Combination of percutaneous thermal ablation and adoptive Th9 cell transfer therapy against non-small cell lung cancer.

BACKGROUND: Non-small cell lung cancer (NSCLC) is one of the predominant malignancies globally. Percutaneous thermal ablation (PTA) has gained widespread use among NSCLC patients, with the potential to elicit immune responses but limited therapeutic efficacies for advanced-stage disease. T-helper type 9 (Th9) cells are a subset of CD4+ effector T cells with robust and persistent anti-tumor effects. This study proposes to develop PTA-Th9 cell integrated therapy as a potential strategy for NSCLC treatment. METHODS: The therapeutic efficacies were measured in mice models with subcutaneously transplanted, recurrence, or lung metastatic tumors. The tumor microenvironments (TMEs) were evaluated by flow cytometry. The cytokine levels were assessed by ELISA. The signaling molecules were determined by quantitative PCR and Western blotting. The translational potential was tested in the humanized NSCLC patient-derived xenograft (PDX) model. RESULTS: We find that PTA combined with adoptive Th9 cell transfer therapy substantially suppresses tumor growth, recurrence, and lung metastasis, ultimately extending the survival of mice with NSCLC grafts, outperforming both PTA and Th9 cell transfer monotherapy. Analysis of TMEs indicates that combinatorial therapy significantly augments tumor-infiltrating Th9 cells, boosts anti-tumor effects of CD8+ T cells, and remodels tumor immunosuppressive microenvironments. Moreover, combinatorial therapy significantly strengthens the regional and circulation immune response of CD8+ T cells in mice with tumor lung metastasis and induces peripheral CD8+ T effector memory cells in mice with tumor recurrence. Mechanically, PTA reinforces the anti-tumor ability of Th9 cells primarily through upregulating interleukin (IL)-1ß and subsequently activating the downstream STAT1/IRF1 pathway, which could be effectively blocked by intercepting IL-1ß signaling. Finally, the enhanced therapeutic effect of combinatorial therapy is validated in humanized NSCLC PDX models. CONCLUSIONS: Collectively, this study demonstrates that combinatorial therapy displays robust and durable anti-tumor efficacy and excellent translational potential, offering excellent prospects for translation and emerging as a promising approach for NSCLC treatment.

Video-Assisted Thoracoscopic Surgery Versus Thoracotomy Following Neoadjuvant Immunochemotherapy in Resectable Stage III Non-Small Cell Lung Cancer Among Chinese Populations: A Multi-Center Retrospective Cohort Study.

BACKGROUND: Immune checkpoint inhibitors have revolutionized non-small cell lung cancer (NSCLC) treatment but may pose greater technical challenges for surgery. This study aims to assess the feasibility and oncological effectiveness of video-assisted thoracoscopic surgery (VATS) for resectable stage III NSCLC after neoadjuvant immunochemotherapy. METHODS: Initial stage IIIA-IIIB NSCLC patients with neoadjuvant immunochemotherapy undergoing either VATS or open lobectomy at 6 medical centers during 2019-2023 were retrospectively identified. Perioperative outcomes and 2-year survival was analyzed. Propensity-score matching (PSM) was employed to balance patient baseline characteristics. RESULTS: Among the total 143 patients, PSM yielded 62 cases each for VATS and OPEN groups. Induction-related adverse events were comparable between the 2 groups. VATS showed a 14.5% conversion rate. Notably, VATS decreased numeric rating scales for postoperative pain, shortened chest tube duration (5[4-7] vs. 6[5-8] days, P = .021), reduced postoperative comorbidities (21.0% vs. 37.1%, P = .048), and dissected less N1 lymph nodes (5[4-6] vs. 7[5-9], P = .005) compared with thoracotomy. Even when converted, VATS achieves perioperative outcomes equivalent to thoracotomy. Additionally, over a median follow-up of 29.5 months, VATS and thoracotomy demonstrated comparable 2-year recurrence-free survival (77.20% vs. 73.73%, P = .640), overall survival (87.22% vs. 88.00%, P = .738), cumulative incidences of cancer-related death, and recurrence patterns. Subsequent subgroup comparisons and multivariate Cox analysis likewise revealed no statistical difference between VATS and thoracotomy. CONCLUSION: VATS is a viable and effective option for resectable stage III NSCLC patients following neoadjuvant immunochemotherapy, leading to decreased surgical-related pain, earlier chest tube removal, reduced postoperative complications, and similar survival outcomes compared to thoracotomy.

DNA-PK-Mediated Cytoplasmic DNA Sensing Stimulates Glycolysis to Promote Lung Squamous Cell Carcinoma Malignancy and Chemoresistance.

Detection of cytoplasmic DNA is an essential biological mechanism that elicits IFN-dependent and immune-related responses. A better understanding of the mechanisms regulating cytoplasmic DNA sensing in tumor cells could help identify immunotherapeutic strategies to improve cancer treatment. Here we identified abundant cytoplasmic DNA accumulated in lung squamous cell carcinoma (LUSC) cells. DNA-PK, but not cGAS, functioned as a specific cytoplasmic DNA sensor to activate downstream ZAK/AKT/mTOR signaling, thereby enhancing the viability, motility, and chemoresistance of LUSC cells. DNA-PK-mediated cytoplasmic DNA sensing boosted glycolysis in LUSC cells, and blocking glycolysis abolished the tumor-promoting activity of cytoplasmic DNA. Elevated DNA-PK-mediated cytoplasmic DNA sensing was positively correlated with poor prognosis of human patients with LUSC. Targeting signaling activated by cytoplasmic DNA sensing with the ZAK inhibitor iZAK2 alone or in combination with STING agonist or anti-PD-1 antibody suppressed the tumor growth and improved the survival of mouse lung cancer models and human LUSC patient-derived xenografts model. Overall, these findings established DNA-PK-mediated cytoplasmic DNA sensing as a mechanism that supports LUSC malignancy and highlight the potential of targeting this pathway for treating LUSC. SIGNIFICANCE: DNA-PK is a cytoplasmic DNA sensor that activates ZAK/AKT/mTOR signaling and boosts glycolysis to enhance malignancy and chemoresistance of lung squamous cell carcinoma.

Robotic Versus Thoracoscopic Sub-lobar Resection for Octogenarians with Clinical Stage IA Non-small Cell Lung Cancer: A Propensity Score-Matched Real-World Study.

BACKGROUND: Minimally invasive sub-lobectomy is sufficient in treating small early-stage non-small cell lung cancer (NSCLC). However, comparison of the feasibility and oncologic efficacy between robot-assisted thoracoscopic surgery (RATS) and video-assisted thoracoscopic surgery (VATS) in performing sub-lobectomy for early-stage NSCLC patients age 80 years or older is scarce. METHODS: Octogenarians with clinical stage IA NSCLC (tumor size, ≤ 2 cm) undergoing minimally invasive wedge resection or segmentectomy at Shanghai Chest Hospital from 2011 to 2020 were retrospectively reviewed from a prospectively maintained database. Propensity score-matching (PSM) with a RATS versus VATS ratio of 1:4 was performed. Perioperative and long-term outcomes were analyzed. RESULTS: The study identified 594 patients (48 RATS and 546 VATS patients), and PSM resulted in 45 cases in the RATS group and 180 cases in the VATS group. The RATS patients experienced less intraoperative bleeding (60 mL [interquartile range (IQR), 50-100 mL] vs. 80 mL [IQR, 50-100 mL]; P = 0.027) and a shorter postoperative hospital stay (4 days [IQR, 3-5 days] vs. 5 days [IQR, 4-6 days]; P = 0.041) than the VATS patients. The two surgical approaches were comparable concerning other perioperative outcomes and postoperative complications (20.00% vs. 26.11%; P = 0.396). Additionally, during a median follow-up period of 66 months, RATS and VATS achieved comparable 5-year overall survival (90.48% vs. 87.93%; P = 0.891), recurrence-free survival (83.37% vs. 83.18%; P = 0.782), and cumulative incidence of death. Further subgroup comparison also demonstrated comparable long-term outcomes between the two approaches. Finally, multivariate Cox analysis indicated that the surgical approach was not independently correlated with long-term outcomes. CONCLUSIONS: The RATS approach shortened the postoperative hospital stay, reduced intraoperative bleeding by a statistically notable but clinically insignificant amount, and achieved long-term outcomes comparable with VATS in performing sub-lobectomy for octogenarians with early-stage small NSCLC.

Short-term outcomes of robot-assisted versus video-assisted thoracoscopic surgery for non-small cell lung cancer patients with neoadjuvant immunochemotherapy: a single-center retrospective study.

Background: Neoadjuvant immunochemotherapy has been increasingly applied to treat non-small cell lung cancer (NSCLC). However, the comparison between robotic-assisted thoracoscopic surgery (RATS) and video-assisted thoracoscopic surgery (VATS) in the feasibility and oncological efficacy following neoadjuvant immunochemotherapy is scarce. This study aims to assess the superiorities of RATS over (VATS) concerning short-term outcomes in treating NSCLC patients with neoadjuvant immunochemotherapy. Methods: NSCLC patients receiving RATS or VATS lobectomy following neoadjuvant immunochemotherapy at Shanghai Chest Hospital from 2019 to 2022 were retrospectively identified. Baseline clinical characteristics, perioperative outcomes, and survival profiles were analyzed. Results: Forty-six NSCLC patients with neoadjuvant immunochemotherapy were included and divided into the RATS (n=15) and VATS (n=31) groups. The baseline clinical characteristics and induction-related adverse events were comparable between the two groups (all p>0.050). The 30-day mortality in the RATS and VATS groups were 0% and 3.23%, respectively (p=1.000). Patients undergoing RATS were associated with reduced surgical-related intensive unit care (ICU) stay than those receiving VATS (0.0 [0.0-0.0] vs. 0.0 [0.0-1.0] days, p=0.026). Moreover, RATS assessed more N1 LNs (6.27 ± 1.94 vs 4.90 ± 1.92, p=0.042) and LN stations (3.07 ± 1.03 vs 2.52 ± 0.57, p=0.038) compared with VATS. By comparison, no difference was found in surgical outcomes, pathological results, and postoperative complications between the RATS and VATS groups (all p>0.050). Finally, RATS and VATS achieved comparable one-year recurrence-free survival (82.96% vs. 85.23%, p=0.821) and the timing of central nervous system, LN, and bone recurrences (all p>0.050). Conclusion: RATS is safe and feasible for NSCLC patients with neoadjuvant immunochemotherapy, reducing surgical-related ICU stay, assessing increased N1 LNs and stations, and achieving similar survival profiles to VATS.

Short- and long-term outcomes of robotic-assisted versus video-assisted thoracoscopic lobectomy in non-small cell lung cancer patients aged 35 years or younger: a real-world study with propensity score-matched analysis.

PURPOSE: This study compared short- and long-term outcomes of robotic-assisted thoracoscopic surgery (RATS) versus video-assisted thoracoscopic surgery (VATS) for lobectomy in young adults aged ≤ 35 years with non-small cell lung cancer (NSCLC), aiming to assess the superiority of RATS over VATS for this special group of patients. METHODS: A total of 1355 consecutive NSCLC cases aged 18-35 years undergoing RATS (n = 105) or VATS (n = 1250) between 2014 and 2021 were retrospectively identified from a prospectively maintained database. Propensity score matching (PSM) was applied to establish a 1:3 RATS versus VATS ratio. Baseline clinicopathological characteristics, perioperative outcomes, lymph node (LN) assessment, and long-term survival were investigated. RESULTS: Following PSM, 105 and 315 cases were in the RATS and VATS groups, respectively. RATS led to a shorter postoperative hospital stay than VATS (4.0 ± 1.5 vs 4.3 ± 1.7 days, p = 0.02). The two groups were comparable in other perioperative outcomes and postoperative complications (all p > 0.05). Moreover, RATS assessed more LNs (9.4 ± 4.4 vs 8.3 ± 3.6, p = 0.03), especially N1 LNs (4.2 ± 3.1 vs 3.5 ± 2.2, p = 0.02), than VATS. By comparison, no difference in 5-year recurrence-free survival (RFS), overall survival (OS), or recurrence or mortality patterns was found between the two groups (all p > 0.05). Further subgroup analyses also observed similar long-term outcomes between the two groups regarding age, gender, and smoking history. Finally, Cox's analyses found that the surgical approach was not independently correlated with RFS or OS. CONCLUSION: RATS shortened postoperative hospital stay, assessed more N1 and total LNs, and achieved comparable long-term outcomes to VATS for very young NSCLC patients.

Short- and medium-term outcomes of video-assisted thoracoscopic surgery versus thoracotomy for carinal lung resection combined with carina reconstruction in locally advanced non-small cell lung cancer patients.

BACKGROUND: The application of video-assisted thoracoscopic surgery (VATS) for complex carina surgeries in treating non-small cell lung cancer (NSCLC) patients with involved carina is controversial. This study compared short- and medium-term outcomes of VATS versus thoracotomy for carinal lung resection with carina reconstruction in treating locally advanced NSCLC, aiming to assess the potential benefit of VATS over thoracotomy for these patients. METHODS: A total of 37 consecutive NSCLC cases receiving VATS (n = 14) or thoracotomy (n = 23) for carinal lung resection with carina reconstruction from 2016 to 2021 were retrospectively identified. Baseline clinicopathological characteristics, perioperative outcomes, and survival profiles were investigated. RESULTS: Patients in the VATS and thoracotomy groups had comparable baseline clinicopathological characteristics (all p > 0.050). VATS decreased postoperative drainage volume compared with thoracotomy (1280 [1170-1510] vs. 1795 [1510-1905] mL, p = 0.012). Regarding surgical-related pains, VATS reduced numeric rating scale scores on the postoperative day 1 (4 [3, 4] vs. 5 [4, 5], p = 0.021) and day 2 (3 [3, 4] vs. 5 [3-5], p = 0.023) than thoracotomy. No difference was found between the VATS and thoracotomy groups in other perioperative outcomes, postoperative complications, and assessment of lymph nodes (LNs) and LN stations (all p > 0.050). Moreover, patients in the two groups had comparable 3-year disease-free survival (DFS), overall survival (OS), and recurrence and mortality patterns. Further subgroup and Cox hazards regression analyses also observed no difference in DFS or OS between the two groups. CONCLUSIONS: VATS reduced postoperative drainage volume and ameliorated surgical-related pain, and achieved comparable medium-term survival compared to thoracotomy for carinal lung resection with carina reconstruction in treating locally advanced NSCLC.

Perioperative and Oncological Outcomes of Robotic-Assisted, Video-Assisted Thoracoscopic and Open Lobectomy for Patients with N1-Metastatic Non-Small Cell Lung Cancer: A Propensity Score-Matched Study.

(1) Background: Despite the fact that robotic-assisted thoracoscopic lobectomy (RATL) has been prevalently applied for early stage non-small cell lung cancer (NSCLC), its superiorities are still to be fully revealed for patients with metastatic N1 lymph nodes (LNs). We aim to evaluate the advantages of RATL for N1 NSCLC. (2) Methods: This retrospective study identified consecutive pathological N1 NSCLC patients undergoing RATL, video-assisted thoracoscopic lobectomy (VATL), or open lobectomy (OL) in Shanghai Chest Hospital between 2014 and 2020. Further, perioperative and oncological outcomes were investigated. (3) Results: A total of 855 cases (70 RATL, 435 VATL, and 350 OL) were included. Propensity score matching resulted in 70, 140, and 140 cases in the RATL, VATL, and OL groups, respectively. RATL led to (1) the shortest surgical time (p = 0.005) and lowest intraoperative blood loss (p < 0.001); (2) the shortest ICU (p < 0.001) and postsurgical hospital (p < 0.001) stays as well as chest tube duration (p < 0.001); and (3) the lowest morbidities of postsurgical complications (p = 0.016). Moreover, RATL dissected more N1 (p = 0.027), more N1 + N2 (p = 0.027) LNs, and led to a higher upstaging incidence rate (p < 0.050) than VATL. Finally, RATL achieved a comparable 5-year disease-free and overall survival in relation to VATL and OL. (4) Conclusions: RATL led to the most optimal perioperative outcomes among the three surgical approaches and showed superiority in assessing N1 and total LNs over VATL, though it did achieve comparable oncological outcomes in relation to VATL and OL for N1 NSCLC patients.

Propensity score-matched comparison of robotic- and video-assisted thoracoscopic surgery, and open lobectomy for non-small cell lung cancer patients aged 75 years or older.

Introduction: Although robot-assisted thoracoscopic surgery (RATS) has been widely applied in treating non-small cell lung cancer (NSCLC), its advantages remain unclear for very old patients. The present study compared the perioperative outcomes and survival profiles among RATS, video-assisted thoracoscopic surgery (VATS), and open lobectomy (OL), aiming to access the superiority of RATS for NSCLC patients aged ≥75 years. Methods: Pathological IA-IIIB NSCLC patients aged ≥75 years who underwent RATS, VATS, or OL between June 2015 and June 2021 in Shanghai Chest Hospital were included. Propensity score matching (PSM, 1:1:1 RATS versus VATS versus OL) was based on 10 key prognostic factors. The primary endpoints were perioperative outcomes, and the secondary endpoints were disease-free (DFS), overall (OS), and cancer-specific survival (CS). Results: A total of 504 cases (126 RATS, 200 VATS, and 178 OL) were enrolled, and PSM led to 97 cases in each group. The results showed that RATS led to: 1) the best surgical-related outcomes including the shortest operation duration (p <0.001) and the least blood loss (p <0.001); 2) the fastest postoperative recoveries including the shortest ICU stay (p = 0.004), chest tube drainage duration (p <0.001), and postoperative stay (p <0.001), and the most overall costs (p <0.001); 3) the lowest incidence of postoperative complications (p = 0.002), especially pneumonia (p <0.001). There was no difference in the resection margins, reoperation rates, intraoperative blood transfusion, and volume of chest tube drainage among the three groups. Moreover, RATS assessed more N1 (p = 0.009) and total (p = 0.007) lymph nodes (LNs) than VATS, while the three surgical approaches dissected similar numbers of N1, N2, and total LN stations and led to a comparable incidence of postoperative nodal upstaging. Finally, the three groups possessed comparable DFS, OS, and CS rates. Further subgroup analysis found no difference in DFS or OS among the three groups, and multivariable analysis showed that the surgical approach was not independently correlated with survival profiles. Conclusion: RATS possessed the superiority in achieving better perioperative outcomes over VATS and OL in very old NSCLC patients, though the three surgical approaches achieved comparable survival outcomes.

A retrospective comparative cohort study on the efficacy and safety of bi-port robotic-assisted lobectomy and multi-port robotic-assisted lobectomy.

Background: The pursuit of less surgical incisions brings better postoperative experience of patients and earns extensive popularity recently. As the update to the da Vinci robotic surgical system has reduced the size of the robotic arm, a new surgical method with fewer ports has become feasible. We performed 20 cases of robotic surgery with only 2 ports and compared the efficacy and safety between bi-port robotic-assisted lobectomy and multi-port robotic-assisted lobectomy. Methods: To compare the efficacy and safety of the different surgery strategies, we retrospectively reviewed 20 cases of bi-port robotic-assisted thoracic surgery (RATS) and 40 cases of multi-port RATS which were performed at the Shanghai Chest Hospital Between February 2021 and May 2021. The baseline characteristics and their perioperative data were collected and analyzed. Chest tube drainage, chest tube removal time, lymphadenectomy outcomes, operation duration were collected to compare the efficacy of the two groups and blood loss, perioperative complications were recorded to value the safety. Results: A total of 60 surgeries in the 2 groups were successfully completed. The baseline characteristics in terms of sex, age, health statues were comparable (P≥0.05). The maximum diameter of the tumor in the bi-port surgery group was 0.5-3.6 cm (2.0±1.0) vs. 0.5-4.0 cm (1.9±0.9) cm in the control group. No significant difference was discovered in terms of tumor location, tumor maximum diameter, tumor histology. The intraoperative blood loss was 60.0±20.5 mL and the average operation time was 95.6±21.4 min in the bi-port surgery group compared to 65.0±30.4 mL and 101.4±25.0 min in the control group. An average of 6.0±1.4 lymph nodes were collected in the bi-port surgery group with a mean diameter of 1.2±0.4 cm, and in the control group, an average of 6.1±1.6 lymph nodes were collected with a mean diameter was 1.2±0.5 cm. The average time of chest drainage was 4.3±1 vs. 5.1±1.3 days in the bi-port surgery group and control group. No statistical significance was found between the two groups (P>0.05). Conclusions: Compared to multi-port RATS, Bi-port robotic-assisted lobectomy was safe and showed promising efficacy in patients with early staged operable lung cancer.

Integration of clinicopathological and mutational data offers insight into lung cancer with tumor spread through air spaces.

BACKGROUND: Tumor spread through air spaces (STAS) was defined as a unique tumor invasion pattern in adenocarcinoma (ADC) by The World Health Organization Classification of Lung Tumors in 2015. Since then, STAS had been shown to be associated with local recurrence and poor survival results, as the typical signature and potential mechanisms of STAS remained unclear. Our objectives were to comprehensively demonstrate the clinicopathological and genetic signatures in STAS-positive lung cancer patients. METHODS: The clinicopathological and gene alteration characteristics of 878 STAS-positive lung cancer patients were presented. Associations between parameters were evaluated using the Chi-square test, Fisher's exact test, and logistic regression. The capture-based targeted next generation sequencing (NGS) with a platform of 68 lung cancer-related genes was conducted in 139 cases, and the mutational spectrum was summarized. RESULTS: STAS was identified in 391 female and 481 male patients, of which ADC accounted for the majority of cases (92.6%). The concomitant solid or micropapillary subtype was observed in 92.12% patients with ADC. Poorly differentiated histological subtypes were more frequent and negatively correlated with tumor size in smaller tumor cases (P=0.036, Pearson's R=-0.075). Furthermore, in the subgroup of nodules within 3 cm, the distribution of the solid and micropapillary subtypes were significantly frequent in lymph node-positive patients (P<0.001). Tumor protein p53 (TP53) alterations were more frequent in smoking patients (27.6%, P=0.007), human epidermal growth factor receptor 2 (HER2) alterations were more common in female (10.8%, P=0.025), while Kirsten rat sarcoma viral oncogene (KRAS) (20.3%, P=0.024) and TP53 (45.9%, P=0.003) were more prevalent in males. CONCLUSIONS: Poorly differentiated histological subtypes likely played a crucial role in promoting the invasiveness of STAS, especially in small tumor-size cases. Epidermal growth factor receptor (EGFR), TP53, KARS, anaplastic lymphoma kinase (ALK), and ROS proto-oncogene 1 (ROS1) were the five most frequent alterations in STAS-positive ADC.

Comparison of perioperative outcomes of robotic-assisted versus video-assisted thoracoscopic right upper lobectomy in non-small cell lung cancer.

BACKGROUND: Robotic-assisted thoracic surgery (RATS) has been widely used in the treatment of lung cancer. The perioperative outcomes of right upper lobectomy (RUL) using RATS and video-assisted thoracic surgery (VATS) were retrospectively investigated and compared. We aimed to summarize a single-center experience of RATS and 4-port unidirectional VATS in RUL, and to discuss the safety and the essentials of the surgery. METHODS: We retrospectively analyzed the 685 with non-small cell lung cancer (NSCLC) patients who underwent minimally invasive RUL in our center by the same surgical group from January 2015 to December 2019. Both RATS and VATS were performed with three ports with utility incision. The 685 participants were divided into RATS (335 cases) and VATS (350 cases) groups according to surgical method. Baseline characteristics and perioperative outcomes including dissected lymph nodes, postoperative duration of drainage, postoperative hospital stay, and incidence of postoperative complications were compared between the groups. RESULTS: In the 685 patients enrolled, the baseline characteristics were comparable, and no postoperative 30-day mortality or intraoperative blood transfusion were observed. Compared with VATS, RATS had less surgical duration (90.22±12.16 vs. 92.68±12.26 min, P<0.001), less length of stay (4.71±1.37 vs. 5.26±1.56 days, P<0.001), and decreased postoperative duration of drainage (3.49±1.15 vs. 4.09±1.57 days, P<0.001). No significant difference was observed in the lymph nodes dissection, blood loss, conversion rate and morbidities. The cost of RATS was much higher than VATS (85,329.41±12,893.44 vs. 68,733.43±14,781.32 CNY, P<0.001). CONCLUSIONS: Robot assisted RUL had similar perioperative outcomes compared to VATS RUL lobectomy using similar three port with utility incision technique. The advantages of RATS included finer dissection of lymph node, relatively less operation time, earlier chest tube removal and discharge.