Exhaled VOC detection in lung cancer screening: a comprehensive meta-analysis.

BACKGROUND: Lung cancer (LC), characterized by high incidence and mortality rates, presents a significant challenge in oncology. Despite advancements in treatments, early detection remains crucial for improving patient outcomes. The accuracy of screening for LC by detecting volatile organic compounds (VOCs) in exhaled breath remains to be determined. METHODS: Our systematic review, following PRISMA guidelines and analyzing data from 25 studies up to October 1, 2023, evaluates the effectiveness of different techniques in detecting VOCs. We registered the review protocol with PROSPERO and performed a systematic search in PubMed, EMBASE and Web of Science. Reviewers screened the studies' titles/abstracts and full texts, and used QUADAS-2 tool for quality assessment. Then performed meta-analysis by adopting a bivariate model for sensitivity and specificity. RESULTS: This study explores the potential of VOCs in exhaled breath as biomarkers for LC screening, offering a non-invasive alternative to traditional methods. In all studies, exhaled VOCs discriminated LC from controls. The meta-analysis indicates an integrated sensitivity and specificity of 85% and 86%, respectively, with an AUC of 0.93 for VOC detection. We also conducted a systematic analysis of the source of the substance with the highest frequency of occurrence in the tested compounds. Despite the promising results, variability in study quality and methodological challenges highlight the need for further research. CONCLUSION: This review emphasizes the potential of VOC analysis as a cost-effective, non-invasive screening tool for early LC detection, which could significantly improve patient management and survival rates.

Muscle-secreted granulocyte colony-stimulating factor functions as metabolic niche factor ameliorating loss of muscle stem cells in aged mice.

The function and number of muscle stem cells (satellite cells, SCs) decline with muscle aging. Although SCs are heterogeneous and different subpopulations have been identified, it remains unknown whether a specific subpopulation of muscle SCs selectively decreases during aging. Here, we find that the number of SCs expressing high level of transcription factor Pax7 (Pax7Hi ) is dramatically reduced in aged mice. Myofiber-secreted granulocyte colony-stimulating factor (G-CSF) regulates age-dependent loss of Pax7Hi cells, as the Pax7Hi SCs are replenished by exercise-induced G-CSF in aged mice. Mechanistically, we show that transcription of G-CSF (Csf3) gene in myofibers is regulated by MyoD in a metabolism-dependent manner. Furthermore, myofiber-secreted G-CSF acts as a metabolic niche factor required for establishing and maintaining the Pax7Hi SC subpopulation in adult and physiological aged mice by promoting the asymmetric division of Pax7Hi and Pax7Mi SCs. Together, our findings uncover that muscles provide a metabolic niche regulating Pax7 SC heterogeneity in mice.

Accuracy of minimal residual disease detection by circulating tumor DNA profiling in lung cancer: a meta-analysis.

BACKGROUND: The sensitivity and specificity of minimal residual disease detected by circulating tumor DNA profiling (ctDNA MRD) in lung cancer, with particular attention to the distinction between landmark strategy and surveillance strategy, for predicting relapse in lung cancer patients after definitive therapy has yet to be determined. METHODS: The prognostic value of ctDNA MRD by landmark strategy and surveillance strategy was evaluated in a large cohort of patients with lung cancer who received definitive therapy using a systemic literature review and meta-analysis. Recurrence status stratified by ctDNA MRD result (positive or negative) was extracted as the clinical endpoint. We calculated the area under the summary receiver operating characteristic curves, and pooled sensitivities and specificities. Subgroup analyses were conducted based on histological type and stage of lung cancer, types of definitive therapy, and ctDNA MRD detection methods (detection technology and strategy such as tumor-informed or tumor-agnostic). RESULTS: This systematic review and meta-analysis of 16 unique studies includes 1251 patients with lung cancer treated with definitive therapy. The specificity of ctDNA MRD in predicting recurrence is high (0.86-0.95) with moderate sensitivity (0.41-0.76), whether shortly after treatment or during the surveillance. The landmark strategy appears to be more specific but less sensitive than the surveillance strategy. CONCLUSIONS: Our study suggests that ctDNA MRD is a relatively promising biomarker for relapse prediction among lung cancer patients after definitive therapy, with a high specificity but suboptimal sensitivity, whether in landmark strategy or surveillance strategy. Although surveillance ctDNA MRD analysis decreases specificity compared with the landmark strategy, the decrease is minimal compared to the increase in sensitivity for relapse prediction of lung cancer.

Acetoacetate promotes muscle cell proliferation via the miR-133b/SRF axis through the Mek-Erk-MEF2 pathway.

Acetoacetate (AA) is an important ketone body that is used as an oxidative fuel to supply energy for the cellular activities of various tissues, including the brain and skeletal muscle. We recently revealed a new signaling role for AA by showing that it promotes muscle cell proliferation in vitro, enhances muscle regeneration in vivo, and ameliorates the dystrophic muscle phenotype of Mdx mice. In this study, we provide new molecular insight into this function of AA. We show that AA promotes C2C12 cell proliferation by transcriptionally upregulating the expression of muscle-specific miR-133b, which in turn stimulates muscle cell proliferation by targeting serum response factor. Furthermore, we show that the AA-induced upregulation of miR-133b is transcriptionally mediated by MEF2 via the Mek-Erk1/2 signaling pathway. Mechanistically, our findings provide further convincing evidence that AA acts as signaling metabolite to actively regulate various cellular activities in mammalian cells.

PK/PD study of tigecycline in severely infected patients with continuous renal replacement therapy.

OBJECTIVE: The aim of this study was to analyze the pharmacokinetics/pharmacodynamics (PK/PD) of higher-dose tigecycline (100 mg q12h) in severely infected intensive care unit (ICU) patients receiving continuous renal replacement therapy (CRRT). MATERIALS AND METHODS: In this prospective single-center observational study, severely infected patients receiving intravenous tigecycline were enrolled. They were divided into a CRRT group (7 cases) and a non-CRRT group (9 cases). The blood samples and CRRT ultrafiltrate were collected. The drug concentration in each sample was determined by a HPLC-UV method. The pharmacokinetic parameters were simulated and calculated with DAS 2.0. The PK/PD parameters were evaluated according to published data. The registration number of this study is NCT02931526 in ClinicalTrials.gov. RESULTS: In the non-CRRT group, Cmax, Cmin, and AUC0-24 were 1.00 ± 0.66 µg×mL-1, 0.20 ± 0.12 µg×mL-1, and 22.12 ± 14.46 µg×h×mL-1, respectively. The clinical efficiency was 55.6%, and the bacterial clearance rate was 77.8%. In the CRRT group, Cmax, Cmin, and AUC0-24 were 0.96 ± 0.31 µg×mL-1, 0.22 ± 0.12 µg×mL-1, and 19.90 ± 8.14 µg×h×mL-1, respectively. The clinical efficiency was 28.6%, and the bacterial clearance rate was 28.6%. The individual differences of tigecycline plasma concentrations in our study were widely variable, and the differences of the two groups' PK/PD parameters had no statistical significance (p < 0.05). CONCLUSION: CRRT may have had little influence in tigecycline metabolism in our study, and therapeutic drug monitoring needs to be introduced for critically ill patients because of various pharmacokinetic parameters.

miR-378 and its host gene Ppargc1ß exhibit independent expression in mouse skeletal muscle.

MicroRNAs (miRNAs) are implicated in multiple biological processes in physiological and pathological settings. Nearly half of the known miRNAs are classified as 'intronic' miRNAs because they are embedded within the introns of protein-coding or noncoding genes. Such miRNAs were thought to be processed from primary host gene transcripts and share the promoter of their host. Recent analyses predicted that some intronic miRNAs might be transcribed and regulated as independent units, but there is little direct evidence for this in a specific biological context. Here, we focused on miR-378, which is located within the first intron of the peroxisome proliferator-activated receptor γ coactivator 1-beta (Ppargc1ß) gene and critically regulates skeletal muscle cell differentiation and muscle regeneration. We demonstrate that miR-378 and Ppargc1ß exhibit distinct expression patterns during skeletal muscle cell differentiation. In terminally differentiated adult skeletal muscle tissues of mice, miR-378 is predominantly expressed in glycolytic muscle, whereas Ppargc1ß is mainly expressed in oxidative soleus muscle. Mechanistically, miR-378, but not Ppargc1ß, is regulated by the transcription factor, MyoD, in muscle cells. Our findings identify a regulatory model of miR-378 expression, thereby helping us to understand its physiological function in skeletal muscle.

A hybrid deep learning framework for bacterial named entity recognition with domain features.

BACKGROUND: Microbes have been shown to play a crucial role in various ecosystems. Many human diseases have been proved to be associated with bacteria, so it is essential to extract the interaction between bacteria for medical research and application. At the same time, many bacterial interactions with certain experimental evidences have been reported in biomedical literature. Integrating this knowledge into a database or knowledge graph could accelerate the progress of biomedical research. A crucial and necessary step in interaction extraction (IE) is named entity recognition (NER). However, due to the specificity of bacterial naming, there are still challenges in bacterial named entity recognition. RESULTS: In this paper, we propose a novel method for bacterial named entity recognition, which integrates domain features into a deep learning framework combining bidirectional long short-term memory network and convolutional neural network. When domain features are not added, F1-measure of the model achieves 89.14%. After part-of-speech (POS) features and dictionary features are added, F1-measure of the model achieves 89.7%. Hence, our model achieves an advanced performance in bacterial NER with the domain features. CONCLUSIONS: We propose an efficient method for bacterial named entity recognition which combines domain features and deep learning models. Compared with the previous methods, the effect of our model has been improved. At the same time, the process of complex manual extraction and feature design are significantly reduced.

Linc-RAM is required for FGF2 function in regulating myogenic cell differentiation.

Myogenic differentiation of skeletal muscle stem cells, also known satellite cells, is tightly orchestrated by extrinsic and intrinsic regulators. Basic fibroblast growth factor (FGF2) is well documented to be implicated in satellite cell self-renewal and differentiation by repressing MyoD. We recently identified a MyoD-regulated and skeletal muscle-specifically expressed long non-coding RNA Linc-RAM which enhances myogenic differentiation by facilitating MyoD/Baf60c/Brg1 complex assembly. Herein, we investigated the transcriptional regulation and intracellular signaling pathway in mediating Linc-RAM gene expression during muscle cell differentiation. Firstly, we demonstrate Linc-RAM is negatively regulated by FGF2 via Ras/Raf/Mek/Erk signaling pathway in muscle cells. Overexpression of MyoD significantly attenuates repression of Linc-RAM promoter activities in C2C12 cells treated with FGF2. Knockout of MyoD abolishes FGF2-mediated repression of Linc-RAM gene transcription in satellite cells sorted from skeletal muscle of MyoD-/-;Pax7-nGFP mice, suggesting inhibition of MyoD is required for FGF2-mediated expression of Linc-RAM. For the functional significance, we show that overexpression of Linc-RAM rescues FGF2-induced inhibition of C2C12 cell differentiation, indicating inhibition of Linc-RAM is required for FGF2-mediated suppression of myogenic differentiation. Consistently, we are able to further corroborate the requirement of Linc-RAM inhibition for FGF2-modulated repression of myogenic differentiation by using an ex vivo cultured single fiber system and satellite cells sorted from Linc-RAM-/-;Pax7-nGFP knockout mice. Collectively, the present study not only reveals the intracellular signaling in FGF2-mediated Linc-RAM gene expression but also demonstrate the functional significance of Linc-RAM in FGF2-mediated muscle cell differentiation.

Acetoacetate Accelerates Muscle Regeneration and Ameliorates Muscular Dystrophy in Mice.

Acetoacetate (AA) is a ketone body and acts as a fuel to supply energy for cellular activity of various tissues. Here, we uncovered a novel function of AA in promoting muscle cell proliferation. Notably, the functional role of AA in regulating muscle cell function is further evidenced by its capability to accelerate muscle regeneration in normal mice, and it ameliorates muscular dystrophy in mdx mice. Mechanistically, our data from multiparameter analyses consistently support the notion that AA plays a non-metabolic role in regulating muscle cell function. Finally, we show that AA exerts its function through activation of the MEK1-ERK1/2-cyclin D1 pathway, revealing a novel mechanism in which AA serves as a signaling metabolite in mediating muscle cell function. Our findings highlight the profound functions of a small metabolite as signaling molecule in mammalian cells.

A stable and convenient protein electrophoresis titration device with bubble removing system.

Moving reaction boundary titration (MRBT) has a potential application to immunoassay and protein content analysis with high selectivity. However, air bubbles often impair the accuracy of MRBT, and the leakage of electrolyte greatly decreases the safety and convenience of electrophoretic titration. Addressing these two issues a reliable MRBT device with modified electrolyte chamber of protein titration was designed. Multiphysics computer simulation was conducted for optimization according to two-phase flow. The single chamber was made of two perpendicular cylinders with different diameters. After placing electrophoretic tube, the resident air in the junction next to the gel could be eliminated by a simple fast electrolyte flow. Removing the electrophoretic tube automatically prevented electrolyte leakage at the junction due to the gravity-induced negative pressure within the chamber. Moreover, the numerical simulation and experiments showed that the improved MRBT device has following advantages: (i) easy and rapid setup of electrophoretic tube within 20 s; (ii) simple and quick bubble dissipates from the chamber of titration within 2 s; (iii) no electrolyte leakage from the two chambers: and (iv) accurate protein titration and safe instrumental operation. The developed technique and apparatus greatly improves the performance of the previous MRBT device, and providing a new route toward practical application.

A highly efficient three-phase single drop microextraction technique for sample preconcentration.

A highly efficient three-phase single drop microextraction (SDME) method is presented by using an organic-aqueous compound droplet. A coupling microdevice is designed to produce compound droplets in different sizes conveniently. In this way, the volume ratio of organic phase to aqueous phase in a compound droplet can be significantly reduced. Good operability and droplet stability were observed during extraction under vigorous stirring conditions. Five statins were used as model compounds and spiked in river water and human serum samples to evaluate the analytical performance of the proposed method. By using a 1.2 µL toluene-aqueous compound droplet (volume ratio 0.2 : 1), a 350 to 1712 fold enrichment of statins was obtained within 4 minutes. The results indicate that the proposed method is a very rapid and efficient sample pretreatment method, and is promising for automated and high-throughput applications.

A new strategy for highly efficient single-drop microextraction with a liquid-gas compound pendant drop.

Herein, a simple assembly was designed via a capillary and a funnel-like cap to achieve liquid-gas compound pendant drop (CPD) microextraction with great convenience. Due to the increased contact area and adhesion force between the capillary tip and the drop, the proposed method provides considerable flexibility in producing CPDs with different air bubble sizes. Four pesticides were chosen as model analytes to evaluate the proposed method. By using a 1 µL chlorobenzene droplet containing a 1 µL air bubble at a stirring rate of 700 rpm, a 70 to 135-fold enrichment of pesticides was obtained within 3.4 minutes. As compared with a typical SDME, the proposed method showed a 2-fold increase of enrichment factors and a 4-fold decrease of extraction time. Improvement of the extraction efficiency could be ascribed to the increased surface area of the droplet, and the thin film phenomena further improved the extraction kinetics through effective agitation. The results indicate that CPD microextraction could serve as a promising sample pretreatment method for automated high-throughput analyses in a wide variety of research areas.

Albumin-bilirubin grade as a predictor of survival in hepatocellular carcinoma patients with thrombocytopenia.

BACKGROUND: The models for assessing liver function, mainly the Child-Pugh (CP), albuminbilirubin (ALBI), and platelet-ALBI (PALBI) classifications, have been validated for use in estimating the prognosis of hepatocellular carcinoma (HCC) patients. However, thrombocytopenia is a common finding and may influence the prognostic value of the three models in HCC. AIM: To investigate and compare the prognostic performance of the above three models in thrombocytopenic HCC patients. METHODS: A total of 135 patients with thrombocytopenic HCC who underwent radical surgery were retrospectively analyzed. Preoperative scores on the CP, ALBI and PALBI classifications were estimated accordingly. Kaplan-Meier curves with log-rank tests and Cox regression models were used to explore the significant factors associated with overall survival (OS) and recurrence-free survival (RFS). RESULTS: The preoperative platelet counts were significantly different among the CP, ALBI and PALBI groups. After a median follow-up of 28 mo, 39.3% (53/135) of the patients experienced postoperative recurrence, and 36.3% (49/135) died. Univariate analysis suggested that α-fetoprotein levels, tumor size, vascular invasion, and ALBI grade were significant predictors of OS and RFS. According to the multivariate Cox regression model, ALBI was identified as an independent prognostic factor. However, CP and PALBI grades were not statistically significant prognostic indicators. CONCLUSION: The ALBI grade, rather than CP or PALBI grade, is a significant prognostic indicator for thrombocytopenic HCC patients.

Loratidine is associated with improved prognosis and exerts antineoplastic effects via apoptotic and pyroptotic crosstalk in lung cancer.

BACKGROUND: Tumor-associated inflammation suggests that anti-inflammatory medication could be beneficial in cancer therapy. Loratadine, an antihistamine, has demonstrated improved survival in certain cancers. However, the anticancer mechanisms of loratadine in lung cancer remain unclear. OBJECTIVE: This study investigates the anticancer mechanisms of loratadine in lung cancer. METHODS: A retrospective cohort of 4,522 lung cancer patients from 2006 to 2018 was analyzed to identify noncancer drug exposures associated with prognosis. Cellular experiments, animal models, and RNA-seq data analysis were employed to validate the findings and explore the antitumor effects of loratadine. RESULTS: This retrospective study revealed a positive association between loratadine administration and ameliorated survival outcomes in lung cancer patients, exhibiting dose dependency. Rigorous in vitro and in vivo assays demonstrated that apoptosis induction and epithelial-mesenchymal transition (EMT) reduction were stimulated by moderate loratadine concentrations, whereas pyroptosis was triggered by elevated dosages. Intriguingly, loratadine was found to augment PPARγ levels, which acted as a gasdermin D transcription promoter and caspase-8 activation enhancer. Consequently, loratadine might incite a sophisticated interplay between apoptosis and pyroptosis, facilitated by the pivotal role of caspase-8. CONCLUSION: Loratadine use is linked to enhanced survival in lung cancer patients, potentially due to its role in modulating the interplay between apoptosis and pyroptosis via caspase-8.

Molecular and immune characterization of Chinese early-stage non-squamous non-small cell lung cancer: a multi-omics cohort study.

Background: Albeit considered with superior survival, around 30% of the early-stage non-squamous non-small cell lung cancer (Ns-NSCLC) patients relapse within 5 years, suggesting unique biology. However, the biological characteristics of early-stage Ns-NSCLC, especially in the Chinese population, are still unclear. Methods: Multi-omics interrogation of early-stage Ns-NSCLC (stage I-III), paired blood samples and normal lung tissues (n=76) by whole-exome sequencing (WES), RNA sequencing, and T-cell receptor (TCR) sequencing were conducted. Results: An average of 128 exonic mutations were identified, and the most frequently mutant gene was EGFR (55%), followed by TP53 (37%) and TTN (26%). Mutations in MUC17, ABCA2, PDE4DIP, and MYO18B predicted significantly unfavorable disease-free survival (DFS). Moreover, cytobands amplifications in 8q24.3, 14q13.1, 14q11.2, and deletion in 3p21.1 were highlighted in recurrent cases. Higher incidence of human leukocyte antigen loss of heterozygosity (HLA-LOH), higher tumor mutational burden (TMB) and tumor neoantigen burden (TNB) were identified in ever-smokers than never-smokers. HLA-LOH also correlated with higher TMB, TNB, intratumoral heterogeneity (ITH), and whole chromosomal instability (wCIN) scores. Interestingly, higher ITH was an independent predictor of better DFS in early-stage Ns-NSCLC. Up-regulation of immune-related genes, including CRABP2, ULBP2, IL31RA, and IL1A, independently portended a dismal prognosis. Enhanced TCR diversity of peripheral blood mononuclear cells (PBMCs) predicted better prognosis, indicative of a noninvasive method for relapse surveillance. Eventually, seven machine-learning (ML) algorithms were employed to evaluate the predictive accuracy of clinical, genomic, transcriptomic, and TCR repertoire data on DFS, showing that clinical and RNA features combination in the random forest (RF) algorithm, with area under the curve (AUC) of 97.5% and 83.3% in the training and testing cohort, respectively, significantly outperformed other methods. Conclusions: This study comprehensively profiled the genomic, transcriptomic, and TCR repertoire spectrums of Chinese early-stage Ns-NSCLC, shedding light on biological underpinnings and candidate biomarkers for prognosis development.

Impact of lymphadenectomy extent on immunotherapy efficacy in postresectional recurred non-small cell lung cancer: a multi-institutional retrospective cohort study.

BACKGROUND: Lymph node (LN) dissection is a common procedure for non-small cell lung cancer (NSCLC) to ascertain disease severity and treatment options. However, murine studies have indicated that excising tumor-draining LNs diminished immunotherapy effectiveness, though its applicability to clinical patients remains uncertain. Hence, the authors aim to illustrate the immunological implications of LN dissection by analyzing the impact of dissected LN (DLN) count on immunotherapy efficacy, and to propose a novel 'immunotherapy-driven' LN dissection strategy. MATERIALS AND METHODS: The authors conducted a retrospective analysis of NSCLC patients underwent anti-PD-1 immunotherapy for recurrence between 2018 and 2020, assessing outcomes based on DLN count stratification. RESULTS: A total of 144 patients were included, of whom 59 had a DLN count less than or equal to 16 (median, IQR: 11, 7-13); 66 had a DLN count greater than 16 (median, IQR: 23, 19-29). With a median follow-up time of 14.3 months (95% CI: 11.0-17.6), the overall median progression-free survival (PFS) was 7.9 (95% CI: 4.1-11.7) months, 11.7 (95% CI: 7.9-15.6) months in the combination therapy subgroup, and 4.8 (95% CI: 3.1-6.4) months in the immunotherapy alone subgroup, respectively. In multivariable Cox analysis, DLN count less than or equal to 16 is associated with an improved PFS in all cohorts [primary cohort: HR=0.26 (95% CI: 0.07-0.89), P =0.03]; [validation cohort: HR=0.46 (95% CI: 0.22-0.96), P =0.04]; [entire cohort: HR=0.53 (95% CI: 0.32-0.89), P =0.02]. The prognostic benefit of DLN count less than or equal to 16 was more significant in immunotherapy alone, no adjuvant treatment, pN1, female, and squamous carcinoma subgroups. A higher level of CD8+ central memory T cell (Tcm) within LNs was associated with improved PFS (HR: 0.235, 95% CI: 0.065-0.845, P =0.027). CONCLUSIONS: An elevated DLN count (cutoff: 16) was associated with poorer immunotherapy efficacy in recurrent NSCLC, especially pronounced in the immunotherapy alone subgroup. CD8+Tcm proportions in LNs may also impact immunotherapy efficacy. Therefore, for patients planned for adjuvant immunotherapy, a precise rather than expanded lymphadenectomy strategy to preserve immune-depending LNs is recommended.

Spatial whole exome sequencing reveals the genetic features of highly-aggressive components in lung adenocarcinoma.

In invasive lung adenocarcinoma (LUAD), patients with micropapillary (MIP) or solid (SOL) components had a significantly poorer prognosis than those with only lepidic (LEP), acinar (ACI) or papillary (PAP) components. It is interesting to explore the genetic features of different histologic subtypes, especially the highly aggressive components. Based on a cohort of 5,933 patients, this study observed that in different tumor size groups, LUAD with MIP/SOL components showed a different prevalence, and patients with ALK alteration or TP53 mutations had a higher probability of developing MIP/SOL components. To control individual differences, this research used spatial whole-exome sequencing (WES) via laser-capture microdissection of five patients harboring these five coexistent components and identified genetic features among different histologic components of the same tumor. In tracing the evolution of components, we found that titin (TTN) mutation might serve as a crucial intratumor potential driver for MIP/SOL components, which was validated by a cohort of 146 LUAD patients undergoing bulk WES. Functional analysis revealed that TTN mutations enriched the complement and coagulation cascades, which correlated with the pathway of cell adhesion, migration, and proliferation. Collectively, the histologic subtypes of invasive LUAD were genetically different, and certain trunk genotypes might synergize with branching TTN mutation to develop highly aggressive components.

The activity and immune dynamics of PD-1 inhibition on high-risk pulmonary ground glass opacity lesions: insights from a single-arm, phase II trial.

Immune checkpoint inhibitors targeting the programmed cell death-1 (PD-1) protein significantly improve survival in patients with advanced non-small-cell lung cancer (NSCLC), but its impact on early-stage ground-glass opacity (GGO) lesions remains unclear. This is a single-arm, phase II trial (NCT04026841) using Simon's optimal two-stage design, of which 4 doses of sintilimab (200 mg per 3 weeks) were administrated in 36 enrolled multiple primary lung cancer (MPLC) patients with persistent high-risk (Lung-RADS category 4 or had progressed within 6 months) GGOs. The primary endpoint was objective response rate (ORR). T/B/NK-cell subpopulations, TCR-seq, cytokines, exosomal RNA, and multiplexed immunohistochemistry (mIHC) were monitored and compared between responders and non-responders. Finally, two intent-to-treat (ITT) lesions (pure-GGO or GGO-predominant) showed responses (ORR: 5.6%, 2/36), and no patients had progressive disease (PD). No grade 3-5 TRAEs occurred. The total response rate considering two ITT lesions and three non-intent-to-treat (NITT) lesions (pure-solid or solid-predominant) was 13.9% (5/36). The proportion of CD8+ T cells, the ratio of CD8+/CD4+, and the TCR clonality value were significantly higher in the peripheral blood of responders before treatment and decreased over time. Correspondingly, the mIHC analysis showed more CD8+ T cells infiltrated in responders. Besides, responders' cytokine concentrations of EGF and CTLA-4 increased during treatment. The exosomal expression of fatty acid metabolism and oxidative phosphorylation gene signatures were down-regulated among responders. Collectively, PD-1 inhibitor showed certain activity on high-risk pulmonary GGO lesions without safety concerns. Such effects were associated with specific T-cell re-distribution, EGF/CTLA-4 cytokine compensation, and regulation of metabolism pathways.

Spatiotemporal distribution of mediastinal neoplasms: A comprehensive multi-center study.

OBJECTIVES: Mediastinal neoplasms are typical but uncommon thoracic diseases with increasing incidence and unfavorable prognoses. A comprehensive understanding of their spatiotemporal distribution is essential for accurate diagnosis and timely treatment. However, previous studies are limited in scale and data coverage. Therefore, this study aims to elucidate the distribution of mediastinal lesions, offering valuable insights into this disease. MATERIALS AND METHODS: This multi-center, hospital-based observational study included 20 nationwide institutions. A retrospective search of electronic medical records from January 1st, 2009, to December 31st, 2020, was conducted, collecting sociodemographic data, computed tomography images, and pathologic diagnoses. Analysis focused on age, sex, time, location, and geographical region. Comparative assessments were made with global data from a multi-center database. RESULTS: Among 7,765 cases, thymomas (30.7%), benign mediastinal cysts (23.4%), and neurogenic tumors (10.0%) were predominant. Distribution varied across mediastinal compartments, with thymomas (39.6%), benign cysts (28.1%), and neurogenic tumors (51.9%) most prevalent in the prevascular, visceral, and paravertebral mediastinum, respectively. Age-specific variations were notable, with germ cell tumors prominent in patients under 18 and aged 18-29, while thymomas were more common in patients over 30. The composition of mediastinal lesions across different regions of China remained relatively consistent, but it differs from that of the global population. CONCLUSION: This study revealed significant heterogeneity in the spatiotemporal distribution of mediastinal neoplasms. These findings provide useful demographic data when considering the differential diagnosis of mediastinal lesions, and would be beneficial for tailoring disease prevention and control strategies.