Multimodal fusion of liquid biopsy and CT enhances differential diagnosis of early-stage lung adenocarcinoma.

This research explores the potential of multimodal fusion for the differential diagnosis of early-stage lung adenocarcinoma (LUAD) (tumor sizes < 2 cm). It combines liquid biopsy biomarkers, specifically extracellular vesicle long RNA (evlRNA) and the computed tomography (CT) attributes. The fusion model achieves an impressive area under receiver operating characteristic curve (AUC) of 91.9% for the four-classification of adenocarcinoma, along with a benign-malignant AUC of 94.8% (sensitivity: 89.1%, specificity: 94.3%). These outcomes outperform the diagnostic capabilities of the single-modal models and human experts. A comprehensive SHapley Additive exPlanations (SHAP) is provided to offer deep insights into model predictions. Our findings reveal the complementary interplay between evlRNA and image-based characteristics, underscoring the significance of integrating diverse modalities in diagnosing early-stage LUAD.

A randomized double-blind trial of TQB2450 with or without anlotinib in pretreated driver-negative non-small cell lung cancer.

OBJECTIVE: Immune monotherapy as second-line treatment confers only modest survival benefit on non-small cell lung cancer (NSCLC) patients with no mutated driver genes, necessitating combination treatment strategies. This phase Ib trial investigated the efficacy and safety of anti-PD-L1 antibody TQB2450 plus antiangiogenic drug anlotinib for NSCLC. MATERIALS AND METHODS: Pretreated stage IIIB or IV NSCLC patients with wild-type EGFR/ALK and minimally one measurable lesion were randomized 1:1:1 to receive TQB2450 1200 mg plus placebo, or TQB2450 1200 mg plus anlotinib 10 or 12 mg. The primary outcome was progression-free survival (PFS) and the secondary outcomes included objective response rate (ORR). RESULTS: Thirty-three patients received TQB2450 plus placebo and 34 patients each received TQB2450 plus anlotinib 10 mg and 12 mg. At the data cutoff, the median PFS was 8.7 months (95% CI 6.1-17.1) in the TQB2450 plus anlotinib group and 2.8 months (95% CI 1.4-4.7) in the TQB2450 only group. The ORR reached 30.9% (95% CI 20.2%-43.3%) in the TQB2450 plus anlotinib group and was 3.0% (95% CI 0.1%-15.8%) in the TQB2450 only group. In patients with PD-L1 ≥ 1%, the ORR was 50.0% (95% CI 33.4%-66.6%) for TQB2450 plus anlotinib and 5.3% (95% CI 0.1%-26.0%) for TQB2450 plus placebo. No new safety signals were observed. CONCLUSION: Anlotinib plus TQB2450 demonstrated promising antitumor activities in advanced NSCLC patients without EGFR and ALK alterations and the toxicities were overall manageable. The study findings support the continued development of TQB2450 plus anlotinib for advanced NSCLC patients without driver gene alterations.

PEG2000-PLA-based nanoscale polymeric micelles reduce paclitaxel-related toxicity in beagle dogs.

Nanoplatform-based drug delivery plays an important role in clinical practice. Polymeric micellar (Pm) nanocarriers have been demonstrated to reduce the toxicity of paclitaxel in rats and non-small cell lung cancer (NSCLC) patients. However, the underlying toxicological profile needs to be further illustrated. Here, we used beagles as study subjects and sought to further observe the toxicological profile of polymeric micellar paclitaxel (Pm-Pac) via acute toxicity tests and short-term and long-term toxicity tests. The results from the acute toxicity test indicated that the lethal dose of Pm-Pac in beagles was 20-30 mg/kg, and the acute toxicity-targeted organs were the digestive system and immuno-haematopoietic system. The short-term toxicity test suggested that paclitaxel-induced toxicity (peripheral neuropathy toxicity, haemopoietic toxicity, heart system toxicity, and so on) in beagles can be reduced when paclitaxel is delivered via the Pm delivery system. The long-term toxicity test suggested that Pm-Pac can reduce haemopoietic toxicity in beagles. Collectively, this study provides novel insight into the toxicological profile of Pm-Pac in healthy beagles and provides a potential basis for promising clinical combination strategies in the future.

Efficacy of ICI-based treatment in advanced NSCLC patients with PD-L1≥50% who developed EGFR-TKI resistance.

Introduction: Platinum-based chemotherapy is still the standard of care for Epidermal growth factor receptor (EGFR) mutated non-small cell lung cancer (NSCLC) patients after developing EGFR-TKI resistance. However, no study focusing on the role of immuno checkpoint inhibitor (ICI) based treatments for EGFR mutated NSCLC patients who carried programmed death ligand 1 (PD-L1) tumor proportion score (TPS) greater than 50% progressed after EGFR-TKI therapy. In this study, we retrospectively investigated the outcomes of ICI-based treatments for EGFR mutated NSCLC patients carried PD-L1 TPS≥50% after developing EGFR-TKI resistance and to explore the population that may benefited from ICI-based treatment. Methods: We retrospectively collected data of advanced NSCLC patients with EGFR mutations and PD-L1 TPS≥50% who have failed prior EGFR-TKI therapies without T790M mutation at Shanghai Chest Hospital between January 2018 and June 2021. Progression-free survival (PFS) and overall survival (OS) were utilized to evaluate the outcomes of this study. Results: A total of 146 patients were included. Up to June 20th, 2022, median follow-up was 36.7 months (IQR, 12.5-44.2 months). Among the population, 66 patients (45.2%) received chemotherapy, the remaning (54.8%) received ICI-based treatment, including 56 patients(70.0%) received ICI combined with chemotherapy (IC) and 24 patients (30.0%) received ICI monotherapy (IM). In IC group,31 patients received ICI combined with chemotherapy,19 patients received ICI combined with antiangiogenic therapy and remaing received ICI combined with chemotherapy and antiangiogenic therapy. Survival analysis shown that patients who received ICI-based treatment had better progress-free survival (PFS) and overall survival (OS) compared with those treated with other therapy (median PFS, 10.0 vs. 4.0 months, P<0.001; median OS, 39.5 vs. 24.2 months, P<0.001). What's more, patients who treated with IC treatment had a superior survival time than those received IM treatment (median PFS, 10.3 vs. 7.0 months, P<0.001; median OS, 41.6 vs. 32.4 months, P<0.001). Subgroup analysis found that the PFS and OS benefit of IC was evident in all subgroups. Conclusions: For advanced NSCLC patients with EGFR mutations and PD-L1 TPS≥50% who have failed prior EGFR-TKI therapies without T790M mutation, ICI-based treatment could provide a more favorable survival than classical chemotherapy. What' s more, compared with ICI monotherapy, ICI combined with chemotherapy seems to be the preferred treatment.

China lung cancer screening (CLUS) version 2.0 with new techniques implemented: Artificial intelligence, circulating molecular biomarkers and autofluorescence bronchoscopy.

OBJECTIVE: The present study, CLUS version 2.0, was conducted to evaluate the performance of new techniques in improving the implementation of lung cancer screening and to validate the efficacy of LDCT in reducing lung cancer-specific mortality in a high-risk Chinese population. METHODS: From July 2018 to February 2019, high-risk participants from six screening centers in Shanghai were enrolled in our study. Artificial intelligence, circulating molecular biomarkers and autofluorescencebronchoscopy were applied during screening. RESULTS: A total of 5087 eligible high-risk participants were enrolled in the study; 4490 individuals were invited, and 4395 participants (97.9%) finally underwent LDCT detection. Positive screening results were observed in 857 (19.5%) participants. Solid nodules represented 53.6% of all positive results, while multiple nodules were the most common location type (26.8%). Up to December 2020, 77 participants received lung resection or biopsy, including 70 lung cancers, 2 mediastinal tumors, 1 tracheobronchial tumor, 1 malignant pleural mesothelioma and 3 benign nodules. Lung cancer patients accounted for 1.6% of all the screened participants, and 91.4% were in the early stage (stage 0-1). CONCLUSIONS: LDCT screening can detect a high proportion of early-stage lung cancer patients in a Chinese high-risk population. The utilization of new techniques would be conducive to improving the implementation of LDCT screening.

Different clinical characteristics and survival between surgically resected pure and combined small cell lung cancer.

BACKGROUND: Small cell lung cancer (SCLC) is the most malignant and common form of neuroendocrine lung cancer with pure (P-SCLC) and combined subtypes (C-SCLC). However, little is known about the differences between these two groups and in this study we aimed to provide a more comprehensive insight into SCLC. METHODS: Data from 580 postoperative patients with pathologically confirmed SCLC in Shanghai Chest Hospital from January 2010 to December 2020 were collected retrospectively. The clinical characteristics and prognosis were analyzed. RESULTS: A total of 357 P-SCLC patients and 223 C-SCLC patients were included. The results indicated that P-SCLC appeared to have a higher proportion of being located in the middle lobe than C-SCLC. The incidences of P-SCLC in patients with visceral pleural invasion (VPI) and in stage II were higher than C-SCLC, while C-SCLC was more likely to be accompanied by higher incidences of epidermal growth factor receptor (EGFR) mutation, anaplastic lymphoma kinase (ALK) rearrangement, and higher levels of CEA, SCCA and CYFRA21-1 than P-SCLC. The most common were SCLC combined with large cell neuroendocrine components among 223 C-SCLCs. Survival analysis confirmed a more favorable disease-free survival (DFS) (p = 0.016) and overall survival (OS) (p = 0.024) in patients with P-SCLCs compared with C-SCLCs. Histological type, tumor location, pN stage, adjuvant chemotherapy, serum NSE and CA125 levels were independent risk factors for survival rate in SCLC. In addition, adjuvant chemotherapy was beneficial in improving stage I P-SCLC and C-SCLC DFS and OS rates, and similar results were not seen in adjuvant radiation therapy. CONCLUSIONS: Patients with C-SCLC have a poorer prognosis than P-SCLC patients. We determined that large cell neuroendocrine carcinoma was the most common additional component of C-SCLC, and patients with this component appeared to have a longer DFS and OS than other combined components.

Safety and efficacy of anlotinib in combination with standard chemotherapy as first-line treatment for extensive-stage small cell lung cancer: A multi-center, prospective study (ACTION-2).

INTRODUCTION: Extensive stage small cell lung cancer (ES-SCLC) is associated with poor prognosis. Recently, anlotinib has demonstrated significant clinical activity as a third-line or further on treatment. This study aimed to evaluate the safety and efficacy of a combination of anlotinib and platinum-etoposide as first-line treatment in patients with ES-SCLC. METHODS: The present multi-center, single-arm, prospective study (NCT04684017) was conducted at three Chinese sites, and included patients with asymptomatic metastasis in the central nervous system. Patients were treated with up to six cycles of chemotherapy comprising etoposide with either carboplatin or cisplatin on day 1 of each cycle. Anlotinib was administered orally once daily on days 1-14 per cycle. The primary end points of the study were safety and investigator assessed objective response rate (ORR). RESULTS: A total of 101 patients were screened from August 2018 to September 2021, of which 86 who had received at least one dose of the treatment were included in the formal analysis. The median follow-up duration was 27.9 months. Complete response and partial response were observed in 2 and 73 patients, respectively, with an ORR of 87.2 % and a disease control rate of 97.7 %. Progression-free survival (PFS) and overall survival (OS) events occurred in 78 and 47 patients, respectively. The median PFS and OS were 9.0 (95 % confidence interval [CI]: 7.5-10.5) and 19 (95 % CI: 16.7-21.3) months, respectively. The incidence of grade 3 or higher adverse events (AEs) was 58.1 % and 24 patients (27.9 %) experienced serious treatment-related AEs. No fatalities consequent to AEs were recorded. CONCLUSION: Given its promising efficacy, safety profile and durability, anlotinib combined with chemotherapy deserves further investigation as first-line anticancer therapy in ES-SCLC (NCT: 04684017).

Different Characteristics and Survival between Surgically Resected Pure and Combined Pulmonary Large Cell Neuroendocrine Carcinoma.

BACKGROUND: Large cell neuroendocrine carcinoma (LCNEC) is a rare high-grade neuroendocrine carcinoma of the lung. Little is known about the differences between the pure and combined LCNEC subtypes, and thus we conducted this study to provide more comprehensive insight into LCNEC. METHODS: We reviewed 221 patients with pure LCNEC (P-LCNEC) and 120 patients with combined LCNEC (C-LCNEC) who underwent pulmonary surgery in our hospital to compare their clinical features, driven genes' status (EGFR/ALK/ROS1/KRAS/BRAF), and adjuvant chemotherapy regimens. Propensity score matching (PSM) was applied to reduce selection bias. RESULTS: The P-LCNEC group included a higher proportion of males and smokers than the C-LCNEC group. Furthermore, the C-LCNEC group had higher incidences of visceral pleural invasion (VPI), EGFR mutation and ALK rearrangement compared with the P-LCNEC group. Expression of neuroendocrine markers (CD56, CGA, and SYN) and recurrence patterns were not significantly different between the two groups. The P-LCNEC group had better disease-free survival (DFS) and overall survival (OS) compared with the C-LCNEC group (median DFS: 67.0 vs. 28.1 months, p = 0.021; median OS: 72.0 vs. 45.0 months, p = 0.001), which was further confirmed by the PSM method (p = 0.004 and p < 0.001, respectively). Adjuvant chemotherapy was also an independent factor for DFS and OS. Subgroup analysis found that regardless of whether it was for the entire LCNEC group or the P- and C-LCNEC subtypes, the small cell lung cancer (SCLC) regimens presented with superior survival compared with the non-small cell lung cancer (NSCLC) regimens. CONCLUSION: P-LCNEC was associated with more favorable prognosis compared with C-LCNEC. SCLC-based adjuvant chemotherapy was more appropriate for LCNEC patients than NSCLC-based regimens, regardless of whether they were the pure or combined LCNEC subtypes. C-LCNEC patients may be the potential beneficiary of targeted therapy.

Pembrolizumab Plus Chemotherapy Versus Chemotherapy Monotherapy as a First-Line Treatment in Elderly Patients (≥75 Years Old) With Non-Small-Cell Lung Cancer.

OBJECTIVE: Several trials have shown that pembrolizumab plus chemotherapy was more effective in patients with advanced non-small-cell lung cancer (NSCLC) than chemotherapy monotherapy. However, whether pembrolizumab plus chemotherapy is still a better choice for first-line treatment in elderly patients (≥75 years old) remain unknown. We retrospectively compared the efficacy and safety of these two treatments in elderly patients. PATIENTS AND METHODS: We collected data of 136 elderly patients with advanced NSCLC who were treated with pembrolizumab plus chemotherapy or chemotherapy monotherapy in our hospital from 2018 to 2020. We compared the progression-free survival (PFS) and overall survival (OS) of patients and analyzed which subgroups might benefit more significantly from pembrolizumab plus chemotherapy. RESULTS: In total population, pembrolizumab plus chemotherapy showed superior PFS and OS than chemotherapy monotherapy (PFS: 12.50 months vs. 5.30 months, P<0.001; OS: unreached vs. 21.27 months, P=0.037). Subgroup analysis showed patients with positive PD-L1 expression, stage IV, good performance score (ECOG-PS <2), fewer comorbidities (simplified comorbidity score <9) or female patients had demonstrated a more evident OS benefit in pembrolizumab plus chemotherapy. In terms of safety, the pembrolizumab plus chemotherapy group had higher treatment discontinuation (26% vs. 5%). CONCLUSIONS: Elderly patients using pembrolizumab plus chemotherapy achieved longer PFS and OS, but were more likely to discontinue due to adverse effects, so disease stage, PD-L1 expression, ECOG-PS and comorbidities should be considered when selecting first-line treatment.

The centromere-associated protein CENPU promotes cell proliferation, migration, and invasiveness in lung adenocarcinoma.

CENPU, encoding an important factor involved in kinetochore assembly during mitosis, is associated with shorter survival rates in lung adenocarcinoma (LUAD) patients. CENPU promotes growth rates and invasive behavior of LUAD cells; however, its mechanism of action in LUAD progression remains to be elucidated. CENPU mRNA and protein expression were elevated in LUAD tumors, and high CENPU gene expression was associated with inferior survival prognosis in LUAD patients. CENPU knockdown inhibited LUAD cell proliferation, clone formation, migration, invasion, and epithelial-mesenchymal transition (EMT) in addition to inducing cell cycle arrest and apoptosis in vitro and reduced LUAD xenograft tumor growth in vivo. Furthermore, we identified CENPU-regulated genes significantly enriched for proliferation and apoptosis pathways, and identified HSP Family Member C10 (DNAJC10) as putative effector of CENPU. CENPU knockdown produced DNAJC10 protein downregulation, and DNAJC10 overexpression partially rescued the phenotypic effects of CENPU knockdown in LUAD cells. Moreover, CENPU's coiled-coil domain was essential for CENPU's phenotypic effects in LUAD cells. In conclusion, the kinetochore component CENPU plays a critical role in LUAD cell proliferation and invasiveness. Targeting CENPU-DNAJC10 axis may inhibit LUAD tumor cell proliferation and metastasis.

Combined large cell neuroendocrine carcinoma: clinical characteristics, prognosis and postoperative management.

OBJECTIVES: Combined large cell neuroendocrine carcinoma (C-LCNEC) is pulmonary large cell neuroendocrine carcinoma (LCNEC) mixed with other components, such as adenocarcinoma (AD) and squamous cell carcinoma (SCC). This study aimed to describe the distinct features between C-LCNEC with different components and explore the treatment strategy. METHODS: We retrospectively collected data of 96 C-LCNEC patients who underwent surgical resection. Propensity score matching was used to balance baseline characteristics of LCNEC combined with AD (LCNEC/AD) and LCNEC combined with SCC (LCNEC/SCC). RESULTS: In our final cohort, 71 (74%) were LCNEC/AD, while 25 (26%) were LCNEC/SCC. LCNEC/AD was more likely to occur in female, younger adults, with visceral pleural invasion and with driver gene expression. However, there was no significant difference in disease-free survival and overall survival between the 2 groups (before matching: P = 0.79 and P = 0.85; after matching: P = 0.87 and P = 0.48), while adjuvant chemotherapy (P = 0.019 and P = 0.043) was an independent predictor. C-LCNEC patients of stage II or III receiving adjuvant chemotherapy had longer disease-free survival and overall survival (P = 0.054 and P = 0.025), and the benefit of etoposide-based chemotherapy was greater than the other regimens (P = 0.010 and P = 0.030). EGFR and ALK mutations were present in 28% (17/60) and 7% (4/60) of C-LCNEC patients, respectively, and they responded well to targeted therapy. CONCLUSIONS: LCNEC/AD was the most common type of C-LCNEC, and there were many differences between different combined components. Adjuvant chemotherapy, especially etoposide-based chemotherapy, was a beneficial option for resected C-LCNEC.Subj collection: 152.

Local consolidative therapy for synchronous oligometastatic non-small cell lung cancer treated with first-line pembrolizumab: A retrospective observational study.

BACKGROUND: Local consolidative therapy (LCT) has emerged as a treatment option in patients with oligometastatic non-small cell lung cancer (NSCLC) undergoing chemotherapy or targeted therapy. However, the current literature lacks evidence as to whether LCT improves survival in NSCLC patients receiving immunotherapy. Our study aimed to assess whether LCT combined with pembrolizumab ± chemotherapy could improve the survival of patients with synchronous oligometastatic NSCLC. METHODS: Patients with NSCLC, without EGFR or ALK genetic aberrations, who were treated with first-line pembrolizumab ± chemotherapy, were included in the study. Survival analysis of the LCT and non-LCT groups was compared. RESULTS: A total of 231 patients were included in the study. The median follow-up time was 15.24 months. Median progression-free survival (PFS) and overall survival (OS) of the entire cohort were 12.00 and 23.43 months, respectively. Of the 231 patients included, 76 patients received LCT combined with pembrolizumab ± chemotherapy (LCT group) while 155 patients received pembrolizumab ± chemotherapy alone (non-LCT group). Of note, the PFS of the LCT and non-LCT groups was 13.97 and 10.08 months (p = 0.016), respectively. The OS were 30.67 and 21.97 months (p = 0.011), respectively. The PFS and OS were significantly improved with LCT for patients with brain or lung metastases but not bone metastases. No significant increase in treatment-related toxicity was observed in the LCT group. CONCLUSIONS: The present study shows that LCT to metastatic sites is an option for consideration in patients with synchronous oligometastatic NSCLC during first-line pembrolizumab treatment, with significantly improved PFS and OS compared with systemic treatment alone.

The clinicopathological and molecular characteristics of resected EGFR-mutant lung adenocarcinoma.

BACKGROUND: Epidermal growth factor receptor (EGFR) mutations were frequently found with concomitant genetic alterations in lung adenocarcinoma (LUAD). This study aimed to investigate the profile of concomitant alterations of EGFR-mutant LUAD ≤3 cm in size and its prognostic effect on recurrence. METHODS: From January 2018 to December 2018, patients with resected LUAD ≤3 cm in size in Shanghai Chest Hospital were identified. All patients underwent capture-based targeted next-generation sequencing (NGS) with a panel of 68 lung cancer-related genes and were found with EGFR mutation. Clinicopathological and molecular characteristics and recurrence-free survival (RFS) were analyzed. RESULTS: A total of 637 patients were enrolled in this study. The top three frequent co-mutational genes were TP53 (179 of 637, 28.1%), PIK3CA (27 of 637, 4.2%), and ATM (22 of 637, 3.5%). The most common amplified genes were EGFR (37 of 637, 5.8%), followed by CDK4 (37 of 637, 5.8%) and MYC (12 of 637, 2.0%). Only TP53 mutation and EGFR amplification were adverse prognostic factors for RFS (all p < 0.001) in univariate analysis. Multivariable analysis further demonstrated that TP53 mutation and EGFR amplification were independent risk factors for RFS [(hazard ratio (HR) 2.07, 95% confidence interval (CI) 1.07-4.00, p = 0.030; HR 3.09, 95% CI 1.49-6.40, p = 0.002, respectively]. CONCLUSIONS: Concomitant TP53 mutation and EGFR amplification were poor prognostic factors for RFS in patients with EGFR-mutant resected LUAD. Our findings provide valuable understanding of the impact of concurrent alterations and implication for better implementation of precision therapy for patients.

DUBR suppresses migration and invasion of human lung adenocarcinoma cells via ZBTB11-mediated inhibition of oxidative phosphorylation.

Long noncoding RNAs (lncRNAs) are involved in a variety of cancers, but the role of LncRNA DUBR in lung adenocarcinoma (LUAD), the most prevalent form of lung cancer, remains unclear. In this study we investigated the expression of DUBR in LUAD to ascertain its association with the clinical pathology and prognosis of LUAD. Analysis of mRNA expression in The Cancer Genome Atlas (TCGA) LUAD database and in-house LUAD cohort (n = 94) showed that DUBR was significantly downregulated in LUAD, and was associated with poor prognosis. In LUAD cell lines (H1975, A549), overexpression of DUBR significantly suppressed the migration and invasion of the LUAD cells. We demonstrated that c-Myc could bind to the promoter of DUBR, and transcriptionally suppressed its expression. Knockdown of c-Myc almost completely blocked the invasion and migration of LUAD cells, whereas knockdown of DUBR partially rescued c-Myc-knockdown suppressed cell migration and invasion. Furthermore, DUBR overexpression significantly increased the expression of a downstream protein of DUBR, zinc finger, and BTB domain containing 11 (ZBTB11), in H1975 and A549 cells; knockdown of ZBTB11 partially rescued the DUBR-overexpression suppressed cell migration and invasion; knockdown of c-Myc significantly upregulated the expression of ZBTB11 in LUAD cells. Finally, we revealed that DUBR/ZBTB11 axis suppressed oxidative phosphorylation in LUAD cells. In short, we demonstrate that c-Myc/DUBR/ZBTB11 axis suppresses migration and invasion of LUAD by attenuating cell oxidative phosphorylation, which provides new insights into the regulatory mechanism of DUBR.

Comparative Study of Pulmonary Combined Large-Cell Neuroendocrine Carcinoma and Combined Small-Cell Carcinoma in Surgically Resected High-Grade Neuroendocrine Tumors of the Lung.

OBJECTIVES: Pulmonary large-cell neuroendocrine carcinoma (LCNEC) and small-cell lung cancer (SCLC) are both classified as pure and combined subtypes. Due to the low incidence and difficult diagnosis of combined LCNEC (C-LCNEC) and combined SCLC (C-SCLC), few studies have compared their clinical features and prognosis. MATERIALS AND METHODS: We compared the clinical features, mutation status of driver genes (EGFR, ALK, ROS1, KRAS, and BRAF), and prognosis between C-LCNEC and C-SCLC. Univariate and multivariate Cox regression analyses were applied for survival analysis. RESULTS: We included a total of 116 patients with C-LCNEC and 76 patients with C-SCLC in the present study. There were significant differences in distribution of smoking history, tumor location, pT stage, pN stage, pTNM stage, visceral pleural invasion (VPI), and combined components between C-LCNEC and C-SCLC (P<0.05 for all). C-SCLC was more advanced at diagnosis as compared to C-LCNEC. The incidence of EGFR mutations in C-LCNEC patients was higher than C-SCLC patients (25.7 vs. 5%, P=0.004). We found that tumor size, pN stage, peripheral CEA level, and adjuvant chemotherapy were independently prognostic factors for DFS and OS in C-LCNEC patients, while peripheral NSE level, pT stage, pN stage, VPI and adjuvant chemotherapy were independently associated with DFS and OS for C-SCLC patients (P<0.05 for all). Propensity score matching with adjustment for the confounders confirmed a more favorable DFS (P=0.032) and OS (P=0.019) in patients with C-LCNEC in comparison with C-SCLC patients upon survival analysis. CONCLUSIONS: The mutation landscape of driver genes seemed to act in different way between C-SCLC and C-LCNEC, likely by which result in clinical phenotype difference as well as better outcome in C-LCNEC.

Pembrolizumab Alone or Combined With Chemotherapy in Advanced NSCLC With PD-L1 ≥50%: Results of a Retrospective Study.

OBJECTIVES: Pembrolizumab plus platinum-based chemotherapy and pembrolizumab monotherapy (PM) both become standard of care in patients with advanced non-small-cell lung cancer (NSCLC) and a programmed death ligand 1 (PD-L1) tumor proportion score (TPS) greater than 50%. This study aimed to figure out the better treatment choice. METHOD: In this retrospective analysis, we compared the clinical efficacy of PM and PC as first-line treatment in NSCLC patients with a PD-L1 ≥50% and negative for genomic alterations in the EGFR and ALK genes. RESULT: Among the population, 115 patients received PC, and 91 patients received PM. Up to Dec 30, 2020, median follow-up was 17.13 months. The median progression-free survival (PFS) rates of PC and PM were 12.37 and 9.60 months (HR: 0.44, p < 0.001), respectively. The median overall survival (OS) rates were NE and 28.91 months (HR: 0.40, p = 0.005), respectively. Subgroup analysis found that the PFS benefit of PC was evident in most subgroups excepting patients with brain metastasis. The 1-year overall survival rates of PC and PM were 89.3% and 76.1%, respectively. The ORR was 61.7 and 46.9% (p = 0.004), respectively. CONCLUSION: In patients with previously untreated, PD-L1 ≥50%, advanced NSCLC without EGFR or ALK mutations, the addition of pembrolizumab to standard platinum-based chemotherapy seems to be the preferred treatment, which needs to be validated by further prospective trials.

Pembrolizumab Plus Chemotherapy or Anlotinib vs. Pembrolizumab Alone in Patients With Previously Treated EGFR-Mutant NSCLC.

OBJECTIVES: More and more encouraging evidence revealed that immunotherapy could improve clinical outcomes in patients with previously treated non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) variations. However, immunotherapy is still a controversy for NSCLC patients with EGFR mutation. METHOD: In this retrospective analysis, we compared the clinical efficacy of pembrolizumab monotherapy (PM), pembrolizumab combined with chemotherapy (P+C) and pembrolizumab combined with anlotinib (P+A) in NSCLC patients with EGFR mutation who had failed on EGFR-TKI and platinum-based chemotherapy. RESULT: Eighty-six patients were included in this study. The overall median progression free survival (PFS) was 3.24 months. Multivariate analysis suggested that EGFR L858R and combined therapy were positive prognostic factors of PFS. The overall median OS was 12.28 months. Multivariate analysis found that high PD-L1 expression (≥50%) and combined therapy seemed to be positive prognostic factors of OS. Among the population, 32 patients received PM, 26 patients received P+C and 28 patients received P+A. Up to Jan 30, 2021, the median progression-free survival was 1.5 months in the PM group, 4.30 months in the P+C group and 3.24 months in the P+A group. The median OS were 7.41, 14.92 and 15.97 months, respectively. The ORR were 3.1%, 23.1% and 21.4%. CONCLUSION: The addition of chemotherapy or antiangiogenic therapy to pembrolizumab resulted in significantly longer PFS, OS and ORR than pembrolizumab alone in our study. EGFR L858R might be a positive prognostic factor of PFS and high PD-L1 expression might be a positive prognostic factor of OS.

Atezolizumab prolongs overall survival over docetaxel in advanced non-small-cell lung cancer patients harboring STK11 or KEAP1 mutation.

Somatic mutations of STK11 or KEAP1 are associated with poor clinical outcomes for advanced non-small-cell lung cancer (aNSCLC) patients receiving immune checkpoint inhibitors (ICIs), chemotherapy, or targeted therapy. Which treatment regimens work better for STK11 or KEAP1 mutated (SKmut) aNSCLC patients is unknown. In this study, the efficacy of atezolizumab versus docetaxel in SKmut aNSCLC was compared. A total of 157 SKmut aNSCLC patients were identified from POPLAR and OAK trials, who were tested by blood-based FoundationOne next-generation sequencing assay. Detailed clinical data and genetic alterations were collected. Two independent cohorts were used for biomarker validation (n = 30 and 20, respectively). Median overall survival was 7.3 months (95% confidence interval [CI], 4.8 to 9.9) in the atezolizumab group versus 5.8 months (95% CI, 4.4 to 7.2) in the docetaxel group (adjusted hazard ratio [HR] for death, 0.70; 95% CI, 0.49 to 0.99; P = .042). Among atezolizumab-treated patients, objective response rate, disease control rate, and durable clinical benefit were higher when blood tumor mutation burden (bTMB) and PD-L1 being higher (biomarker 1, n = 61) or with FAT3 mutation-positive tumors (biomarker 2, n = 83) than otherwise. The interactions for survival between these two biomarkers and treatments were significant, which were further validated in two independent cohorts. In SKmut patients with aNSCLC, atezolizumab was associated with significantly longer overall survival in comparison to docetaxel. Having FAT3 mutation or high TMB and PD-L1 expression potentially predict favorable response in SKmut patients receiving atezolizumab.

PlGF knockdown attenuates hypoxia-induced stimulation of cell proliferation and glycolysis of lung adenocarcinoma through inhibiting Wnt/ß-catenin pathway.

BACKGROUND: Angiogenic placental growth factor (PlGF) plays a role in hypoxia-induced angiogenesis. Here, we aimed to investigate the biological roles of PlGF in cell proliferation and glycolysis of lung adenocarcinoma (LUAD) and the underlying molecular mechanisms. METHODS: PlGF was knocked down in H358 and H1975 cells by lentiviruses, which were then cultured under hypoxia (90% N2, 5%CO2 and 5%O2) for 24 h. PlGF was overexpressed in PC9 cells treated with XAV939, inhibitor of Wnt/ß-catenin signaling pathway. PlGF-silencing H1975 cells were implanted into mice, and tumor xenografts were harvested and analyzed. RESULTS: Hypoxia treatment led to up-regulation of PlGF, C-myc, lactate dehydrogenase A (LDHA), and ß-catenin, promotion of cell proliferation and glycolysis in H358 and H1975 cells, which were obviously reversed by knocking down PlGF. In tumors, PlGF knockdown significantly prohibited cell proliferation and glycolysis, and decreased expression of C-myc, LDHA, and ß-catenin. PlGF overexpression markedly strengthened cell proliferation, which was inhibited by ß-catenin knockdown. Consistently, XAV939, inhibitor of Wnt/ß-catenin pathway, also inhibited PlGF-induced cell proliferation, glycolysis, and ß-catenin expression in PC9 cells. CONCLUSION: PlGF knockdown inhibited the stimulatory effect of hypoxia on cell proliferation and glycolysis of LUAD through deactivating Wnt/ß-catenin pathway.

Clinical significance of visceral pleural and lymphovascular invasion in surgically resected adenosquamous lung cancer.

OBJECTIVES: The aim of this study was to assess the relationship between visceral pleural invasion (VPI), lymphovascular invasion (LVI) and other clinicopathological characteristics and their prognostic impact on surgically resected adenosquamous carcinoma (ASC). METHODS: We retrospectively reviewed 256 patients with radically resected ASC between January 2010 and December 2015. Patients were divided into 2 groups: those with VPI and those with LVI. The effects of VPI and LVI on disease-free survival and overall survival were evaluated, further stratified by tumour size and lymph node status. RESULTS: Finally, 213 patients with ASC were enrolled in our study. VPI was correlated with tumour location (P < 0.001), pT stage (P < 0.001) and pN stage (P = 0.012). LVI was related to age (P = 0.005) and pN stage (P = 0.003). Both VPI and LVI were adverse prognostic factors for disease-free survival (P = 0.008, P = 0.028) and overall survival (P = 0.005, P = 0.009) using the Kaplan-Meier method. In multivariable analysis only, VPI was an independent risk factor for disease-free survival [hazard ratio (HR) 0.61, 95% confidence interval (CI) 0.42-0.87; false discovery rate, adjusted P = 0.020] and overall survival (HR 0.60, 95% CI 0.42-0.86; false discovery rate, adjusted P = 0.017). When the prognostic value of VPI was stratified by tumour size and lymph node status, we observed that only patients with VPI in tumours ≤4 cm and patients with N0 status had a worse prognosis than those without visceral invasion (P < 0.05). CONCLUSIONS: VPI and LVI were poor prognostic factors in patients with ASC, but only VPI was an independent factor for survival, especially in patients with tumours ≤4 cm and pN0 status.