A Comprehensive Proteogenomic and Spatial Analysis of Innate and Acquired Resistance of Metastatic Melanoma to Immune Checkpoint Blockade Therapies.

While a subset of patients with metastatic melanoma achieves durable responses to immune checkpoint blockade (ICB) therapies, the majority ultimately exhibit either innate or acquired resistance to these treatments. However, the molecular mechanisms underlying resistance to ICB therapies remain elusive and are warranted to elucidate. Here, we comprehensively investigated the tumor and tumor immune microenvironment (TIME) of paired pre- and post-treatment tumor specimens from metastatic melanoma patients who were primary or secondary resistance to anti-CTLA-4 and/or anti-PD-1/PD-L1 therapies. Differentially expressed gene (DEG) analysis and single-sample gene set enrichment analysis (ssGSEA) with transcriptomic data identified cell cycle and c-MYC signaling as pathway-based resistance signatures. And weighted gene co-expression network analysis (WGCNA) revealed the activation of a cross-resistance meta-program involving key signaling pathways related to tumor progression in ICB resistant melanoma. Moreover, spatially-resolved, image-based immune monitoring analysis by using NanoString's digital spatial profiling (DSP) and Cyclic Immunofluorescence (CyCIF) showed infiltration of suppressive immune cells in the tumor microenvironment of melanoma with resistance to ICB therapies. Our study reveals the molecular mechanisms underlying resistance to ICB therapies in patients with metastatic melanoma by conducting such integrated analyses of multi-dimensional data, and provides rationale for salvage therapies that will potentially overcome resistance to ICB therapies. Statement of translational relevance: This study paves the way for the creation of innovative therapeutic strategies, aimed at subverting resistance to immune checkpoint blockade (ICB) therapies in metastatic melanoma patients. By unraveling the specific molecular mechanisms underlying resistance, scientists can design effective alternative treatments that target pathways such as pathways associated with cell cycle dysregulation and c-MYC signaling. Furthermore, through the application of advanced immune monitoring techniques such as NanoString Digital Spatial Profiling (DSP) and Cyclic Immunofluorescence (CyCIF), this study has significantly enriched our understanding of the tumor microenvironment. This enhanced characterization facilitates the discovery of potential biomarkers that may forecast a patient's response to ICB treatment. Ultimately, these advancements could potentially refine patient outcomes and foster the development of more personalized cancer treatments in the future.

A clinically effective model based on cell-free DNA methylation and low-dose CT for risk stratification of pulmonary nodules.

Accurate, non-invasive, and cost-effective tools are needed to assist pulmonary nodule diagnosis and management due to increasing detection by low-dose computed tomography (LDCT). We perform genome-wide methylation sequencing on malignant and non-malignant lung tissues and designed a panel of 263 differential DNA methylation regions, which is used for targeted methylation sequencing on blood cell-free DNA (cfDNA) in two prospectively collected and retrospectively analyzed multicenter cohorts. We develop and optimize an integrative model for risk stratification of pulmonary nodules based on 40 cfDNA methylation biomarkers, age, and five simple computed tomography (CT) imaging features using machine learning approaches and validate its good performance in two cohorts. Using the two-threshold strategy can effectively reduce unnecessary invasive surgeries, overtreatment costs, and injury for patients with benign nodules while advising immediate treatment for patients with lung cancer, which can potentially improve the overall diagnosis of lung cancer following LDCT/CT screening.

A nomogram predicting the risk of extrathoracic metastasis at initial diagnosis of T≤3cmN0 lung cancer.

Background: The risk and risk factors of extrathoracic metastasis at initial diagnosis in T≤3cmN0 lung cancer patients are not fully understood. We aimed to develop a model to predict the risk of extrathoracic metastasis in those patients. Methods: Clinicopathological data of patients were collected from Surveillance, Epidemiology, and End Results (SEER) database. Univariable and multivariable analyses using logistic regression were conducted to identify risk factors. A predictive model and corresponding nomogram were developed based on the risk factors. The model was assessed using the area under the receiver operating characteristic curve (AUC), Hosmer-Lemeshow test, and decision curve. Results: A total of 20,057 T≤3cmN0 patients were enrolled, of whom 251 (1.25%) were diagnosed with extrathoracic metastasis at the initial diagnosis. Aged ≤50 [odds ratio (OR): 2.05, 95% confidence interval (CI): 1.19-3.53, P=0.01] and aged ≥81 [1.65 (1.05-2.58), P=0.03], Hispanic [1.81 (1.20-2.71), P=0.004], location of bronchus [3.18 (1.08-9.35), P=0.04], larger tumor size, pleural invasion, and a history of colorectal cancer [2.01 (1.01-4.00), P=0.046] were independent risk factors. In the training cohort and validation cohort, the AUCs of the developed model were 0.727, 0.728 respectively, and the results of Hosmer-Lemeshow test were P=0.47, P=0.61 respectively. The decision curve showed good clinical meaning of the model. Conclusions: Extrathoracic metastasis at initial diagnosis in T≤3cmN0 lung cancer patients was not rare. The model based on the risk factors showed good performance in predicting the risk of extrathoracic metastasis.

Branched-chain amino acids and risk of lung cancer: insights from mendelian randomization and NHANES III.

Background: Recent studies have observed the relationships of circulatory and dietary intake of branched-chain amino acids (BCAAs) with long-term risk of certain cancers. However, the exact causality of BCAA with lung cancer (LUCA) and its pathological subtypes remains obscure. The aim of this study is to investigate the association between BCAA metabolism and risk of LUCA. Methods: Here we conducted Mendelian randomization (MR) and observational epidemiological analyses to investigate the association between BCAA and risk of LUCA. With single nucleotide polymorphism (SNP)-phenotype association data extracted from genome-wide association studies (GWAS), we performed univariate and multivariate MR analyses to infer the causal effect of circulatory BCAA concentrations on LUCA. We further investigated the effects of several potential mediators and quantified the mediation effects. Population-level analyses were performed in the National Health and Nutrition Examination Survey (NHANES) III. Results: Our results demonstrated that genetically predicted circulatory valine concentrations causally increased the risk of overall LUCA [odds ratio (OR) =1.324, 95% confidence interval (CI): 1.058-1.658, P=0.01]. For pathological subgroups, elevated levels of leucine, isoleucine, valine, and total BCAA were founded to be significantly associated with a higher risk of squamous cell lung cancer (LUSC); however, they did not significantly affect lung adenocarcinoma (LUAD). Moreover, body mass index (BMI) mediated approximately 3.91% (95% CI: 1.22-7.18%) of the total effect of leucine on LUSC. In the NHANES III population, dietary total BCAA intake was significantly associated with BMI ≥30 kg/m2, while no non-linear relationships were observed. Conclusions: This study provides genetic evidence for the histology-specific causality of BCAA on LUCA and implies the mediation role of BMI in this relationship. Further studies are needed to confirm these findings and elucidate the underlying mechanisms.

Lymph node dissection of station 8 improves the survival of T≤3 cmN0M0 lung adenocarcinoma patients.

Background: Mediastinal station 8 lymph node dissection (8LND) is recommended by guidelines but not routinely performed in real world clinical practice. This study aimed to investigate the effect of 8LND on the prognosis of pT≤3 cmN0M0 lung adenocarcinoma. Methods: Patients undergoing lobectomy were retrospectively enrolled from West China Hospital from 2011 to 2019. Kaplan-Meier method and log-rank test were used to investigate the effects of 8LND on the progression-free survival (PFS), overall survival (OS), and cancer-specific survival (CSS). Propensity score matching (PSM) was used to reduce the confounding effects. Multivariable analysis was conducted to evaluate the effect of 8LND in the matched patients. Subgroup analyses were conducted to further identify patients who might benefit from 8LND. Results: A total of 1,209 patients were enrolled and 261 (21.59%) patients underwent 8LND. Before PSM, for patients who received 8LND (8LND+ patients) and who did not (8LND- patients), the 5-year PFS was 91.34%, 88.03% (P=0.03) respectively, the 5-year OS was 97.10%, 92.78% (P=0.03) respectively, and the 5-year CSS was 97.67%, 93.59% (P=0.05) respectively. After PSM, 8LND+ patients still had better PFS (P=0.006), OS (P=0.01), and CSS (P=0.03) as compared to 8LND- patients. Multivariable analyses showed that 8LND was associated with lower risk of disease progression [hazard ratio (HR): 0.46; 95% confidence interval (CI): 0.26-0.80; P=0.007], and lower risk of death (HR: 0.33; 95% CI: 0.13-0.85; P=0.02). The survival benefit of 8LND was still found in subgroup analyses in male patients, smokers, patients with a pT2 tumor (≤3 cm), and patients with a poorly differentiated tumor. Conclusions: 8LND could improve the survival of T≤3 cmN0M0 lung adenocarcinoma patients. Routine 8LND is recommended, especially in male, smokers, patients with a pT2 tumor (≤3 cm), and patients with a poorly differentiated tumor.

Plasma proteometabolome in lung cancer: exploring biomarkers through bidirectional Mendelian randomization and colocalization analysis.

Unlike other cancers with widespread screening (breast, colorectal, cervical, prostate, and skin), lung nodule biopsies for positive screenings have higher morbidity with clinical complications. Development of non-invasive diagnostic biomarkers could thereby significantly enhance lung cancer management for at-risk patients. Here, we leverage Mendelian Randomization (MR) to investigate the plasma proteome and metabolome for potential biomarkers relevant to lung cancer. Utilizing bidirectional MR and co-localization analyses, we identify novel associations, highlighting inverse relationships between plasma proteins SFTPB and KDELC2 in lung adenocarcinoma (LUAD) and positive associations of TCL1A with lung squamous cell carcinoma (LUSC) and CNTN1 with small cell lung cancer (SCLC). Additionally, our work reveals significant negative correlations between metabolites such as theobromine and paraxanthine, along with paraxanthine-related ratios, in both LUAD and LUSC. Conversely, positive correlations are found in caffeine/paraxanthine and arachidonate (20:4n6)/paraxanthine ratios with these cancer types. Through single-cell sequencing data of normal lung tissue, we further explore the role of lung tissue-specific protein SFTPB in carcinogenesis. These findings offer new insights into lung cancer etiology, potentially guiding the development of diagnostic biomarkers and therapeutic approaches.

Differential expression profiles and functional prediction of circular RNAs in lung cancer patients with chronic obstructive pulmonary disease: a pilot study.

Chronic obstructive pulmonary disease (COPD), characterized by clinical sub-phenotypes such as emphysema (E) and chronic bronchitis (CB), is associated with a greater risk of lung cancer (LC). This study aimed to assess the expression patterns of circRNA and their potential functional involvement in LC patients with COPD. A circRNA microarray was used to characterize differentially expressed circRNAs (DEcircRNAs) profiles. A total of 176, 240, 163, and 243 DEcircRNAs were identified in comparisons between CB vs. LC patients (Con), E vs. Con, E vs. CB, and CBE vs. Con, respectively. DEcircRNAs in all comparison groups were primarily associated with immune-related GO terms and were also enriched in immune and inflammatory pathways. In total, 49 DEcircRNAs were significantly correlated with the infiltration of multiple immune cells. Among them, hsa-MROH9_0001 and hsa-RP11-35J10_0013 were positively and negatively correlated with plasma cells and T-cell CD4 memory resting cells, respectively; these two DEcircRNA-sponged miRNAs have good diagnostic performance. WGCNA identified six key circRNAs associated with CB progression. The expression patterns of hsa-MROH9_0001 and circRNA_21729 in E and CB groups were confirmed by RT-qPCR. In conclusion, we reported circRNA profiles and the findings demonstrated that hsa-MROH9_0001 and circRNA_21729 may be potential therapeutic targets for LC with COPD.

Clinical characteristics and outcomes of lung transplantation in patients with severe COVID-19 infection: A systematic review and meta-analysis.

OBJECTIVES: To synthesize the clinical experience of patients with COVID-19-associated acute respiratory distress syndrome (ARDS) or pulmonary fibrosis (PF) receiving lung transplantation (LTx) and compare the characteristics and outcomes of COVID-19 and non-COVID-19 LTx patients. METHODS: A literature search of online databases (PubMed, Web of Science, Embase, the Cochrane Library, China Science and Technology Journal Database, and Wan Fang databases) was performed regarding LTx for COVID-19-associated ARDS or PF. This study was registered on PROSPERO (CRD2024507647). RESULTS: Eight eligible studies were included with 478 COVID-19 LTx patients and 163 non-COVID-19 LTx patients. In COVID-19 LTx patients, the pooled hospital mortality and follow-up survival rate was 0.00% (95% CI 0.00-0.03) and 87.40% (95% CI 0.76-0.96). Compared to non-COVID-19 LTx patients, COVID-19 LTx patients were associated with significantly higher rate of primary graft dysfunction (odds ratio [OR] 8.72, 95% CI 3.54-21.47, P < 0.001) but significantly higher follow-up survival rate (OR 2.48, 95% CI 1.02-6.01, P = 0.04), within an overall similar follow-up period. CONCLUSIONS: For patients with COVID-19-associated ARDS or PF, LTx offers acceptable short-term outcomes and is suggested as a viable lifesaving treatment.

The prognostic value of visceral pleural infiltration in ≤3cm non-small cell lung cancer presenting with ground glass opacity: An inverse probability of treatment weighting study.

BACKGROUND: Visceral pleural infiltration (VPI) has been identified as an important risk factor in non-small cell lung cancer (NSCLC) for many decades. However, for patients who present with ground glass opacity (GGO), the prognostic value of VPI is still elusive. We aimed to investigate whether the VPI is a significant prognostic factor in surgically resected ≤3 cm stage I NSCLC who presented with GGO. MATERIALS AND METHODS: Patients with primary NSCLC who underwent surgical resection between December 2009 and December 2018 were collected. Stage I tumors that presented as GGO nodule with a tumor size of less than 3 cm were included and divided into two groups based on VPI status (positive and negative). Clinical, pathological, and prognostic data were prospectively collected and retrospectively reviewed. Inverse probability of treatment weighting (IPTW) was used to balance baseline characteristics. Overall survival (OS) and recurrence-free survival (RFS) were analyzed using the Cox proportional hazards model and Kaplan-Meier method. RESULTS: A total of 2043 patients were included in this study (VPIs were found in 196 patients). After IPTW weighting, all factors between the two groups were balanced. The median follow-up time was 67.3 months. According to the multivariable Cox models, the VPI was not a significant prognostic factor for OS (HR = 2.00, 95% CI, 0.96-4.17; P= 0.063), but was significant for RFS (HR =2.00, 95% CI, 1.12-3.55; P= 0.019). In subgroup analysis, we found VPI was significant for OS (HR=3.17, 95%CI: 1.09-9.26, P=0.035) and RFS (HR=4.07, 95%CI: 1.76-9.40, P=0.001) in patients with a tumor size >1 cm and a consolidation to tumor ratio (CTR) >50%. For patients with a tumor size ≤1 cm or a CTR ≤50%, the VPI was not significant. CONCLUSIONS: VPI may be a significant risk factor for GGOs in NSCLC patients with a tumor size >1 cm and a CTR >50%. Further prospective studies conducted across multi-centers with a larger sample size are needed.

Genetic perturbation of IL-6 receptor signaling pathway and risk of multiple respiratory diseases.

Dysregulation of inflammation can lead to multiple chronic respiratory diseases, such as chronic obstructive pulmonary disease (COPD) and asthma. Interleukin-6 (IL6) is crucial in regulating the inflammatory cascade, but the causal link between IL6 signaling downregulation and respiratory diseases risk is unclear. This study uses Mendelian randomization to examine the effects of IL6R blockade on respiratory diseases. Analyzing data from 522,681 Europeans, 26 genetic variants were obtained to mimic IL6R inhibition. Our findings show that IL6R blockade significantly reduces the risk of COPD (OR = 0.71, 95% CI = 0.60-9.84) and asthma (OR = 0.82, 95% CI = 0.74-0.90), with protective trends for bronchitis, pulmonary embolism, and lung cancer. Results were consistent across methods, with no significant heterogeneity or pleiotropy. These insights suggest IL6R downregulation as a potential therapeutic target for respiratory diseases, meriting further clinical investigation.

Association between postoperative radiotherapy for young-onset nonsmall cell lung cancer and risk of second primary malignancies: comparative study.

BACKGROUND: The most common form of therapy for nonsmall cell lung cancer (NSCLC) in early stage is surgery-based combination therapy, including radiotherapy and immunotherapy. However, postoperative radiotherapy (PORT) of cancer is correlated with increasing risk of second primary malignancy (SPM), especially young-onset cancer cases. The authors aimed to quantify the risks of SPM associated with PORT treatment for young­onset NSCLC in early stage. METHODS: The authors screened for SPM that developed over 5 years since the diagnosis of NSCLC. Using the data from the Surveillance, Epidemiology, and End Results database, PORT-correlated risks were estimated with multivariate Logistic regression analysis. Moreover, Fine-Gray's competing risk regression analysis was used to calculate the cumulative incidence of SPMs. RESULTS: Among the 30 308 young-onset NSCLC patients in early stage undergoing surgery, a total of 3728 patients have received PORT. Logistic regression analyses showed that PORT showed substantial correlation with elevated risks of second solid malignancies [relative risks (RR)=1.31; 95% CI: 1.17-1.46], lung cancer (RR=1.23; 95% CI: 1.07-1.42), breast cancer (RR=1.74; 95% CI: 1.16-2.74), and colon and rectum cancers (RR=1.37; 95% CI: 1.07-2.06) as well as a negligible risk of second hematologic malignancies (RR=1.15; 95% CI: 0.82-1.67). The cumulative incidence of SPMs revealed similar findings. Higher RR was obtained in NSCLC patients aged 60-69 years (RR=1.33), in white race (RR=1.36), diagnosed in 1975-2000 (RR=1.23) and 2001-2015 (RR=1.40), or diagnosed with lung adenocarcinoma (RR=1.55). CONCLUSION: PORT for young-onset NSCLC in early stage was correlated with elevated risks of SPMs (lung cancer, breast cancer, as well as colon and rectum cancers), supporting the need for long-term surveillance of these patients.

Effect of histological subtype on the efficacy of perioperative chemotherapy in pulmonary sarcomatoid carcinoma: a retrospective study based on SEER population.

Background: The efficacy of perioperative chemotherapy (PC) in pulmonary sarcomatoid carcinoma (PSC) is controversial. We conducted this study to investigate the effect of different histological subtypes on the efficacy of PC in PSC patients. Methods: Clinicopathological data of 811 PSC patients of different histological subtypes were collected from the Surveillance, Epidemiology, and End Results (SEER) database. Kaplan-Meier method and log-rank test were used to evaluate the effects of PC on the overall survival (OS) and cancer-specific survival (CSS) in different subtypes of PSC patients. Propensity score matching (PSM) was used to reduce potential confounding effects. Subgroup analyses were conducted to further investigate the efficacy of PC in patients with different characteristics. Results: A total of 210 (25.89%) enrolled PSC patients received PC. PC was not associated with OS or CSS benefit in pleomorphic carcinoma, giant cell carcinoma, or spindle cell carcinoma patients, neither before nor after matching. But survival benefit of PC was observed in carcinosarcoma patients both before (5-year OS: 48.79% vs. 38.75%, P=0.01) and after (5-year OS: 51.29% vs. 17.54%, P=0.003) matching. Subgroup analyses showed that in patients whose tumor larger than 4 cm, PC was still associated with improved survival in carcinosarcoma, but not in the other histological subtypes of PSC. Conclusions: The efficacy of PC varies between different subtypes of PSC. Survival benefit of PC was only observed in carcinosarcoma patients, but not in pleomorphic carcinoma, giant cell carcinoma, or spindle cell carcinoma patients. Histological subtype should be considered when treating PSC patients with PC.

Intentional wedge resection versus segmentectomy for ≤2 cm ground-glass-opacity-dominant non-small cell lung cancer: a real-world study using inverse probability of treatment weighting.

BACKGROUND: Whether wedge resection is oncological suitable for ground glass opacity (GGO)-dominant non-small cell lung cancer (NSCLC) ≤2 cm is still debatable. The aim of this study is to investigate the short-term and long-term outcomes of intentional wedge resection and segmentectomy for those patients. MATERIALS AND METHODS: This was a real-world study from one of the largest thoracic surgery centers in West China. Patients who underwent intentional wedge resection or segmentectomy for ≤2 cm CTR (consolidation-to-tumor) ≤0.5 NSCLC were consecutively included between December 2009 and December 2018. Data were prospectively collected and retrospectively reviewed. Inverse probability of treatment weighting (IPTW) was used to balance baseline characteristics. Long-term outcomes, including overall survival (OS), recurrence-free survival (RFS), and lung cancer-specific survival (LCSS), were analyzed using Cox proportional model. RESULTS: A total of 1209 patients were included (497 in the wedge resection group, 712 in the segmentectomy group). Compared to segmentectomy, wedge resection had a significantly lower rate of complications (3.8 vs. 7.7%, P =0.008), a shorter operating time (65 min vs. 114 min, P <0.001), and a shorter postoperative stay (3 days vs. 4 days, P <0.001). The median follow-up was 70.1 months. The multivariate Cox model indicated that wedge resection had survival outcomes that were similar to segmentectomy in terms of 5-year OS (98.8 vs. 99.6%, HR=1.98, 95% CI: 0.59-6.68, P =0.270), 5-year RFS (98.8 vs. 99.5%, HR=1.88, 95% CI: 0.56-6.31, P =0.307) and 5-year LCSS (99.9 vs. 99.6%, HR=1.76, 95% CI: 0.24-13.15, P =0.581). CONCLUSION: Intentional wedge resection is an appropriate choice for ≤2 cm GGO-dominant NSCLC.

Multicellular ecotypes shape progression of lung adenocarcinoma from ground-glass opacity toward advanced stages.

Lung adenocarcinoma is a type of cancer that exhibits a wide range of clinical radiological manifestations, from ground-glass opacity (GGO) to pure solid nodules, which vary greatly in terms of their biological characteristics. Our current understanding of this heterogeneity is limited. To address this gap, we analyze 58 lung adenocarcinoma patients via machine learning, single-cell RNA sequencing (scRNA-seq), and whole-exome sequencing, and we identify six lung multicellular ecotypes (LMEs) correlating with distinct radiological patterns and cancer cell states. Notably, GGO-associated neoantigens in early-stage cancers are recognized by CD8+ T cells, indicating an immune-active environment, while solid nodules feature an immune-suppressive LME with exhausted CD8+ T cells, driven by specific stromal cells such as CTHCR1+ fibroblasts. This study also highlights EGFR(L858R) neoantigens in GGO samples, suggesting potential CD8+ T cell activation. Our findings offer valuable insights into lung adenocarcinoma heterogeneity, suggesting avenues for targeted therapies in early-stage disease.

Tet methylcytosine dioxygenase 2 (TET2) deficiency elicits EGFR-TKI (tyrosine kinase inhibitors) resistance in non-small cell lung cancer.

Despite epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) have shown remarkable efficacy in patients with EGFR-mutant non-small cell lung cancer (NSCLC), acquired resistance inevitably develops, limiting clinical efficacy. We found that TET2 was poly-ubiquitinated by E3 ligase CUL7FBXW11 and degraded in EGFR-TKI resistant NSCLC cells. Genetic perturbation of TET2 rendered parental cells more tolerant to TKI treatment. TET2 was stabilized by MEK1 phosphorylation at Ser 1107, while MEK1 inactivation promoted its proteasome degradation by enhancing the recruitment of CUL7FBXW11. Loss of TET2 resulted in the upregulation of TNF/NF-κB signaling that confers the EGFR-TKI resistance. Genetic or pharmacological inhibition of NF-κB attenuate the TKI resistance both in vitro and in vivo. Our findings exemplified how a cell growth controlling kinase MEK1 leveraged the epigenetic homeostasis by regulating TET2, and demonstrated an alternative path of non-mutational acquired EGFR-TKI resistance modulated by TET2 deficiency. Therefore, combined strategy exploiting EGFR-TKI and inhibitors of TET2/NF-κB axis holds therapeutic potential for treating NSCLC patients who suffered from this resistance.

Subsequent surgical treatment or maintenance immunotherapy in stage III lung cancer patients achieving a favorable response following neoadjuvant immunotherapy: A matched retrospective cohort study from the surgical perspective.

BACKGROUND: Current treatment strategies for advanced non-small cell lung cancer (NSCLC) are highly individualized and subject to ongoing debates. In the era of immunotherapy, surgery assumes a critical role. The aim of this study was to investigate if subsequent surgical intervention, following a favorable response to immunotherapy and chemotherapy, could yield a more favorable prognosis for patients with advanced stage III NSCLC compared to the continuation of immunotherapy and chemotherapy. METHODS: We included patients whose tumors exhibited a favorable response (including partial response [PR] and complete response [CR]) to immunotherapy and chemotherapy. These patients were categorized into two groups based on their subsequent treatment plans: surgical and nonsurgical (continuation of maintenance immunotherapy and chemotherapy). The efficacy and long-term prognosis of these groups were compared after matching them in a 1:1 ratio using propensity scores. RESULTS: In total, 186 patients (93 in each group) were included in this study after matching via propensity scores. The 1- and 3-year overall survival (OS) and progression-free survival (PFS) rates were 96.0%, 88.5%, and 93.1%, 80.7% in the surgical group, and 93.2%, 83.1%, and 57.7%, 50.4% in the nonsurgical group, respectively. Patients in the surgical group exhibited significantly superior PFS and OS compared to those in the nonsurgical group (p = 0.025 and p = 0.00086). Univariate and multivariate analyses confirmed ΔBMI, Δtumor size reduction, tumor response, earlier clinical stage (IIIb vs. IIIa), and surgery as independent protective factor for patient prognosis. We further selected 101 patients with CR (39 in the surgical group and 62 in the nonsurgical group) and found that patients in the surgical group were significantly better in both PFS and OS. Our subgroup analysis in postoperative patients demonstrated that different surgical strategies did not significantly affect the long-term prognosis of patients (PFS and OS) but could impact their perioperative experience. CONCLUSION: Patients with advanced stage III NSCLC, whose tumors achieved PR and CR after 2-4 cycles of immunotherapy combined with chemotherapy, experience a more promising prognosis with subsequent surgical intervention compared with the continued immunotherapy. Despite encountering formidable obstacles, such as protracted surgical procedures and associated trauma, we must rise to the challenge and unleash the power of surgery after immunotherapy in advanced NSCLC.

The Clinical Outcomes of Thoracoscopic Versus Open Lobectomy for Non-Small-Cell Lung Cancer After Neoadjuvant Therapy: A Multi-Center Retrospective Cohort Study.

BACKGROUND: The safety and efficacy of video-assisted thoracic surgical (VATS) versus open lobectomy for non-small-cell lung cancer (NSCLC) following neoadjuvant therapy remained controversial. The aim of this study was to compare the outcomes of VATS with those of open lobectomy for NSCLC after neoadjuvant therapy. METHODS: Patients who had undergone VATS or open lobectomy for NSCLC following neoadjuvant therapy in nine hospitals in China from July 2014 to July 2020 were retrospectively reviewed. The clinical characteristics and overall survival (OS) of patients were analyzed using Cox regression models and propensity score matching. RESULTS: We identified 685 patients, 436 (63.6%) who had undergone VATS lobectomy and 249 (36.4%) who had undergone open lobectomy. Patients who had undergone VATS lobectomy tended to have had fewer nodes removed than those who had undergone open lobectomy. However, compared with open group, the VATS group had a better perioperative outcome, such as smaller blood loss volumes and shorter postoperative stays. The groups had a similar operation durations and postoperative complications, and there was a nonsignificant difference between their 30-day mortality rates. After propensity score matching, there was no significant different between the OS of the groups, and only postoperative adjuvant therapy was associated with worse OS. CONCLUSION: This multi-center analysis of patients with NSCLC who had undergone surgery subsequent to neoadjuvant therapy reveals that VATS lobectomy tended to have a better perioperative outcome, and have a similar OS compared to open lobectomy. These findings suggest that VATS lobectomy is appropriate for NSCLC following neoadjuvant therapy.

Perioperative outcomes of uniportal versus three-port video-assisted thoracoscopic surgery in lung cancer patients aged ≥ 75 years old: a cohort study.

BACKGROUND: Increasing attention has been raised on the surgical option for lung cancer patients aged ≥75 years, however, few studies have focused on whether uniportal video-assisted thoracoscopic surgery (VATS) is safe and feasible for these patients. This study aimed to evaluate short-term results of uniportal versus three-port VATS for the treatment of lung cancer patients aged ≥75 years. METHODS: We retrospectively evaluated 582 lung cancer patients (≥75 years) who underwent uniportal or three-port VATS from August 2007 to August 2021 based on the Western China Lung Cancer Database. The baseline and perioperative outcomes between uniportal and three-port VATS were compared in the whole cohort (WC) and the patients undergoing lobectomy (lobectomy cohort, LC) respectively. Propensity score matching (PSM) was used to minimize confounding bias between the uniportal and three-port cohorts in WC and LC. RESULTS: Intraoperative blood loss was significantly less in the uniportal than three-port LC (50 mL vs. 83 mL, P = 0.007) before PSM and relatively less in the uniportal than three-port LC (50 mL vs. 83 mL, P = 0.05) after PSM. Significantly more lymph nodes harvested (13 vs. 9, P = 0.007) were found in the uniportal than three-port LC after PSM. In addition, in WC and LC, there were no significant differences between uniportal and three-port cohorts in terms of operation time, the rate of conversion to thoracotomy during surgery, nodal treatments (dissection or sampling or not), the overall number of lymph node stations dissected, postoperative complications, volume and duration of postoperative thoracic drainage, hospital stay after operation and hospitalization expenses before and after PSM (P > 0.05). CONCLUSIONS: There were no significant differences in short-term outcomes between uniportal and three-port VATS for lung cancer patients (≥75 years), except relatively less intraoperative blood loss (P < 0.05 before PSM and P = 0.05 after PSM) and significantly more lymph nodes harvested (P < 0.05 after PSM) were found in uniportal LC. It is reasonable to indicate that uniportal VATS is a safe, feasible and effective operation procedure for lung cancer patients aged ≥75 years.

Risk factors and a prognostic model for patients with borderline resectable locally advanced T3-4N0-1 non-small cell lung cancer: a population-based study.

Background: Non-small cell lung cancer (NSCLC) is a malignant disease with a significant morbidity rate. For patients diagnosed with borderline resectable locally advanced (T3-4 invasion and N0-1) NSCLC, the optimal treatment and prognosis are still under debate. This study aimed to develop a predictive nomogram that could assess the prognosis of these patients and optimize clinical decision-making. Methods: Between 2010 to 2015, the survival, demographic and clinical characteristics of patients with borderline resectable locally advanced T3-4N0-1 NSCLC were obtained from the Surveillance, Epidemiology, and End Results (SEER) database. Cox proportional hazard regression analyses were conducted to identify potential factors, which were further utilized to develop a dynamic nomogram for personalized prediction. Internal and external validation were conducted to verify the predictive accuracy of the nomogram. Results: Totally, 5,054 eligible records were enrolled into the study cohort. The included patients were divided into a training cohort (n=3,538) and a validation cohort (n=1,516) in a 7:3 ratio. Nine independent prognostic factors (including age, gender, primary site, lymph node removal, differentiation grade, T stage, N stage, histology and adjuvant chemotherapy) were finally included into the nomogram. The developed nomogram exhibited favorable discriminative ability with the C-index =0.71. Moreover, the calibration curves demonstrated excellent agreement between predicted and observed outcomes in both the training and validation cohorts. Notably, subgroup analyses revealed that neoadjuvant chemotherapy was significantly associated with a better overall survival (OS) (P<0.05) in patients staged as T3-4N1. Conclusions: In this study, we developed and validated a prognostic model to assist in clinical decision-making for patients with borderline resectable locally advanced T3-4N0-1 NSCLC. Our findings suggested that patients with T3-4N1 stage disease may derive significant benefits from neoadjuvant chemotherapy.