Thoracic Cancer最新文献

Background: Improving the "cold" tumor immune microenvironment (TIME) of small-cell lung cancer (SCLC) represents a promising therapeutic approach. The metabolite lactate plays a crucial role in shaping the immune-cold tumor microenvironment (TME) and facilitating tumor progression. Phosphoglycerate kinase 1 (PGK1) is a key enzyme involved in tumor lactate metabolism. This study demonstrates that ACT001 improves the TIME of SCLC through inhibiting lactate production by targeting PGK1.

Methods: The cytotoxic effects of ACT001 on SCLC cell lines NCI-H1688 and NCI-H446 were evaluated using MTT assay, clone formation, EdU incorporation, wound healing, and invasion assays. To elucidate the mechanism of action of ACT001, proteomic techniques, pull-down assays, LC-MS/MS, surface plasmon resonance, immunofluorescence, lactate generation, glucose uptake, and western blot assays were conducted. A xenograft model was used to assess the in vivo anti-tumor activity of ACT001.

Results: ACT001 inhibited the proliferation, invasion, and metastasis of SCLC both in vitro and in vivo. Additionally, it reduced lactate accumulation and M2 macrophage polarization. Mechanistically, ACT001 released micheliolide, which covalently modified Cys316 of PGK1 under physiological conditions. This suppressed PGK1 activity and restored the distribution of PGK1 in mitochondria and the cytoplasm under hypoxic conditions.

Conclusions: ACT001 inhibits the malignant progression of SCLC by suppressing lactate production, modulating macrophage polarization, and restraining tumor metastasis through PGK1 targeting.

Background: Recently, the treatment needs of elderly lung cancer patients have become comparable with those of younger patients. This study evaluated the efficacy and safety of first-line immune checkpoint inhibitors (ICI) in elderly patients with nonsmall-cell lung cancer (NSCLC), stratified by immune-related adverse events (irAEs) severity, and identified key prognostic factors.

Methods: This retrospective study targeted patients with advanced or recurrent NSCLC who received ICI therapy as first-line treatment between April 2017 and March 2023.

Result: Of the 138 patients enrolled in this study, 81 and 57 patients were classified into the elderly (aged 70 and above) and nonelderly (under 70 years old) groups, respectively. Severe irAEs were significantly associated with shorter overall survival (OS) in the elderly group (severe irAEs vs. others, 9.9 vs. 24.7 months; p = 0.043) and favorable OS in nonelderly group (severe irAEs vs. others, NR [not reached] vs. 21.0 months, p = 0.026). The OS of patients with severe irAEs was significantly worse in the elderly group than in the nonelderly group (elderly group vs. nonelderly group, 9.9 vs. NR months, p = 0.001). In the multivariate analysis, mild irAEs were associated with a favorable prognosis in elderly patients (hazard ratio, 0.446; p = 0.032).

Conclusion: Severe irAEs demonstrated different outcomes in elderly and nonelderly patients. Contrastingly, mild irAEs were associated with a favorable prognosis in elderly patients, emphasizing the need for appropriate patient selection, early intervention for irAEs and new tools to accurately predict irAE severity in elderly patients.

Background: As the global population ages, the prevalence of early-stage nonsmall cell lung cancer (NSCLC) among octogenarians is rising. This demographic frequently presents with comorbid conditions, diminished cardiopulmonary function, and increased frailty, which elevate the risks associated with standard treatments. While lobectomy combined with lymph node dissection is still considered the gold standard for managing NSCLC, octogenarians are at significantly higher risk of perioperative mortality. Although wedge resection has been suggested as a less invasive option, previous research has insufficiently explored the influence of visceral pleural invasion (VPI) on postoperative outcomes. This study seeks to evaluate whether wedge resection can provide survival outcomes equivalent to those of anatomical resection in this high-risk population.

Methods: We conducted a retrospective analysis using SEER data from 2010 to 2019, focusing on octogenarians diagnosed with stage I NSCLC and VPI. Propensity score matching, Kaplan-Meier survival analysis, log-rank testing, and Cox multivariate regression were employed to evaluate and compare the outcomes associated with two different surgical techniques.

Results: We identified 523 octogenarians with stage I NSCLC and VPI, from a cohort of 1587 patients. In this study cohort, 372 (71.1%) patients received anatomical resection, while 151 (28.9%) patients underwent wedge resection. Following multivariable adjustment and propensity score matching, there were no statistically significant differences in lung cancer-specific survival (CSS; HR 0.99, 95% CI: 0.57-1.73) or overall survival (OS; HR 1.02, 95% CI: 0.68-1.53) observed between the two surgical groups. Additionally, multivariate Cox regression analysis indicated that the choice of surgical approach was not an independent prognostic factor for either CSS (HR 1.29, 95% CI: 0.62-2.69) or OS (HR 1.50, 95% CI: 0.68-1.62).

Conclusions: This study demonstrates that wedge resection is a viable surgical option for octogenarians with stage I NSCLC and VPI. Notably, the addition of lymph node dissection to wedge resection significantly enhances survival outcomes compared to wedge resection performed without lymph node dissection.

Retraction: H. Ju, Y. Li, X. Xing, X. Miao, Y. Feng, Y. Ren, J. Qin, D. Liu, Z. Chen, and Z. Yang, "Manganese-12 Acetate Suppresses the Migration, Invasion, and Epithelial-Mesenchymal Transition by Inhibiting Wnt/β-Catenin and PI3K/AKT Signaling Pathways in Breast Cancer Cells," Thoracic Cancer 9, no. 3 (2018): 353-359, https://doi.org/10.1111/1759-7714.12584. The above article, published online on 08 January 2018 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the authors; the journal Editor-in-Chief, Tateaki Naito; and John Wiley & Sons Australia, Ltd. The retraction has been agreed upon following an investigation into concerns raised by a third party which revealed inappropriate image panel duplications between this (Figure 1a and b) and three other articles from the same institute published in a different scientific context. The authors admitted to the image compilation error and stated that during the experimental work, the author groups shared a laboratory which could have led to the error in reusing the images. Due to the number of errors identified in the published figures, the authors and the editors have lost confidence in the presented data and consider the conclusions substantially compromised.

Background: To investigate the clinical implications of serum carcinoembryonic antigen (CEA), neuron specific enolase (NSE), and pro-gastrin-releasing peptide (ProGRP) in small cell esophageal carcinoma (SCEC).

Methods: Receiver operating characteristic (ROC) curves were used to determine the area under the curve (AUC), sensitivity, and specificity of serum markers for differentiating SCEC from patients with esophageal squamous carcinoma (ESCC), esophageal adenocarcinoma (EAC) and healthy subjects.

Results: The combination of ProGRP and NSE demonstrated significant diagnostic efficacy in distinguishing SCEC from ESCC, EAC, and healthy individuals. After treatment, serum levels of ProGRP, NSE, and CEA in SCEC patients with disease control decreased significantly compared to pre-treatment levels. Conversely, the serum levels of ProGRP and NSE in patients with disease progression after treatment were significantly increased compared to those before treatment. Compared with those in the follow-up phase, the levels of ProGRP, NSE, and CEA significantly increased after tumor progression in SCEC patients. This study further exhibited that serum levels of ProGRP above 45.15 pg/mL and NSE above 14.70 ng/mL during follow-up after first-line treatment in SCEC patients were associated with poor progression-free survival (PFS). Moreover, significant associations were observed between baseline serum concentrations of ProGRP, NSE, CEA and both PFS and cancer-specific survival (CSS) in SCEC patients.

Conclusions: ProGRP and NSE have significant value in the diagnosis and differential diagnosis of SCEC, and are also associated with the clinical stage and prognosis of SCEC patients, as well as are effective indicators for evaluating therapeutic efficacy and disease recurrence.

Introduction: The purpose of this study is to determine the efficacy and safety of metronomic chemotherapy with all-oral combination of low-dose etoposide/capecitabine in patients with metastatic breast cancer (MBC) previously treated with anthracyclines and/or taxanes.

Methods: Metronomic chemotherapy, giving lower, more frequent doses of chemotherapy drugs over an extended period, often without long breaks between cycles. With oral low-dose etoposide + capecitabine was administered to patients who had postoperative MBC resistant to anthracycline/taxanes: etoposide 30 mg/m²/day, qd for 7 days + capecitabine 1400 mg/m²/day, administered in two equal dose for 14 days, with 21 days as a cycle. Patients received treatments if complete response, partial response, or stable disease was obtained until disease progressed or became intolerable. RECIST criteria were used for standard efficacy evaluation and NCI-CTC version 3.0 was used for evaluation of side effects.

Results: From June 2008 to May 2020, 85 patients received the aforesaid treatment; 67 of these patients were eligible for efficacy and side effects evaluation. After treatment, 6 (8.96%) patients obtained partial response, 41 (61.19%) patients had stable disease, and 20 (29.85%) patients had disease progression. The overall response rate (complete response + partial response) was 8.96%, and disease control rate (complete response + partial response + stable of disease) was 70.15%. Clinical benefits (complete response + partial response + stable of disease ≥ 24 weeks) were obtained for 50% of the patients. The median and mean treatment to progression time was 5 months and 6.06 months (95% CI: 3.43~8.70), respectively. The most common grade I/II side effects were leukopenia and fatigue (15.8%).

Conclusions: For patients with postoperative MBC resistant to anthracycline/taxanes, oral low-dose etoposide + capecitabine was effective with tolerable safety. The patients did not need antiemetics or leukocytic drugs, and the treatment was cost-effective because the patients did not need to be hospitalized for intravenous infusion.

Background: Subsolid lung nodules represent a distinct group of lung cancers with less-aggressive biological behavior and favorable survival. We aimed to examine the prognostic impact of the ground-glass opacity (GGO) in clinical stage IA (cIA) lung adenocarcinoma with high metabolic activity.

Methods: A retrospective study was conducted among patients with resected hypermetabolic and/or pure-solid cIA lung adenocarcinoma from a single institution database. The primary outcome was recurrence-free survival (RFS). The secondary outcomes included overall survival, pathological nodal upstaging, and recurrence rate.

Results: A total of 621 patients were reviewed and classified into three groups: patients with low metabolic, solid nodules (SNs) into group A (N = 128), patients with hypermetabolic ground-glass nodules (GGNs) into group B (N = 105), and patients with hypermetabolic SNs into group C (N = 388). The five-year RFS of group B was significantly better than that of group C in the cT1a + T1b (93.3% vs. 72.5%, p = 0.002) subgroup but not in the cT1c (73.4% vs. 69.0%, p = 0.23) subgroup. Multivariable analysis showed that GGO component was an independent prognostic factor of RFS (hazard ratio [HR] = 0.41, 95% confidence interval [CI]: 0.19-0.89, p = 0.02) and protective factor of nodal upstaging (odds ratio [OR] = 0.44, 95% CI: 0.21-0.94, p = 0.03) among the hypermetabolic subgroup. All except one postoperative recurrence occurred in GGNs with solid component size > 2 cm.

Conclusions: The presence of GGO component was an independent prognostic factor even in hypermetabolic cIA lung adenocarcinoma. However, the oncologic outcomes of hypermetabolic GGNs were not equally favorable in different T categories.

Objective: This study was conducted to investigate the safety of neoadjuvant immunotherapy combined with chemotherapy in patients undergoing surgery for resectable stage III non-small cell lung cancer (NSCLC).

Methods: Overall, 68 surgical patients with stage III NSCLC who underwent neoadjuvant therapy at the Thoracic Surgery Department of Beijing Chaoyang Hospital from June 2019 to September 2021 were included, including 19 patients who underwent neoadjuvant chemotherapy combined with immunotherapy and 49 who underwent neoadjuvant chemotherapy alone. Both groups of patients were diagnosed with NSCLC before treatment and had resectable stage III tumors. The surgical duration, blood loss volume, average postoperative hospital length of stay, intensive care unit length of stay, and complication rate were compared between the two groups.

Results: The group treated with neoadjuvant chemotherapy combined with immunotherapy demonstrated higher values than the group treated with chemotherapy alone for surgical duration, blood loss volume, and rate of conversion to thoracotomy; however, the differences were not statistically significant. The incidence of postoperative complications in the group treated with neoadjuvant immunotherapy combined with chemotherapy was significantly higher than that of the group treated with neoadjuvant chemotherapy alone (p = 0.02).

Conclusion: Neoadjuvant immunotherapy combined with chemotherapy was safe and effective and did not increase the difficulty of surgery for NSCLC; however, it was associated with a higher incidence of complications than neoadjuvant chemotherapy alone (p < 0.05).

Background: Chemo-resistance is a major obstacle to the treatment of esophageal squamous cell carcinoma (ESCC). Interferon alpha-inducible protein 27 (IFI27) has been reported to be associated with ESCC progression. This study is designed to explore the role and mechanism of IFI27 in the cisplatin (DDP) resistance of ESCC.

Methods: IFI27 and Ubiquitin-specific peptidase 18 (USP18) levels were detected by real-time quantitative polymerase chain reaction (RT-qPCR). IFI27, multidrug resistance-associated protein 1 (MRP1), USP18, and Homeobox A5 (HOXA5) protein levels were determined using western blot. DDP resistance, cell viability, proliferation, apoptosis, invasion, and migration were assessed using MTT, EdU, flow cytometry, transwell, and wound healing. Interaction between USP18 and IFI27 was verified using Co-immunoprecipitation (CoIP) assay. Binding between HOXA5 and USP18 promoter was predicted by JASPAR and validated using Chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays.

Results: IFI27 was upregulated in DDP-resistant ESCC tissues and cells. IFI27 knockdown repressed DDP resistance, cell proliferation, invasion, migration, and induced cell apoptosis in vitro. Mechanistically, USP18 induced the deubiquitination of IFI27 and prevented its degradation. Furthermore, HOXA5 was a transcription factor of USP18 and activated the transcriptional activity of USP18 via binding to its promoter region.

Conclusion: USP18 transcriptionally mediated by HOXA5 could promote cell malignant behaviors and DDP resistance through deubiquitinating IFI27, providing a promising therapeutic target for ESCC treatment.

Fibroblast Growth Factor (FGF) ligands and their receptor have been identified as the potent target in non-small cell lung cancer (NSCLC). However, the clinicopathological and microenvironmental characteristics of FGF/FGFR in NSCLC remain poorly elucidated. Here, we summarize 4656 NSCLCs and analyze clinicopathological features in 478 FGF/FGFR altered cases. AI analysis and multiplex immunofluorescence staining are used to reveal microenvironment features. First, around 10.27% NSCLC carry FGF/FGFR variant. Squamous cell carcinoma (41.95%) is much more than adenocarcinoma (8.32%). In 118 pathogenic variant (PV) cases, the most frequent variant is FGF/FGFR copy number increase (83.05%), the second is FGFR gene fusion (11.86%). Surprisingly, CCND1 always co-amplifies with FGF19 (100.00%). Furthermore, FGF PV is an independent risk factor for poor outcomes (overall survival: HR = 3.781, disease-free survival: HR = 3.340). And one-third of FGFR3-TACC3 fusion cases show clear cytoplasm in histology. Either CCND1/FGF19 co-amplification or KRAS co-mutation is closely related to cigarette exposure, and KRAS co-mutation acts as an independent factor of poor prognosis. Finally, the FGF/FGFR1/NOTCH1 within RB1 variant group has a remarkably high ratio of inner-tumor CD8+ T cell infiltration, non-exhausted T cells, exhausted T^{CD8+PD-1+LAG3-} cells, and T_RM ^{CD8+CD69+CD103+}cells. Overall, this study provides a comprehensive analysis of FGF/FGFR alteration in NSCLC. The FGF/FGFR alteration mainly arises in squamous cell carcinoma. Both FGF PV and KRAS are the independent factors for poor prognosis. To our knowledge, this is the first report to describe an inflamed microenvironment recruited by NOTCH1/RB1 co-mutation, indicating potential benefit from immunotherapy.