First-line penpulimab combined with paclitaxel and carboplatin for metastatic squamous non-small-cell lung cancer in China (AK105-302): a multicentre, randomised, double-blind, placebo-controlled phase 3 clinical trial.

BACKGROUND: Penpulimab is a novel programmed death (PD)-1 inhibitor. This study aimed to establish the efficacy and safety of first line penpulimab plus chemotherapy for advanced squamous non-small-cell lung cancer. METHODS: This multicentre, randomised, double-blind, placebo-controlled, phase 3 clinical trial enrolled patients with locally advanced or metastatic squamous non-small-cell lung cancer from 74 hospitals in China. Eligible participants were aged 18-75 years, had histologically or cytologically confirmed locally advanced (stage IIIb or IIIc) or metastatic (stage IV) squamous non-small-cell lung cancer, were ineligible to complete surgical resection and concurrent or sequential chemoradiotherapy, had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, did not have previous systemic chemotherapy for locally advanced or metastatic non-small-cell lung cancer, and had one or more measurable lesions according to RECIST (version 1.1). Participants were randomly assigned (1:1) to receive intravenous penpulimab 200 mg or placebo (excipient of penpulimab injection), plus paclitaxel 175 mg/m2 and carboplatin AUC of 5 intravenously on day 1 every 3 weeks for four cycles, followed by penpulimab or placebo as maintenance therapy. Stratification was done according to the PD-L1 tumour proportion score (<1% vs 1-49% vs ≥50%) and sex (male vs female). The participants, investigators, and other research staff were masked to group assignment. The primary outcome was progression-free survival assessed by the masked Independent Radiology Review Committee in the intention-to-treat population and patients with a PD-L1 tumour proportion score of 1% or more (PD-L1-positive subgroup). The primary analysis was based on the intention-to-treat analysis set (ie, all randomly assigned participants) and the PD-L1-positive subgroup. The safety analysis included all participants who received at least one dose of study drug after enrolment. This trial was registered with ClinicalTrials.gov (NCT03866993). FINDINGS: Between Dec 20, 2018, and Oct 10, 2020, 485 patients were screened, and 350 participants were randomly assigned (175 in the penpulimab group and 175 in the placebo group). Of 350 participants, 324 (93%) were male and 26 (7%) were female, and 347 (99%) were of Han ethnicity. In the final analysis (June 1, 2022; median follow-up, 24·7 months [IQR 0-41·4]), the penpulimab group showed an improved progression-free survival compared with the placebo group, both in the intention-to-treat population (median 7·6 months, 95% CI 6·8--9·6 vs 4·2 months, 95% CI 4·2-4·3; HR 0·43, 95% CI 0·33-0·56; p<0·0001) and in the PD-L1-positive subgroup (8·1 months, 5·7-9·7 vs 4·2 months, 4·1-4·3; HR 0·37, 0·27-0·52, p<0·0001). Grade 3 or worse treatment-emergent adverse events occurred in 120 (69%) 173 patients in the penpulimab group and 119 (68%) of 175 in the placebo group. INTERPRETATION: Penpulimab plus chemotherapy significantly improved progression-free survival in patients with advanced squamous non-small-cell lung cancer compared with chemotherapy alone. The treatment was safe and tolerable. Penpulimab combined with paclitaxel and carboplatin is a new option for first-line treatment in patients with this advanced disease. FUNDING: The National Natural Science Foundation of China, Shanghai Municipal Health Commission, Chia Tai Tianqing Pharmaceutical, Akeso.

PLAGL2 promotes the stemness and is upregulated by transcription factor E2F1 in human lung cancer.

This study mainly focuses on revealing the role of PLAGL2 in lung cancer stemness. In vitro and in vivo experiments were performed to evaluate the effects of PLAGL2 on lung cancer cell stemness. Mechanistic analysis using luciferase reporter and ChIP assays were implemented to reveal the underlying mechanisms. The transcriptional factor E2F1 transcriptionally activated PLAGL2 expression via directly binding to PLAGL2 promoter in lung cancer cells. Moreover, PLAGL2 promoted the stemness of lung cancer cells dependent on E2F1-mediated transcriptional activation. This study provides a potential target for lung cancer progression.

[Clinical features of severe acute respiratory syndrome coronavirus 2 Omicron variant infection in children: an analysis of 201 cases]. / 201ä¾‹å„¿ç«¥æ–°åž‹å† çŠ¶ç— æ¯’Omicronå˜å¼‚æ ªæ„ŸæŸ“çš„ä¸´åºŠç‰¹å¾åˆ†æž.

OBJECTIVES: To study the clinical features of children with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant infection. METHODS: A retrospective analysis was performed on the medical data of 201 children with coronavirus disease 2019 (COVID-19) who were hospitalized and diagnosed with SARS-CoV-2 Omicron variant infection in Quanzhou First Hospital from March 14 to April 7, 2022. Among the 201 children, there were 34 children with asymptomatic infection and 167 with symptomatic infection. The two groups were compared in terms of clinical features, results of experimental examinations, and outcome. RESULTS: Of all the 201 children, 161 (80.1%) had a history of exposure to COVID-19 patients and 132 (65.7%) had a history of COVID-19 vaccination. Among the 167 children with symptomatic infections, 151 had mild COVID-19 and 16 had common COVID-19, with no severe infection or death. Among the 101 children who underwent chest CT examination, 16 had ground glass changes and 20 had nodular or linear opacities. The mean time to nucleic acid clearance was (14±4) days for the 201 children with Omicron variant infection, and the symptomatic infection group had a significantly longer time than the asymptomatic infection group [(15±4) days vs (11±4) days, P<0.05]. The group vaccinated with one or two doses of COVID-19 vaccine had a significantly higher positive rate of IgG than the group without vaccination (P<0.05). The proportions of children with increased blood lymphocyte count in the symptomatic infection group was significantly lower than that in the asymptomatic infection group (P<0.05). Compared with the asymptomatic infection group, the symptomatic infection group had significantly higher proportions of children with increased interleukin-6, increased fibrinogen, and increased D-dimer (P<0.05). CONCLUSIONS: Most of the children with Omicron variant infection have clinical symptoms, which are generally mild. The children with symptomatic infection are often accompanied by decreased or normal blood lymphocyte count and increased levels of interleukin-6, fibrinogen, and D-dimer, with a relatively long time to nucleic acid clearance. Some of them had ground glass changes on chest CT.

Serum neuron-specific enolase: A promising biomarker of silicosis.

BACKGROUND: Silicosis is a type of chronic pulmonary fibrosis caused by long-term inhalation of silica dust particles. There has been no ideal biomarker for the diagnosis and differential diagnosis of silicosis until now. Studies have found that elevated neuron-specific enolase (NSE) concentration in the serum of silicosis patients is helpful for diagnosis and severity assessment of the disease. However, the number of cases in these studies was not enough to arouse attention. AIM: To investigate the clinical significance of serum NSE in the diagnosis and staging of silicosis. METHODS: From January 2017 to June 2019, 326 cases of silicosis confirmed in Quanzhou First Hospital Affiliated to Fujian Medical University were included in the silicosis group. A total of 328 healthy individuals or medical patients without silicosis were included in the control group. Serum NSE concentrations of all subjects were determined by electrochemical luminescence. RESULTS: There were no significant differences in sex, age, smoking index and complications between the silicosis and control groups. The mean serum NSE concentration was 26.57 ± 20.95 ng/mL in the silicosis group and 12.42 ± 2.68 ng/mL in the control group. The difference between the two groups was significant (U = 15187, P = 0.000). Among the 326 patients with silicosis, 103 had stage I silicosis, and the mean serum NSE concentration was 15.55 ± 6.23 ng/mL. The mean serum NSE concentration was 21.85 ± 12.05 ng/mL in 70 patients with stage II silicosis. The mean serum NSE concentration was 36.14 ± 25.72 ng/mL in 153 patients with stage III silicosis. Kruskal-Wallis H test suggested that the difference in serum NSE concentration in silicosis patients in the three groups was significant (H = 130.196, P = 0.000). Receiver operating characteristic curve analysis indicated that the area under the curve was 0.858 (95% confidence interval: 0.828-0.888; P = 0.000). When the NSE concentration was 15.82 ng/mL, the Jorden index was the largest, the sensitivity was 72%, and the specificity was 90%. CONCLUSION: Serum NSE concentration may be a promising biomarker for the diagnosis and assessment of severity of silicosis.

Enhanced Antitumor Efficacy of Docetaxel-Loaded Monomethoxy Poly(ethylene glycol)-Poly(D, L-lactide-co-glycolide) Amphiphilic Copolymer Against Non-Small Cell Lung Cancer.

Lung cancer, including non-small cell lung cancer (NSCLC), is one of the mainly diagnosed cancer and becomes as the leading cause of death induced by cancer worldwide. Conventional antitumor drugs, such as docetaxel (DTX), exhibit excellent therapeutic efficacy, however, serious adverse effects have occurred due to their side effect, which limits their clinical use. Therefore, it is necessary to develop the novel drug delivery systems for antitumor therapy. Herein, we successfully developed mPEG-PLGA nanoparticles for the encapsulation of the clinically relevant drug DTX (NP-DTX) via an improved green method by emulsion. The mPEG-PLGA nanoparticles could target A549 and increased the cytotoxicity of DTX, NP-DTX showed significantly enhanced antitumor effect and therapeutic efficacy on NSCLC in vitro and in vivo. Compared with free DTX, NP-DTX significantly inhibited tumor growth and reduced the side effect of DTX. Therefore, we have shown a promising strategy to construct a novel therapeutic platform for targeted anti-tumor drug delivery.

The diagnostic value of D-dimer with simplified Geneva score (SGS) pre-test in the diagnosis of pulmonary embolism (PE).

BACKGROUND: Pulmonary embolism (PE) is the third most common cardiovascular syndrome with an average annual incidence rate of 77 per 100,000 population in the worldwide. The diagnose algorithms for suspected PE are generally include clinical scoring assessment and plasma D-dimer evaluation, patients with high risk of PE require computed tomographic pulmonary angiogram (CTPA) detection for confirmation. METHODS: In this retrospective analysis, 1035 patients with suspected PE were recruited. All the patients were clinically received simplified Geneva score (SGS) pre-test, determination of plasma D-dimer level, and CTPA detection. All enrolled patients were grouped according to the CTPA results: PE patients and non-PE patients. Then, receiver operating characteristic (ROC) curve were constructed to determine the optimal D-dimer cutoff point value which is based on Yonden's index (YI). RESULTS: 294 (28.4%) patients were confirmed with PE and 741(71.6%) individuals were regarded as non-PE cases by CTPA detection. Using the SGS pre-test, 829 (80.1%) patients were classified PE-unlikely (SGS ≤ 2) and 206 (19.9%) patients were PE-likely (SGS ≥ 3). Patients with D-dimer levels above 1.96 mg/L had a significant risk to suffer from PE (area under curve (AUC), 0.707; 95% CI, 0.678-0.735; p < 0.05). Meanwhile, in patients with SGS ≥ 3, the D-dimer cutoff point value moved to 2.2 mg/L (AUC, 0.644; 95% CI, 0.574-0.709; p < 0.05). CONCLUSION: D-dimer test in combination with SGS pre-test could improve the accuracy of PE diagnosis. Patients with D-dimer levels over 1.96 mg/L (4 times of the normal level) have a significant risk for PE. In patients with SGS ≥ 3, the D-dimer cutoff point concentration for PE risk moves to the levels of 2.2 mg/L.

Preliminary study on the clinical significance of kinesin Kif18a in nonsmall cell lung cancer: An analysis of 100 cases.

The aim of this study was to investigate the expression of Kif18A in cancerous and paracancerous tissues from 100 patients with nonsmall cell lung cancer (NSCLC).This was a prospective study of 100 patients with pathologically confirmed NSCLC (adenocarcinoma and squamous cell carcinoma [SCC], n = 50/group) that were operated at the Quanzhou First Hospital Affiliated to Fujian Medical University between June 2015 and December 2016. Kif18A protein expression in cancerous and paracancerous normal tissues was detected by western blot and immunohistochemistry.The expression of the Kif18A protein was higher in adenocarcinoma and SCC tissues than in the corresponding paracancerous normal tissues. The expression of the Kif18A protein was higher in highly differentiated tumors, in patients with lymph node metastasis (vs no lymph node metastasis), adenocarcinoma, and in stage III NSCLC. There were no associations between Kif18A expression and age, gender, and pathologic type.The expression of the Kif18A protein by immunohistochemistry was higher in NSCLC tissues than in normal tissues, and was associated with tumor differentiation, lymph node metastasis, and TNM staging. These results could provide a theoretical basis for novel molecular targeted therapies against NSCLC.

Correlated low IGF2BP1 and FOXM1 expression predicts a good prognosis in lung adenocarcinoma.

IGF2BP1 and FOXM1 are shown to be critical in the regulation of caner progression. However, the prognostic value of IGF2BP1 in lung adenocarcinoma and its relationship with FOXM1 still remains unclear. In this study, the expression and biological significance of both IGF2BP1 and FOXM1 were evaluated in 188 lung adenocarcinoma, at mRNA and protein levels. We showed that mRNA and protein levels of IGF2BP1 and FOXM1 were upregulated in lung adenocarcinoma compared to adjacent non-cancerous tissues. High IGF2BP1 expression was correlated with a poor prognosis for lung adenocarcinoma patients. Moreover, IGF2BP1 expression was positively associated with FOXM1 expression. Meanwhile, the findings indicated that low IGF2BP1 combined with low FOXM1 expression, was negatively correlated with pathological stage and lymph node metastasis, predicted good outcomes for lung adenocarcinoma patients. Additionally, low IGF2BP1 and FOXM1 expression status, is an independent prognostic factor for lung adenocarcinoma after surgical resection. We demonstrate that low IGF2BP1 and FOXM1 expression can serve as a potential factor for the clinical diagnosis and prognosis of lung adenocarcinoma, and targeted inhibition of IGF2BP1 and FOXM1 might be an alternative strategy for the management of lung adenocarcinoma.

Clinical features and therapeutic options in non-small cell lung cancer patients with concomitant mutations of EGFR, ALK, ROS1, KRAS or BRAF.

BACKGROUND: Although oncogenic driver mutations were thought to be mutually exclusive in non-small cell lung cancer (NSCLC), certain tumors harbor co-occurring mutations and represent a rare molecular subtype. The evaluation of the clinical features and therapeutic response associated with this NSCLC subtype will be vital for understanding the heterogeneity of treatment response and improving the management of these patients. METHODS: This retrospective study included 3774 samples from patients diagnosed with NSCLC. All samples were screened for EGFR, ALK, ROS1, KRAS, and BRAF mutation using the amplification-refractory mutation system. The relationship between concomitant driver mutations and clinicopathologic characteristics, and patient clinical outcomes were evaluated. RESULTS: Sixty-three (1.7%) samples had more than one driver gene mutation. Among these, 43 were coalterations with an EGFR mutation, 20 with an ALK rearrangement, and eight with an ROS1 rearrangement. Except for ROS1 concomitant mutations that were more frequent in male patients (87.5%, P = 0.020), the clinicopathological features of the concomitant mutation patients were not significantly different from those harboring a single EGFR, ALK, or ROS1 mutation. Furthermore, first-line EGFR-TKI treatment did not significantly improve the progression-free survival (PFS) of patients harboring EGFR concomitant mutation, compared to patients harboring a single EGFR mutation. However, for EGFR concomitant mutation patients, TKI therapy was more effective than chemotherapy (median PFS of 10.8 vs 5.2 months, P = 0.023). Lastly, KRAS mutations did not influence the EGFR-TKI therapy treatment effect. CONCLUSION: In this study, concomitant mutations were found in 1.7% of the NSCLC. EGFR-TKI therapy was more effective than chemotherapy for patients harboring EGFR concomitant mutation, and ROS1 concomitant mutations were more frequent in male patients. For patients harboring coalterations with an ALK or ROS1 rearrangement, we should be cautious when considering the therapeutic options.

Sulforaphane suppresses EMT and metastasis in human lung cancer through miR-616-5p-mediated GSK3ß/ß-catenin signaling pathways.

Sulforaphane is a common antioxidant selectively abundant in cruciferous plants, which exhibits effective anti-cancer actions in control of tumorigenesis or progression of various cancers. A recent study has shown that sulforaphane attenuates the EGFR signaling pathway in non-small cell lung cancer (NSCLC), suggesting its potential anti-metastatic effects. In this study we assessed the involvement of sulforaphane and miR-616-5p in epithelial-mesenchymal transition (EMT) and NSCLC metastasis. Sulforaphane suppressed the cell proliferation in human NSCLC cell lines H1299, 95C and 95D with IC50 values of 9.52±1.23, 9.04±1.90 and 17.35±2.03 µmol/L, respectively. At low concentrations (1-5 µmol/L), sulforaphane dose-dependently inhibited the migration and invasion of 95D and H1299 cells with relatively high metastatic potential. The anti-metastatic action of sulforaphane was confirmed in 95D and H1299 cell xenografts in vivo. In fresh NSCLC tissue samples from 179 patients, miR-616-5p levels were upregulated in late-stage NSCLCs, and strongly correlated with risk of NSCLC recurrence and metastasis. Consistent with the clinic observation, miR-616-5p levels in the 3 NSCLC cell lines were correlated with their metastatic ability, and were decreased by sulforaphane treatment. Silencing miR-616-5p markedly suppressed the migration and invasion of 95D cells in vitro and NSCLC metastasis in vivo. Further studies revealed that miR-616-5p directly targeted GSK3ß and decreased its expression, whereas sulforaphane decreased miR-616-5p levels by histone modification, and followed by inactivation of the GSK3ß/ß-catenin signaling pathway and inhibition of EMT, which was characterized by loss of epithelial markers and acquisition of a mesenchymal phenotype in NSCLC cells. Our findings suggest that sulforaphane is a potential adjuvant chemotherapeutic agent for the prevention of NSCLC recurrence and metastasis, and miR-616-5p can be clinically utilized as a biomarker or therapeutic target to inhibit metastasis.

Seed Oil of Brucea javanicaInduces Cell Cycle Arrest and Apoptosis via Reactive Oxygen Species-Mediated Mitochondrial Dysfunction in Human Lung Cancer Cells.

Brucea javanica oil (BJO), a traditional herbal medicine extracted from the seeds of B. javanica, has been clinically used to treat non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) in combination with chemotherapy or radiotherapy in China. However, how BJO exerts this antitumor effect is still largely unknown. Here, effects of BJO on the growth of NSCLC and SCLC cell lines were investigated by the 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenytetrazolium Bromide (MTT) assay, and the results showed that BJO inhibited the proliferation of A549 cells (NSCLC) and H446 cells (SCLC). Further studies revealed that BJO induced G0/G1 arrest partly via regulating p53 and cyclin D1 in these two cell lines. BJO also has pro-apoptotic effect on H446 and A549 cells through mitochondria/caspase-mediated pathway, which was initiated by the accumulation of intracellular reactive oxygen species (ROS). These findings thus revealed the molecular mechanisms underlying the antitumor effect of BJO on SCLC and NSCLC, which may benefit the further clinical application of BJO.

[Transbronchoscopic balloon detection and selective bronchial occlusion for intractable pneumothorax].

OBJECTIVE: To evaluate the effect, complications and safety of transbronchoscopic balloon detection (TBD) and selective bronchus occlusion (SBO) for intractable pneumothorax. METHODS: Forty cases of pneumothorax from 5 teaching hospitals in Fujian province were included for this study. TBD was performed in all the 40 cases for whom chest tube drainage had lasted for more than 7days but failed to close the pleura fistulae. Bronchi leading to pleura fistulae (the target bronchus) were detected by balloon-catheter (Olympus B7-2C) through bronchoscope. After the target bronchus was located, SBO procedures were performed. Autologous blood (20 ml to 30 ml) was injected into the target bronchus and followed by thrombin solution (1000 U) through balloon-catheter. In 10 cases, oxygenation and pulse rate were recorded by pulse-oximeter (Healthdyne 920M) during TBD and SBO. Another 10 cases undergoing bronchoscope without performing TBD and SBO served as the controls. Thorax CT, white blood cell count, neutrophil count and body temperature were measured after SBO. RESULTS: Bronchi leading to pleura fistulae were located by TBD in 34 out of the 40 cases. Air leakage was stopped after the first occlusion in 30 cases, but 5 of which underwent a second occlusion because of recurrence in 72 h. Of the 5 cases, air leakage was stopped in 3, and surgery was required in 2. Taken together, 28 of the 34 cases were cured by SBO and 6 failed. There were no statistically differences between the treatment group and the control group in oxygenation changes during TBD and SBO procedures. In 10 cases thorax CT scan was followed up in 7 days after SBO, and no obstructive atelectasis was found. In 20 cases peripheral white blood cell count was followed up 72 hours after SBO. Leukocytosis (> 10.0 x 10(9)/L) was found in 3, in which pulmonary infection was diagnosed, and leukocytosis was present in 2 cases before the procedure. Five patients (5/34) experienced mild to moderate fever, which resolved quickly. CONCLUSION: TBD/SBO are safe and effective procedures for intractable pneumothorax.