Potential clinical utility of liquid biopsy in early-stage non-small cell lung cancer.

BACKGROUND: Liquid biopsy has been widely researched for early diagnosis, prognostication and disease monitoring in lung cancer, but there is a need to investigate its clinical utility for early-stage non-small cell lung cancer (NSCLC). METHODS: We performed a meta-analysis and systematic review to evaluate diagnostic and prognostic values of liquid biopsy for early-stage NSCLC, regarding the common biomarkers, circulating tumor cells, circulating tumor DNA (ctDNA), methylation signatures, and microRNAs. Cochrane Library, PubMed, EMBASE databases, ClinicalTrials.gov, and reference lists were searched for eligible studies since inception to 17 May 2022. Sensitivity, specificity and area under the curve (AUC) were assessed for diagnostic values. Hazard ratio (HR) with a 95% confidence interval (CI) was extracted from the recurrence-free survival (RFS) and overall survival (OS) plots for prognostic analysis. Also, potential predictive values and treatment response evaluation were further investigated. RESULTS: In this meta-analysis, there were 34 studies eligible for diagnostic assessment and 21 for prognostic analysis. The estimated diagnostic values of biomarkers for early-stage NSCLC with AUCs ranged from 0.84 to 0.87. The factors TNM stage I, T1 stage, N0 stage, adenocarcinoma, young age, and nonsmoking contributed to a lower tumor burden, with a median cell-free DNA concentration of 8.64 ng/ml. For prognostic analysis, the presence of molecular residual disease (MRD) detection was a strong predictor of disease relapse (RFS, HR, 4.95; 95% CI, 3.06-8.02; p < 0.001) and inferior OS (HR, 3.93; 95% CI, 1.97-7.83; p < 0.001), with average lead time of 179 ± 74 days between molecular recurrence and radiographic progression. Predictive values analysis showed adjuvant therapy significantly benefited the RFS of MRD + patients (HR, 0.27; p < 0.001), while an opposite tendency was detected for MRD - patients (HR, 1.51; p = 0.19). For treatment response evaluation, a strong correlation between pathological response and ctDNA clearance was detected, and both were associated with longer survival after neoadjuvant therapy. CONCLUSIONS: In conclusion, our study indicated liquid biopsy could reliably facilitate more precision and effective management of early-stage NSCLC. Improvement of liquid biopsy techniques and detection approaches and platforms is still needed, and higher-quality trials are required to provide more rigorous evidence prior to their routine clinical application.

I n situ tumor vaccine with optimized nanoadjuvants and lymph node targeting capacity to treat ovarian cancer and metastases.

Tumor vaccine, a promising modality of tumor immunotherapy, needs to go through the process of tumor antigen generation and loading, antigen drainage to lymph nodes (LNs), antigen internalization by dendritic cells (DCs), DC maturation, and antigen cross-presentation to activate T-cells. However, tumor vaccines are often unable to satisfy all the steps, leading to the limitation of their application and efficacy. Herein, based on a smart nanogel system, an in situ nano-vaccine (CpG@Man-P/Tra/Gel) targeting LNs was constructed to induce potent anti-tumor immune effects and inhibit the recurrence and metastasis of ovarian cancer. The CpG@Man-P/Tra/Gel exhibited MMP-2-sensitive release of trametinib (Tra) and nano-adjuvant CPG@Man-P, which generated abundant in situ depot of whole-cell tumor antigens and formed in situ nano-vaccines with CpG@Man-P. Benefiting from mannose (Man) modification, the nano-vaccines targeted to LNs, promoted the uptake of antigens by DCs, further inducing the maturation of DCs and activation of T cells. Moreover, CpG@Man-P with different particle sizes were prepared and the effective size was selected to evaluate the antitumor effect and immune response in vivo. Notably, combined with PD-1 blocking, the vaccine effectively inhibited primary tumor growth and induced tumor-specific immune response against tumor recurrence and metastasis of ovarian cancer.

Engineering mouse cell fate controller by rational design.

Cell fate is likely regulated by a common machinery, while components of this machine remain to be identified. Here we report the design and testing of engineered cell fate controller NanogBiD, fusing BiD or BRG1 interacting domain of SS18 with Nanog. NanogBiD promotes mouse somatic cell reprogramming efficiently in contrast to the ineffective native protein under multiple testing conditions. Mechanistic studies further reveal that it facilitates cell fate transition by recruiting the intended Brg/Brahma-associated factor (BAF) complex to modulate chromatin accessibility and reorganize cell state specific enhancers known to be occupied by canonical Nanog, resulting in precocious activation of multiple genes including Sall4, miR-302, Dppa5a and Sox15 towards pluripotency. Although we have yet to test our approach in other species, our findings suggest that engineered chromatin regulators may provide much needed tools to engineer cell fate in the cells as drugs era.

Prevalence of suicide ideation, self-harm, and suicide among Chinese patients with schizophrenia: a systematic review and meta-analysis.

Aims: Suicide ideation, self-harm, and suicide are common in patients with schizophrenia, but the reported prevalence vary largely across studies. Improved prevalence estimates and identification of moderators of the above self-directed violence are needed to enhance recognition and care, and to guide future management and research. This systematic review aims to estimate the pooled prevalence and identify moderators of suicide ideation, self-harm, and suicide among patients diagnosed with schizophrenia in China. Methods: Relevant articles published until September 23, 2021, were searched using PubMed, EBSCO, Web of Science, Embase, Science Direct, CNKI, CBM, VIP, and Wanfang databases. Eligible studies published in English or Chinese which reported the prevalence of suicide ideation, self-harm, or suicide among Chinese patients with schizophrenia were collected. All studies passed a quality evaluation. This systematic review was registered with PROSPERO (registration number CRD42020222338). PRISMA guidelines were used in extracting and reporting data. Random-effects meta-analyses were generated using the meta package in R. Results: A total of 40 studies were identified, 20 of which were evaluated as high-quality studies. Based on these studies, the prevalence of lifetime suicide ideation was 19.22% (95% CI: 7.57-34.50%), prevalence of suicide ideation at the time of investigation was 18.06% (95% CI: 6.49-33.67%), prevalence of lifetime self-harm was 15.77% (95% CI: 12.51-19.33%), and prevalence of suicide was 1.49% (95% CI: 0.00-7.95%). Multivariate meta-regression analysis revealed that age (ß = - 0.1517, p = 0.0006) and dependency ratio (ß = 0.0113, p < 0.0001) were associated with the lifetime prevalence of self-harm. Study assessment score (ß = 0.2668, p < 0.0001) and dependency ratio (ß = 0.0050, p = 0.0145) were associated with the lifetime prevalence of suicide ideation. Results of the spatial analysis showed that the prevalence of self-directed violence varied greatly across different provinces. Conclusion: This systematic review provides estimates of the prevalence of self-directed violence among Chinese patients with schizophrenia and explores its moderators and spatial patterns. Findings also have important implications for allocating prevention and intervention resources to targeted high-risk populations in high prevalence areas.

Multi-omics integrated circulating cell-free DNA genomic signatures enhanced the diagnostic performance of early-stage lung cancer and postoperative minimal residual disease.

BACKGROUND: Liquid biopsy is a promising non-invasive alternative for cancer screening and minimal residual disease (MRD) detection, although there are some concerns regarding its clinical applications. We aimed to develop an accurate detection platform based on liquid biopsy for both cancer screening and MRD detection in patients with lung cancer (LC), which is also applicable to clinical use. METHODS: We applied a modified whole-genome sequencing (WGS) -based High-performance Infrastructure For MultIomics (HIFI) method for LC screening and postoperative MRD detection by combining the hyper-co-methylated read approach and the circulating single-molecule amplification and resequencing technology (cSMART2.0). FINDINGS: For early screening of LC, the LC score model was constructed using the support vector machine, which showed sensitivity (51.8%) at high specificity (96.3%) and achieved an AUC of 0.912 in the validation set prospectively enrolled from multiple centers. The screening model achieved detection efficiency with an AUC of 0.906 in patients with lung adenocarcinoma and outperformed other clinical models in solid nodule cohort. When applied the HIFI model to real social population, a negative predictive value (NPV) of 99.92% was achieved in Chinese population. Additionally, the MRD detection rate improved significantly by combining results from WGS and cSMART2.0, with sensitivity of 73.7% at specificity of 97.3%. INTERPRETATION: In conclusion, the HIFI method is promising for diagnosis and postoperative monitoring of LC. FUNDING: This study was supported by CAMS Innovation Fund for Medical Sciences, Chinese Academy of Medical Sciences, National Natural Science Foundation of China, Beijing Natural Science Foundation and Peking University People's Hospital.

Research Progress on Postoperative Minimal/Molecular Residual Disease Detection in Lung Cancer.

Lung cancer is the leading cause of cancer-related deaths worldwide. Approximately 10%-50% of patients experience relapse after radical surgery, which may be attributed to the persistence of minimal/molecular residual disease (MRD). Circulating tumor DNA (ctDNA), a common liquid biopsy approach, has been demonstrated to have significant clinical merit. In this study, we review the evidence supporting the use of ctDNA for MRD detection and discuss the potential clinical applications of postoperative MRD detection, including monitoring recurrence, guiding adjuvant treatment, and driving clinical trials in lung cancer. We will also discuss the problems that prevent the routine application of ctDNA MRD detection. Multi-analyte methods and identification of specific genetic and molecular alterations, especially methylation, are effective detection strategies and show considerable prospects for future development. Interventional prospective studies based on ctDNA detection are needed to determine whether the application of postoperative MRD detection can improve the clinical outcomes of lung cancer patients, and the accuracy, sensitivity, specificity, and robustness of different detection methods still require optimization and refinement.

Comparison of Clinical and Pathological Characteristics Between Extremely Multiple GGNs and Single GGNs.

OBJECTIVE: This study aims to compare the clinical and pathological characteristics between patients undergoing surgery for extremely multiple ground-glass nodules (GGNs) and those for single GGN. METHODS: We defined extremely multiple GGNs as follows: (i) number of GGNs ≥3, (ii) GGN diameter between 3 and 30 mm, and (iii) no less than three nodules that were surgically removed and pathologically diagnosed. Patients with extremely multiple GGNs and single GGNs who underwent surgery at the same time were retrospectively analyzed. The patients were divided into three groups according to the number of nodules: exceedingly multiple nodules (EMN) group (>10), highly multiple nodules (HMN) group (three to 10), and single nodule (SN) group. The clinical and pathological characteristics, surgical methods and prognosis were analyzed. RESULTS: Ninety-nine patients with single nodules and 102 patients with extremely multiple nodules were enrolled. Among the patients with extremely multiple nodules, 43 (42.2%) had >10 nodules. There were no significant differences in demographic characteristics, such as age, sex, and smoking history, between the groups, but there were differences in tumor characteristics. All patients with >10 nodules showed bilateral pulmonary nodules and presented with both pure and mixed GGNs. The single GGNs were smaller in diameter, and the proportion of mixed GGNs and pathologically invasive adenocarcinoma was lower than that of the primary nodules in the exceedingly multiple GGNs group (p < 0.05). However, the proportion of both mixed GGNs and malignant nodules decreased significantly with the increasing number of total lesions. During postoperative follow-up, one patient in the highly multiple nodules group had a local recurrence, and 16 (15.7%) patients in the extremely multiple GGNs group and 10 (9.8%) patients in the single GGN group had enlarged unresected GGNs or additional GGNs. CONCLUSIONS: Our study revealed the clinical and pathologic characteristics, surgical methods, and prognosis of patients with extremely multiple GGNs and compared them with those of patients with a single GGN. Although the primary nodules in extremely multiple GGNs may have higher malignancy than those in the single nodule group, the proportion of both mGGNs and malignant nodules decreased significantly with the increasing number of lesions, and the prognosis of patients with extremely multiple GGNs was satisfied.

Molecular Alterations in Lung Adenocarcinoma With Ground-Glass Nodules: A Systematic Review and Meta-Analysis.

BACKGROUND AND AIMS: Nodular ground-glass lesions have become increasingly common with the increased use of computed tomography (CT), while the genomic features of ground-glass opacities (GGOs) remain unclear. This study aims to comprehensively investigate the molecular alterations of GGOs and their correlation with radiological progression. METHODS: Studies from PubMed, Embase, Cochrane Library, and Web of Science, using PCR, targeted panel sequencing, whole exosome sequencing, and immunohistochemistry, and reporting genomic alterations or PD-L1 expressions in lung nodules presenting as GGOs until January 21, 2021 were included in this study. Chi-square test, random-effects model, and Z-test analysis were adopted to analyze the data. RESULTS: A total of 22 studies describing mutations in lung adenocarcinoma (LUAD) with GGOs were analyzed. EGFR was the most frequently mutative gene (51%, 95%CI 47%-56%), followed by TP53 (18%, 95%CI 6%-31%), HER2 (10%, 95%CI 0%-21%), ROS1 (6%, 95%CI 0%-18%), and KRAS (6%, 95%CI 3%-9%). The correlation between the frequency of EGFR mutation and radiological was observed and the differences were found to be not statistically significant in the subgroups, which are listed as below: radiological: gGGO 47.40%, 95%CI [38.48%; 56.40%]; sGGO 51.94%, 95%CI [45.15%; 58.69%]. The differences of the frequency of KRAS mutation in the different subgroups were also consistent with this conclusion, which are listed as: radiological gGGO 3.42, 95%CI [1.35%; 6.13%]; sGGO 12.27%, 95%CI [3.89%; 23.96%]. The pooled estimated rate of PD-L1 was 8.82%, 95%CI [5.20%-13.23%]. A total of 11.54% (3/26) of the SMGGNs were confirmed to be intrapulmonary spread by WES. CONCLUSIONS: Somatic genetic alterations are considered in early-stage GGO patients without distinct changes of the frequency following the progress of the tumor. This review sheds insight on molecular alterations in LUAD with GGOs.