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Abstract The incidence of multiple primary lung cancer (MPLC) is increasing, with some of our surgical patients exhibiting numerous lesions. We defined lung cancer with five or more primary lesions as super MPLCs. Elucidating the genomic characteristics of this special MPLC subtype can help reduce disease burden and understand tumor evolution. In our cohort of synchronous super early-stage MPLCs (PUMCH-ssesMPLC), whole-exome sequencing on 130 resected malignant specimens from 18 patients provided comprehensive super-MPLC genomic landscapes. Mutations are enriched in PI3k-Akt and MAPK pathways. Their BRAF mutation frequency (31.5%) is significantly higher than MPLC with fewer lesions and early-stage single-lesion cancer, while EGFR mutations are significantly fewer (13.8%). As lesion counts increase, BRAF mutations gradually become dominant. Also, invasive lesions more tend to have classic super-MPLC mutation patterns. High-frequency BRAF mutations, especially Class II, and low-frequency EGFR mutations could be a reason for the limited effectiveness of targeted therapy in super-MPLC patients.

Abstract Despite the pivotal role of stannum doping in achieving ultrahigh piezoelectric performance in barium titanate-based ceramics, the fundamental mechanisms underlying this enhancement remain elusive. Here, we introduce a single variable nonstoichiometric stannum strategy in lead-free barium titanate-based ceramics with giant piezoelectricity, revealing that stannum doping contributes intrinsically and extrinsically to enhance piezoelectricity. Density functional theory calculations elucidate the intrinsic enhancement of polarization arising from lattice distortion and increased space for titanium-oxygen bonds induced by optimal stannum doping, which is corroborated by Rayleigh analysis. A phase transition from ferroelectric multiphase coexistence to paraelectric phase is observed, alongside a rapid miniaturized and eventually disappeared domains with increasing stannum doping. This evolution in phase structure and domain configuration induces a nearly vanishing polarization anisotropy and low domain wall energy, facilitating easy polarization rotation and domain wall motion, thereby significantly contributing to the extrinsic piezoelectric response. Consequently, the origins of ultrahigh performance can be attributed to the synergistic effect of stannum-induced intrinsic and extrinsic contributions in barium titanate-based ceramics. This study provides fundamental insights into the role of doping elements and offers guidance for the design of high-performance piezoelectrics.

Abstract In recent years, significant improvement has been made in the management of non‐small cell lung cancer (NSCLC), primarily driven by advances in targeted therapy and immunotherapy. Research on neoadjuvant targeted therapy has also experienced considerable development, primarily directed towards NSCLC harboring epidermal growth factor receptor or anaplastic lymphoma kinase mutations. Nevertheless, there remains a dearth of studies investigating neoadjuvant targeted therapy in the context of BRAF (V‐Raf murine sarcoma viral oncogene homolog B) V600E mutant NSCLC. Herein, we describe the clinical trajectory of a stage IIIA NSCLC patient who underwent a two‐month course of neoadjuvant targeted therapy comprising BRAF and MEK (mitogen‐activated extracellular signal‐regulated kinase) inhibitors prior to surgical intervention, and subsequent postoperative evaluation unveiled a pathological complete response. The case reported here indicates the efficacy and safety of combining BRAF and MEK inhibitors as neoadjuvant targeted therapy in BRAF V600E‐mutant NSCLC and suggests the potential viability of such a therapeutic modality in improving treatment outcomes in this subset of NSCLC.

Abstract Background Lung adenocarcinoma (LUAD) is the most common type of lung cancer and closely associated with the immune system. Emerging evidence suggests that blood immune cell phenotypes in patients with LUAD may undergo alterations. Nevertheless, the limited amount of relevant research makes it difficult to understand the causal links between LUAD and changes in the immune cells. This study aimed to reveal the potential causal relationships between 731 immune cell phenotypes and LUAD. Methods A bidirectional two‐sample Mendelian randomization (MR) analysis was used to clarify causal relationships. Four types of immune phenotypes, absolute cell counts, relative cell counts, median fluorescence intensities (MFIs) of surface antigens, and morphological parameters, were investigated in this study. Heterogeneity tests, horizontal pleiotropy tests, and leave‐one‐out analyses were performed to validate the reliability of our study. Results A total of 26 immune cell characteristics were identified as contributing to the occurrence of LUAD. Memory B cells, IgD−CD38br cells, CD4+ regulatory T cells (Tregs), and plasmacytoid dendritic cells (DCs) may play a role in the development of LUAD. Through reverse MR, our study discovered that the presence of LUAD also induced changes in the expression levels of 16 immune cell traits involving specific surface markers and various types of immune cells, some of which pertain to antigen presentation and immune activation processes. Conclusion Our study demonstrated causal links between several immune cell phenotypes and LUAD, thereby providing indications of the potentially oncogenic physiological state and early screening biomarkers for future research.

The continuous advancement of molecular detection technology has greatly propelled the development of precision medicine for lung cancer. However, tumor heterogeneity is closely associated with tumor metastasis, recurrence, and drug resistance. Additionally, different lung cancer patients with the same genetic mutation may exhibit varying treatment responses to different therapeutic strategies. Therefore, the development of modern precision medicine urgently requires the precise formulation of personalized treatment strategies through personalized tumor models. Lung cancer organoid (LCO) can highly simulate the biological characteristics of tumor in vivo, facilitating the application of innovative drugs such as antibody-drug conjugate in precision medicine for lung cancer. With the development of co-culture model of LCO with tumor microenvironment and tissue engineering technology such as microfluidic chip, LCO can better preserve the biological characteristics and functions of tumor tissue, further improving high-throughput and automated drug sensitivity experiment. In this review, we combine the latest research progress to summarize the application progress and challenges of LCO in precision medicine for lung cancer.

Abstract Inflammatory arthritis (IA) is a common rheumatic adverse event following immune checkpoint inhibitors treatment. The clinical disparities between IA and rheumatoid arthritis (RA) imply disease heterogeneity and distinct mechanisms, which remain elusive. Here, we profile CD45+ cells from the peripheral blood or synovial fluid (SF) of patients with PD-1-induced IA (PD-1-IA) or RA using single-cell RNA sequencing. We report the predominant expansion of IL1B hi myeloid cells with enhanced NLRP3 inflammasome activity, in both the SF and peripheral blood of PD-1-IA, but not RA. IL1B hi macrophages in the SF of PD-1-IA shared similar inflammatory signatures and might originate from peripheral IL1B hi monocytes. Exhausted CD8+ T cells (Texs) significantly accumulated in the SF of patients with PD-1-IA. IL1B hi myeloid cells communicated with CD8+ Texs possibly via the CCR1-CCL5/CCL3 and CXCL10-CXCR3 axes. Collectively, these results demonstrate different cellular and molecular pathways in PD-1-IA and RA and highlight IL1B hi macrophages as a possible therapeutic target in PD-1-IA.

Due to the advancement of 16S rRNA sequencing technology, the lower respiratory tract microbiota, which was considered non-existent, has been revealed. The correlation between these microorganisms and diseases such as tumor has been a hot topic in recent years. As the bacteria in the surrounding can infiltrate the tumors, researchers have also begun to pay attention to the biological behavior of tumor bacteria and their interaction with tumors. In this review, we present the characteristic of the lower respiratory tract bacteria and summarize recent research findings on the relationship between these microbiota and lung cancer. On top of that, we also summarize the basic feature of bacteria in tumors and focus on the characteristic of the bacteria in lung cancer. The relationship between bacteria in lung cancer and tumor development is also been discussed. Finally, we review the potential clinical applications of bacterial communities in the lower respiratory tract and lung cancer, and summarize key points of sample collection, sequencing, and contamination control, hoping to provide new ideas for the screening and treatment of tumors.

Minute pulmonary meningothelial-like nodules (MPMNs) are benign small lesions in the lungs, with similar pathological characteristics to the meningeal epithelium. MPMNs have similar imaging manifestations to malignant tumors, which can lead to misdiagnosis in clinical practice. There is no consensus on the pathogenesis of MPMNs, with some suggest that MPMNs derive from reactive proliferation, while others suggest that MPMNs share a common origin and molecular mechanism with meningiomas in the central nervous system. Understanding the characteristics of MPMNs and studying their pathogenesis will help improve the understanding and diagnosis of MPMNs. In this article, we reviewed the clinical, pathological, imaging characteristics, differential diagnosis and pathogenesis of MPMNs. We also analyze the existing research advances regarding the pathogenesis and propose prospects for further research.

Abstract Background With the rapidly increasing morbidity and mortality, lung cancer has been considered one of the serious malignant tumors, affecting millions of patients globally. Currently, the pathogenesis of lung cancer remains unclear, hindering the development of effective treatment. This study aims to investigate the mechanisms of lung cancer and develop an effective therapeutic approach for intervention in preventing lung cancer progress. Methods The USP5 levels are detected in lung cancerous and paracancerous tissue by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting methods to explore their roles in lung cancer progression. MTT, colony assay, and transwell chamber approaches are employed to measure cell viability, proliferation, and migration, respectively. Further, flow cytometry experiments are performed to examine the effect of USP5 on lung cancer. Finally, the investigations in vivo are executed using the mice subcutaneous tumor model to identify the effect of USP5 in promoting lung cancer development. Results Notably, USP5 is highly expressed in lung cancer, USP5 overexpression promoted the proliferation and migration in the lung cancer cell lines, H1299 and A549, while knockdown of USP5 inhibited these via regulating the PARP1-mediated mTOR signaling pathway. Furthermore, the subcutaneous tumors model was established in C57BL/6 mice, and the volume of subcutaneous tumors was significantly reduced after silencing USP5, while increased after USP5 overexpression and decreased significantly with shRARP1 treatment at the same time. Conclusions Together, USP5 could promote the progression of lung cancer cells by mTOR signaling pathway and interacting with PARP1, indicating that USP5 may become a new target for lung cancer treatment.

Lung cancer is one of the leading causes of cancer-related morbidity and mortality. Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) have become the standard treatment for EGFR-mutated advanced non-small cell lung cancer (NSCLC). Unfortunately, drug resistance is inevitable in most cases. EGFR-TKI combined with angiogenesis inhibitors is a treatment scheme being explored to delay the therapeutic resistance, which is called “A+T treatment”. Several clinical trials have demonstrated that the A+T treatment can improve the progression free survival (PFS) of the NSCLC patients. However, compared to EGFR-TKI monotherapy, the benefits of the A+T treatment based on different EGFR-TKIs, as well as its safety and exploration prospects are still unclear. Therefore, we reviewed the literature related to all three generations EGFR-TKIs combined with angiogenesis inhibitors, and summarized the mechanism, benefit, safety, optimal target population of A+T treatment.

Microsatellite instability (MSI), high tumor mutation burden (TMB-H) and programmed cell death 1 ligand 1 (PD-L1) expression are hot biomarkers related to the improvement of immunotherapy response. Two cohorts of non-small-cell lung cancer (NSCLC) were collected and sequenced via targeted next-generation sequencing. Drug analysis was then performed on the shared genes using three different databases: Drugbank, DEPO and DRUGSURV. A total of 27 common genes were mutated in at least two groups of TMB-H-, MSI- and PD-L1-positive groups. AKT1, SMAD4, SCRIB and AXIN2 were severally involved in PI3K-activated, transforming growth factor beta (TGF-β)-activated, Hippo-repressed and Wnt-repressed pathways. This study provides an understanding of the mutated genes related to the immunotherapy biomarkers of NSCLC.

Abstract Early detection can benefit cancer patients with more effective treatments and better prognosis, but existing early screening tests are limited, especially for multi-cancer detection. This study investigated the most prevalent and lethal cancer types, including primary liver cancer (PLC), colorectal adenocarcinoma (CRC), and lung adenocarcinoma (LUAD). Leveraging the emerging cell-free DNA (cfDNA) fragmentomics, we developed a robust machine learning model for multi-cancer early detection. 1,214 participants, including 381 PLC, 298 CRC, 292 LUAD patients, and 243 healthy volunteers, were enrolled. The majority of patients (N = 971) were at early stages (stage 0, N = 34; stage I, N = 799). The participants were randomly divided into a training cohort and a test cohort in a 1:1 ratio while maintaining the ratio for the major histology subtypes. An ensemble stacked machine learning approach was developed using multiple plasma cfDNA fragmentomic features. The model was trained solely in the training cohort and then evaluated in the test cohort. Our model showed an Area Under the Curve (AUC) of 0.983 for differentiating cancer patients from healthy individuals. At 95.0% specificity, the sensitivity of detecting all cancer reached 95.5%, while 100%, 94.6%, and 90.4% for PLC, CRC, and LUAD, individually. The cancer origin model demonstrated an overall 93.1% accuracy for predicting cancer origin in the test cohort (97.4%, 94.3%, and 85.6% for PLC, CRC, and LUAD, respectively). Our model sensitivity is consistently high for early-stage and small-size tumors. Furthermore, its detection and origin classification power remained superior when reducing sequencing depth to 1× (cancer detection: ≥ 91.5% sensitivity at 95.0% specificity; cancer origin: ≥ 91.6% accuracy). In conclusion, we have incorporated plasma cfDNA fragmentomics into the ensemble stacked model and established an ultrasensitive assay for multi-cancer early detection, shedding light on developing cancer early screening in clinical practice.

Abstract Red blood cells (RBC) are commonly known as cells with no nucleus or mitochondria and are assumed to be a transportation vehicle. This study confirms that RBC contain long DNA fragments inside with stain by both microscope and flow cytometry, which covers most nuclear and mitochondrial genome regions by next‐generation sequencing (NGS). Such characteristics demonstrate a significant difference compared with A549 cell line or paired peripheral blood mononuclear cell as nucleated cells. To further explore the characteristics of RNA DNA, DNA from 20 RBC samples is sequenced by NGS. Interestingly, several gaps and multiple regions with copy number variation are observed significantly different between different samples, which could be used to distinguish samples with different health status accurately. Using an in vitro co‐culture system, it is shown that RBC could absorb DNA‐bearing tumorigenic mutations from cancer cell lines but requires cell‐to‐cell contact. Finally, based on a small scale clinical trial, it is confirmed that common genetic mutations of cancer tissues could be detected in RBC from patients with early‐stage non‐small‐cell lung cancer. This study highlights a new biological phenomenon involving RBC and its translational potential as a novel liquid biopsy technology platform for early cancer screening and diagnosis of malignancy.

The conventional two-dimensional (2D) tumor cell lines in Petri dishes have played an important role in revealing the molecular biological mechanism of lung cancer. However, they cannot adequately recapitulate the complex biological systems and clinical outcomes of lung cancer. The three-dimensional (3D) cell culture enables the possible 3D cell interactions and the complex 3D systems with co-culture of different cells mimicking the tumor microenvironments (TME). In this regard, patient-derived models, mainly patient-derived tumor xenograft (PDX) and patient-derived organoids discussed hereby, are with higher biological fidelity of lung cancer, and regarded as more faithful preclinical models. The significant Hallmarks of Cancer is believed to be the most comprehensive coverage of current research on tumor biological characteristics. Therefore, this review aims to present and discuss the application of different patient-derived lung cancer models from molecular mechanisms to clinical translation with regards to the dimensions of different hallmarks, and to look to the prospects of these patient-derived lung cancer models.

Abstract The treatment of stage IIIB non‐small cell lung cancer (NSCLC) is complicated, the best strategy is chosen individually and surgery is usually not recommended. A 50‐year‐old female was diagnosed with locally advanced lung adenocarcinoma (stage IIIB, T2bN3M0). Fluorescence in situ hybridization (FISH) analysis revealed an ALK rearrangement. Crizotinib was administered and progression was seen after five months. The patient then received ceritinib with a palliative intent, which led to downstaging (IIIA[N2]) with a radiological and metabolic response. Right lower lobe lobectomy was performed at 12 months post‐surgery, and the patient is still disease‐free according to the last computed tomography (CT) scan. The unintended downstaging from ceritinib provided a chance for resection in our patient who had ALK‐positive stage IIIB NSCLC after the failure of first‐line crizotinib, indicating potential usage of ceritinib in the neoadjuvant setting. Future perspective trials are warranted to investigate the role of ceritinib in earlier stages as a primary drug.

Summary: Background: Early diagnosis benefits lung cancer patients with higher survival, but most patients are diagnosed after metastasis. Although cell-free DNA (cfDNA) analysis holds promise, its sensitivity for detecting early-stage lung cancer is unsatisfying. We leveraged cfDNA fragmentomics to develop a predictive model for invasive stage I lung adenocarcinoma (LUAD). Methods: 292 stage I LUAD patients from three medical centers were included together with 230 healthy controls whose plasma cfDNA samples were profiled by whole-genome sequencing (WGS). Multiple cfDNA fragmentomic motif features and machine learning models were compared in the training cohort to select the best model. Model performance was assessed in the internal and external validation cohorts and an additional dataset. Findings: A logistic regression model using the 6bp-breakpoint-motif feature was selected. It yielded 98·0% sensitivity and 94·7% specificity in the internal validation cohort [Area Under the Curve (AUC): 0·985], while 92·5% sensitivity and 90·0% specificity were achieved in the external validation cohort (AUC: 0·954). It is sensitive for early-stage (100% sensitivity for minimally invasive adenocarcinoma, MIA) and

BackgroundGenomic profiling of cerebrospinal fluid (CSF) can be used to detect actionable mutations and guide clinical treatment of non-small cell lung cancer (NSCLC) patients with central nervous system (CNS) metastases. Examining the performance of CSF samples in real-world settings can confirm the potential of CSF genotyping for guiding therapy in clinical practice.Patients and MethodsWe included 1,396 samples from 970 NSCLC patients with CNS metastases in real-world settings. All samples underwent targeted next-generation sequencing of 1,021 cancer-relevant genes. In total, 100 CSF samples from 77 patients who had previously received targeted treatment were retrospectively analyzed to explore the mechanisms of TKI-resistance.ResultsFor NSCLC patients with CNS metastases, CSF samples were slightly more often used for genomic sequencing in treated patients with only distant CNS metastases compared to other patients (10.96% vs. 0.81–9.61%). Alteration rates in CSF samples were significantly higher than those in plasma, especially for copy number variants (CNV). The MSAFs of CSF samples were significantly higher than those of plasma and tumor tissues (all p

Background and objective Perioperative treatment has become an increasingly important aspect of the management of patients with non-small cell lung cancer (NSCLC). Small-scale clinical studies performed in recent years have shown improvements in the major pathological remission rate after neoadjuvant therapy, suggesting that it will soon become an important part of NSCLC treatment. Nevertheless, neoadjuvant immunotherapy may be accompanied by serious adverse reactions that lead to delay or cancelation of surgery, additional illness, and even death, and have therefore attracted much attention. The purpose of the clinical recommendations is to form a diagnosis and treatment plan suitable for the current domestic medical situation for the immune-related adverse event (irAE). Methods This recommendation is composed of experts in thoracic surgery, oncologists, thoracic medicine and irAE related departments (gastroenterology, respirology, cardiology, infectious medicine, hematology, endocrinology, rheumatology, neurology, dermatology, emergency section) to jointly complete the formulation. Experts make full reference to the irAE guidelines, large-scale clinical research data published by thoracic surgery, and the clinical experience of domestic doctors and publicly published cases, and repeated discussions in multiple disciplines to form this recommendation for perioperative irAE. Results This clinical recommendation covers the whole process of prevention, evaluation, examination, treatment and monitoring related to irAE, so as to guide the clinical work comprehensively and effectively. Conclusion Perioperative irAE management is an important part of immune perioperative treatment of lung cancer. With the continuous development of immune perioperative treatment, more research is needed in the future to optimize the diagnosis and treatment of perioperative irAE.

Abstract Background The incidence of stage I and stage II lung adenocarcinoma (LUAD) is likely to increase with the introduction of annual screening programs for high-risk individuals. We aimed to identify a reliable prognostic signature with immune-related genes that can predict prognosis and help making individualized management for patients with early-stage LUAD. Methods The public LUAD cohorts were obtained from the large-scale databases including 4 microarray data sets from the Gene Expression Omnibus (GEO) and 1 RNA-seq data set from The Cancer Genome Atlas (TCGA) LUAD cohort. Only early-stage patients with clinical information were included. Cox proportional hazards regression model was performed to identify the candidate prognostic genes in GSE30219, GSE31210 and GSE50081 (training set). The prognostic signature was developed using the overlapped prognostic genes based on a risk score method. Kaplan–Meier curve with log-rank test and time-dependent receiver operating characteristic (ROC) curve were used to evaluate the prognostic value and performance of this signature, respectively. Furthermore, the robustness of this prognostic signature was further validated in TCGA-LUAD and GSE72094 cohorts. Results A prognostic immune signature consisting of 21 immune-related genes was constructed using the training set. The prognostic signature significantly stratified patients into high- and low-risk groups in terms of overall survival (OS) in training data set, including GSE30219 (HR = 4.31, 95% CI 2.29–8.11; P = 6.16E−06), GSE31210 (HR = 11.91, 95% CI 4.15–34.19; P = 4.10E−06), GSE50081 (HR = 3.63, 95% CI 1.90–6.95; P = 9.95E−05), the combined data set (HR = 3.15, 95% CI 1.98–5.02; P = 1.26E−06) and the validation data set, including TCGA-LUAD (HR = 2.16, 95% CI 1.49–3.13; P = 4.54E−05) and GSE72094 (HR = 2.95, 95% CI 1.86–4.70; P = 4.79E−06). Multivariate cox regression analysis demonstrated that the 21-gene signature could serve as an independent prognostic factor for OS after adjusting for other clinical factors. ROC curves revealed that the immune signature achieved good performance in predicting OS for early-stage LUAD. Several biological processes, including regulation of immune effector process, were enriched in the immune signature. Moreover, the combination of the signature with tumor stage showed more precise classification for prognosis prediction and treatment design. Conclusions Our study proposed a robust immune-related prognostic signature for estimating overall survival in early-stage LUAD, which may be contributed to make more accurate survival risk stratification and individualized clinical management for patients with early-stage LUAD.

Background Patients who have previously undergone surgical resection of initial primary lung cancer (IPLC) are at high risk of developing second primary lung cancer (SPLC). There are still no standard treatments for SPLC. This study aimed to identify the prognostic factors and compare survival between the different SPLC treatment groups. Methods SPLC patients in the Surveillance, Epidemiology, and End Results (SEER) database between 2007 and 2016 were retrospectively reviewed. Prognostic factors for SPLC were identified, using the least absolute shrinkage and selection operator (LASSO) regression and univariate Cox analysis to select variables for multivariate Cox analysis. Kaplan‐Meier method plus log‐rank test and restricted mean survival time (RMST) were used to compare survival outcome. Results A total of 665 SPLC patients were finally enrolled into the study. Multivariate Cox regression analysis revealed that male vs. female (HR = 1.82, 95% CI: 1.29–2.59, P = 0.001), tumor size of SPLC ≥1 cm vs. 0.05). Patients that received radiotherapy for SPLC also demonstrated similar survival when compared with those that underwent surgery (P > 0.05). Conclusions Radiotherapy and sublobar resection can be considered reasonable alternative treatments for SPLC, especially when patients are unable to tolerate lobectomy.

Precision medicine is an approach to rational treatment selection in the overall management of lung cancer nowadays. The introduction of the patient-derived organoid (PDO) model has established the “black-box” decision-making system from the perspective of in-vitro functional models. This may assist as a complement to the treatment selection strategy based on gene-drug correlation. Further validation must be done in multi-dimensional characteristics recapitulation of the primary tumor in organoids and in large-scale randomized controlled clinical trials. This article will give an introduction to the organoid model and review the application scenarios of organoids in the context of the precise treatment of existing lung cancer.

Abstract Background Synchronous multiple primary lung cancers (sMPLC) are rare forms of lung cancer, and their diagnosis remains as a significant challenge. Distinguishing sMPLC from advanced disease is important as their prognoses and therapeutic management vary dramatically. Case presentation The patient was a 56-year-old Chinese male who exhibited six synchronous invasive adenocarcinomas at diagnosis [T2(6)N0M0], and who achieved durable clinical benefit under adjuvant chemotherapy for 41 months following wedge resection and lobectomy. Whole-exome sequencing revealed that two lesions (L4 and L6) in the left upper lobe of the patient’s lung shared 28 nonsynonymous mutations; thus, suggesting that the lesions may have arisen from a common ancestor at the early stages of tumorigenesis, and spread into distinct histologic subtypes. Moreover, while L5 was in the same lobe as L4 and L6, it represented a distinct lineage as it did not share any mutations with other lesions. Notably, the BRAF V600E oncogenic mutation was exclusive to L5. In addition, the KRAS G12C mutation was identified in three lesions (L1-L3) located in the right lung, which may have resulted from convergent evolution. Conclusion We report a patient with six synchronous invasive adenocarcinomas who demonstrated durable clinical benefits under adjuvant chemotherapy following surgical treatment. While cancer staging is one of the many challenges associated with sMPLC, the data generated through next-generation sequencing can provide information on lesion origins, and thus, advance the era of precision medicine.

Abstract Background A number of studies have reported an association between the occurrence of immune-related adverse events (irAEs) and clinical efficacy in patients undergoing treatment with immune checkpoint inhibitors (ICIs), but the results remain controversial. Methods Under the guidance of a predefined protocol and Preferred Reporting Items for Systematic Reviews and Meta-analyses statement, this meta-analysis included cohort studies investigating the association of irAEs and efficacy of ICIs in patients with cancer. The primary outcome was overall survival (OS), and the secondary outcome was progression-free survival (PFS). Subgroup analyses involving the cancer type, class of ICIs, combination therapy, sample size, model, landmark analysis, and approach used to extract the data were performed. Specific analyses of the type and grade of irAEs were also performed. Results This meta-analysis included 30 studies including 4971 individuals. Patients with cancer who developed irAEs experienced both an OS benefit and a PFS benefit from ICI therapy compared to patients who did not develop irAEs (OS: hazard ratio (HR), 0.54, 95% confidence interval (CI), 0.45–0.65; p

Tumour lysis syndrome (TLS) represents a group of fatal metabolic derangements resulting from the rapid breakdown of tumour cells. TLS typically occurs soon after the administration of chemotherapy in haematologic malignancies but is rarely observed in solid tumours. Here, we report a case of brigatinib-induced TLS after treatment with sequential anaplastic lymphoma kinase (ALK) inhibitors in a patient with advanced ALK-rearranged lung adenocarcinoma. The patient was treated sequentially with crizotinib, alectinib, and ensartinib. High-throughput molecular profiling after disease progression indicated that brigatinib may overcome ALK resistance mutations, so the patient was administered brigatinib as the fourth-line treatment. After 22 days of therapy, he developed oliguria, fever, and progressive dyspnoea. Clinical manifestations and laboratory findings met the diagnostic criteria for TLS. The significant decrease in the abundance of ALK mutations in plasma indicated a therapeutic response at the molecular level. Consequently, the diagnosis of brigatinib-induced TLS was established. To the best of our knowledge, this is the first case of TLS induced by sequential targeted therapy in non-small cell lung cancer. With the extensive application of sequential therapy with more potent next-generation targeted therapeutic drugs, special attention should be given to this rare but severe complication.

IntroductionThymic epithelial tumors (TETs) are malignancies arising from the epithelium of the thymic gland, rare but with relatively favorable prognosis. TETs have different pathological subtypes: thymomas and thymic carcinoma, and they show different clinical characteristics regarding prognosis, pathology, and molecular profiles, etc. Although some studies have investigated the pathogenesis of TETs, more molecular data is still needed to further understand the underlying mechanisms among different TETs subtypes and populations.MethodsIn this study, we performed targeted gene panel sequencing and whole transcriptome sequencing on the tumor tissues from 27 Chinese TET patients, including 24 thymomas (A, AB, and B subtypes) and 3 thymic squamous cell carcinomas. We analyzed the genetic variations and differentially expressed genes among multiple TET subtypes. Moreover, we compared our data with the published The Cancer Genome Atlas (TCGA) TET data on both the genetic and transcriptomic levels.ResultsCompared with the TCGA TET genomic data, we found that NF1 and ATM were the most frequently mutated genes (each with a frequency of 11%, 3/27). These mutations were not mutually exclusive, since one B1 thymoma showed mutations of both genes. The GTF2I mutation was mainly enriched in subtype A and AB thymomas, consistent with the previous reports. RNA-seq results unveiled that the genes related to thymus development (FGF7, FGF10 and CLDN4) were highly expressed in certain TET subtypes, implicating that the developmental process of thymus might be linked to the tumorigenesis of these subtypes. We found high expression of CD274 (PD-L1) in B2 and B3 thymoma samples, and validated its expression using immunohistochemistry (IHC). Based on the expression profiles, we further established a machine learning model to predict the myasthenia gravis status of TET patients and achieved 90% sensitivity and 70.6% specificity in the testing cohort.ConclusionThis study provides the first genomic and transcriptomic analysis of a Chinese TET cohort. The high expression of genes involved in thymus developmental processes suggests the potential association between tumorigenesis of TETs and dysregulation of developmental pathways. The high expression of PD-L1 in B2 and B3 thymomas support the potential application of immunotherapy on certain thymoma subtypes.

IntroductionLittle evidence exists on the safety and efficacy of the rechallenge of immune checkpoint inhibitors (ICIs) after immune-related adverse events (irAEs) in patients with cancer.MethodsWe searched PubMed, Web of Science, Embase, and Cochrane for articles on ICI rechallenge after irAEs for systemic review and meta-analysis. The outcomes included the incidence and associated factors for safety and objective response rate (ORR) and disease control rate (DCR) for efficacy.ResultsA total of 789 ICI rechallenge cases from 18 cohort studies, 5 case series studies, and 54 case reports were included. The pooled incidence of all-grade and high-grade irAEs after rechallenge in patients with cancer was 34.2% and 11.7%, respectively. Compared with initial ICI treatment, rechallenge showed a higher incidence for all-grade irAEs (OR, 3.81; 95% CI, 2.15–6.74; p < 0.0001), but similar incidence for high-grade irAEs (p > 0.05). Types of initial irAEs (pneumonitis and global irAEs) and cancer (non-small cell lung cancer and multiple cancer) recapitulated these findings. Gastrointestinal irAEs and time interval between initial irAEs and ICI rechallenge were associated with higher recurrence of high-grade irAEs (p < 0.05), whereas initial anti-PD-1/PD-L1 antibodies were associated with a lower recurrence (p < 0.05). Anti-PD-1/PD-L1 antibodies rechallenge was associated with a lower all-grade irAE recurrence (p < 0.05). The pooled ORR and DCR after rechallenge were 43.1% and 71.9%, respectively, showing no significant difference compared with initial ICI treatment (p > 0.05).ConclusionsICI rechallenge after irAEs showed lower safety and similar efficacy outcomes compared with initial ICI treatment.Systematic Review RegistrationPROSPERO, identifier CRD42020191405.

Abstract Background Non-small-cell lung cancer (lung cancer) has become one of the leading causes worldwide and the underlying mechanism is not fully understood. The transcriptional factor Kruppel like factor 8 (KLF8) is involved in the initiation, progression, transformation, and metastasis of diverse cancers. However, the roles of KLF8 in human non-small cell lung cancer remain unknown. Methods CCK-8 kit and colony formation assay were performed to determine the cell growth of lung cancer cells. Flow cytometry analysis was used to evaluate apoptosis and cell cycle of lung cancer cells. Luciferase reporter assay was used to examine the activation of JMJD2A promoter by KLF8. Chromatin immunoprecipitation assay was performed to evaluate the binding of KLF8 to JMJD2A promoter. Western blot and polymerase chain reaction were applied to analyze the expression of interested genes. Results The mRNA and protein levels of KLF8 in human non-small cell lung cancer tissues were overexpressed compared with the non-cancer tissues. KLF8 was knocked down with lentivirus-mediated short-hairpin RNA (shRNA) in human lung cancer cells (A549 and H1299 cells). The phenotypic results showed that KLF8 knockdown decreased the proliferation rate and colony formation of lung cancer cells. By contrast, lentivirus-mediated KLF8 overexpression promoted the growth of lung cancer cells (A549 and H1299 cells) and non-cancerous bronchial epithelial cell line BEAS-2B. Next, we showed that KLF8 regulated cell cycle at the G0 phase but not regulates cellular apoptosis of lung cancer cells. KLF8 regulated the expression of the cell cycle regulators P21 and CDK4 in a JMJD2A-dependent manner and JMJD2A knockdown significantly blocked the functions of KLF8 in regulating cell cycle and proliferation of lung cancer cells. Finally, we observed that KLF8 bound the promoter of JMJD2A and facilitated the expression of JMJD2A. Conclusions Our evidence demonstrated that KLF8 upregulation in human lung cancer promotes the cell proliferation and colony formation of lung cancer cells. KLF8 binds to the promoter of JMJD2A and subsequently regulates the expression of P21 and CDK4, which contributes to the regulation of cell cycle by KLF8. KLF8 may serve as a target for the treatment of human lung cancer.

Lung cancer is the leading cause of cancer-related deaths worldwide, and its occurrence is related to the accumulation of gene mutations and immune escape of the tumor. Sequencing of the T-cell receptor (TCR) repertoire can reveal the immunosurveillance status of the tumor microenvironment, which is related to tumor escape and immunotherapy. This study aimed to determine the characteristics and clinical significance of the TCR repertoire in lung cancer. To comprehensively profile the TCR repertoire, results from high-throughput sequencing of samples from 93 Chinese patients with lung cancer were analyzed. We found that the TCR clonality of tissues was related to smoking, with higher clonality in patients who had quit smoking for less than 1 year. As expected, TCR clonality was correlated with stages: patients with stage IV disease showed higher clonality than others. The correlation between TCR repertoire and epidermal growth factor receptor (EGFR) status was also investigated. Patients with EGFR non-L858R mutations showed higher clonality and a lower Shannon index than other groups, including patients with EGFR L858R mutation and wild-type EGFR. Furthermore, we analyzed the TCR similarity metrics—that is, the TCR shared between postoperative peripheral blood and tissue of patients with non-distant metastasis of lung cancer. A similar trend was found, in which patients with EGFR L858R mutations had lower overlap index (OLI) and Morisita index (MOI) scores. Moreover, the OLI showed a positive correlation with several clinical characteristics, including the tumor mutational burden of tissues and the maximum somatic allele frequency of blood; OLI showed a negative correlation with the ratio of CD4+CD28+ in CD4+ cells and the ratio of CD8+CD28+ in CD8+ cells. In conclusion, TCR clonality and TCR similarity metrics correlated with clinical characteristics of patients with lung cancer. Differences in TCR clonality, Shannon index, and OLI across EGFR subtypes provide information to improve understanding about varied responses to immunotherapy in patients with different EGFR mutations.

Background: Lymph node metastasis (LNM) status is critical to the treatment. Fewer studies has focused on LNM in patients with small-size non-small cell lung cancer (NSCLC). This study aims to investigate clinicopathological characteristics associated with skip N2 (SN2) and non-skip N2 (NSN2) metastasis, and their metastatic patterns in NSCLC with tumor size of 1–2 cm.Methods: We reviewed the records of NSCLC patients with tumor size of 1–2 cm who underwent lobectomy with systematic lymph node dissection (LND) between January 2013 and June 2019. Clinical, radiographical, and pathological characteristics were compared among N1, SN2, and NSN2 groups. Metastatic patterns of mediastinal lymph node were analyzed based on final pathology.Results: A total of 63 NSCLC patients with tumor size of 1–2 cm were staged as pN2, including 25 (39.7%) SN2 and 38 (60.3%) NSN2. The incidence rates of SN2 and NSN2 were 2.8% (25/884) and 4.3% (38/884), respectively. For all clinicopathological characteristics, no significant difference was observed among the groups of N1, SN2, and NSN2. For the tumor located in each lobe, specific nodal drainage stations were identified: 2R/4R for right upper lobe; 2R/4R and subcarinal node (#7) for right middle lobe and right lower lobe; 4L and subaortic node (#5) for left upper lobe; #7 for left lower lobe. However, there were still a few patients (10.9%, 5/46) had the involvement of lower zone for tumors of upper lobe and the involvement of upper zone for lower lobe.Conclusions: SN2 occurs frequently in patients with small-size NSCLC. Whether lobe-specific selective LND is suitable for all small-size patients deserves more studies to confirm. Surgeons should be more careful when performing selective LND for tumors located in the lower and upper lobes.

Background: Lymph node metastasis (LNM) status is of key importance for the decision-making on treatment and survival prediction. There is no reliable method to precisely evaluate the risk of LNM in NSCLC patients. This study aims to develop and validate a dynamic nomogram to evaluate the risk of LNM in small-size NSCLC.Methods: The NSCLC ≤ 2 cm patients who underwent initial pulmonary surgery were retrospectively reviewed and randomly divided into a training cohort and a validation cohort as a ratio of 7:3. The training cohort was used for the least absolute shrinkage and selection operator (LASSO) regression to select optimal variables. Based on variables selected, the logistic regression models were developed, and were compared by areas under the receiver operating characteristic curve (AUCs) and decision curve analysis (DCA). The optimal model was used to plot a dynamic nomogram for calculating the risk of LNM and was internally and externally well-validated by calibration curves.Results: LNM was observed in 12.0% (83/774) of the training cohort and 10.1% (33/328) of the validation cohort (P = 0.743). The optimal model was used to plot a nomogram with six variables incorporated, including tumor size, carcinoembryonic antigen, imaging density, pathological type (adenocarcinoma or non-adenocarcinoma), lymphovascular invasion, and pleural invasion. The nomogram model showed excellent discrimination (AUC = 0.895 vs. 0.931) and great calibration in both the training and validation cohorts. At the threshold probability of 0–0.8, our nomogram adds more net benefits than the treat-none and treat-all lines in the decision curve.Conclusions: This study firstly developed a cost-efficient dynamic nomogram to precisely and expediently evaluate the risk of LNM in small-size NSCLC and would be helpful for clinicians in decision-making.

Background: Lymph node metastasis (LNM) is difficult to precisely predict before surgery in patients with early-T-stage non-small cell lung cancer (NSCLC). This study aimed to develop machine learning (ML)-based predictive models for LNM.Methods: Clinical characteristics and imaging features were retrospectively collected from 1,102 NSCLC ≤ 2 cm patients. A total of 23 variables were included to develop predictive models for LNM by multiple ML algorithms. The models were evaluated by the receiver operating characteristic (ROC) curve for predictive performance and decision curve analysis (DCA) for clinical values. A feature selection approach was used to identify optimal predictive factors.Results: The areas under the ROC curve (AUCs) of the 8 models ranged from 0.784 to 0.899. Some ML-based models performed better than models using conventional statistical methods in both ROC curves and decision curves. The random forest classifier (RFC) model with 9 variables introduced was identified as the best predictive model. The feature selection indicated the top five predictors were tumor size, imaging density, carcinoembryonic antigen (CEA), maximal standardized uptake value (SUVmax), and age.Conclusions: By incorporating clinical characteristics and radiographical features, it is feasible to develop ML-based models for the preoperative prediction of LNM in early-T-stage NSCLC, and the RFC model performed best.

Small extracellular vesicles (sEVs) carry molecular information from their source cells and are desired biomarkers for cancer diagnosis. We establish a machine learning-assisted dual-marker detection method to analyze the expression of epidermal growth factor receptor (EGFR) and C-X-C chemokine receptor 4 (CXCR4) in serum sEVs for the diagnosis and prognosis prediction of non-small cell lung cancer (NSCLC). We find that the serum sEV EGFR and CXCR4 are significantly higher in advanced stage NSCLC (A/NSCLC) patients compared to early stage NSCLC (E/NSCLC) patients and the healthy donors (HDs). A receiver operating characteristic curve (ROC) analysis demonstrates that the combination of EGFR and CXCR4 in serum sEVs as an efficient diagnostic index and malignant degree indicator for NSCLC. Machine learning further shows a diagnostic accuracy of 97.4% for the training cohort and 91.7% for the validation cohort based on the combinational marker. Moreover, this machine leaning-assisted serum sEV analysis successfully predicts the possibility of tumor relapse in three NSCLC patients by comparing their serum sEVs before and three days after surgery. This study provides an intelligent serum sEV-based assay for the diagnosis and prognosis prediction of NSCLC, and will benefit the precision management of NSCLC.

Background Integrins play a crucial role in the regulation process of cell proliferation, migration, differentiation, tumor invasion and metastasis. ITGA11, ITGB4 and ITGB8 are three encoding genes of integrins family. Accumulative evidences have proved that abnormal expression of ITGA11, ITGB4 and ITGB8 are a common phenomenon in different malignances. However, their expression patterns and prognostic roles for patients with non-small cell lung cancer (NSCLC) have not been completely illustrated. Methods We investigated the expression patterns and prognostic values of ITGA11, ITGB4 and ITGB8 in patients with NSCLC through using a series of databases and various datasets, including ONCOMINE, GEPIA, HPA, TCGA and GEO datasets. Results We found that the expression levels of ITGA11 and ITGB4 were significantly upregulated in both LUAD and LUSC, while ITGB8 was obviously upregulated in LUSC. Additionally, higher expression level of ITGB4 revealed a worse OS in LUAD. Conclusion Our findings suggested that ITGA11 and ITGB4 might have the potential ability to act as diagnostic biomarkers for both LUAD and LUSC, while ITGB8 might serve as diagnostic biomarker for LUSC. Furthermore, ITGB4 could serve as a potential prognostic biomarker for LUAD.

Background and objective The methods of detection for recurrence and metastasis in patients with non-small cell lung cancer (NSCLC) have hysteresis and one-sidedness. This study summarizes the relationship between the circulating tumor cell (CTC) in peripheral blood, expression of fibroblast growth factor receptor 1 (FGFR1) and clinic pathological features in 30 patients with NSCLC so as to provide new ideas for the detection of tumor recurrence and metastasis. Methods To analyze the clinical data and CTC detection data of 30 cases of NSCLC in Department of Thoracic Surgery, Peking Union Medical College Hospital from November 2016 to June 2017. Results Data analysis showed that the positive rate of CTC in peripheral blood was remarkably correlated with the smoking history (P=0.016). There was no significant correlation among the pathological type and CTC positive rate and the expression of FGFR1 (P=0.202, P=0.806). There was no significant difference in the expression of FGFR1 in different type CTC cells (P=0.094). Conclusion The positive rate of CTC was significantly correlated with the smoking history of patients with NSCLC. There was no significant difference in CTC classification and FGFR1 expression in different pathological types of NSCLC. There was no significant difference in the expression of FGFR1 between different types of CTCs. We look forward to a larger sample size and inclusion of follow-up data to arrive at more clinically relevant conclusions about CTC and FGFR1 gene expression.

Due to emphasis on early screening for lung cancer, the detection rate of multiple ground glass opacities (GGOs) on computed tomography (CT) image increases in recent years, and research on multifocal adenocarcinomas presented by GGOs has been thriving. It is more common in women and non-smokers and has excellent prognosis both in patients with natural history and after surgery. These clinical features suggest that it is likely to be a distinct disease entity. From the perspective of molecular genetics, lesions in the same individual are likely to have distinct clonal features. Therefore, genetic heterogeneity is the most prominent feature of multifocal pulmonary adenocarcinomas with GGOs. The genetic heterogeneity is expected to assist the diagnosis of multifocal pulmonary adenocarcinoma and intrapulmonary metastasis, and also suggests that genetic testing of the GGO lesions is of great therapeutic significance. Some GGO lesions may harvest the similar clonal feature, which provide new evidence for the theory of spread through air spaces (STAS).

The ability to differentiate between benign, suspicious, and malignant pulmonary nodules is imperative for definitive intervention in patients with early stage lung cancers. Here, we report that plasma protein functional effector sncRNAs (pfeRNAs) serve as non-invasive biomarkers for determining both the existence and the nature of pulmonary nodules in a three-stage study that included the healthy group, patients with benign pulmonary nodules, patients with suspicious nodules, and patients with malignant nodules. Following the standards required for a clinical laboratory improvement amendments (CLIA)-compliant laboratory-developed test (LDT), we identified a pfeRNA classifier containing 8 pfeRNAs in 108 biospecimens from 60 patients by sncRNA deep sequencing, deduced prediction rules using a separate training cohort of 198 plasma specimens, and then applied the prediction rules to another 230 plasma specimens in an independent validation cohort. The pfeRNA classifier could (1) differentiate patients with or without pulmonary nodules with an average sensitivity and specificity of 96.2% and 97.35% and (2) differentiate malignant versus benign pulmonary nodules with an average sensitivity and specificity of 77.1% and 74.25%. Our biomarkers are cost-effective, non-invasive, sensitive, and specific, and the qPCR-based method provides the possibility for automatic testing of robotic applications.

Non–small cell lung cancer is one of the most common types of cancer, and the prognosis of non–small cell lung cancer is still poor. Recent evidence has proved that long noncoding RNA is involved in tumorigenesis. For non–small cell lung cancer, the expression profile of long noncoding RNA has been studied. Here, we identified a novel long noncoding RNA TRPM2-AS from published dataset and found TRPM2-AS is widely upregulated in non–small cell lung cancer tissues compared with adjacent non-tumor tissues. Higher expression level of TRPM2-AS was correlated with higher TNM stages and larger tumor size. Patients with high TRPM2-AS expression level had poor survival than those with low TRPM2-AS level. We silenced TRPM2-AS by small interfering RNA and found that cell proliferation was significantly inhibited after knockdown of TRPM2-AS. Annexin V/propidium iodide staining and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay confirmed that cell apoptosis increased after TRPM2-AS knockdown. Further experiments showed that silence of TRPM2-AS upregulated SHC1 and silence of SHC1 partially reversed cell apoptosis after TRPM2-AS knockdown. In summary, the novel long noncoding RNA TRPM2-AS upregulated in non–small cell lung cancer, and downregulation of TRPM2-AS promotes apoptosis in vitro.