Efficacy of neoadjuvant chemo-immunotherapy in non-small cell lung cancer: a real-world, multicenter, retrospective study.

Background: Resectable non-small cell lung cancer (NSCLC) patients have a high risk of recurrence. Multiple randomized controlled trials (RCTs) have shown that neoadjuvant chemo-immunotherapy brings new hope for these patients. The study aims to evaluate the safety, surgery-related outcomes and oncological outcomes for neoadjuvant chemo-immunotherapy in real-world setting with a large sample size and long-term follow-up. Methods: Patients with clinical stage IB-IIIB NSCLC who received neoadjuvant chemo-immunotherapy at two Chinese institutions were included in this retrospective cohort study. Surgical and oncological outcomes of the enrolled NSCLC patients were collected and analyzed. Results: There were 158 patients identified, of which 124 (78.5%) were at stage IIIA-IIIB and the remaining 34 (21.5%) were at stage IB-IIB. Forty-one patients (25.9%) received two cycles of neoadjuvant treatment, 80 (50.6%) had three cycles, and 37 (23.4%) had four cycles. Twenty-four patients (15.2%) experienced grade 3 or worse immune-related adverse events. The median interval time between the last neoadjuvant therapy and surgery was 37 [interquartile range (IQR), 31-43] days. Fifty-eight out of 96 (60.4%) central NSCLC patients who were expected to undergo complex surgery had the scope or the difficulty of operation reduced. Ninety-five (60.1%) patients achieved major pathologic response (MPR), including 62 (39.2%) patients with pathologic complete response (pCR). Multivariate regression analysis showed that no clinical factor other than programmed death-ligand 1 (PD-L1) expression was predictive of the pathological response. The median follow-up time from diagnosis was 27.1 months. MPR and pCR were significantly associated with improved progression-free survival (PFS) and overall survival (OS). Neither stage nor PD-L1 expression was significantly associated with long-term survival. Conclusions: The neoadjuvant chemo-immunotherapy is a feasible strategy for NSCLC with a favorable rate of pCR/MPR, modified resection and 2-year survival. No clinical factor other than PD-L1 expression was predictive of the pathological response. pCR/MPR may be effective surrogate endpoint for survival in NSCLC patients who received neoadjuvant chemo-immunotherapy.

How long can pulmonary resection surgery be performed after SARS-CoV-2 infection? A multicenter retrospective study.

BACKGROUND: No studies to date have focused on the timing of pulmonary resection in patients with previous severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In the present study, the authors analyzed the surgical outcomes and evaluated the optimal time point of pulmonary resection surgery following SARS-CoV-2 infection. MATERIALS AND METHODS: In this multicenter retrospective cohort study, patients were divided into different groups according to the time interval between SARS-CoV-2 diagnosis and pulmonary resection. The primary outcome measure was postoperative complications within 30 days after surgery, which was investigated to determine the optimal time point of pulmonary resection. Logistic regression models were used to calculate the risk factors for postoperative complications. RESULTS: In total, 400 patients were enrolled, and the postoperative pathologic examination of 322 (80.5%) patients showed lung cancer. As the interval between SARS-CoV-2 infection and pulmonary resection increased, the incidence of complications gradually decreased in each group. The incidence of grade ≥II complications was higher in the ≤2-week and 2-week to 4-week groups than in the 4-week to 6-week, 6-week to 8-week and >8-week groups [3 (21.4%), 17 (20.2%), 10 (10.6%), 13 (7.9%), and 3 (6.5%), respectively] ( P <0.05). Multiclassification regression analysis showed that the risk of grade ≥II complications in the ≤2-week and 2-week to 4-week groups was significantly higher than that in the >8-week group [odds ratio (95% CI), 3.937 (1.072-14.459), P =0.039 and 3.069 (1.232-6.863), P =0.015]. The logistic regression analysis suggested that underlying disease, persistent SARS-CoV-2 symptoms, and surgical timing (≤4 weeks) were independent risk factors for complications of pulmonary resection after SARS-CoV-2 infection. CONCLUSION: Pulmonary resection should be delayed for at least 4 weeks following SARS-CoV-2 infection to reduce the risk of postoperative complications.

Organ preservation strategies after neoadjuvant chemoimmunotherapy in resectable non-small cell lung cancer: a multicenter retrospective cohort study.

BACKGROUND: Neoadjuvant chemoimmunotherapy has shown a good therapeutic effect on non-small cell lung cancer (NSCLC), which also opens up the possibility of applying organ preservation strategies. This study investigated the feasibility of modified surgery after potent neoadjuvant chemoimmunotherapy in central type NSCLC. METHODS: In this multicenter retrospective cohort study, patients with central type NSCLC who received 2-4 cycles of neoadjuvant chemoimmunotherapy between January 2019 and June 2022 at Air Force Medical University Tangdu Hospital and Peking University People's Hospital were eligible. Patients were divided into modified and nonmodified groups according to the extent of surgery, after which, the safety and long-term prognosis of surgery were investigated. RESULTS: A total of 84 patients were enrolled. Of 36 (42.9%) patients who underwent modified surgery, 21 patients underwent lobectomy, 12 patients underwent lobectomy with bronchoplasty, 2 patients underwent sleeve lobectomy, and 1 patient underwent bilobectomy. The modification rate for the initially estimated pneumonectomy, sleeve lobectomy, and bilobectomy was 48.6, 44.8, and 30%, respectively. Grades II-V postoperative complications were found in 5 (13.9%) patients in the modified group and 17 (35.4%) patients in the nonmodified group (relative risk, 0.393; 95% CI, 0.016-0.963; P =0.026). No significant difference was observed regarding the surgical approach, operative duration, blood loss, or R0 resection rate. The 2-year local recurrence rate was 3.7% (95% CI, 0.004-0.175) and 5.2% (95% CI, 0.012-0.168) in the modified group and nonmodified group, respectively. The 1-year PFS rate of modified and nonmodified groups was 97.1% (95% CI, 83.7-99.8) and 86.9% (95% CI, 73.4-94.4), respectively, while 2-year PFS were 89.8% (95% CI, 74.1-96.9) and 71.8% (95% CI, 56.7-83.4), respectively. CONCLUSION: Applying organ preservation strategies, that is, undergoing modified surgery after neoadjuvant chemoimmunotherapy, is feasible for selected central type NSCLC patients with favorable safety and long-term survival.

Cuproptosis-related gene PDHX and heat stress-related HSPD1 as potential key drivers associated with cell stemness, aberrant metabolism and immunosuppression in esophageal carcinoma.

BACKGROUND: Heat stress is fundamental to esophageal carcinoma (ESCA) oncogenesis and progression. Heat stress damages epithelial structure, causing aberrant 'cell death-repair' patterns of esophagus cells and thereby driving tumor occurrence and progression. However, due to the distinctive functions and crosstalk of regulatory cell death (RCD) patterns, the specific cell deaths in ESCA malignancy are still unclear. METHODS: We analyzed the key regulatory cell death genes involved in heat stress and ESCA progression by using The Cancer Genome Atlas-ESCA database. The least absolute shrinkage and selection operator (LASSO) algorithm was used to filter the key genes. The one-class logistic regression (OCLR) and quanTIseq methods were used to evaluate the cell stemness and immune cell infiltration in ESCA samples. Cell counting kit-8 (CCK8) and wound healing assays were performed to assess the proliferation and migration of cells. RESULTS: We found that cuproptosis may be a potential risk factor of heat stress-related ESCA. Two interrelated genes, HSPD1 and PDHX, were associated with heat stress and cuproptosis and played a role in cell survival, proliferation, migration, metabolism and immunosuppression. CONCLUSIONS: We found that cuproptosis promoted ESCA related to heat stress, offering a new therapeutic opportunity to treat this malignant disorder.

Circ-HSP90A expedites cell growth, stemness, and immune evasion in non-small cell lung cancer by regulating STAT3 signaling and PD-1/PD-L1 checkpoint.

BACKGROUND: Circular RNAs (circRNAs) are important participators in tumor progression for their stable structure and high tissue-specific expression. The purpose of this research was to clarify the potential and mechanism of a novel circRNA-circ-HSP90A in non-small cell lung cancer (NSCLC). METHODS: Biological potentials of circ-HSP90A in NSCLC were measured by functional assays. Molecular interaction was assessed by bioinformatics analysis and mechanical assays. RESULTS: Results depicted that circ-HSP90A was cyclization from its host gene heat shock protein 90 alpha (HSP90A) and was up-regulated in NSCLC cells. Circ-HSP90A depletion retarded proliferation, migration, invasion, and immune evasion. Mechanistically, circ-HSP90A recruited ubiquitin specific peptidase 30 (USP30) to stabilize HSP90A and then stimulated the signal transducer and activator of transcription 3 (STAT3) signaling. Meanwhile, circ-HSP90A sponged miR-424-5p to programmed cell death ligand 1 (PD-L1). CONCLUSIONS: Our study firstly showed that circ-HSP90A promoted cell growth, stemness, and immune evasion in NSCLC through regulating STAT3 signaling and programmed cell death 1 (PD-1)/PD-L1 checkpoint, mirroring that targeting circ-HSP90A might become a novel target of immunotherapy in NSCLC.

Lung Nodule Segmentation and Recognition Algorithm Based on Multiposition U-Net.

Lung nodules are the main lesions of the lung, and conditions of the lung can be directly displayed through CT images. Due to the limited pixel number of lung nodules in the lung, doctors have the risk of missed detection and false detection in the detection process. In order to reduce doctors' work intensity and assist doctors to make accurate diagnosis, a lung nodule segmentation and recognition algorithm is proposed by simulating doctors' diagnosis process with computer intelligent methods. Firstly, the attention mechanism model is established to focus on the region of lung parenchyma. Then, a pyramid network of bidirectional enhancement features is established from multiple body positions to extract lung nodules. Finally, the morphological and imaging features of lung nodules are calculated, and then, the signs of lung nodules can be identified. The experiments show that the algorithm conforms to the doctor's diagnosis process, focuses the region of interest step by step, and achieves good results in lung nodule segmentation and recognition.

SOX18 enhances the proliferation and migration of airway smooth muscle cells induced by tumor necrosis factor-α via the regulation of Notch1 signaling.

Childhood asthma is a frequent chronic disease of pediatric populations. The excessive proliferation and migration of airway smooth muscle cells contribute to airway remodeling during asthma pathogenesis. Sex-determining region on the Y chromosome-related high mobility group box 18 (SOX18) has been reported to be over-expressed in asthma. However, whether SOX18 plays a role in modulating the airway remodeling of asthma is not fully understood. The purposes of this work were to assess the potential role of SOX18 in modulating airway remodeling using tumor necrosis factor-α (TNF-α)-stimulated airway smooth muscle cells in vitro. Our results showed that SOX18 expression was increased following TNF-α stimulation in airway smooth muscle cells. The silencing of SOX18 markedly prohibited the proliferation and migration of airway smooth muscle cells induced by TNF-α, whilst the over-expression of SOX18 produced the opposite effects. Further investigation revealed that SOX18 promoted the expression of Notch1, and enhanced the activation of Notch1 signaling in airway smooth muscle cells stimulated by TNF-α. The inhibition of Notch1 markedly diminished SOX18-over-expression-evoked promotion effects on TNF-α-induced proliferation and migration of airway smooth muscle cells. In addition, the reactivation of Notch1 signaling markedly reversed the SOX18-silencing-induced suppressive effect on the TNF-α-induced proliferation and the migration of airway smooth muscle cells. In summary, the findings of this work demonstrate that SOX18 regulates the proliferation and migration of airway smooth muscle cells induced by TNF-α via the modulation of Notch1 signaling. This study indicates a potential role for SOX18 in promoting airway remodeling during asthma pathogenesis.

Development and Validation of Machine Learning-based Model for the Prediction of Malignancy in Multiple Pulmonary Nodules: Analysis from Multicentric Cohorts.

PURPOSE: Nodule evaluation is challenging and critical to diagnose multiple pulmonary nodules (MPNs). We aimed to develop and validate a machine learning-based model to estimate the malignant probability of MPNs to guide decision-making. EXPERIMENTAL DESIGN: A boosted ensemble algorithm (XGBoost) was used to predict malignancy using the clinicoradiologic variables of 1,739 nodules from 520 patients with MPNs at a Chinese center. The model (PKU-M model) was trained using 10-fold cross-validation in which hyperparameters were selected and fine-tuned. The model was validated and compared with solitary pulmonary nodule (SPN) models, clinicians, and a computer-aided diagnosis (CADx) system in an independent transnational cohort and a prospective multicentric cohort. RESULTS: The PKU-M model showed excellent discrimination [area under the curve; AUC (95% confidence interval (95% CI)), 0.909 (0.854-0.946)] and calibration (Brier score, 0.122) in the development cohort. External validation (583 nodules) revealed that the AUC of the PKU-M model was 0.890 (0.859-0.916), higher than those of the Brock model [0.806 (0.771-0.838)], PKU model [0.780 (0.743-0.817)], Mayo model [0.739 (0.697-0.776)], and VA model [0.682 (0.640-0.722)]. Prospective comparison (200 nodules) showed that the AUC of the PKU-M model [0.871 (0.815-0.915)] was higher than that of surgeons [0.790 (0.711-0.852), 0.741 (0.662-0.804), and 0.727 (0.650-0.788)], radiologist [0.748 (0.671-0.814)], and the CADx system [0.757 (0.682-0.818)]. Furthermore, the model outperformed the clinicians with an increase of 14.3% in sensitivity and 7.8% in specificity. CONCLUSIONS: After its development using machine learning algorithms, validation using transnational multicentric cohorts, and prospective comparison with clinicians and the CADx system, this novel prediction model for MPNs presented solid performance as a convenient reference to help decision-making.

Video-assisted thoracic surgery for thymoma: long-term follow-up results and prognostic factors-single-center experience of 150 cases.

BACKGROUND: The use of video-assisted thoracic surgery (VATS) in the treatment of thymoma is becoming more and more common. The aim of this study was to evaluate safety and effectiveness of thoracoscopic treatment of thymoma and, more importantly, to report long-term follow-up results of a large single-center cohort. METHODS: A retrospective review of a prospective database was performed. In total, 150 patients who underwent VATS resection for thymoma at Peking University People's Hospital from April 2001 to November 2014 were retrospectively reviewed. RESULTS: Average operation time was 140.1±54.2 min, median blood loss was 50 mL (range, 10-700 mL), median post-operative drainage time was 3 days (range, 1-11 days), and median length of post-op stay was 5 days (range, 2-20 days); 134 patients (89.3%) were followed up successfully. Median follow-up was 59.5 months (range, 2-187 months). Five- and 10-year recurrence free survival (RFS) rates of entire group were 96.5% and 94.4%, respectively; 5- and 10-year RFS rates for Masaoka stages I + II were 98.1% and 98.1%, respectively; 5- and 6-year RFS rates for Masaoka stage III were 90% and 60%, respectively. One case of recurrence in five Masaoka stage IV patients was observed, and 4-year RFS was 80%. Multivariable analysis indicated that recurrence tended to occur in Masaoka stages III + IV patients (P=0.037, HR =12.69, 95% CI: 1.17-138.22) and older patients had a lower risk of recurrence (P=0.029, HR =0.87, 95% CI: 0.77-0.99). Myasthenia gravis (MG) presented in 44 patients (29.3%), of which 36 patients (81.8%) were followed up. Nine patients achieved complete remission, and 19 patients had symptom improvement after surgery. Overall response rate of MG was 77.8% (28/36). CONCLUSIONS: VATS was a safe and effective procedure for treatment of thymomas with satisfactory prognosis. MG with thymoma treated by VATS had comparable neurological outcome to that associated with the trans-sternal approach.

Role of circulating tumor DNA in the management of early-stage lung cancer.

Lung cancer is one of the most common cancers and the predominant cause of cancer-related death in the world. The low accuracy of early detection techniques and high risk of relapse greatly contribute to poor prognosis. An accurate clinical tool that can assist in diagnosis and surveillance is urgently needed. Circulating tumor DNA (ctDNA) is free DNA shed from tumor cells and isolated from peripheral blood. The genomic profiles of ctDNA have been shown to closely match those of the corresponding tumors. With the development of approaches with high sensitivity and specificity, ctDNA plays a vital role in the management of lung cancer as a result of its reproducible, non-invasive, and easy-to-obtain characteristics. However, most previous studies have focused on advanced lung cancer. Few studies have investigated ctDNA in the early stages of the disease. In this review, we focus on ctDNA obtained from patients in the early stage of lung cancer, provide a summary of the related literature to date, and describe the main approaches to ctDNA and the clinical applications.

Dynamic changes of circulating tumour DNA in surgical lung cancer patients: protocol for a prospective observational study.

INTRODUCTION: Circulating tumour DNA (ctDNA) has potential applications in cancer management. Most previous studies about ctDNA focused on advanced stage cancer patients. We have completed a clinical prospective study (NCT02645318) and showed the feasibility and clinical application of ctDNA detection in early stage non-small cell lung cancer (NSCLC) patients. The aim of this study is to investigate the elimination rate of ctDNA level after surgery. This is the first prospective study to evaluate the perioperative dynamic changes of ctDNA in surgical lung cancer patients. METHODS AND ANALYSIS: This is a prospective observational study to determine the elimination rate of circulating tumour DNA after surgery. Consecutive patients with suspected lung cancer who undergo curative-intent lung resection will be enrolled. 10 mL blood samples are taken by intravenous puncture. Plasma samples are obtained before surgery (time A) and at a series of scheduled time-points (2 min to 72 hours, time B to F) after tumour resection. DNA is prepared from 4 mL of purified plasma. A multiplex assay based on circulating single-molecule amplification and resequencing technology (cSMART) is used to simultaneously detect and quantitate hot spot EGFR, KRAS, BRAF, ERBB2, PIK3CA, TP53, ALK, RET and MET plasma DNA variants. Positive plasma mutations are validated in tumour tissue and normal lung tissue by targeted sequencing. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the Peking University People's Hospital Medical Ethics Committee (2016PHB156-01). Results will be disseminated through presentations at scientific meetings and publications in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT02965391; Pre-results.

Near-infrared Intraoperative Imaging of Thoracic Sympathetic Nerves: From Preclinical Study to Clinical Trial.

The sympathetic nervous system controls and regulates the activities of the heart and other organs. Sympathetic nervous system dysfunction leads to disease. Therefore, intraoperative real-time imaging of thoracic sympathetic nerves (ITSN) would be of great clinical significance for diagnosis and therapy. The aim of this experimental study was to evaluate the feasibility and validity of intraoperative ITSN using indocyanine green (ICG). METHODS: ITSN using ICG was performed on 10 rabbits to determine its feasibility. Animals were allocated to two groups. The rabbits in one group received the same dose of ICG, but were observed at different times. The rabbits in the other group were administered different doses of ICG, but were observed at the same time. Signal to background ratio (SBR) was measured in regions of interest in all rabbits. Furthermore, fifteen consecutive patients with pulmonary nodules were intravenously injected with ICG 24 h preoperatively and underwent near-infrared (NIR) fluorescence imaging (FI) thoracoscopic surgeries between July 2015 and June 2016. A novel self-developed NIR and white-light dual-channel thoracoscope system was used. SBRs of thoracic sympathetic nerves were calculated in all patients. RESULTS: In the preclinical study, we were able to precisely recognize each rabbit's second (T2) to fifth (T5) thoracic ganglia on both sides of the spine using ITSN with ICG. In addition, we explored the relationship between SBR and the injection time of ICG and that between SBR and the dose of ICG. Using the novel dual-channel thoracoscope system, we were able to locate the ganglia from the stellate ganglion (SG) to the sixth thoracic ganglion (T6), as well as the chains between these ganglia in all patients with a high SBR value of 3.26 (standard deviation: 0.57). The pathological results confirmed our findings. CONCLUSION: We were able to use ICG FI to distinguish thoracic sympathetic nerves during NIR thoracoscopic surgery. The technique may replace the rib-oriented method as standard practice for mapping the thoracic sympathetic nerves.