Efficacy and safety of immune checkpoint inhibitors for individuals with advanced EGFR-mutated non-small-cell lung cancer who progressed on EGFR tyrosine-kinase inhibitors: a systematic review, meta-analysis, and network meta-analysis.

BACKGROUND: The clinical benefits of immune checkpoint inhibitor (ICI)-based treatments in treating individuals with advanced EGFR-mutated non-small-cell lung cancer (NSCLC) who have progressed on EGFR tyrosine-kinase inhibitors (TKIs) remain controversial. We aimed to review the literature to comprehensively investigate the individual and comparative clinical outcomes of various ICI-based treatment strategies in this population. METHODS: In this systematic review and meta-analysis, we used single-arm, pairwise, and network meta-analytical approaches. We searched PubMed, Embase, Cochrane Library, Web of Science, ClinicalTrials.gov, and relevant international conference proceedings from database inception to Jan 31, 2024, without language restrictions, to identify eligible clinical trials that assessed ICI-based treatments for individuals with advanced EGFR-mutated NSCLC who progressed on EGFR-TKIs. Studies considered eligible were published and unpublished phase 1, 2, or 3 clinical trials enrolling participants with histologically or cytologically confirmed advanced EGFR-mutated NSCLC who had progressed after at least one EGFR-TKI treatment, and that evaluated ICI-based treatment strategies on at least one of the clinical outcomes of interest. The primary outcome analysed was progression-free survival. The protocol is registered with PROSPERO, CRD42021292626. FINDINGS: 17 single-arm trials and 15 randomised controlled trials, involving 2886 participants and seven ICI-based treatment strategies (ICI monotherapy, ICI plus chemotherapy [ICI-chemo], ICI plus antiangiogenesis [ICI-antiangio], ICI plus antiangiogenesis plus chemotherapy [ICI-antiangio-chemo], dual ICIs [ICI-ICI], dual ICIs plus chemotherapy [ICI-ICI-chemo], and ICI plus EGFR-TKI [ICI-TKI]), were included. Three of these strategies-ICI monotherapy, ICI-antiangio-chemo, and ICI-chemo-had sufficient data across the included studies to perform a pairwise meta-analysis. The pairwise meta-analysis showed that, compared with chemotherapy, ICI monotherapy led to shorter progression-free survival (hazard ratio [HR] 1·73 [95% CI 1·30-2·29], I2=0%), whereas ICI-antiangio-chemo (HR 0·54 [0·44-0·67], I2=0%) and ICI-chemo (HR 0·77 [0·67-0·88], I2=0%) prolonged progression-free survival. The network meta-analysis showed that ICI-antiangio-chemo yielded the best progression-free survival results, with substantial benefits over ICI-chemo (HR 0·71 [95% credible interval 0·59-0·85]), ICI monotherapy (HR 0·30 [0·22-0·41]), and non-ICI treatment strategies including antiangio-chemo (HR 0·76 [0·58-1·00]) and chemotherapy alone (HR 0·54 [0·45-0·64]). ICI-antiangio-chemo was associated with higher risks of both any-grade and grade 3 or worse adverse events over ICI-chemo and chemotherapy in the network meta-analysis. INTERPRETATION: For individuals with advanced EGFR-mutated NSCLC who progressed on EGFR-TKIs, ICI-antiangio-chemo was identified as the optimal treatment option. The toxicity of this treatment was acceptable but needs careful attention. ICI-chemo showed appreciably greater efficacy than the standard-of-care chemotherapy. These findings clarified the roles of ICI-based treatment strategies in this difficult-to-treat refractory population, potentially complementing recent guidelines. FUNDING: None.

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.

A new gene signature associated with disulfidptosis that forecasts myasthenia gravis and suggests infiltration of immune microenvironment in thymoma patients.

Introduction: The mechanism of thymoma-associated myasthenia gravis (TAMG) is currently unknown, although patients with TAMG experience more severe myasthenic symptoms and have worse prognoses compared to regular thymoma patients. The objective of this research is to create a transcriptome map of TAMG using genes linked to disulfidptosis, detect possible biomarkers, and examine the disparities in the tumor immune microenvironment (TIME) among different thymoma patients. The findings will offer valuable knowledge for personalized treatment alternatives. Methods: Thymoma samples' RNA-seq data, along with their corresponding clinical data, were acquired from the TCGA database using methods. Next, genes and disulfidptosis-related lncRNAs(DRLs) were chosen through correlation analysis. Then, a prediction model of TAMG was established by LASSO regression. Subsequent to that, an analysis of the mutation data, the tumor mutational burden (TMB), and the assessment of immune and stromal elements within the tumor microenvironment were conducted. Results: A total of 87 patients diagnosed with thymoma were included in the study, with 29 of them having TAMG. We discovered a group of 325 lncRNAs in this sample that showed significant associations with genes related to disulfidptosis, with 25 of them displaying significantly altered expression. Moreover, utilizing LASSO regression, we constructed a predictive model incorporating 11 DRLs. The analysis revealed an area under the curve (AUC) of 0.934 (CI 0.879-0.989), a cut-off value of 0.797, along with a sensitivity of 82.8 % and specificity of 93.1 %. Furthermore, we examined the TIME in both the high-risk and low-risk groups, and observed noteworthy disparities in B cells, T cells, and APC among the two groups (p < 0.05). Conclusion: This research offers the initial examination of genes associated with disulfidptosis and TAMG through genomic and transcriptomic analysis. Furthermore, a strong risk forecasting model was created and the significance of TIME in TAMG was also clarified. The discoveries offer significant understanding into the molecular processes of TAMG and present possible indicators for categorizing risk.

Th17/Treg balance: the bloom and wane in the pathophysiology of sepsis.

Sepsis is a multi-organ dysfunction characterized by an unregulated host response to infection. It is associated with high morbidity, rapid disease progression, and high mortality. Current therapies mainly focus on symptomatic treatment, such as blood volume supplementation and antibiotic use, but their effectiveness is limited. Th17/Treg balance, based on its inflammatory property, plays a crucial role in determining the direction of the inflammatory response and the regression of organ damage in sepsis patients. This review provides a summary of the changes in T-helper (Th) 17 cell and regulatory T (Treg) cell differentiation and function during sepsis, the heterogeneity of Th17/Treg balance in the inflammatory response, and the relationship between Th17/Treg balance and organ damage. Th17/Treg balance exerts significant control over the bloom and wanes in host inflammatory response throughout sepsis.

Upfront surgery for stage IIIA/B non-small cell lung cancer: retrospective cohort study.

BACKGROUND: Stage III non-small cell lung cancer is a heterogeneous disease. Several international guidelines recommend neoadjuvant treatment before surgery; however, upfront surgery is the preferred approach for technically resectable non-small cell lung cancer in East Asia. The aim of this retrospective study was to evaluate the long-term outcomes of curative-intent upfront surgery in stage IIIA/B non-small cell lung cancer. METHODS: Patients who underwent curative-intent upfront surgery with stage cIIIA/B non-small cell lung cancer were identified. The clinical and pathological variables and survival outcomes were evaluated. RESULTS: Overall, 664 patients were identified, of whom 320 (48.8%) had N2 disease, 66.7% were males, 49.4% had a smoking history, and 61.2% had lung adenocarcinoma. Lobectomy was the most performed surgical procedure (84.9%). A total of 40 patients (6.02%) had positive margins (R1/R2). The grade III adverse event rate was 2.0% (13 of 664). The median follow-up was 30.6 (range 1.9-97.7) months. At follow-up, the mortality rate was 13.3% (88 of 664) and 37.2% of patients (247 of 664) had recurrence. Lung (101 of 247 (40.9%)) and brain (53 of 247 (21.5%)) were the most common sites of recurrence. The median overall survival was 60.0 (95% c.i. 51.5 to 67.6) months, with overall survival probability at 1, 2, 3, and 5 years being 89.6%, 77.8%, 67.2%, and 49.0% respectively. The R0 cohort showed an improved median overall survival compared with the R1/R2 cohort (67.4 versus 26.5 months respectively; P = greater than 0.001). The multivariable analysis revealed that age greater than or equal to 65 years (HR 1.51, 95% c.i. 1.08 to 2.12; reference = age less than 65 years), tumour size (greater than or equal to 5 cm (HR 2.13, 95% c.i. 1.41 to 3.21) and greater than or equal to 3 cm but less than 5 cm (HR 1.15, 95% c.i. 0.78 to 1.71); reference = less than 3 cm), and adjuvant treatment (chemotherapy (HR 0.69, 95% c.i. 0.49 to 0.96) and targeted therapy (HR 0.30, 95% c.i. 0.12 to 0.76); reference = none) significantly predicted overall survival. CONCLUSION: Upfront surgery is an option for the management of stage IIIA/B non-small cell lung cancer.

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.

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.

Microbiota modulate lung squamous cell carcinoma lymph node metastasis through microbiota-geneset correlation network.

Background: The tumor-resident microbiota in lung squamous cell carcinoma (LUSC) has been reported to be associated with the initiation and progression of cancer. And the gut microbiome can modulate the efficacy of immunotherapies. However, it remains to be understood whether the tumor-resident microbiome promotes lymph node (LN) metastasis, which is important for clinical decision-making and prediction of a patient's prognosis. To investigate the potential role of tumor-resident microbiota in LN metastasis, we worked on the microbiota-geneset interaction profiles to characterize the molecular pathogenesis. Methods: RNA sequencing data and their matched clinical and genomic information were obtained from The Cancer Genome Atlas database. The matched microorganism quantification data were accessed via the cBioPortal database. The mutational signature analysis, transcriptome analysis, gene set enrichment analysis, immune infiltration, and microbiota-geneset network analysis were performed. Results: In this paper, we identified the tumor microbiota composition and microbial biomarkers in patients with and without LN metastases. In addition, significantly upregulated gene sets characterize the transcript profiles of patients with LN metastases, for example, Myc Targets, E2F Targets, G2M Checkpoint, Mitotic Spindle, DNA Repair, and Oxidative Phosphorylation. Finally, we found that Proteus and Bacteroides were strongly correlated with gene sets related to tumor development and energy metabolism in the networks of patients with LN metastases. Conclusions: We found the associations between intratumor microbiota and transcripts. Our results shed light on the correlation network of Proteus and Bacteroides, which may serve as a novel strategy for modulating LN metastasis.

"Major pathologic response" in lymph nodes: a modified nodal classification for non-small cell lung cancer patients treated with neoadjuvant immunochemotherapy.

We aim to examine the prognostic value of major pathologic response in metastatic lymph nodes (mLN-MPR) after immunochemotherapy in non-small cell lung cancer (NSCLC), and demonstrate the pathological characteristic of regression in mLN. Adult patients consecutively undergone neoadjuvant immunochemotherapy and radical-intent surgery for initial stage cIII NSCLC between 2020 and 2021 were included. Hematoxylin- and eosin-stained slides of paraffinembedded sections of the degree of pathologic response in the primary tumor (PT) and its paired involved LNs were reviewed. Imaging mass cytometry was conducted to quantify the immunological status. With 10% as residual viable tumor (RVT) cutoff, mLN-MPR (HR: 0.34, 95%CI: 0.14-0.78; P = 0.011, ref: mLN-MPR(-)) showed more significant correlation with DFS than ypN0 (HR: 0.40, 95%CI: 0.17-0.94; P = 0.036, ref: ypN1-N2). And mLN-MPR combined with PT-MPR, compared with ypN stage combined with PT-MPR (p-value: 0.030 vs. 0.117), can better distinguished the DFS curves of the 4 subgroups of patients. mLN-MPR(+)/PT-MPR(+) patients had the best prognosis compared with other subgroups. Pathologic responses of RVT in PT and paired regional LNs [MPR inconsistency rate: 21/53 (39.6%)], and across different LNs could be inconsistent, especially in squamous cell carcinoma. RVT% in mLNs after immunochemotherapy appeared to be polarized [16 (30.2%) cases with RVT ≥ 70%; 34 (64.2%) with RVT ≤ 10%]. Partial regression of LN metastasis could present with distinct immune subtypes: immune-inflamed or immune-evacuation subtype, and the former presented with higher CD3, CD8, and PD-1 expression in the invasive margin. mLN-MPR demonstrated a potential prognostic value in predicting DFS in patients treated with neoadjuvant immunochemotherapy, but further research is needed to validate its usefulness for other survival outcomes, including OS.

Risk mapping of lung cancer: a comprehensive appraisal of published meta-analyses incorporating Mendelian randomization studies.

INTRODUCTION: A comprehensive appraisal of published meta-analyses incorporating Mendelian randomization studies was performed to map the different risk factors and assess the causality for lung cancer. METHODS: Systematic reviews and meta-analyses of observational and interventional studies were reviewed based on PubMed, Embase, Web of Science, and Cochrane Library. Mendelian randomization analyses were conducted to validate the causal associations of those various exposures with lung cancer using summary statistics from 10 genome-wide association studies (GWAS) consortia and other GWAS databases in MR-Base platform. RESULTS: In the review of meta-analyses, 105 risk factors associated with lung cancer were identified from 93 articles. It was found that 72 risk factors were nominally significant (P < 0.05) associated with lung cancer. Mendelian randomization analyses were performed to analyze 36 exposures based on 551 SNPs and 4,944,052 individuals, finding that 3 exposures had a consistent risk/protective effect on lung cancer with the results of the meta-analysis. In Mendelian randomization anaylses, smoking (OR 1.44, 95% CI 1.18-1.75; P = 0.001) and blood copper (OR 1.14, 95% CI 1.01-1.29; P = 0.039) significantly associated with increased risk of lung cancer, whereas aspirin use (OR 0.67, 95% CI 0.50-0.89; P = 0.006) showed protective effects. CONCLUSION: This study mapped putative associations of risk factors for lung cancer, revealing the causal hazard effect of smoking, blood copper, and the protective effect of aspirin use in the development of lung cancer. CLINICAL TRIAL REGISTRY: This study is registered with PROSPERO (CRD42020159082).

Impact of the interval between neoadjuvant immunochemotherapy and surgery on surgical-pathological outcomes in non-small cell lung cancer.

Introduction: The interval between neoadjuvant immunochemotherapy and surgery in patients with non-small cell lung cancer (NSCLC) has not been well characterized. This study investigated the association between the time-to-surgery (TTS) interval and surgical-pathological outcomes. Method: Clinical data of patients who received neoadjuvant immun-ochemotherapy followed by surgery for NSCLC between January 2019 and September 2021 were collected. The patients were divided into three groups based on TTS interval: the early-surgery group (ESG), the standard-surgery group (SSG), and the delayed-surgery group (DSG). The primary outcomes were objective response rate (ORR), major pathological response (MPR), and pathological complete response (pCR). The secondary endpoint was surgical outcome. Results: Of the 171 patients, 16 (9.4%) received surgery in ≤28 days, 49 (28.7%) received surgery within 29-42 days, and 106 (61.9%) received surgery in ≥43 days after neoadjuvant immunochemotherapy, with a median TTS of 46 days. The postoperative drainage of the ESG group (455.1 ml) was significantly less than that of the SSG group (680.7 ml) and the DSG group (846.5 ml; p = 0.037). However, the TTS interval did not influence the duration of the operation (P = 0.54), the extent of intraoperative bleeding (P = 0.60), or the length of postoperative hospital stay (P = 0.17). The ORR was observed in 69%, 51%, and 56% of patients in the ESG, the SSG, and the DSG, respectively (P = 0.46), and MPR occurred in 50%, 47%, and 58% (P = 0.38) of patients in the ESG, the SSG, and the DSG, respectively. Similarly, no statistically significant difference was found for pCR (ESG: 31%; SSG: 27%; DSG: 42%; P = 0.14). Conclusion: This retrospective study indicated that TTS exerts no significant effect on the feasibility and safety of surgery in the neoadjuvant immunochemotherapy setting of NSCLC. Analysis of the TTS interval revealed a tendency for delayed surgery to be associated with a pathological response in NSCLC, although this association was not statistically significant.

Predicting EGFR mutation status in lung adenocarcinoma presenting as ground-glass opacity: utilizing radiomics model in clinical translation.

OBJECTIVES: This study aimed to establish a non-invasive radiomics model based on computed tomography (CT), with favorable sensitivity and specificity to predict EGFR mutation status in GGO-featured lung adenocarcinoma subsequently guiding the administration of targeted therapy. METHODS: Clinical-pathological information and preoperative CT images of 636 lung adenocarcinoma patients (464, 100, and 72 in the training, internal, and external validation sets, respectively) that underwent GGO lesions resection were included. A total of 1476 radiomics features were extracted with gradient boosting decision tree (GBDT). RESULTS: The established radiomics model containing 102 selected features showed an encouraging discrimination performance of EGFR mutation status (mutant or wild type), and the predictive ability was superior to that of the clinical model (AUC: 0.838 vs. 0.674, 0.822 vs. 0.730, and 0.803 vs. 0.746 for the training, internal validation, and external validation sets, respectively). The combined radiomics plus clinical model showed no additional benefit over the radiomics model in predicting EGFR status (AUC: 0.846 vs. 0.838, 0.816 vs. 0.822, and 0.811 vs. 0.803, respectively, in three cohorts). Uniquely, this model was validated in a cohort of lung adenocarcinoma patients who have undertaken adjuvant EGFR-TKI treatment and harbored unresected GGOs during the medication, leading to a significantly improved potency of EGFR-TKIs (response rate: 25.9% vs. 53.8%, p = 0.006; before and after prediction, respectively). CONCLUSION: This presented radiomics model can be served as a non-invasive and time-saving approach for predicting the EGFR mutation status in lung adenocarcinoma presenting as GGO. KEY POINTS: • We developed a GGO-specific radiomics model containing 102 radiomics features for EGFR mutation status differentiation. • An AUC of 0.822 and 0.803 in the internal and external validation cohorts, respectively, were achieved. • The radiomics model was utilized in clinical translation in an adjuvant EGFR-TKI treatment cohort with unresected GGOs. A significant improvement in the potency of EGFR-TKIs was achieved (response rate: 25.9% vs. 53.8%, p = 0.006; before and after prediction).

PD-L1 expression and Tumor mutation burden as Pathological response biomarkers of Neoadjuvant immunotherapy for Early-stage Non-small cell lung cancer: A systematic review and meta-analysis.

To date, there is no approved biomarker for predicting pathological response in neoadjuvant programmed cell death (ligand) 1 (PD-(L)1) blockades treated early-stage non-small cell lung cancer (NSCLC). Databases including PubMed, Embase, ClinicalTrials.gov, and Conference abstracts were searched for clinical trials of neoadjuvant PD-1/PD-L1 blockades for resectable NSCLC. Data regarding major pathological response (MPR), pathological complete response (pCR) in patients with high/low pretreatment PD-L1 expression, and tumor mutation burden (TMB) were synthesized using fixed-model meta-analysis and evaluated by odds ratio with 95 % confidence interval. This analysis included 10 studies involving 461 NSCLC patients. Compared with PD-L1 expression <1%, PD-L1 expression ≥1% is associated with a higher rate of MPR and pCR. High-TMB associated with MPR and pCR. Similar findings were observed in subgroup analyses despite mono-PD-1/PD-L1 blockade or their combination with chemotherapy. Notably, 50 % as the cutoff value for PD-L1 expression demonstrated better prediction efficacy for MPR than that of 1%.

Preoperative immunochemotherapy for locally advanced non-small cell lung cancer: an analysis of the clinical outcomes, optimal number of cycles, and peripheral immune markers.

Background: This retrospective study aimed to evaluate the real-world efficacy of neoadjuvant immunochemotherapy in locally advanced stage III non-small cell lung cancer (NSCLC), with a particular focus on analyzing the optimal treatment cycle and peripheral immune markers. Methods: Eligible patients with biopsy-confirmed stage III NSCLC who underwent neoadjuvant immunochemotherapy between January 1st, 2018 and March 30th, 2021 were identified, and their oncological outcomes were collected. Results: A total of 115 patients were identified, among whom 61, 51, and three cases were classified as clinical stage IIIA, IIIB, and IIIC at presentation, respectively. The objective response rate was 61.7% (71/115) after immunochemotherapy. The most frequent surgical procedure was lobectomy, performed in 91 (79.1%) cases, and all patients had microscopic-free margins. Major pathological response (MPR) was observed in 64 (55.7%) patients, among whom 44 (38.3%) achieved a complete pathological response; pathological-confirmed lymph node downstage (cN2-3 to ypN0-1) was described in 73.6% (67/91) of patients with cN2-3 diseases. The median disease-free survival (DFS) of all enrolled patients was 23.6 [95% confidence interval (CI): 15.9-31.3] months, while for patients with residual tumors of more than 10%, the median DFS was 18.1 (95% CI: 12.5-23.8) months. The post-hoc multivariable analysis showed that three [odds ratio (OR), 4.78; 95% CI: 1.17-19.55] and four (OR: 6.50; 95% CI: 1.12-37.54) cycles of neoadjuvant immunochemotherapy were prone to higher MPR rates compared to two cycles in patients that were classified as complete/partial response (CR/PR). However, adding over five cycles was not associated with a higher MPR rate (OR, 0.91; 95% CI: 0.15-5.47). The pretreatment lymphocyte count level (1.89±0.68 vs. 1.59±0.63, P=0.019) and monocyte count level (0.71±0.32 vs. 0.59, P=0.020) were significantly higher in MPR patients compared to non-MPR patients. Conclusions: The present study confirmed a favorable real-world tumor downstage efficacy of neoadjuvant immunochemotherapy in locally advanced NSCLC. Even though CR/PR was achieved, it is still beneficial when extended into 3-4 cycles of neoadjuvant immunochemotherapy.

Development of an acute kidney injury risk prediction model for patients undergoing extracorporeal membrane oxygenation.

Background: Some studies have reported to use some predictors before extracorporeal membrane oxygenation (ECMO) initiation to predict the acute kidney injury (AKI) risk. However, injury during the ECMO operation and the response of patients to ECMO may significantly influence the prognosis, and they are unpredictable before ECMO initiation. This study aims to develop a potential model based clinical characteristics at the 2-hour time point during ECMO for the early prediction of AKI in patients receiving ECMO. Methods: 139 patients who underwent ECMO were enrolled in this study. The clinical characteristics and the laboratory examinations at 2-hour time point during ECMO were recorded. The least absolute shrinkage and selection operator (LASSO) regression method was performed to select predictors, and logistic regression and a nomogram were used to establish the prediction model. The area under curve (AUC) of the receiver operating characteristic and calibration curve were used to analyze the discrimination and calibration of the model. K-fold cross-validation method was performed to validate the accuracy of this model. Results: Among the 139 patients receiving ECMO, 106 participants (76.26%) developed AKI. Four predictive variables including ECMO model, serum creatinine (Scr-2h), uric acid(UA-2h), and serum lactate (Lac-2h) at the 2-hour time point during ECMO were filtered from 39 clinical parameters by LASSO regression. These four predictors were incorporated to develop a model for predicting AKI risk using logistic regression. The AUC of the model was 0.905 (0.845-0.965), corresponding to 81.1% sensitivity, 90.9% specificity and 83.5% accuracy. Moreover, this model showed good consistency between observed and predicted probability based on the calibration curve (P > 0.05). The validation performed by K-fold cross-validation method showed that the accuracy was 0.874 ± 0.006 in training sets, 0.827 ± 0.053 in test sets, indicating a good capability for AKI risk prediction. Finally, a nomogram based on this model was constructed to facilitate its use in clinical practice. Conclusion: The nomogram incorporating Scr-2h,Lac-2h, UA-2h, and ECMO model may facilitate the individualized prediction of the AKI risk among patients undergoing ECMO.

Radical Minimally Invasive Surgery After Immuno-chemotherapy in Initially-unresectable Stage IIIB Non-small cell Lung Cancer.

INTRODUCTION: Use of neoadjuvant immunotherapy agent in advanced stage NSCLC is controversial. Herein, we aim to report on a case series of successful conversion from initial unresectable stage cIIIB NSCLC to radical minimally invasive surgery through immunochemotherapy; with particular attention given to surgical outcomes and survival benefit of surgery. METHODS: Fifty-one patients with initial stage cIIIB NSCLC who received PD-1 agents plus platinum-based chemotherapy between May, 2018 to August, 2020 were retrospectively identified. Surgical and oncological outcomes of enrolled patients were collected. RESULTS: Of 31 patients who underwent subsequent resection, 23 (74.2%) patients underwent lobectomy, 1 (3.2%) underwent pneumonectomy, 5 (16.1%) underwent sleeve lobectomy, and 2 (6.5%) with bilobectomy. The median surgical time was 205 minutes (range, 100-520). The average blood loss was 185 (range: 10-1100) ml. Dense adhesions or fibrosis was noted in 15 cases. The median postoperative hospital stay was 6 (range: 3-13) days. No surgical-related mortality was recorded, only 5 patients (16.1%) experienced any postoperative morbidity (no grade 3 complications). Ten patients (32.3%) had major pathological response, with mediastinal down-staging been observed in 22/31 (71.0%) patients. With a median after up of 15.4 months, thirty-one patients that had surgery had relatively longer median DFS/PFS compared to that of either non-responders or responders that without surgery (27.5 vs. 4.7 vs. 16.7 months, respectively). CONCLUSIONS: Radical surgery after chemoimmunotherapy in initial unresectable stage IIIB NSCLC seems to be safe with low surgical-related mortality and morbidity, and was favorably associated with longer DFS/PFS compared to those without surgery.

Nonintubated Robotic-assisted Thoracic Surgery for Tracheal/Airway Resection and Reconstruction: Technique Description and Preliminary Results.

OBJECTIVE: We aim to report a novel surgical technique that RATS combined with nonintubated spontaneous ventilation to perform tracheal/airway surgery. SUMMARY OF BACKGROUND DATA: Our team has demonstrated video-assisted transthoracic surgery can be used for thoracic tracheal diseases with satisfactory outcomes. Our team has also demonstrated that tracheal/airway resection and reconstruction under spontaneous ventilation can improve the anastomosis and operating time. Recently, RATS emerged as an available alternative minimally invasive approach for lung cancer, with lower perioperative mortality and conversion rate to open. METHODS: Five patients fulfilling the criteria for nonintubated approach underwent RATS tracheal/airway surgery. Patient 1 has a tumor in the thoracic trachea; patient 2 had involving secondary carina; patient 3 had involving trachea carina, and patient 4 had involving left main bronchus. Patient 5 had involving mid-tracheal. RESULTS: All patients had an uneventful procedure. The total operative time ranged from 5 hours 5 minutes to 9 hours 55 minutes. The postoperative hospital stays ranged from 4 days to 14 days. Fiber-optic bronchoscopy performed 1 month after the procedure showed good anastomotic healing with no stricture. CONCLUSION: This is the first report on RATS use in tracheal/airway surgery, in combination with nonintubation spontaneous ventilation. In selected patients, this novel combined approach is feasible and safe. A patient can potentially benefit from the combined advantages of both techniques. More cases and longer-term data are required to establish its role in tracheal/airway surgery.

Role of lymphatic endothelial cells in the tumor microenvironment-a narrative review of recent advances.

BACKGROUND: As lymphatic vessel is a major route for solid tumor metastasis, they are considered an essential part of tumor drainage conduits. Apart from forming the walls of lymphatic vessels, lymphatic endothelial cells (LECs) have been found to play multiple other roles in the tumor microenvironment, calling for a more in-depth review. We hope that this review may help researchers gain a detailed understanding of this fast-developing field and shed some light upon future research. METHODS: To achieve an informative review of recent advance, we carefully searched the Medline database for English literature that are openly published from the January 1995 to December 2020 and covered the topic of LEC or lymphangiogenesis in tumor progression and therapies. Two different authors independently examined the literature abstracts to exclude possible unqualified ones, and 310 papers with full texts were finally retrieved. RESULTS: In this paper, we discussed the structural and molecular basis of tumor-associated LECs, together with their roles in tumor metastasis and drug therapy. We then focused on their impacts on tumor cells, tumor stroma, and anti-tumor immunity, and the molecular and cellular mechanisms involved. Special emphasis on lung cancer and possible therapeutic targets based on LECs were also discussed. CONCLUSIONS: LECs can play a much more complex role than simply forming conduits for tumor cell dissemination. Therapies targeting tumor-associated lymphatics for lung cancer and other tumors are promising, but more research is needed to clarify the mechanisms involved.

Early extubation in operating room after single-lung transplantation: a single institutional experience.

BACKGROUND: Early endotracheal extubation in operating room (E-OR) after lung transplantation is rarely reported worldwide. Herein, we aim to explore the feasibility and safety of E-OR after lung transplantation and demonstrate its potential benefits. METHODS: This study is a single-center retrospective database analysis of 18 patients. All lung transplantation patients with E-OR attempted between June 2018 and September 2019 were included retrospectively. Perioperative variables, including ischemia time, total blood loss, blood lactic acid, the partial pressure of oxygen, partial pressure of oxygen/fraction of inspiration oxygen ratio, time of semi-open pulmonary artery occlusion clamp, extubation rate, and complications after E-OR, were analyzed. Data were compared using non-parametric tests and expressed as the median or number (percentage). RESULTS: Clinical data of 18 patients with E-OR attempted were collected. Overall, 15/18 (83.33%) patients successfully underwent E-OR without reintubation. Reintubation occurred in 3/18 (16.67%) patients; one patient presented with decreased blood oxygen saturation and unconsciousness, while two patients developed hypoxemia and respiratory failure after E-OR. Extracorporeal membrane oxygenation (ECMO) was not used postoperatively. No grade 3 primary graft dysfunction was observed and all eighteen patients were alive 1 year after the transplant. No postoperative hemodialysis and tracheotomy occurred. The median length of stay in the intensive care unit (ICU) for E-OR patients was 120 hours, the median length of postoperative hospital stay was 19 days, and the median hospitalization cost was 35,577 USD. CONCLUSIONS: Early endotracheal extubation in operating room was feasible and did not delay postoperative recovery in these 18 lung transplantation recipients.