Albendazole ameliorates aerobic glycolysis in myofibroblasts to reverse pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic and lethal lung disorder for which effective treatments remain limited. Recent investigations revealed a potential link between altered glucose metabolism and the activation of fibroblasts, the key cells responsible for generating and depositing extracellular matrix proteins within the lung interstitium during IPF development. METHOD: In this study, we aimed to investigate the potential therapeutic impact of albendazole on fibroblast to myofibroblast transition in IPF. We assess albendazole's effectiveness in attenuating the activation of fibroblasts. We focused on elucidating the mechanism underlying albendazole's impact on TGF-ß1-induced aerobic glycolysis in both lung tissues and fibroblasts obtained from patients with IPF and other lung fibrosis types. Furthermore, the antifibrotic effects of oral administration of albendazole were investigated in mouse models of pulmonary fibrosis induced by BLM or SiO2. Human precision-cut lung slices were employed to evaluate the impact of albendazole following TGF-ß1 stimulation. RESULT: In this work, we demonstrated that albendazole, a first-line broad-spectrum anthelmintic drug, effectively attenuated fibroblast to myofibroblast transition through alleviating TGF-ß1-induced aerobic glycolysis dependent on the LRRN3/PFKFB3 signaling pathway. Additionally, LRRN3 expression was downregulated in both lung tissues and fibroblasts from patients with IPF and other types of lung fibrosis. Importantly, the levels of LRRN3 correlated with the progression of the disease. Notably, oral administration of albendazole exerted potent antifibrotic effects in mouse models of pulmonary fibrosis induced by BLM or SiO2, and in human precision-cut lung slices after TGF-ß1 stimulation, as evidenced by improvements in lung morphology, reduced myofibroblast formation, and downregulation of α-SMA, collagen type 1 and Fibronectin expression in the lungs. CONCLUSION: Our study implies that albendazole can act as a potent agonist of LRRN3 during fibroblast to myofibroblast differentiation and its oral administration shows potential as a viable therapeutic approach for managing IPF.

A disproportionality analysis of sunitinib in the FDA adverse event reporting system (FAERS).

Objective: This study aimed to analyze the FAERS database to identify adverse event associated with sunitinib to offer valuable insights for the judicious utilization of medication in clinical settings. Methods: Various disproportionality analysis techniques, such as the reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPN), and multi-gamma Poisson shrinkage (MGPS), were employed to analyze adverse drug reaction (ADR) reports pertaining to sunitinib in the FAERS database from its market introduction up to the first quarter of 2023. Subsequently, a secondary screening process was conducted to identify reliable positive signals. Results: The analysis of sunitinib adverse event signals at the system-organ classification level encompassed 27 organ systems, with gastrointestinal and endocrine disorders emerging as the predominant SOCs. A total of 237 significant adverse events meeting all four algorithms were detected. Notably, this study revealed previously unreported adverse events, including pleural effusion and ascites, while potential adrenal toxicity-related adverse events, highlighted in the drug's specification, were not identified in this analysis. The study examined the relationship between the duration of sunitinib dosing and the onset of adverse events, revealing a median onset of 48 days (IQR, 15-160 days). The findings indicated that a majority of adverse events manifested early in the dosing period, with tumor progression, disease progression, and mortality becoming more prevalent after one year of treatment. Conclusion: In the clinical utilization of sunitinib, vigilant monitoring of potential adverse reactions is imperative during the initial phase of drug administration. In addition to the documented adverse reactions outlined in the drug specification, healthcare providers should remain attentive to potential adverse reactions such as pleural effusion, ascites, and tumor development.

Bazedoxifene Inhibits Cell Viability, Colony-Forming Activity, and Cell Migration in Human Non-Small Cell Lung Cancer Cells and Improves the Treatment Efficacy of Paclitaxel and Gemcitabine.

BACKGROUND: Bazedoxifene is a third-generation selective estrogen receptor modulator that inhibits the IL6/IL6R/GP130 signaling pathway by inhibiting IL6-induced homodimerization of GP130. Considering that the IL6/IL6R/GP130 signaling pathway is important in tumorigenesis and metastasis, bazedoxifene is thought to have an antitumor effect, which has been proven preliminarily in breast cancer and pancreatic cancer but has not yet been studied in non-small cell lung cancer (NSCLC). This study is aimed at evaluating the antitumor effect of bazedoxifene in NSCLC. METHODS: A549 and H1299 NSCLC cell lines were employed and exposed to various concentrations of bazedoxifene, paclitaxel, gemcitabine, and their combinations for cell viability, colony formation, and wound healing assays to demonstrate the antitumor effect of bazedoxifene with or without paclitaxel or gemcitabine. RESULTS: MTT cell viability, colony formation, and wound healing assays showed that bazedoxifene was capable of inhibiting cell viability, colony formation, and cell migration in a dose-dependent manner. In addition, bazedoxifene was capable of working with paclitaxel or gemcitabine synergistically to inhibit cell viability, colony formation, and cell migration. CONCLUSION: This study demonstrated the potential antitumor effect of bazedoxifene and its ability to improve the treatment efficacy of paclitaxel and gemcitabine.

Cerebrovascular events and thrombolysis in pulmonary embolism-induced cardiac arrest: a case series and key challenges.

BACKGROUND AND PURPOSE: Cerebrovascular events during thrombolysis in cardiac arrest (CA) caused by pulmonary embolism (PE) is a life-threatening condition. However, the balance between cerebrovascular events and thrombolytic therapy in PE-induced CA remains a great challenge. METHODS: In this study, we reported three unique cases regarding main concerns surrounding cerebrovascular events in thrombolytic therapy in PE-induced CA. RESULTS: The patient in the case 1 treated with thrombolysis during CPR and finally discharged neurologically intact. The patient in the case 2 received delayed thrombolysis and died eventually. The patient in the case 3 was contraindicated to thrombolysis due to the complication of subarachioid hemorrahage and died within days. CONCLUSIONS: Our case series highlights three proposed approaches to consider before administering thrombolysis as a treatment option in PE-induced CA patients: (1) prolonging the resuscitation, (2) administering thrombolysis promptly, and (3) ruling out cerebrovascular events.

Lung cancer cell-intrinsic IL-15 promotes cell migration and sensitizes murine lung tumors to anti-PD-L1 therapy.

BACKGROUND: IL-15 plays a vital role in enhancing NK cell- and T-cell-mediated antitumor immune responses; however, the direct effect of IL-15 on tumor cells has not been fully elucidated. Herein, we investigated the effect of IL-15 on lung adenocarcinoma cells. METHODS: Silencing and overexpression techniques were used to modify endogenous IL-15 expression in tumor cells. Transwell assays were used to assess tumor cell migration and invasion; a live-cell analysis system was used to evaluate cell motility; cellular morphological changes were quantified by confocal fluorescence microscopy; the molecular mechanisms underlying the effect of IL-15 on tumor cells were analyzed by western blotting; and RhoA and Cdc42 activities were evaluated by a pulldown assay. NCG and C57BL/6 mouse models were used to evaluate the functions of IL-15 in vivo. RESULTS: Cancer cell-intrinsic IL-15 promoted cell motility and migration in vitro and metastasis in vivo via activation of the AKT-mTORC1 pathway; however, exogenous IL-15 inhibited cell motility and migration via suppression of the RhoA-MLC2 axis. Mechanistic analysis revealed that both the intracellular and extracellular IL-15-mediated effects required the expression of IL-15Rα by tumor cells. Detailed analyses revealed that the IL-2/IL-15Rß and IL-2Rγ chains were undetected in the complex formed by intracellular IL-15 and IL-15Rα. However, when exogenous IL-15 engaged tumor cells, a complex containing the IL-15Rα, IL-2/IL-15Rß, and IL-2Rγ chains was formed, indicating that the differential actions of intracellular and extracellular IL-15 on tumor cells might be caused by their distinctive modes of IL-15 receptor engagement. Using a Lewis lung carcinoma (LLC) metastasis model, we showed that although IL-15 overexpression facilitated the lung metastasis of LLC cells, IL-15-overexpressing LLC tumors were more sensitive to anti-PD-L1 therapy than were IL-15-wild-type LLC tumors via an enhanced antitumor immune response, as evidenced by their increased CD8+ T-cell infiltration compared to that of their counterparts. CONCLUSIONS: Cancer cell-intrinsic IL-15 and exogenous IL-15 differentially regulate cell motility and migration. Thus, cancer cell-intrinsic IL-15 acts as a double-edged sword in tumor progression. Additionally, high levels of IL-15 expressed by tumor cells might improve the responsiveness of tumors to immunotherapies.

Localized Administration of Bcar3 siRNA via Nano-Self-Assembly to Treat Idiopathic Pulmonary Fibrosis by Disrupting Macrophage-Fibroblast Crosstalk.

Background: Idiopathic pulmonary fibrosis (IPF) is a severe interstitial lung disease characterized by chronic lung injury leading to macrophage infiltration and fibroblast activation. However, there is no effective therapeutic strategy targeting the crucial crosstalk between macrophages and fibroblasts to halt IPF progression. Methods: Studies were conducted in IPF patients and fibrotic mice models to elucidate the role of Bcar3 in the pathogenesis of pulmonary fibrosis. The effect of Bcar3 on macrophage polarization, fibroblast activation, and related signaling pathways were next investigated to unravel the underlying mechanisms. Results: Our study elucidates a marked increase in Bcar3 expression in lung tissues from IPF patients and fibrotic mice, recording 1.7 and 7.8-fold increases compared to control subjects, respectively. Additionally, Bcar3 was found to significantly enhance macrophage activation and fibroblast differentiation, observable in both in vivo and in vitro settings. Mechanistically, the upregulation of Bcar3 in macrophages was reliant on Stat6, while in fibroblasts, it depended on TGFßR1/Smad3. Furthermore, Bcar3 augmented IL-4/Stat6 pathway in macrophages and TGF-ß/Smad3 pathway in fibroblasts, supporting a synergistic activation loop that expedited lung fibrogenesis. Notably, intratracheal injection of liposomes containing Bcar3 siRNA precisely delivered gene therapeutics to lung macrophages and fibroblasts, effectively reducing Bcar3 expression to 59% of baseline levels. Importantly, this intervention protected mice from lung fibrosis induced by either FITC or bleomycin, as well as human precision-cut lung slices against TGF-ß1 stimulation. Conclusion: Our study underscores the pivotal role of Bcar3 in orchestrating the macrophage-fibroblast crosstalk during pulmonary fibrosis progression. Targeting Bcar3 emerges as a novel therapeutic avenue to halt IPF progression and enhance patient prognosis.

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

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

"Low-age, low-frequency" lung cancer screening strategies maybe adaptable to the situation in China.

BACKGROUND: The object was to compare changes in patients undergoing lung surgery before and after COVID-19 outbreak, and to explore the impact of COVID-19 on lung surgery and its coping strategies. METHOD: A retrospective review of patients undergoing thoracic surgery at a single institution was conducted. Group A included patients treated between January 23, 2019, and January 23, 2020, while Group B included patients treated between June 1, 2020, and June 1, 2021, at our center. We compared the reasons of seeking medical treatment, the general characteristics of patients, imaging features, pathological features, surgical methods and postoperative recovery. RESULT: Compared to Group A, the number of patients with pulmonary nodules screened by routine check-up increased in Group B (57.6% vs 46.9%, p < 0.05). Female patient increased (55.2%vs 44.7%). Patient without smoking history or with family history of lung cancer increased (70.7% vs 60.7%) (10.1%vs 7.8%). Early stage lung cancer increased. Lobectomy decreased (53.4% vs 64.1%). Segmental resection increased (33.3% vs 12.7%). Patients without postoperative comorbidities increased (96.1%vs 85.7%). In the case of patients with Ground Glass Opacity(GGO), their age was comparatively lower (52 ± 9.9 vs. 55 ± 10.7), the female patients increased, patient without smoking history, tumor history, family history of tumor increased, small GGO increased. Lobectomy decreased (35.2% vs 49.7%). Segmental resection increased (49.6% vs 21.2%). Patients without postoperative comorbidities increased (96.5% vs 87.4%). CONCLUSION: Since COVID-19 outbreak, more young, non-smoking, female lung cancers, more Ground Glass Opacity, none high risk patients have been detected through screening, suggesting that our current screening criteria for lung cancer may need to be revised. Higher requirements, including the selection of the timing of nodular surgery, surgical methods were put forward for thoracic surgeons' skills.

Accurate and non-invasive localization of multi-focal ground-glass opacities via electromagnetic navigation bronchoscopy assisting video-assisted thoracoscopic surgery: a single-center study.

Background: Accurate localization of multi-focal ground-glass opacities (GGOs) is crucial for successful video-assisted thoracoscopic surgery (VATS). Electromagnetic navigation bronchoscopy (ENB) provides a minimally invasive and dependable approach for precise localization. This study assessed the accuracy and safety of ENB-guided localization in cases involving multi-focal GGOs. Methods: This retrospective study presents a single-center investigation into ENB-guided localization, utilizing methylene blue, for multi-focal GGOs assisting VATS. Clinical, surgical, and pathological data were collected from patients who underwent ENB-guided localization between 23 December 2019 and 31 August 2022. Results: The study examined 57 patients with multi-focal GGOs who underwent ENB-guided localization and VATS. A total of 150 GGOs were treated, with ENB-guided localization taking a median time of 65 min. Following localization, all patients proceeded to VATS, with a median duration of 170 min. The median lesion size measured 7.8 mm, with a 5-mm distance between GGO and pleura or fissure. When the distance between GGO and pleura/fissure exceeded 1 cm, an additional location point was introduced below the pleura or fissure based on GGO location. No complications related to localization were observed. The overall malignancy rate stood at 66%. Location precision was confirmed by measuring the marker-to-GGO lesion distance, resulting in a 94% (141/150) accuracy rate for GGO localization. Conclusion: ENB-guided methylene blue injection is a safe and precise method to treat multi-focal GGOs, potentially minimizing operation time and simplifying lesion detection.

Identifying luteolin as a potential drug for treating lung adenocarcinoma with COVID-19 affection based on integration analysis of pharmacology and transcriptome.

BACKGROUND: Lung adenocarcinoma (LUAD) is a major type of lung cancer worldwide, and under the pandemic coronavirus disease 2019 (COVID-19), its cancer burden is enlarged. This study aimed to explore potential drug targets and potential drugs for developing effective treatments for patients with both lung cancer and COVID-19. METHOD: The interaction network of molecule compounds-target genes was constructed based on Traditional Chinese Medicines (TCMs) and gene expression data from public databases. The potential effectiveness of drugs was analyzed by molecular docking and molecular dynamics simulation. Western blot, transfection assay, Immunohistochemistry (IHC) staining, and flow cytometry were performed to investigate the function of HSP90AA1 in LUAD cells. RESULT: Eight target genes (GSK3B, HMOX1, HSP90AA1, ICAM1, MAPK1, PLAU, RELA and TNFSF15.) were identified, and two of them (HSP90AA1 and RELA) were significantly associated with LUAD prognosis. Luteolin was discovered to bind with HSP90AA1. Moreover, In vitro cell experiments demonstrated that HSP90AA1 had higher expression in A549 cells, promoted cell viability and suppressed apoptosis in A549 cells and H1299 cells. CONCLUSION: HSP90AA1 was a target gene for further designing effective drugs for LUAD patients. Luteolin was a potential drug for treating patients with both LUAD and COVID-19.

Treatment and survival analysis for 40-year SEER data on upper esophageal cancer.

Background: Upper esophageal cancer (UEC) is rare in both Eastern and Western countries. The epidemiological characteristics and long-term survival of UEC patients are less known. In addition, the choice of optimal treatment for UEC has been controversial. Methods: Cases of UEC (C15.3 and C15.0) arising during the period from 1973 to 2013 were identified and selected using the SEER database. Student's t-test and Pearson's chi-square test were used to compare the differences in parameters among different groups. Esophageal cancer-specific survival (ECSS) and overall survival (OS) rates were calculated by using the Kaplan-Meier method. Cox proportional hazard regression was used to analyze predictive factors. Results: In the past 40 years, the cases of UEC have gradually increased, and the proportion of adenocarcinoma (AD) has gradually increased (from 3.6% to 11.8%, p < 0.001). There has been a significant increase (1973-1982 vs. 2004-2013) in median OS (7 months vs. 10 months, p < 0.001) and median ECSS (7 months vs. 11 months, p < 0.001) among UEC patients from 1973 to 2013. For the impact of different treatments, the results showed that the ECSS and OS of surgery without radiation (SWR) and radiation plus surgery (R+S) were superior to those of radiation without surgery (RWS). Subgroup analysis showed that ECSS and OS were highest among patients treated with SWR compared with R+S and RWS for patients with localized disease. For regional disease, ECSS and OS were highest among patients with R+S compared with SWR or RWS. Among patients with regional-stage squamous cell carcinoma (SCC), OS was higher with neoadjuvant radiotherapy or adjuvant radiotherapy compared with SWR. Multivariate analysis showed that radiotherapy sequence was dependently associated with OS among patients with regional-stage SCC. Conclusion: Although the long-term survival of UEC remains poor, it has gradually increased since 1973. This should be closely related to the improvement of medical care over the past 40 years. Different treatment methods have a great influence on the long-term survival of UEC. For localized diseases, surgery may be a better choice. For regional disease, surgery plus adjuvant or neoadjuvant radiotherapy may be more beneficial to improve the long-term prognosis of UEC patients.

TGFß Antagonizes IFNγ-Mediated Adaptive Immune Evasion via Activation of the AKT-Smad3-SHP1 Axis in Lung Adenocarcinoma.

IFNγ-mediated signaling in tumor cells can induce immunosuppressive responses and cause tumor resistance to immunotherapy. Blocking TGFß promotes T lymphocyte infiltration and turns immunologically cold tumors into hot tumors, thereby improving the efficacy of immunotherapy. Several studies have shown that TGFß inhibits IFNγ signaling in immune cells. We thus sought to determine whether TGFß affects IFNγ signaling in tumor cells and plays a role in the development of acquired resistance to immunotherapy. TGFß stimulation of tumor cells increased SHP1 phosphatase activity in an AKT-Smad3-dependent manner, decreased IFNγ-mediated tyrosine phosphorylation of JAK1/2 and STAT1, and suppressed the expression of STAT1-dependent immune evasion-related molecules, e.g., PD-L1, IDO1, herpes virus entry mediator (HVEM), and galectin-9 (Gal-9). In a lung cancer mouse model, dual blockade of TGFß and PD-L1 led to superior antitumor activity and prolonged survival compared with anti-PD-L1 therapy alone. However, prolonged combined treatment resulted in tumor resistance to immunotherapy and increased expression of PD-L1, IDO1, HVEM, and Gal-9. Interestingly, after initial anti-PD-L1 monotherapy, dual TGFß and PD-L1 blockade promoted both immune evasion gene expression and tumor growth compared with that in tumors treated with continuous PD-L1 monotherapy. Alternatively, treatment with JAK1/2 inhibitor following initial anti-PD-L1 therapy effectively suppressed tumor growth and downregulated immune evasion gene expression in tumors, indicating the involvement of IFNγ signaling in immunotherapy resistance development. These results demonstrate an unappreciated effect of TGFß on the development of IFNγ-mediated tumor resistance to immunotherapy. SIGNIFICANCE: Blocking TGFß facilitates IFNγ-mediated resistance to anti-PD-L1 therapy due to the role of TGFß in inhibiting IFNγ-induced immunoevasion by increasing SHP1 phosphatase activity in tumor cells.

Real-world surgical treatment patterns and clinical outcomes in patients with stages IA-IIIA non-small cell lung cancer: a retrospective multicentric observational study involving 11,958 patients.

PURPOSE: Surgical resection is cornerstone treatment for early-stage non-small cell lung cancer (NSCLC) and offers a chance for cure. This study was conducted to determine current surgical treatment patterns and outcomes of Chinese patients with NSCLC. METHODS: Data of patients with histologically confirmed NSCLC of stages IA-IIIA and who underwent surgery between July 2014 and July 2020 were retrospectively collected from 9 tertiary hospitals in China. Cox model was used for multivariate analyses. RESULTS: This study included 11,958 patients, among whom 59.1%, 19.2%, and 21.7% were in stages I, II, and IIIA, respectively. Lobectomy was the most common operation method (78.4%), followed by wedge resection (8.2%), segmentectomy (5.4%), pneumonectomy (5.2%), and bronchial sleeve lobectomy (2.8%). Among patients who underwent wedge resection and segmentectomy, majority had stage I NSCLC (87.2% and 93.3%, respectively), and sublobectomy accounted for 20.7% of stage I operations. With a median follow-up time of 30.2 months, disease-free survival (DFS) and overall survival (OS) rates of entire population were 88.9% and 96.1% at 1 year, 75.2% and 85.1% at 3 years, and 65.3% and 77.0% at 5 years, respectively. The 5-year OS rates for stages IA, IB, IIA, IIB, and IIIA disease were 93.2%, 82.7%, 70.3%, 67.0%, and 52.1%, respectively. CONCLUSION: This is the largest real-world cohort study of patients with NSCLC who underwent surgery in China, where we described characteristics of surgical treatment and survival outcomes. The results of our study provide insights into real-world surgical treatment status for surgeons and clinicians.

Case report: Drainage tube penetrating anastomosis as a rare cause for long-term nonunion of esophagogastric anastomosis in neck.

Anastomotic leakage is a life-threatening complication for esophageal cancer patients who received McKeown esophagectomy. Cervical drainage tube penetrating anastomosis is a rare but noteworthy cause of long-term nonunion of esophagogastric anastomosis. Here we reported two cases of esophageal cancer patients who received McKeown esophagectomy. The first case acquired the anastomotic leakage on postoperative day (POD) 7, and lasted for 56 days. The cervical drainage tube was removed at POD 38, and the leakage healed in 25 days. The second case acquired the anastomotic leakage on POD 8 and lasted for 95 days. The cervical drainage tube was removed at POD 57, and the leakage healed in 46 days. The two cases demonstrated the duration-prolonging effect of drainage tube penetrating anastomosis, which should not be overlooked in clinical practice. We suggested paying attention to the duration of leakage, the drainage fluids amounts and characteristics, and the imaging manifestations to help diagnose. If the cervical drainage tube penetrated the anastomosis, the tube should be eliminated as soon.

Shenlingcao oral liquid for patients with non-small cell lung cancer receiving adjuvant chemotherapy after radical resection: A multicenter randomized controlled trial.

BACKGROUND: Low quality of life (QoL) in patients with non-small cell lung cancer (NSCLC) receiving adjuvant chemotherapy after radical resection is a major global health issue. High-quality evidence for the effectiveness of Shenlingcao oral liquid (SOL) as a complementary treatment in this patients is lacking at present. PURPOSE: To determine whether complementary SOL treatment in NSCLC patients receiving adjuvant chemotherapy would yield greater improvements in QoL than chemotherapy alone. STUDY DESIGN: We conducted a multicenter, randomized controlled trial of stages IIA-IIIA NSCLC patients undergoing adjuvant chemotherapy in seven hospitals. METHODS: Using stratified blocks, participants were randomized in a 1:1 ratio to receive SOL combined with conventional chemotherapy or conventional chemotherapy alone. The primary outcome was the change in global QoL from baseline to the fourth chemotherapy cycle, and intention-to-treat analysis was applied with a mixed-effect model. Secondary outcomes were functional QoL, symptoms, and performance status scores at the 6-month follow-up. Missing data were handled with multiple imputation and a pattern-mixture model. RESULTS: Among 516 randomized patients, 446 (86.43%) completed the study. After the fourth chemotherapy cycle, in comparison with the control group, patients receiving SOL showed a lower reduction in mean global QoL (-2.76 vs. -14.11; mean difference [MD], 11.34; 95% confidence interval [CI], 8.28 to 14.41), greater improvement in physical function (MD, 11.61; 95% CI, 8.57 to 14.65), role function (MD, 10.15; 95% CI, 5.75 to 14.54), and emotional function (MD, 4.71; 95% CI, 1.85 to 7.57), and greater improvements in lung cancer-related symptoms (e.g., fatigue, nausea/vomiting, and appetite loss) and performance status during the 6-month follow-up period (treatment main effect, p < 0.05). CONCLUSION: SOL treatment for NSCLC patients receiving adjuvant chemotherapy can significantly improve QoL and performance status within 6 months after radical resection. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03712969.

Distinct cellular immune profiles in lung adenocarcinoma manifesting as pure ground glass opacity versus solid nodules.

INTRODUCTION: Ground glass opacity featured lung adenocarcinomas (GGO-LUAD) display more indolent biological behavior than solid nodule featured lung adenocarcinomas (SN-LUAD) and have an excellent prognosis. However, the cellular immune characteristics of GGO-LUAD remain poorly understood. METHODS: Immunohistochemistry technique was performed to stain related immune markers (CD8, CD103, CD20, CD138, CD4, FOXP3, CD68, CD163, PD-1 and PD-L1) and TGF-ß from 15 patients with pure GGO-LUAD and 15 patients with SN-LUAD tissue sections (Paired cohort), and then, the related markers with significant differences were verified on 10 patients (Verified cohort) with both pure GGO-LUAD and SN-LUAD. For localization analysis of CD68 + tumor-associated macrophages (TAMs) and FOXP3 + Terg cells in tumor areas, pure GGO-LUAD and SN-LUAD were also stained for simultaneous detection of pan-CK, CD68 and FOXP3 by multiplex immunofluorescence. RESULTS: In the Paired cohort, compared with SN-LUAD, only the infiltration of TAMs and Treg cells was significantly lower in GGO-LUAD. The infiltration of the remaining immune cells including CD8 + T cells, CD4 + T cells, CD103 + T cells, CD20 + B cells and CD138 + Plasma cells in GGO-LUAD, although relatively low, was not significantly different. Meanwhile, the expression of TGF-ß was significantly higher in SN-LUAD. And the above results have also been confirmed in the Verified cohort. Moreover, there was no significantly difference in PD-L1 expression in GGO-LUAD compared to SN-LUAD both in the Paired cohort and Verified cohort. CONCLUSIONS: GGO-LUAD demonstrates an overall less active immune landscape as compared with SN-LUAD. TAMs and TGF-ß may play an important role in the progression of GGO-LUAD. More importantly, PD-L1 expression in GGO-LUAD is comparable to that in SN-LUAD, indicating that there may be other reasons for the insensitivity of GGO-LUAD to immunotherapy.

CD4+ Cytotoxic T Lymphocytes in Cancer Immunity and Immunotherapy.

CD4+ T cells have the ability to differentiate into relatively specialized effector subsets after exposure to innate immune signals. The remarkable plasticity of CD4+ T cells is required to achieve immune responses in different tissues and against various pathogens. Numerous studies have shown that CD4+ T cells can play direct and indispensable roles in protective immunity by killing infected or transformed cells. Although the lineage decision of commitment to the CD4+ or CD8+ cell lineage is once thought to be inflexible, the identification of antigen-experienced CD4+ T cells with cytotoxic activity suggests the existence of unexpected plasticity for these cells. The recognition of CD4+ cytotoxic T lymphocytes (CTLs) and the mechanisms driving the differentiation of this particular cell subset create opportunities to explore the roles of these effector cells in protective immunity and immune-related pathology. CD4+ CTLs are proven to play a protective role in antiviral immunity. Here, the latest investigations on the phenotypic and functional features of CD4+ CTLs and their roles in antitumor immunity and immunotherapy are briefly reviewed.

Minimally invasive versus open esophagectomy for resectable thoracic esophageal cancer (NST 1502): a multicenter prospective cohort study.

Background: Whether minimally invasive esophagectomy (MIE) is superior to open esophagectomy (OE) in the treatment of esophageal squamous cell carcinoma (ESCC) is still uncertain. Therefore, this multicenter prospective study aimed to compare MIE with OE in postoperative parameters and long-term survival. Methods: All hospitalized patients with cT1b-3N0-1M0 thoracic ESCC treated by MIE or OE were enrolled from 19 selected centers from April 1, 2015 to December 31, 2018. The propensity score matching (PSM) was performed to minimize the selection bias. The basic clinicopathological characteristics and 3-year overall survival (OS) as well as disease-free survival (DFS) of two groups were compared by R version 3.6.2. Results: MIE were performed in 1,387 patients and OE in 335 patients. 335 cases in each group were finally matched by PSM, and no significant differences in the essential demographic characteristics were observed between the MIE and OE groups after PSM. Compared with OE, MIE had significantly less intraoperative bleeding, less total drainage volume, shorter postoperative hospital stay, and harvested significantly more lymph nodes (LNs) (all P < 0.001). There were no significant differences in the major postoperative complications and death rates between MIE and OE. The 3-year OS and DFS were 77.0% and 68.1% in the MIE group versus 69.3% and 60.9% in the OE group (OS: P = 0.03; DFS: P = 0.09), and the rates were 75.1% and 66.5% in the MIE group versus 66.9% and 58.6% in the OE group for stage cII patients (OS: P = 0.04, DFS: P = 0.09), respectively. Conclusions: Compared with OE, MIE is a safe and effective treatment approach with similar mortality and morbidity. It has the advantages in harvesting more LNs, improving postoperative recovery and survival of stage cII ESCC patients.

Ground-glass opacity in a patient with right aortic arch and no left pulmonary artery.

BACKGROUND: Here we report a case of patients with mixed ground glass opacity in the left lung combined with congenital right aortic arch, which is only present in 0.01-0.1% of adults. CASE PRESENTATION: A 60-year-old woman was referred to our department with a mixed ground-glass opacity (GGO) in the upper lobe of her left lung. She had congenital right aortic arch, and the left pulmonary artery was absent. Enhanced chest computed tomography, pulmonary perfusion imaging, and three-dimensional reconstruction were performed to confirm the blood supply in the left lung and the exact location of the GGO. Because of the unusual left pulmonary vascular structure, wedge resection was performed to prevent massive hemorrhage. The final pathological examination revealed that the mixed GGO was a well-differentiated pulmonary adenocarcinoma. CONCLUSION: The surgical options should be evaluated carefully in view of the complications and the prognosis of the patient, when ground glass opacity is combined with congenital cardiovascular anomalies.