Cyclic Peptide Modified Gold Clusters Induce Lung Tumor Cell Apoptosis via Generating Intracellular Oxidative Stress

Metastatic lung cancer is the leading cause of death for cancer patients. Although many chemical drugs were developed for cancer treatment, metastatic cancer mortality did not decrease significantly. In this article, we designed an Au clusters (AuCs) modified by cyclic RGD peptides which well target the integrin of human lung carcinoma cells (A549). The RGD-AuCs could well induce A549 cells apoptosis, but have no cytotoxicity on the human bronchial epithelial cells (16HBE), which are normal cells support respiratory system. The AuCs could be internalized and localized in the lysosomes of A549 tumor cells and further release into cytoplasma. We found the ROS level was increased by AuCs, and such high ROS level finally leads to depolarization of mitochondria. Eventually, the AuCs stimulating mitochondria related apoptosis pathway to induce A549 tumor cells apoptosis. We deduce the gold clusters would be an effective therapeutic candidate to against metastatic lung tumor in the future studies.

Treatment outcomes of re-irradiation using stereotactic ablative radiotherapy to lung: a propensity score matching analysis

Background The purpose of this study was to compare the treatment efficacy and safety of re-irradiation (re-RT) using stereotactic ablative radiotherapy (SABR) and initial SABR for primary, recurrent lung cancer or metastatic lung tumor. Methods A retrospective review of the medical records of 336 patients who underwent lung SABR was performed. Re-RT was defined as the overlap of the 70% isodose line of second-course SABR with that of the initial radiotherapy, and 20 patients were classified as the re-RT group. The median dose of re-RT using SABR was 54 Gy (range 48–60 Gy), and the median fraction number was 4 (range 4–6). One-to-three case-matched analysis with propensity score matching was used, and 60 patients were included in the initial SABR group of the matched cohort. Results The 1- and 2-year local control rates for the re-RT group were 73.9% and 63.3% and those for the initial SABR group in the matched cohort were 92.9% and 87.7%, respectively (P = 0.013). There was no difference in distant metastasis-free, progression-free, and overall survival rates. The crude grade ≥ 2 toxicity rates were 40.0% for the re-RT group and 25.0% for the initial SABR group (P = 0.318). Re-RT group had higher acute grade ≥ 2 toxicity rates (25.0% vs 5.0%, P = 0.031). One incident of grade 3 toxicity (pulmonary) was reported in the re-RT group; there was no grade 4‒5 toxicity. Conclusions The local control rate of the in-field re-RT SABR was lower than that of the initial SABR without compromising the survival rates. The toxicity of re-RT using SABR was acceptable.

Automated monitoring of respiratory rate as a novel humane endpoint: A refinement in mouse metastatic lung cancer models

In oncology research, while xenograft tumor models are easily visualized and humane endpoints can be clearly defined, metastatic tumor models are often based on more subjective clinical observations as endpoints. This study aimed at identifying objective non-invasive criteria for predicting imminent distress and mortality in metastatic lung tumor-bearing mice. BALB/c and C57BL/6 mice were inoculated with CT26 or B16F10 cells, respectively. The mice were housed in Vium smart cages to continuously monitor and stream respiratory rate and locomotion for up to 28 days until scheduled euthanasia or humane endpoint criteria were met. Body weight and body temperature were measured during the study. On days 11, 14, 17 and 28, lungs of subsets of animals were microCT imaged in vivo to assess lung metastasis progression and then euthanized for lung microscopic evaluations. Beginning at day 21, most tumor-bearing animals developed increased respiratory rates followed by decreased locomotion 1–2 days later, compared with the baseline values. Increases in respiratory rate did not correlate to surface tumor nodule counts or lung weight. Body weight measurement did not show significant changes from days 14–28 in either tumor-bearing or control animals. We propose that increases in respiratory rate (1.3–1.5 X) can be used to provide an objective benchmark to signal the need for increased clinical observations or euthanasia. Adoption of this novel humane endpoint criterion would allow investigators time to collect tissue samples prior to spontaneous morbidity or death and significantly reduce the distress of mice in the terminal stages of these metastatic lung tumor models.

Repeat pulmonary resection for lung malignancies does not affect the postoperative complications: a retrospective study

Background Although repeat pulmonary resection (RPR) for multiple lung cancer has been performed for non-small cell lung cancer and metastatic lung tumor, with the prognostic benefit detailed in several reports, the risk of RPR has not been well analyzed. Methods Patients with lung malignancies who underwent complete resection at Kanazawa Medical University between January 2010 and October 2019 were analyzed. The relationship between postoperative complications and preoperative and perioperative factors was analyzed. Postoperative complications were categorized into five grades according to the Clavien–Dindo classification system. Results A total of 41 patients who were received RPR were enrolled in this study. Primary lung tumor was found in 31 patients, and metastatic lung tumor was found in 10 patients. The postoperative complication rate of the first operation was 29%, and that of the second operation was 29%. While there were no significant factors for an increased incidence of postoperative complication in a multivariate analysis, an operation time over 2 h at the second operation tended to affect the incidence of postoperative complication (p = 0.06). Furthermore, the operation time was significantly longer (p = 0.02) and wound length tended to be longer (p = 0.07) in the ipsilateral group than in the contralateral group. The rate of postoperative complications and the length of the postoperative hospital stay were not significantly different between the two groups. Conclusion RPR is safely feasible and is not associated with an increased rate of postoperative complications, even on the ipsilateral side.

Development of novel immunotherapy based on nanoparticle co-delivering PLK1 and PD-L1 inhibitors for lung cancer treatment

Immune checkpoint inhibitors (ICIs) targeting PD-L1 and PD-1 have improved survival in a subset of patients with advanced non-small cell lung cancer (NSCLC). However, only a minority of NSCLC patients respond to ICIs, highlighting the need for superior immunotherapy. Herein, we developed a nanoparticle-based immunotherapy termed ARAC (Antigen Release Agent and Checkpoint Inhibitor) to enhance the efficacy of PD-L1 inhibitor. ARAC is nanoparticle co-delivering PLK1 inhibitor, volasertib, and PD-L1 antibody. PLK1 is a key mitotic kinase that is overexpressed in various cancers including NSCLC and drives cancer growth. Inhibition of PLK1 selectively kills cancer cells and upregulates PD-L1 expression in surviving cancer cells thereby providing opportunity for ARAC targeted delivery in a positive feedback manner. ARAC reduced effective doses of volasertib and PD-L1 antibody by 5-fold in a metastatic lung tumor model and the effect was mainly mediated by CD8 + T cells. We also observed abscopal effect of ARAC in bilateral NSCLC tumor model and achieved complete cures in some mice when incorporating immune-stimulant CpG onto ARAC. Further, ARAC was well-tolerated in non-human primates. This study highlights a rationale combination strategy to augment existing therapies by utilizing our nanoparticle platform that can load multiple cargo types at once.

Repeat pulmonary resection for lung malignancies does not affect the postoperative complications: a retrospective study

Background: Although repeat pulmonary resection (RPR) for multiple lung cancer (MLC) has been performed for non-small cell lung cancer (NSCLC) and metastatic lung tumor, with the prognostic benefit detailed in several reports, the risk of RPR has not been well analyzed.Methods: Patients with lung malignancies who underwent complete resection at Kanazawa Medical University between January 2010 and October 2019 were analyzed. The relationship between postoperative complications and preoperative and perioperative factors was analyzed. Postoperative complications were categorized into five grades according to the Clavien–Dindo classification system.Results: A total of 41 patients who were received RPR were enrolled in this study. Primary lung tumor was found in 31 patients, and metastatic lung tumor was found in 10 patients. The postoperative complication rate of the first operation was 29%, and that of the second operation was 29%. While there were no significant factors for an increased incidence of postoperative complication in a multivariate analysis, an operation time over 2 h at the second operation tended to affect the incidence of postoperative complication (p=0.06). Furthermore, the operation time was significantly longer (p=0.02) and wound length tended to be longer (p=0.07) in the ipsilateral group than in the contralateral group. The rate of postoperative complications and the length of the postoperative hospital stay were not significantly different between the two groups.Conclusion: RPR is safely feasible and is not associated with an increased rate of postoperative complications, even on the ipsilateral side.

Different Patterns of Pneumothorax in Patients With Soft Tissue Tumors Treated With Pazopanib

Background: To investigate the patterns of pneumothorax in pazopanib treatment, focusing on the positional relationship between the visceral pleura and metastatic lung tumor. Methods: We examined 20 patients with advanced soft tissue tumor who developed lung metastases before pazopanib treatment during 2012–2019. Pneumothorax was classified into two types based on the location of the metastatic lesion around the visceral pleural area before pazopanib treatment: subpleural type, within 5 mm from the pleura; central type, > 5 mm from the pleura. We investigated the rates of pneumothorax and the risk factors. Results: Overall, 5 patients experienced pneumothorax (3 subpleural and 2 central type). Cavitation preceded pneumothorax in 80% of the patients and led to connection of the cavitated cyst of the metastatic lesion to the chest cavity in a shorter term in those with the subpleural type. Conversely, a more gradual increase in cavity and sudden cyst rupture were observed in the central type. The risk factors for pneumothorax were cavitation after the initiation of pazopanib and previous intervention before pazopanib including ablation or surgery. The locations of metastatic lesion were not risk factor for the occurrence of pneumothorax.Conclusion: Pneumothorax is an adverse event of pazopanib treatment. Therefore, attention must be paid to the predisposing factors such as the formation of cavitation after pazopanib initiation and previous interventions on the lungs. Moreover, as the subpleural pneumothorax tends to occur earlier than the central type, the different time course can be anticipated based on the positional relationships of the metastatic lesions to the visceral pleura.

Repeat pulmonary resection for lung malignancies does not affect the postoperative complications: a retrospective study

Background: Although repeat pulmonary resection (RPR) for multiple lung cancer (MLC) has been performed for non-small cell lung cancer (NSCLC) and metastatic lung tumor, with the prognostic benefit detailed in several reports, the risk of RPR has not been well analyzed.Methods: Patients with lung malignancies who underwent complete resection at Kanazawa Medical University between January 2010 and October 2019 were analyzed. The relationship between postoperative complications and preoperative and perioperative factors was analyzed. Postoperative complications were categorized into five grades according to the Clavien–Dindo classification system.Results: A total of 41 patients who were received RPR were enrolled in this study. Primary lung tumor was found in 31 patients, and metastatic lung tumor was found in 10 patients. The postoperative complication rate of the first operation was 29%, and that of the second operation was 29%. While there were no significant factors for an increased incidence of postoperative complication in a multivariate analysis, an operation time over 2 h at the second operation tended to affect the incidence of postoperative complication (p=0.06). Furthermore, the operation time was significantly longer (p=0.02) and wound length tended to be longer (p=0.07) in the ipsilateral group than in the contralateral group. The rate of postoperative complications and the length of the postoperative hospital stay were not significantly different between the two groups.Conclusion: RPR is safely feasible and is not associated with an increased rate of postoperative complications, even on the ipsilateral side.