, 75.8% and 75.8%. On stratification according to TNM stage, the 1-, 3- and 5-year of patients with stage I cancer (20 patients) were 100%, 77.2% and 77.2%, not statistically significant with those for the entire cohort (1,290 patients; 95.4%, 80.5% and 66.2%, P=0.455). Conclusions: When the patient’s physical condition and tumor-related factors permit it, surgery should be the first choice of treatment for MPLC; it is associated with an equivalent efficacy to that of surgery for single primary lung cancer.

Mutations in the genes encoding nuclear factor (erythroid-derived 2)-like 2 (NRF2), Kelch-like ECH-associated protein 1 (KEAP1), and cullin 3 (CUL3) are commonly observed in human esophageal squamous cell carcinoma (ESCC) and result in activation of the NRF2 signaling pathway. Moreover, hyperactivity of the transcription factor Nrf2 has been found to cause esophageal hyperproliferation and hyperkeratosis in mice. However, the underlying mechanism is unclear. In this study, we aimed to understand the molecular mechanisms of esophageal hyperproliferation in mice due to hyperactive Nrf2. Esophageal tissues were obtained from genetically modified mice that differed in the status of the Nrf2 gene and genes in the same pathway (Nrf2(−/−), Keap1(−/−), K5Cre;Pkm2(fl/fl);Keap1(−/−), and WT) and analyzed for metabolomic profiles, Nrf2 ChIP-seq, and gene expression. We found that hyperactive Nrf2 causes metabolic reprogramming and up-regulation of metabolic genes in the mouse esophagus. One of the glycolysis genes encoding pyruvate kinase M2 (Pkm2) was not only differentially up-regulated, but also glycosylated and oligomerized, resulting in increased ATP biosynthesis. However, constitutive knockout of Pkm2 failed to inhibit this esophageal phenotype in vivo, and this failure may have been due to compensation by Pkm1 up-regulation. Transient inhibition of NRF2 or glycolysis inhibited the growth of human ESCC cells in which NRF2 is hyperactive in vitro. In summary, hyperactive Nrf2 causes metabolic reprogramming in the mouse esophagus through its transcriptional regulation of metabolic genes. Blocking glycolysis transiently inhibits cell proliferation and may therefore have therapeutically beneficial effects on NRF2(high) ESCC in humans.

It remains unclear whether postoperative chemotherapy improves survival among patients with esophageal squamous cell carcinoma who have undergone preoperative chemotherapy and radical resection.Patients treated between January 2000 and December 2016 were reviewed. Eligible patients were divided into two groups: perioperative chemotherapy (preoperative and postoperative chemotherapy) and neoadjuvant chemotherapy only. The primary endpoint was disease-free survival; the secondary endpoints were overall survival and toxicities attributable to postoperative chemotherapy. To minimize the effect of patient heterogeneity between the two groups, we used propensity score matching. The survival analysis was performed using univariate analysis and a multivariable Cox regression model.In total, 252 patients were included in the study. Most were men (208 of 252; 82.5%); median age was 59 years. The follow-up rate was 93.3%. Age, performance status, minimally invasive surgery, and Clavien-Dindo classification were statistically different between the groups (P.05). After propensity score matching, each group had 59 patients. Five-year disease-free survival (52.4% vs 43.6%, P = .372) and overall survival (68.6% vs 62.4%, P = .359) were not statistically different between the neoadjuvant chemotherapy group and the perioperative chemotherapy group. Cox regression identified both pathologic nodal stage and tumor regression grade are independent prognostic factors for disease-free survival and overall survival (P .05); adjuvant chemotherapy did not influence disease-free survival (hazard ratio 1.049, 95% confidence interval, 0.587 to 1.876, P = .872) or overall survival (hazard ratio 1.297; 95% confidence interval, 0.606 to 2.775, P = .504). In the perioperative chemotherapy group, 8.5% of patients (5 of 59) had grade 3 or greater toxicity.Adjuvant chemotherapy is not indicated for patients with locally advanced esophageal squamous cell carcinoma after neoadjuvant platinum-based chemotherapy and surgery.

Background The current study aimed to determine the oncological efficacy and surgical safety of multiple pulmonary resections (MPRs) after prior curative surgery for local regional recurrent or second primary lung cancers. Methods All cases of lung cancer included in our prospective database between January 2000 and July 2015 were retrospectively reviewed. The oncological efficacy endpoints for synchronous and metachronous MPR were five‐year overall survival (OS), disease‐free survival (DFS), and progression‐free survival (PFS) rates after the second surgery. The surgical safety endpoints were postoperative mortality and complications (Clavien‐Dindo classification) within 30 days. Results In total, 67 MPR cases were identified. There were no significant differences in the five‐year OS and DFS between the synchronous MPR group (n = 50) and the propensity score‐matched solitary major pulmonary resection group (n = 250) (5‐year OS 84.5% vs. 69.0%, log rank P = 0.112; DFS 64.4% vs. 58.0%, log rank P = 0.278). The five‐year OS and PFS of the metachronous MPR group (n = 17) were significantly better than those in the non‐surgical control group (n = 19) (5‐year OS 94.1% vs. 50.7%, log rank P = 0.005; 5‐year PFS 53.9% vs. 10.5%, log rank P = 0.020). No postoperative mortality or severe complications occurred in the MPR group. Conclusion The oncological efficacy of MPR is superior to the non‐surgical approach for the management of local regional recurrent or second primary lung cancer, with comparable postoperative mortality and complications.

Inducing DNA damage is known to be one of the mechanisms of cytotoxic chemotherapy agents for cancer such as cisplatin. The endogenous DNA damage response confers chemoresistance to these agents by repairing DNA damage. The initiation and transduction of the DNA damage response (DDR) signaling pathway, which is dependent on the activation of ATM (ataxia-telangiectasia mutated) and ATR (ataxia telangiectasia and Rad3-related), is essential for DNA damage repair, the maintenance of genomic stability and cell survival. Therefore, ATM or ATR inhibition is considered as a promising strategy for sensitizing cancer cells to chemotherapy. This study is aimed to explore the effect of ATR inhibitor on sensitizing ESCC (esophageal squamous cell carcinoma) cells to cisplatin, and whether ATM deficiency could impact the sensitization. We found that 21.5% of ESCC cases had ATM deficiency and that patients with ATR activation after neoadjuvant chemotherapy had worse chemotherapy response and poorer overall survival than that without ATR activation (32 mons vs. >140mons). Then, it was shown that VE-822 inhibited ATR-CHK1 pathway activation, leading to the accumulation of cisplatin-modified DNA. And it inhibited cell proliferation, induced cell cycle arrest in G1 phase and enhanced cell apoptosis. Moreover, VE-822 significantly sensitized ESCC cells to cisplatin, and these two drugs had synergistic effects, especially in ATM-deficient cells, in vitro and in vivo. Our results suggest that ATR inhibition combining with cisplatin is a new strategy for managing patients with ESCC, especially those with ATM-deficiency. However, this is an idea that requires further validation.

BACKGROUND Chemoresistance often develops in esophageal squamous cell carcinoma (ESCC), leading to poor prognosis. HOX genes play a crucial role in embryonic development and cell differentiation. Studies have recently linked HOX with chemoresistance, thus we explored whether HOXA13 is involved in ESCC chemoresistance. METHODS One hundred thirty-one ESCC patients who received neoadjuvant chemotherapy were enrolled. HOXA13 expression was examined by immunohistochemistry. RNA interference was used to knock down the HOXA13 expression in KYSE70 and transfected HOXA13 plasmid to overexpress HOXA13 in KYSE510 cells. We examined half-maximal inhibitory concentration of cisplatin, apoptosis, and epithelial-to-mesenchymal transition (EMT) in ESCC cell lines with different HOXA13 expression levels by cell counting kit-8, flow cytometry, and transwell analysis. RESULTS The median survival of patients with high HOXA13 expression was significantly shorter than those with low expression (P = 0.027). HOXA13 was associated with worse tumor regression grade (P = 0.009). Low HOXA13 expressed cells decreased the half-maximal inhibitory concentration of cisplatin (P

The weak correlation between pain and structural changes in knee osteoarthritis is widely reported. In a previous within-person, knee-matched case-control study among Caucasians, the severity of radiographic osteoarthritis (ROA) was strongly associated with both the presence of frequent knee pain and pain severity. We studied the association between ROA and knee pain in five racial/ethnic populations by using the same method. Subjects were selected from China; Japan; Korea and the United States. Among subjects with knees discordant for either frequent knee pain or pain severity, we examined the relationship between ROA and the presence of frequent knee pain using conditional logistic regression, and between ROA and pain severity using a stratified proportional odds model with an amalgamating conditional likelihood. In total, 252 urban Chinese, 221 rural Chinese, 297 Japanese, 122 Korean, 1,735 Caucasian, and 394 African-American patients were included. There was a strong dose-response relationship between the severity of ROA and the prevalence of frequent knee pain in all five racial/ethnic populations. Even mild ROA was significantly associated with frequent knee pain. In addition, ROA was also strongly associated with the severity of knee pain. These results show that structural pathology is associated with knee pain in different ethnic populations.

Non-small cell lung cancer (NSCLC) accounts for 80 % of lung cancers, and lung adenocarcinoma (ADC) is one of the main types of NSCLC. Although there are several studies on the relationship between lung ADC immunohistochemical diagnostic markers (thyroid transcription factor 1 (TTF-1) and Napsin A) and survival, some aspects of those studies could be improved. We examined the significance of the commonly used lung ADC diagnostic markers, including TTF-1, Napsin A, and CK7, in the prognosis of early-stage lung ADC. One hundred and nineteen cases of early-stage lung ADC (N0) were selected from the prospective database of lung cancer (Jan 2000 to Dec 2009). The expression levels of TTF-1, Napsin A, and CK7 in inventoried specimens were analyzed using tissue microarray (TMA) and immunohistochemical (IHC) analysis, and the effect of the expression level of each marker on patients’ survival was examined. The diagnostic sensitivity and specificity of each marker for lung ADC were as follows: TTF-1, 87.0 and 90.1 %; Napsin A, 72.2 and 90.4 %; and CK7, 94.6 and 76.0 %, respectively. Patients with high expression levels of TTF-1 and Napsin A, and high co-expression levels of TTF-1/Napsin A had better survival rates than those with low levels of expression (P

BACKGROUND: Non-small cell lung cancer (NSCLC) accounts for 80% of lung cancers, and lung squamous cell carcinoma (SQCC) is one of the main types. Advances in the treatment of lung SQCC are lacking when compared to lung adenocarcinoma. The main treatment for early-stage SQCC is surgery. However, factors affecting the efficacy of surgical treatments for early-stage lung SQCC remain unclear. In this study, we examined the significance of commonly used lung SQCC diagnostic markers p63, p40, and cytokeratin (CK)5/6 in prognosis. METHODS: Seventy-six cases of early-stage lung SQCC (N0) were obtained from our lung cancer database (January 2000 to December 2009). Tissue microarray and immunohistochemical (IHC) staining were used to detect the expression of p63, p40, and CK5/6. The effect of the expression level of each marker on patients' survival was examined. RESULTS: Sensitivity and specificity of each marker for detecting lung SQCC was 87.0% and 81.0% for p63, 75.9% and 97.9% for p40, and 78.9% and 97.7% for CK5/6. Survival rates of patients with high expression levels of p63 or CK5/6 or both were higher than in patients with low expression levels (P 0.05). Multivariate analysis showed that high levels of p63 expression p63+CK5/6 co-expression were independent prognostic factors for good survival. CONCLUSION: IHC staining detection of p63 and CK5/6 in specimens should be routinely performed in postoperative early-stage lung SQCC patients. Its significance lies not only in differential diagnosis, but also in determining prognosis.

Background It is not uncommon for imaging examinations of invasive bone and soft tissue sarcoma patients during initial treatment or postoperative follow-up to detect pulmonary nodules. This has important significance in determining the nature of nodules either for tumor staging and therapeutic regimen selection or for prognosis evaluation. Methods A review was carried out of invasive bone and soft tissue sarcoma patients diagnosed and treated in the department of orthopedic oncology of Beijing Jishuitan Hospital from June 2002 to June 2012. Data from patients who developed pulmonary metastases, diagnosed by imaging and treated surgically, were analyzed for consistency between imaging and postoperative pathological diagnoses. Results A total of 45 patients with pulmonary metastasis diagnosed by imaging and treated with resection of pulmonary lesions were included in the study. Thirty-eight cases with pulmonary metastases (84.4%) and seven cases without pulmonary metastases (15.6%) were confirmed by postoperative pathological examination. The most common pathological type in the latter patients was tuberculosis, with a total of four cases (57.1%). Conclusion There is a certain degree of misdiagnosis when using imaging for diagnosis of pulmonary metastasis, and attention should be paid to the pathological diagnosis of pulmonary metastasis in order to avoid overtreatment. Tuberculosis is most common in invasive bone and soft tissue sarcoma patients with pulmonary benign lesions, and it should be distinguished.

mRNA splicing is an important mechanism to regulate mRNA expression. Abnormal regulation of this process may lead to lung cancer. Here, we investigated the associations of 11,966 single-nucleotide polymorphisms (SNPs) in 206 mRNA splicing-related genes with lung cancer risk by using the summary data from six published genome-wide association studies (GWASs) of Transdisciplinary Research in Cancer of the Lung (TRICL) (12,160 cases and 16,838 controls) and another two lung cancer GWASs of Harvard University (984 cases and 970 controls) and deCODE (1,319 cases and 26,380 controls). We found that a total of 12 significant SNPs with false discovery rate (FDR) ≤0.05 were mapped to one novel gene PRPF6 and two previously reported genes (DHX16 and LSM2) that were also confirmed in this study. The six novel SNPs in PRPF6 were in high linkage disequilibrium and associated with PRPF6 mRNA expression in lymphoblastoid cells from 373 Europeans in the 1000 Genomes Project. Taken together, our studies shed new light on the role of mRNA splicing genes in the development of lung cancer.

Esophageal squamous cell carcinoma (ESCC), a common disease in China, is mainly treated surgically. We established a prospective database of patients with esophageal cancer between January 2000 and December 2010, including 486 subjects with ESCC who underwent surgical treatment. In this study, we explored the prognostic significance of the expressions of HOXC6 and HOXC8, responsible for embryonic development, by studying the specimens collected from clinical subjects during strict follow-up periods.Immunohistochemistry was used to detect the expressions of HOXC6 and HOXC8 in 274 ESCC subjects including 138 ESCC subjects treated with surgery alone and 136 ESCC subjects treated with neoadjuvant chemotherapy. Survival analysis was performed from the day of surgery to August 2013.The 5-y survival rate of the 274 ESCC subjects was 44.2%, with a median survival time of 44.12 mo. For the 274 ESCC subjects involved in the investigation of HOXC6 and HOXC8 expressions, the median survival time of subjects with high-level expressions of HOXC6 and HOXC8 was shorter than that for subjects with low-level expressions (P = 0.001, P 0.001, respectively). Similar results were obtained from the analysis of the prognostic value of HOXC6 and HOXC8 in the group treated with surgery alone and the group treated with neoadjuvant chemotherapy. Multivariate analysis demonstrated that HOXC6 and HOXC8 expressions were independent prognostic factors in patients with ESCC.The HOXC6 and HOXC8 genes can be used as prognostic markers in patients with ESCC, but prospective studies are still needed to confirm.