Predicting therapeutic response to neoadjuvant immunotherapy based on an integration model in resectable stage IIIA (N2) non-small cell lung cancer.

OBJECTIVE: Accurately predicting response during neoadjuvant chemoimmunotherapy for resectable non-small cell lung cancer (NSCLC) remains clinically challenging. In this study, we investigate the effectiveness of blood-based tumor mutational burden (bTMB) and a deep learning (DL) model in predicting major pathologic response (MPR) and survival from a phase II trial. METHODS: Blood samples were prospectively collected from 45 stage IIIA (N2) NSCLC patients undergoing neoadjuvant chemoimmunotherapy. An integrated model, combining the CT-based DL score, bTMB, and clinical factors, was developed to predict tumor response to neoadjuvant chemoimmunotherapy. RESULTS: At baseline, bTMB were detected in 77.8% (35 of 45) of patients. Baseline bTMB ≥11 Muts/Mb was associated with significantly higher MPR rates (77.8% vs. 38.5%, p = 0.042), and longer disease-free survival (DFS, p = 0.043), but not overall survival (p = 0.131), compared to bTMB < 11 Muts/Mb in 35 patients with bTMB available. The developed DL model achieved an area under the curve (AUC) of 0.703 in all patients. Importantly, the predictive performance of the integrated model improved to an AUC of 0.820 when combining the DL score with bTMB and clinical factors. Baseline circulating tumor DNA (ctDNA) status was not associated with pathological response and survival. Compared to ctDNA residual, ctDNA clearance before surgery was associated with significantly higher MPR rates (88.2% vs. 11.1%, p < 0.001) and improved DFS (p = 0.010). CONCLUSIONS: The integrated model shows promise as a predictor of tumor response to neoadjuvant chemoimmunotherapy. Serial ctDNA dynamics provide a reliable tool for monitoring tumor response.

Spread Through Air Spaces in Residual Tumor Classification for Clinical IA Lung Adenocarcinoma.

BACKGROUND: We aimed to validate the prognostic implication of uncertain resection, R(un), proposed by International Association for the Study of Lung Cancer (IASLC) and evaluate the prognostic value of spread through air spaces (STAS) in reclassifying the R classification among patients with lung adenocarcinoma after segmentectomy. METHODS: We enrolled 1007 patients who underwent segmentectomy for c-stage IA lung adenocarcinoma between 2014 and 2017. Recurrence-free survival (RFS) and overall survival (OS) were compared to evaluate the prognostic value of IASLC-R(un) and STAS. Whether STAS would skip into complementary lobectomy was evaluated in a prospective cohort. RESULTS: The current IASLC-R(un) failed to significantly stratify the RFS (P = .078) in segmentectomy, and STAS was a stronger risk factor of poor prognosis for both RFS and OS (P < .001). Moreover, the presence of STAS was associated with increased locoregional recurrence in patients undergoing segmentectomy (P < .001) but not in those treated with lobectomy (P = .187), indicating that only STAS-positive segmentectomy was consistent with the concept of R(un) in relapse pattern. After reclassifying STAS-positive segmentectomy into the R(un) category, the proposed R(un) showed an improvement in prognosis stratification. In addition, 2 of 30 patients (6.2%) in the prospective cohort who underwent initial segmentectomy and complementary lobectomy had STAS clusters in the complementary lobectomy specimens. CONCLUSIONS: Unfavorable prognosis, relapse patterns consistent with R(un), and pathologic verification that saltatory spread of STAS observed in complementary lobectomy specimens supported reclassifying STAS-positive segmentectomy as R(un). STAS is a critical concern for the surgical completeness evaluation after segmentectomy.

Incorporation of the lepidic component as an additional pathological T descriptor for non-small cell lung cancer: Data from 3335 cases of lung adenocarcinoma.

OBJECTIVES: The Lepidic Component (LP) identifies a subgroup with an excellent prognosis for lung adenocarcinoma (LUAD). Our research aimed to propose an improved pathological T (pT) stage for LUAD based on LP. MATERIALS AND METHODS: Totally, 3335 surgical patients with pathological stage I LUAD were incorporated. Factors affecting survival were investigated by analyzing recurrence-free survival (RFS) and overall survival (OS) using the Kaplan-Meier method and Cox regression analyses. Subgroup analysis based on Lepidic Ratio (LR) was further evaluated. The net benefit from the modified pT category (pTm) was assessed using the Area Under the time-dependent Receiver Operating Curve (AUC), Harrell's Concordance Index (C-index), Reclassification Improvement (NRI), and Integrated Discrimination Improvement (IDI). RESULTS: The presence of LP (LP+) was identified in 1425 (42.7 %) patients, indicating a significantly better RFS (P < 0.001) and OS (P < 0.001) than those without LP, and similar results were reproduced in pT1a-pT2a subcategory (P < 0.050 for all). Multivariable Cox analysis revealed LP+ as an independent prognostic factor for both RFS (HR, 0.622; P < 0.001) and OS (HR, 0.710; P = 0.019). However, lepidic ratio (LR) was not independently associated with both RFS and OS for LP+ patients. The 5-year RFS and OS rates between T1a (LP-) and T1b (LP+), T1b (LP-) and T1c (LP+), and T1b (LP-) and T2a (LP+) were comparable (P > 0.050 for all). After modification, compared with current 8th edition pT stage system (pT8), pTm independently predicted RFS and OS, and AUCs, c-index, NRI, and IDI analysis all demonstrated pTm holds better discrimination performances than pT8 for LUAD prognosis. CONCLUSION: LP can be an additional down-staged T descriptor for pathological stage I LUAD and improve the survival predictive performance of reclassification.

Validation of the Proposed International Association for the Study of Lung Cancer Residual Tumor Classification to Upgrade Extracapsular Extension of Tumor in Nodes From R0 to Incomplete Resection.

INTRODUCTION: The International Association for the Study of Lung Cancer (IASLC) proposed a revised R classification to upstage extracapsular extension (ECE) of tumor in nodes from R0 to R1. Nevertheless, evidence to confirm this proposal is insufficient. METHODS: The study included 4061 surgical patients with NSCLC. After reclassification by IASLC-R classification, overall survival (OS) was analyzed to compare patients with ECE with those with R0, R(un), and incomplete resection (R1 and R2). The recurrence pattern of ECE was evaluated to determine whether it correlated with incomplete resection. RESULTS: Among 1136 patients with N disease, those without ECE (n = 754, 67%) had a significantly better OS than those with ECE (n = 382, 33%) (p < 0.001). This negative prognostic significance was consistent across multiple subgroups. Multivariate analysis revealed that ECE was an independent prognostic risk factor (p < 0.001). When patients with ECE were separated from the IASLC-R1 group, their OS was significantly worse than that of IASLC-R(un) patients, but comparable to that of the remaining patients in the IASLC-R1 patients when analyzing all patients and patients with N disease. Moreover, patients with ECE had an increased risk of local recurrence in the mediastinum (p < 0.001), ipsilateral lung (p = 0.031), and malignant pleural effusion or nodes (p = 0.004) but not distant recurrence including contralateral or both lungs (p = 0.268), liver (p = 0.728), brain (p = 0.252), or bone (p = 0.322). CONCLUSIONS: The prognosis of ECE patients is comparable with that of R1 patients. Moreover, their higher risk of local recurrence strongly suggests the presence of occult residual tumor cells in the surgical hemithoracic cavity. Therefore, upgrading ECE into incomplete resection is reasonable.

Brief Report: Acetaminophen Reduces Neoadjuvant Chemoimmunotherapy Efficacy in Patients With NSCLC by Promoting Neutrophil Extracellular Trap Formation: Analysis From a Phase 2 Clinical Trial.

Introduction: Neoadjuvant chemoimmunotherapy has recently been the standard of care for resectable locally advanced NSCLC. Factors affecting the neoadjuvant immunotherapy efficacy, however, remain elusive. Metabolites have been found to modulate immunity and associate with immunotherapeutic efficacy in advanced tumors. Therefore, we aimed to investigate the impact of plasma metabolites on the pathologic response after neoadjuvant chemoimmunotherapy. Methods: Patients with stage IIIA (N2) NSCLC who underwent neoadjuvant chemoimmunotherapy in a prospective phase 2 clinical trial (NCT04422392) were enrolled. Metabolomic profiling of the plasma before treatment was performed using liquid chromatography-mass spectrometry. A Lewis lung carcinoma mouse model was further used to investigate the underlying mechanisms. Proteomics and multiplexed immunofluorescence of the mice tumor were performed. Results: A total of 39 patients who underwent three cycles of anti-programmed cell death-protein 1 (anti-PD-1) (sintilimab) and chemotherapy were included. The level of acetaminophen (APAP) was found to be significantly elevated in patients who did not achieve major pathologic response. The level of APAP remained an independent predictor for major pathologic response in multivariate logistic analysis. In the Lewis lung carcinoma mouse model, combination of APAP and anti-PD-1 treatment significantly reduced the treatment efficacy compared with anti-PD-1 treatment alone. Proteomics of the tumor revealed that myeloid leukocyte activation and neutrophil activation pathways were enriched after APAP treatment. Tumor microenvironment featuring analysis also revealed that the combination treatment group was characterized with more abundant neutrophil signature. Further multiplexed immunofluorescence confirmed that more neutrophil extracellular trap formation was observed in the combination treatment group. Conclusions: APAP could impair neoadjuvant chemoimmunotherapy efficacy in patients with NSCLC by promoting neutrophil activation and neutrophil extracellular trap formation.

The number of metastatic lymph nodes is more predictive of prognosis than location-based N stage for nonsmall cell lung cancer: a retrospective cohort study.

BACKGROUND: The eighth edition of nodal classification is defined only by the anatomical location of metastatic lymph nodes and has limited prognostic discrimination power. The authors aimed to evaluate the prognostic significance and discriminatory capability of the number of metastatic lymph nodes (nN) in resected nonsmall cell lung cancer. MATERIALS AND METHODS: Patients with stage IA to IIIB resected nonsmall cell lung cancer between 1 January 2009 and 31 December 2013 were analyzed as a Chinese cohort. The optimal thresholds for the nN classification were determined by the X-tile. The receiver operating characteristic curve, net reclassification improvement and standardized net benefit calculated by decision curve analysis was estimated to quantify the nN classification's performance in prognostic stratification. External validation in the surveillance, epidemiology, and end results database was performed to test the robustness of the nN classification. RESULTS: Both cohorts showed a stepwise prognosis deterioration with increasing nN. One to three, four to six, and more than six were selected as optimal thresholds of nN classification in the Chinese cohort, which included 4432 patients, then validated in the SEER cohort ( n =28 022 patients). Multivariate Cox analysis showed the nN classification was an independent predictive factor for overall survival in both cohorts (Chinese cohort and SEER cohort: N 0 vs. N 1-3 , P <0.001; N 0 vs. N 3-6 , P <0.001; N 0 vs. N >6 , P <0.001). And prognostic discriminatory capability was improved in the nN classification compared with location-based N classification [5-year NRI score, 0.106 (95% CI: 0.049-0.132) and 5-year time-independent AUC, 0.593 (95% CI: 0.560-0.625) vs. 0.554 (95% CI: 0.520-0.588), P <0.001]. CONCLUSIONS: The nN classification tended to be a superior prognostic indicator than the location-based N classification. The number of metastatic lymph nodes should be considered in the future revision of the TNM system.

Clinical utility of [18F]FDG PET/CT in the assessment of mediastinal lymph node disease after neoadjuvant chemoimmunotherapy for non-small cell lung cancer.

OBJECTIVES: The performance of positron emission tomography/computed tomography (PET/CT) for the prediction of ypN2 disease in non-small cell lung cancer (NSCLC) after neoadjuvant chemoimmunotherapy has not been reported. This multicenter study investigated the utility of PET/CT to assess ypN2 disease in these patients. METHODS: A total of 181 consecutive patients (chemoimmunotherapy = 86, chemotherapy = 95) at four institutions were enrolled in this study. Every patient received a PET/CT scan prior to surgery and complete resection with systematic nodal dissection. The diagnostic performance was evaluated through area under the curve (AUC). Kaplan-Meier method and Cox analysis were performed to identify the risk factors affecting recurrences. RESULTS: The sensitivity, specificity, and accuracy of PET/CT for ypN2 diseases were 0.667, 0.835, and 0.779, respectively. Therefore, the AUC was 0.751. Compared with the false positive cases, the mean value of max standardized uptake value (SUVmax) (6.024 vs. 2.672, p < 0.001) of N2 nodes was significantly higher in true positive patients. Moreover, the SUVmax of true positive (7.671 vs. 5.976, p = 0.365) and false (2.433 vs. 2.339, p = 0.990) positive cases were similar between chemoimmunotherapy and chemotherapy, respectively. Survival analysis proved that pathologic N (ypN) 2 patients could be stratified by PET/CT-N2(+ vs. -) for both chemoimmunotherapy (p = 0.023) and chemotherapy (p = 0.010). CONCLUSIONS: PET/CT is an accurate and non-invasive test for mediastinal restaging of NSCLC patients who receive neoadjuvant chemoimmunotherapy. The ypN2 patients with PET/CT-N2( +) are identified as an independent prognostic factor compared with PET/CT-N2(-). CLINICAL RELEVANCE STATEMENT: Imaging with 18F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) plays an integral role during disease diagnosis, staging, and therapeutic response assessments in patients with NSCLC. PET/CT could be an effective non-invasive tool for predicting ypN2 diseases after neoadjuvant chemoimmunotherapy. KEY POINTS: • PET/CT could serve as an effective non-invasive tool for predicting ypN2 diseases. • The ypN2 patients with PET/CT-N2( +) were a strong and independent prognostic factor. • The application of PET/CT for restaging should be encouraged in clinical practice.

The additional radiotherapy to adjuvant chemotherapy improves the prognosis of stage III-N2 with highest mediastinal lymph node metastasis in non-small cell lung cancer.

INTRODUCTION: The benefits of adjuvant chemoradiation therapy (CRT) for heterogeneous pathological N2 (pN2) diseases remain unclear in non-small cell lung cancer (NSCLC). This study aimed to investigate suitable pN2 patients for adjuvant CRT. MATERIAL AND METHODS: This study retrospectively reviewed the data of patients with pN2 NSCLC in Shanghai Pulmonary Hospital from January 2012 to December 2016. Included cases were subdivided as highest mediastinal lymph node (HM) (n = 732) metastasis and non-HM metastasis (n = 677) groups according to the International Association for the Study of Lung Cancer (IASLC). Furthermore, the Kaplan-Meier and Cox models were used to evaluate the prognostic benefits of adjuvant CRT in heterogeneous pN2 subgroups. RESULTS: A total of 1409 patients were enrolled in this study, with a median follow-up time of 63.8 months. Patients with HM involvement had worse prognoses (p < 0.001 for recurrence-free survival (RFS) and overall survival (OS)). Furthermore, the survival improvement of adjuvant CRT was significant for these patients (p < 0.001 for RFS and p = 0.032 for OS), regardless of whether it was single (p < 0.001 for RFS and p = 0.029 for OS) or multiple pN2 (p < 0.001 for RFS and p = 0.026 for OS) diseases. According to multivariable cox analysis, the long-term RFS and OS in the cancerous HM group were independently predicted by pathological N stage (p = 0.002 for RFS and p < 0.001 for OS) and adjuvant CRT (p < 0.001 for RFS and p = 0.011 for OS). CONCLUSION: Metastatic HM was associated with a worse prognosis in pN2 disease. Our analysis supported that adjuvant CRT significantly improved both RFS and OS for these patients.

Targeting CXCR1 alleviates hyperoxia-induced lung injury through promoting glutamine metabolism.

Although increasing evidence suggests potential iatrogenic injury from supplemental oxygen therapy, significant exposure to hyperoxia in critically ill patients is inevitable. This study shows that hyperoxia causes lung injury in a time- and dose-dependent manner. In addition, prolonged inspiration of oxygen at concentrations higher than 80% is found to cause redox imbalance and impair alveolar microvascular structure. Knockout of C-X-C motif chemokine receptor 1 (Cxcr1) inhibits the release of reactive oxygen species (ROS) from neutrophils and synergistically enhances the ability of endothelial cells to eliminate ROS. We also combine transcriptome, proteome, and metabolome analysis and find that CXCR1 knockdown promotes glutamine metabolism and leads to reduced glutathione by upregulating the expression of malic enzyme 1. This preclinical evidence suggests that a conservative oxygen strategy should be recommended and indicates that targeting CXCR1 has the potential to restore redox homeostasis by reducing oxygen toxicity when inspiratory hyperoxia treatment is necessary.

Hybrid uniportal robotic-assisted thoracoscopic surgery using video-assisted thoracoscopic surgery staplers: technical aspects and results.

Background: The clinical efficacy of robot-assisted thoracic surgeries has been explored by numerous recent studies. Nonetheless, since current standard robotic systems (da Vinci Xi system) were intended for multiportal surgical processes and robotic staplers were still unavailable in the developing world, obstacles still remain concerning the feasibility of uniportal robotic surgeries. Methods: A hybrid uniportal robotic-assisted thoracoscopic surgery (RATS) modality utilizing video-assisted thoracoscopic surgery (VATS) staplers was investigated in Shanghai Pulmonary Hospital. Clinicopathological characteristics and perioperative outcomes concerning patients receiving hybrid uniportal RATS between August 2022 and September 2022 were collected. Results: A total of 40 patients were included in this study. Most of the patients (23/40, 57.5%) received hybrid uniportal RATS lobectomies. One conversion from uniportal RATS to biportal process was encountered due to extensive adhesions discovered intraoperatively. The median procedural duration was 76 min [interquartile range (IQR), 61-99 min], and the median blood loss volume was 50 mL (IQR, 50-50 mL). A median stay length of three days (IQR, 2-4 days) was recorded. Eleven patients (27.5%) developed Clavien-Dindo grade I-II postoperative complications, while no grade III-IV complications were observed. Aside from this, none of the patients were readmitted or died within 30 days post-surgery. Conclusions: The feasibility of hybrid uniportal RATS procedures using VATS staplers has been preliminarily validated. For early-stage non-small cell lung cancer patients, such a procedure might clinical efficacy comparable to that of uniportal RATS utilizing robotic staplers.

Utility of 18F-FDG PET/CT uptake values in predicting response to neoadjuvant chemoimmunotherapy in resectable non-small cell lung cancer.

INTRODUCTION: Reliable predictive markers are lacking for resectable non-small cell lung cancer (NSCLC) patients treated with neoadjuvant chemoimmunotherapy. The present study investigated the utility of SUVmax values acquired from PET/CT to predict the response to neoadjuvant chemoimmunotherapy for resectable NSCLC. MATERAL AND METHODS: SUVmax, clinical and pathological outcomes, were collected from patients in 5 hospitals. Patients who received dynamic PET/CT surveillance were divided into cohorts A (chemoimmunotherapy) and B (chemotherapy), respectively, while cohort C (chemoimmunotherapy) comprised patients undergoing post-therapy PET/CT. Associations between SUVmax and major pathologic response (MPR) were evaluated through receiver operating characteristic (ROC) curves. RESULTS: A total of 129 cases with an MPR rate of 46.5 % was identified. In neoadjuvant chemoimmunotherapy, ΔSUVmax% (AUC: 0.890, 95 % CI: 0.761-0.949) and post-therapy SUVmax (AUC: 0.933, 95 % CI: 0.802-0.959) could accurately predict MPR. On the contrary, the baseline SUVmax was not associated with MPR (p = 0.184). Furthermore, an independent cohort C proved that post-therapy SUVmax could serve as an independent predictor (AUC: 0.928, 95 % CI: 0.823-0.958). In addition, robust predictive performance could be observed when we use the optimal cut-off point of both ΔSUVmax% (54.4 %, AUC: 0.912, 95 % CI: 0.824-0.994) and post-therapy SUVmax (3.565, AUC: 0.912, 95 % CI: 0.824-0.994) in neoadjuvant chemoimmunotherapy. The RNA data revealed that the expression of PFKFB4, a key enzyme in glycolysis, was positively correlated with SUVmax value and tumor cell proliferation after neoadjuvant chemoimmunotherapy. CONCLUSION: These findings highlighted that the ΔSUVmax% and remained SUVmax were accurate and non-invasive tests for the prediction of MPR after neoadjuvant chemoimmunotherapy.

The IASLC grading system for invasive pulmonary adenocarcinoma: a potential prognosticator for patients receiving neoadjuvant therapy.

Background: Grading system for resected invasive pulmonary adenocarcinoma proposed by the International Association for the Study of Lung Cancer (IASLC) was validated as a strong prognostic indicator. Nonetheless, the efficacy of utilizing such grading system in prognostic assessment of patients receiving neoadjuvant therapy still needs elucidating. Methods: A retrospective study was conducted including patients with resected adenocarcinoma following neoadjuvant chemotherapy or targeted therapy from August 2012 to December 2020 in Shanghai Pulmonary Hospital. All the surgical specimens were re-evaluated and graded. The prognostic value of the grading system was further validated. Results: Ultimately, a total of 198 patients were enrolled in this study, and subdivided into three cohorts according to the grading system. There were 13 (6.6%), 37 (18.7%), and 148 (74.7%) patients belonging to Grades 1, 2, and 3, respectively. IASLC grading system demonstrated significant power in prognosis differentiation of the entire cohort [recurrence-free survival (RFS), p < 0.001; overall survival (OS), p < 0.001] and the neoadjuvant chemotherapy and targeted therapy cohorts separately, and was further verified as a significant prognostic indicator for RFS and OS in multivariable Cox analysis. Since the majority of the patients (84.8%) did not achieve major pathologic response (MPR), representing a wide spectrum of survival, the prognostic value of grading system in non-MPR cohort was further evaluated. Similar results were also obtained that IASLC grading system was assessed significant in univariable analysis of RFS (p < 0.001) and univariable analysis of OS (p = 0.001). Conclusions: The prognostic efficacy of pathological evaluation of the residual proportion of pulmonary adenocarcinoma post-neoadjuvant therapy using IASLC grading system was preliminarily verified. Such grading system might assist prognostic evaluation of neoadjuvant cohort other than traditional pathological parameters.

Establishment of a risk prediction model for prolonged mechanical ventilation after lung transplantation: a retrospective cohort study.

BACKGROUND: Prolonged mechanical ventilation (PMV), mostly defined as mechanical ventilation > 72 h after lung transplantation with or without tracheostomy, is associated with increased mortality. Nevertheless, the predictive factors of PMV after lung transplant remain unclear. The present study aimed to develop a novel scoring system to identify PMV after lung transplantation. METHODS: A total of 141 patients who underwent lung transplantation were investigated in this study. The patients were divided into PMV and non-prolonged ventilation (NPMV) groups. Univariate and multivariate logistic regression analyses were performed to assess factors associated with PMV. A risk nomogram was then established based on the multivariate analysis, and model performance was further examined regarding its calibration, discrimination, and clinical usefulness. RESULTS: Eight factors were finally identified to be significantly associated with PMV by the multivariate analysis and therefore were included as risk factors in the nomogram as follows: the body mass index (BMI, P = 0.036); primary diagnosis as idiopathic pulmonary fibrosis (IPF, P = 0.038); pulmonary hypertension (PAH, P = 0.034); primary graft dysfunction grading (PGD, P = 0.011) at T0; cold ischemia time (CIT P = 0.012); and three ventilation parameters (peak inspiratory pressure [PIP, P < 0.001], dynamic compliance [Cdyn, P = 0.001], and P/F ratio [P = 0.015]) at T0. The nomogram exhibited superior discrimination ability with an area under the curve of 0.895. Furthermore, both calibration curve and decision-curve analysis indicated satisfactory performance. CONCLUSION: A novel nomogram to predict individual risk of receiving PMV for patients after lung transplantation was established, which may guide preventative measures for tackling this adverse event.

Exosomal RBP4 potentiated hepatic lipid accumulation and inflammation in high-fat-diet-fed mice by promoting M1 polarization of Kupffer cells.

Exosomes containing various biological cargoes have potential to be novel diagnostic biomarkers for metabolic diseases. In this study, retinol-binding protein 4 (RBP4) was found to be enriched in serum exosomes, and its increased levels could be considered as an independent risk factor for the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Exosomal RBP4 (exo-RBP4), primarily derived from hepatocytes, significantly enhanced the M1-like polarization of Kupffer cells (KCs) via promoting the activation of NOX2 and NF-κB and reactive oxygen species (ROS) accumulation, resulting in the over-production of inflammatory cytokines including TNF-α. Subsequently, those excess cytokines remarkably increased the levels of intracellular free fatty acid uptake and lipogenesis-related genes (FAS and SREBP-1c) but decreased fatty acid degradation-related genes (CPT-1 and PPARα) in palmitic acid-treated LO2 cells. More notably, TNF-α significantly elevated RBP4 transcription by activating STAT3 in hepatocytes, playing a positive role in NAFLD development. Intravenous injection with RBP4 (50 µg/kg) potentiated hepatic lipid accumulation, M1-type KC proportion, and serum pro-inflammatory cytokine levels in the hepatic tissues of high-fat-diet-fed mice. Collectively, these data indicated that exo-RBP4 converted KCs to M1 subtype by mediating the NOX2/ROS/NF-κB pathway, subsequently promoting de novo lipogenesis in hepatocytes by TNF-α secretion to activate the JAK2/STAT3 signaling pathway. Therefore, this study uncovered a novel intercellular communication between the inflammatory microenvironment and lipid metabolism for fostering NAFLD progression and found the potential of exo-RBP4 as a novel diagnostic biomarker and therapeutic target for NAFLD.

The predictive value of inflammatory biomarkers for major pathological response in non-small cell lung cancer patients receiving neoadjuvant chemoimmunotherapy and its association with the immune-related tumor microenvironment: a multi-center study.

BACKGROUND: Inflammatory biomarkers in the peripheral blood have been established as predictors for immunotherapeutic efficacy in advanced non-small cell lung cancer (NSCLC). Whether they can also predict major pathological response (MPR) in neoadjuvant setting remains unclear. METHODS: In this multi-center retrospective study, 122 and 92 stage I-IIIB NSCLC patients from six hospitals who received neoadjuvant chemoimmunotherapy followed by surgery were included in the discovery and external validation cohort, respectively. Baseline and on-treatment neutrophil-to-lymphocyte ratio (NLR), derived NLR (dNLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR) and systemic immune-inflammation index (SII) were calculated and associated with MPR. Furthermore, resected tumor samples from 37 patients were collected for RNA-sequencing to investigate the immune-related tumor microenvironment. RESULTS: In both the discovery and validation cohorts, the on-treatment NLR, dNLR, PLR, and SII levels were significantly lower in the patients with MPR versus non-MPR. On-treatment SII remained an independent predictor of MPR in multivariate logistic regression analysis. The area under the curve (AUC) of on-treatment SII for predicting MPR was 0.75 (95%CI, 0.67-0.84) in the discovery cohort. Moreover, the predictive value was further improved by combining the on-treatment SII and radiological tumor regression data, demonstrating an AUC of 0.82 (95%CI, 0.74-0.90). The predictive accuracy was validated in the external cohort. Compared with the SII-high group, patients with SII-Low were associated with the activated B cell receptor signaling pathway and a higher intratumoral immune cell infiltration level. CONCLUSIONS: On-treatment SII was independently associated with MPR in NSCLC patients receiving neoadjuvant chemoimmunotherapy. Further prospective studies are warranted.

Genopathomic profiling identifies signatures for immunotherapy response of lung adenocarcinoma via confounder-aware representation learning.

Immunotherapy shows durable response but only in a subset of patients, and test for predictive biomarkers requires procedures in addition to routine workflow. We proposed a confounder-aware representation learning-based system, genopathomic biomarker for immunotherapy response (PITER), that uses only diagnosis-acquired hematoxylin-eosin (H&E)-stained pathological slides by leveraging histopathological and genetic characteristics to identify candidates for immunotherapy. PITER was generated and tested with three datasets containing 1944 slides of 1239 patients. PITER was found to be a useful biomarker to identify patients of lung adenocarcinoma with both favorable progression-free and overall survival in the immunotherapy cohort (p < 0.05). PITER was significantly associated with pathways involved in active cell division and a more immune activating microenvironment, which indicated the biological basis in identifying patients with favorable outcome of immunotherapy. Thus, PITER may be a potential biomarker to identify patients of lung adenocarcinoma with a good response to immunotherapy, and potentially provide precise treatment.

Reconsidering T component of cancer staging for T3/T4 non-small-cell lung cancer with additional nodule.

Background: Non-small-cell lung cancer (NSCLC) with additional nodule(s) located in the same lobe or ipsilateral different lobe were designated as T3 and T4, respectively, which was merely defined by anatomical location of additional nodule(s), regardless of other prognostic factors. Methods: A total of 4711 patients with T1-4, N0-2, M0 NSCLC undergoing complete resection were identified between 2009 and 2014, including 145 patients with additional nodule(s) in the same lobe (T3-Add) and 174 patients with additional tumor nodule(s) in ipsilateral different lobe (T4-Add). Overall survival (OS) was compared using multivariable Cox regression models and propensity score matching analysis (PSM). Results: T3-Add patients [T3-Add versus T3, hazard ratio (HR), 0.695; 95% confidence interval (CI), 0.528-0.915; p = 0.009] and comparable OS with T2b patients through multivariable Cox analysis, and further validated by PSM. T4-Add patients carried a wide spectrum of prognosis, and the largest diameter of single tumor was screened out as the most effective indicator for distinguishing prognosis. T4-Add (⩽3 cm) patients had better OS than T4 patients [T4-Add (⩽3 cm) versus T4, HR, 0.629; 95% CI, 0.455-0.869; p = 0.005] and comparable OS with T3 patients. And T4-Add (>3 cm) patients had comparable OS with T4 patients. Conclusion: NSCLC patients with additional nodule(s) in the same lobe and ipsilateral different lobe (maximum tumor diameter ⩽ 3 cm) should be further validated and considered restaging as T2b and T3 in the forthcoming 9th tumor, node, and metastasis staging system.

Comparison of perioperative outcomes among non-small cell lung cancer patients with neoadjuvant immune checkpoint inhibitor plus chemotherapy, EGFR-TKI, and chemotherapy alone: a real-world evidence study.

Background: The utilization of neoadjuvant immune checkpoint inhibitor (ICI) plus chemotherapy has increased significantly for resectable non-small cell lung cancer (NSCLC). It is still unclear whether such a treatment paradigm affects perioperative outcomes compared with other neoadjuvant treatment. We aimed to evaluate the perioperative outcomes of pulmonary resection after neoadjuvant ICI plus chemotherapy and to compare them with neoadjuvant epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) and neoadjuvant chemotherapy alone for resectable NSCLC. Methods: A retrospective cohort including 194 stage IB-IIIB NSCLC underwent surgical resection after neoadjuvant treatment between 2018 and 2020 were reviewed. Perioperative complications were evaluated using the Common Terminology Criteria for Adverse Events, and were compared using one-way analysis of variance for continuous variables and Pearson chi-square test. Results: There were 42, 54, and 98 patients in the neoadjuvant ICI plus chemotherapy, EGFR-TKI, and chemotherapy alone groups, respectively. The tumor size before neoadjuvant treatment was well balanced among the three groups (P=0.122). A shorter median surgical time was observed in the EGFR-TKI group than ICI plus chemotherapy group and chemotherapy group alone (120 vs. 150 vs. 146 min, P=0.041). Video-assisted thoracoscopic surgery was performed in 37 (88.1%), 49 (90.7%), and 57 (58.7%) patients in the three groups, respectively (P<0.001). A higher incidence of pneumonia (P=0.014) was found in the chemotherapy group. Perioperative mortality was observed in 1 patient (2.4%) in the ICI plus chemotherapy group and in 3 patients (3.1%) in the chemotherapy alone group (P=0.440). Patients in the ICI plus chemotherapy group had higher proportions of pathological complete response (40.5% vs. 11.1% vs. 6.1%, P<0.001) and downstaging of clinical N2 status (68.6% vs. 42.9% vs. 31.7%, P=0.012) than patients in EGFR-TKI group and chemotherapy alone group. Conclusions: Surgical resection for NSCLC following neoadjuvant ICI plus chemotherapy was safe and feasible, the perioperative outcomes were similar with neoadjuvant EGFR-TKI and chemotherapy alone without unexpected perioperative complications. Additional prospective studies are necessary to validate our findings.

Real-world clinical outcomes of neoadjuvant immunotherapy combined with chemotherapy in resectable non-small cell lung cancer.

OBJECTIVES: Early stage non-small cell lung cancer (NSCLC) patients who undergo complete resection continue to demonstrate high risk of recurrence and death. The advent of the neoadjuvant regimen has brought new hope for these patients. The present study aims to further demonstrate the efficacy of neoadjuvant chemoimmunotherapy. MATERIALS AND METHODS: A real-world observational study was conducted concerning patients who received neoadjuvant pembrolizumab or nivolumab combined with chemotherapy between January 2018 and December 2020 in Shanghai Pulmonary Hospital. The primary endpoint was major pathologic response (MPR), and the secondary endpoints were objective response rate (ORR), pathologic complete response (pCR), disease-free survival (DFS) and toxicity. RESULTS: A total of 76 patients were analyzed and divided into the pembrolizumab (n = 42) and nivolumab groups (n = 34) with a median follow-up time of 12.2 months. Most patients (92%) had stage III disease, with 41 (54%) and 29 (38%) patients initially diagnosed clinical stage IIIA and IIIB, respectively. Fifty (66%), 21 (28%) and 5 (6%) patients received two, three and four cycles of neoadjuvant treatment, separately, achieving an ORR of 75%. None of them needed a reduced initial dose or delay due to intolerable adverse events. Forty-nine (64%) and 28 (37%) patients achieved MPR and pCR, respectively. RNA sequencing showed that MPR associated with increased infiltration of cytotoxic immune cells with tertiary lymphoid structures (TLSs). Histological evaluation highlighted the localization of B cells within TLSs. Forty-two (69%) patients with clinically N2 disease at baseline were downstaged to pathological N0 (39 patients) or N1 (3 patients). One-year-PFS rate of stage III patients was 91%. No difference in baseline characteristics and treatment outcomes was observed between 2 groups. CONCLUSION: The feasibility of neoadjuvant chemoimmunotherapy for resectable NSCLC was further validated, with a high MPR rate and manageable adverse events.