Savolitinib versus crizotinib for treating MET positive non-small cell lung cancer.

BACKGROUND: The c-MET protein, encoded by the mesenchymal-epithelial transition factor (MET) gene, can regulate cell proliferation, migration and invasion. Studies have shown that it is one of the essential driver genes for non-small cell lung cancer (NSCLC). Currently, several clinical studies have carried out objective assessments on the efficacy and safety of different types of MET tyrosine kinase inhibitors (TKIs). However, direct cross-sectional comparisons between different agents are still not available. METHODS: Our study was a single-center retrospective clinical study, which collected the data from MET positive NSCLC patients treated with MET TKIs at the Lung Cancer Center of Peking Union Medical College Hospital. We explored the efficacy and safety of crizotinib versus savolitinib in patients with METex14 skipping and MET amplification, separately. RESULTS: Patients with METex14 skipping (median PFS = 10.7 months) had a better clinical response to MET TKIs than MET amplification patients (median PFS = 4.1 months). In the METex14 skipping subgroup, savolitinib did not show better survival benefit with significance than crizotinib (p > 0.05). In the MET amplification subgroup, savolitinib (median PFS = 7.1 months) demonstrated a better progression-free survival benefit than crizotinib (median PFS = 1.4 months), p = 0.05. The most common adverse effects of both MET TKIs were peripheral edema (41.2%), gastrointestinal reactions (23.5%), and liver injury (14.7%). The incidence rate of peripheral edema was higher in savolitinib than crizotinib. CONCLUSION: In METex14 skipping NSCLC patients, the efficacy of savolitinib and crizotinib did not show significant difference. In MET amplification patients, savolitinib showed better efficacy than crizotinib.

Incidence rate and treatment strategy of immune checkpoint inhibitor mediated hepatotoxicity: A systematic review.

Background: A hepatic adverse event (HAE) is defined as a liver injury that occurs following immune checkpoint inhibitor (ICI) administration in oncology Patients. Immune-mediated hepatotoxicity (IMH) is a type of HAE directly caused by ICI and is associated with immune system hyperactivation. HAE incidence varies across different clinical studies. This study aimed to explore the risk factors of HAE and establish a personalized IMH treatment strategy. Methods: Randomized controlled trials (RCTs) on ICIs and case reports related to IMH were collected and summarized separately. Meta-analysis was performed using Review Manager (version 5.0), whereas correlation analysis and linear regression were performed using SPSS (version 24.0) to evaluate any correlations between the two variables. Results: Overall, 36 RCTs containing 18,515 patients and 39 case reports met our inclusion criteria. The ICI administration increased the HAE risk (risk ratio [RR] â€‹= â€‹1.40) as well as severe HAE (RR â€‹= â€‹2.55). The overall HAE incidence and severe incidence were about 15.3% and 4.3%, respectively. Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors have a higher incidence of HAE than programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors. Finally, we found a positive correlation between the onset time of IMH and the recovery time of liver injury. Conclusions: ICI administration increased the incidence risk of HAE, especially in patients treated with CTLA-4 inhibitors. Regarding IMH treatment, the glucocorticoid dosage must be individually reduced according to the severity and onset time of HAE.

Corrigendum: Peripheral blood lymphocyte subsets predict the efficacy of immune checkpoint inhibitors in non- small cell lung cancer.

[This corrects the article DOI: 10.3389/fimmu.2022.912180.].

Peripheral Blood Lymphocyte Subsets Predict the Efficacy of Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer.

Background: Non-small cell lung cancer (NSCLC) has entered the era of immunotherapy. However, only partial patients were able to benefit from immune checkpoint inhibitors (ICIs). Currently, biomarkers for predicting patients' response to ICIs are primarily tumor tissue dependent and have limited accuracy. There is an urgent need to explore peripheral blood-based biomarkers to predict the efficacy and safety of ICI therapy. Methods: To explore the correlation between lymphocyte subsets and the efficacy and safety of ICIs, we retrospectively analyzed peripheral blood lymphocyte subsets and survival prognosis data of 136 patients with stage IV NSCLC treated with ICIs. Results: The two factors that had the greatest impact on the prognosis of patients with NSCLC treated with ICIs were CD4+CD45RA- T cell (HR = 0.644, P = 0.047) and CD8+ T/lymphocyte (%) (HR = 1.806, P = 0.015). CD4+CD45RA- T cell showed excellent predictive efficacy (AUC = 0.854) for ICIs monotherapy, with a sensitivity of 75.0% and specificity of 91.7% using CD4+CD45RA- T cell >311.3 × 106/L as the threshold. In contrast, CD8+ T/lymphocyte (%) was only associated with the prognosis but had no predictive role for ICI efficacy. CD4+ T cell and its subsets were significantly higher in patients with mild (grades 1-2) immune-related adverse events (irAEs) than those without irAEs. CD8+CD38+ T cell was associated with total irAEs and severe (grades 3-4) irAEs but was not suitable to be a predictive biomarker. Conclusion: Peripheral blood CD4+CD45RA- T cell was associated with the prognosis of patients with NSCLC applying ICIs, whereas CD8+CD38+ T cell was associated with irAEs and severe irAEs.

Real-World Data of Different Immune Checkpoint Inhibitors for Non-Small Cell Lung Cancer in China.

Background: Patients treated with immunotherapy in the real-world may have significantly different responses to those meeting inclusion criteria for random controlled clinical studies. There is a partial overlap in approved indications for the use of the different immune checkpoint inhibitors (ICIs) currently available. A comprehensive assessment of the efficacy, safety and economic effects of various ICIs is a problem that clinicians need to address. Methods: Analyzed real-world data was collected from non-small cell lung cancer (NSCLC) patients who were treated with ICIs from hospitalized patients in the Lung Cancer Center of Peking Union Medical College Hospital between 2018 and 2021. The objectives were to evaluate the efficacy and safety of different ICIs for the treatment of NSCLC in China and to investigate the factors affecting their curative effects. Results: Overall, 351 patients were included in the retrospective study. The median PFS for the NSCLC patient cohort treated with medication regimens that included ICIs was 9.5 months, with an ORR of 47.3%. There were no significant discrepancies in efficacy and safety between the different ICIs administered. Factors that had the greatest impact on the efficacy of ICIs were the disease stage, ECOG-PS scores and treatment lines. Gender, age, smoking history, PD-L1 TPS expression, history of targeted therapy and irAEs all had a degree of influence on patient prognosis. Conclusions: The study reports the experience of real-world usage of ICIs for the treatment of NSCLC patients in China. The results were generally consistent with those of clinical trials, while the efficacy and safety of different ICIs exhibited no statistically significant differences. Therefore, physicians can make a comprehensive choice based on the indications and cost of different ICIs and the preferences of patients.

Second primary tumor after immune checkpoint inhibitor therapy: A case report.

Immune checkpoint inhibitors (ICIs) are used to treat many types of cancers. However, the effect of ICIs on second primary tumors is still unclear. Some studied have concluded that ICIs could reduce the incidence of second primary tumors, while others found an increased overall risk of second primary cancer after the introduction of ICIs to the treatment of melanoma. Here, we report the case of a patient with advanced non-small cell lung cancer (NSCLC) who was treated with ICIs in combination with antiangiogenic drugs, and subsequently developed a second primary tumor in the context of a favorable curative effect of the primary lung cancer. From this case, we know that good efficacy of ICIs for a primary tumor does not mean that a second primary tumor will never develop, which reminds clinicians to consider the possibility of a second primary tumor rather than treating it directly as disease progression.

Pyrotinib-associated acute kidney injury: A case report.

Pyrotinib is a novel human epidermal growth factor receptor 2 (HER2) tyrosine kinase inhibitor (TKI). Previous studies of pyrotinib showed that it is mainly excreted through the gastrointestinal tract rather than the kidneys, with little effect on renal function. Here, we report a patient with HER2-mutated nonsmall cell lung cancer who developed acute kidney injury (AKI) after receiving pyrotinib treatment. This case alerts clinicians to the adverse renal effects of HER2 TKIs, especially in patients with chronic kidney disease. However, tumor treatment should remain a priority in clinical practice. In this case, AKI induced by pyrotinib was reversible. Therefore, there is no need to restrict the use of HER2 TKIs due to concerns about possible nephrotoxicity.

Stem cell therapy for chronic obstructive pulmonary disease.

ABSTRACT: Chronic obstructive pulmonary disease (COPD), characterized by persistent and not fully reversible airflow restrictions, is currently one of the most widespread chronic lung diseases in the world. The most common symptoms of COPD are cough, expectoration, and exertional dyspnea. Although various strategies have been developed during the last few decades, current medical treatment for COPD only focuses on the relief of symptoms, and the reversal of lung function deterioration and improvement in patient's quality of life are very limited. Consequently, development of novel effective therapeutic strategies for COPD is urgently needed. Stem cells were known to differentiate into a variety of cell types and used to regenerate lung parenchyma and airway structures. Stem cell therapy is a promising therapeutic strategy that has the potential to restore the lung function and improve the quality of life in patients with COPD. This review summarizes the current state of knowledge regarding the clinical research on the treatment of COPD with mesenchymal stem cells (MSCs) and aims to update the understanding of the role of MSCs in COPD treatment, which may be helpful for developing effective therapeutic strategies in clinical settings.

Treatment of steroid-resistant checkpoint inhibitor pneumonitis with pirfenidone: A case report.

With the increased use of immune checkpoint inhibitors (ICIs) in lung cancer, which are of great benefit to patients, more and more immune-related adverse events (irAEs) are being reported. Checkpoint inhibitor pneumonitis (CIP) is one of the most challenging adverse events, which pose a huge challenge to clinical diagnosis and treatment, and its incidence in the real world is greatly underestimated. Currently, the treatment of CIP mainly depends on the use of glucocorticoids. As for steroid-resistant CIP, there is no unified standardized treatment strategy. Herein, we report a case of steroid-resistant CIP induced by pembrolizumab in a patient with advanced non-small cell lung cancer (NSCLC), in which their symptoms were successfully controlled with pirfenidone.

Application of Immune Checkpoint Inhibitors in Solid Organ Transplantation Recipients: A Systematic Review.

BACKGROUND: Solid organ transplantation (SOT) is a treatment method for end-stage organ diseases and improve their life quality, while using long-term immunosuppressant drugs (ISD) is needed to suppress the function of the immune system. Immune checkpoint inhibitors (ICIs) are a class of anti-tumor drugs that kill tumors by activating the autoimmune system. The primary objective of our systematic review is to investigate the risk factors for organ rejection and the efficacy of ICIs in solid organ transplantation recipients (SOTRs). METHODS: We searched four databases to find relevant articles up to January 2021. A total of 61 articles involving 106 SOTRs met the screening criteria and were included in our systematic review. The collected data were statistical described, and the risk factors were analyzed by logistic regression. RESULTS: Forty-four patients (41.5%) developed host-versus-graft response (HVGR) after ICIs. mTOR inhibitors (pre-ICIs) (p = 0.069, OR = 0.377, 95% CI 0.132-1.078) and calcineurin inhibitors (post-ICIs) (p = 0.056, OR = 0.375, 95%CI 0.137-1.025) may help reduce the incidence of HVGR. Hormones (pre-ICIs) (p = 0.026, OR = 3.150, 95%CI 1.150-8.628) and anti-metabolites (pre-ICIs) (p = 0.022, OR = 3.214, 95%CI 1.185-8.720) may adversely affect the efficacy of ICIs. Only 35.6% of patients both responded well to ICIs treatment and did not develop HVGR. CONCLUSIONS: Our systematic review summarizes the use of ICIs in SOTRs and evaluates the efficacy of ICIs and the risk factors that induce HVGR. Through risk factor analysis, we found that mTOR inhibitors and calcineurin inhibitors may help to reduce the occurrence of HVGR; hormones and anti-metabolic drugs may have adverse effects on the efficacy of ICIs. In addition, there is a contradictory relationship between the occurrence of HVGR and the efficacy of ICIs.

Dopamine receptor agonists ameliorate bleomycin-induced pulmonary fibrosis by repressing fibroblast differentiation and proliferation.

Idiopathic pulmonary fibrosis (IPF) is the most common fatal interstitial lung disease, with limited therapeutic options. The abnormal and uncontrolled differentiation and proliferation of fibroblasts have been confirmed to play a crucial role in driving the pathogenesis of IPF. Therefore, effective and well-tolerated antifibrotic agents that interfere with fibroblasts would be an ideal treatment, but no such treatments are available. Remarkably, we found that dopamine (DA) receptor D1 (D1R) and DA receptor D2 (D2R) were both upregulated in myofibroblasts in lungs of IPF patients and a bleomycin (BLM)-induced mouse model. Then, we explored the safety and efficacy of DA, fenoldopam (FNP, a selective D1R agonist) and sumanirole (SMR, a selective D2R agonist) in reversing BLM-induced pulmonary fibrosis. Further data showed that DA receptor agonists exerted potent antifibrotic effects in BLM-induced pulmonary fibrosis by attenuating the differentiation and proliferation of fibroblasts. Detailed pathway analysis revealed that DA receptor agonists decreased the phosphorylation of Smad2 induced by TGF-ß1 in primary human lung fibroblasts (PHLFs) and IMR-90 cells. Overall, DA receptor agonists protected mice from BLM-induced pulmonary fibrosis and may be therapeutically beneficial for IPF patients in a clinical setting.

Suppressing Sart1 to modulate macrophage polarization by siRNA-loaded liposomes: a promising therapeutic strategy for pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic and diffuse form of interstitial lung disease of unknown etiology with a fatal outcome. Although various strategies for IPF have been developed over the last few decades, no significant positive impact on the prognosis of IPF has been observed. According to the current paradigm, macrophages have been recognized to play a significant role in IPF pathogenesis. Here, we report a potential nanomedicine-based gene therapy for IPF based on regulate macrophage polarization. Method: C57BL/6 mice were obtained and used to establish a bleomycin (BLM)-induced pulmonary fibrosis animal model, and Sart1 siRNA-loaded liposomes were designed for in vivo experiment. The experimental animals were administered BLM intratracheally on day 0 and treated with Sart1 siRNA on days 14 and 17. In the in vitro experiment, we further examined the function of Sart1 in macrophages. Results: Our data indicated that the liposomes could passively target the fibrotic area in the lung and efficiently accumulate in macrophages. The suppression of Sart1 by siRNA-loaded liposomes significantly protected mice against BLM-induced lung injury and fibrosis, which was attributed to attenuated M2 macrophage infiltration in the lung. Conclusion: Our study provides a valuable reference for modulating macrophage polarization and a promising strategy for the treatment of pulmonary fibrosis in clinical settings.

Advanced pneumonic type of lung adenocarcinoma: survival predictors and treatment efficacy of the tumor.

PURPOSE: To retrospectively explore the survival predictors and treatment efficacy of advanced pneumonic-type lung adenocarcinoma (P-ADC). METHODS: Retrospective analysis of clinical data and survival follow-up was undertaken on 41 patients with advanced P-ADC from January 1, 2009, to April 30, 2019. Analysis on tumor biomarkers such as carcinoembryonic antigen (CEA), neuron-specific enolase (NSE), and the cytokeratin-19-fragment (Cyfra21-1) were undertaken. The patients in this study were divided into three groups based on usage of tyrosine kinase inhibitor (TKI): TKI therapy group (including combination with chemotherapy), non-TKI therapy group (chemotherapy alone), and palliative care group. RESULTS: More than half of the patients had higher levels of tumor biomarkers and the incidence of NSE was highest (81.8%), followed by CEA (74.4%) and Cyfra21-1 (74.1%). All patients had abnormal findings on chest computed tomography and with adenocarcinoma pathology. The overall survival (OS) time was 10.4 months in TKI group, 8.8 months in the non-TKI group, and 2.1 months in the palliative care group. Patients with higher level of serum Cyfra21-1 had insignificantly shorter survival time compared to those with normal Cyfra21-1 (p = 0.067). TKI therapy and non-TKI therapy provided a better prognosis prediction compared to palliative care. TKI therapy improved prognosis compared to non-TKI therapy. The comprehensive based TKI therapy provided improved OS vs the non-TKI therapy. CONCLUSION: TKI-based therapy could improve the prognosis and OS for advanced P-ADC. This study recommends the analysis of EGFR mutations for all patients with advanced P-ADC.

Indirubin alleviates bleomycin-induced pulmonary fibrosis in mice by suppressing fibroblast to myofibroblast differentiation.

BACKGROUND AND OBJECTIVE: Idiopathic pulmonary fibrosis (IPF) is a chronic fibrosing interstitial lung disease with a poor prognosis. Indirubin, a compound obtained from indigo-bearing plants or mollusks of the family Muricidae, has various bioactivities, including anti-tumor activity and anti-inflammation effect. However, whether indirubin could mediate its therapeutic effects on bleomycin (BLM)-induced pulmonary fibrosis has not been addressed. METHODS: The impacts of indirubin on bleomycin (BLM)-induced pulmonary fibrosis were evaluated by pathological staining, western blot, RT-PCR and immunofluorescent staining. The effects of indirubin on fibroblast differentiation and related signaling were next investigated to demonstrate the underlying mechanisms. RESULTS: The results indicated that indirubin-treated mice exhibited a definitively improved survival rate than that of the BLM-induced mice in a dose-depend manner. Additionally, administration of indirubin significantly alleviated inflammatory cells infiltration in BLM mice. Importantly, indirubin provided protection for mice against BLM-induced pulmonary fibrosis as manifested by the attenuating expression of fibrotic hallmarks, including fibronectin, collagen I and α-smooth muscle actin (α-SMA). Subsequently, we providedin vitro evidence revealing that indirubin suppressed fibroblast to myofibroblast differentiation by repressed TGF-ß/Smad signaling in a dose-dependent manner. Notably, our data showed that indirubin seemed to be safe in mice and fibroblasts. CONCLUSION: Overall, indirubin could protect the mice against BLM-induced pulmonary fibrosis by alleviated fibroblast differentiation and may be therapeutically beneficial for IPF patients.

Scutellarein inhibits BLM-mediated pulmonary fibrosis by affecting fibroblast differentiation, proliferation, and apoptosis.

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a progressive and irreversible interstitial pulmonary disease that has a poor prognosis. Scutellarein, which is extracted from the traditional Chinese medicine Erigeron breviscapus, is used to treat a variety of diseases; however, the use of scutellarein for the treatment of pulmonary fibrosis and the related mechanisms of action have not been fully explored. METHODS: This study was conducted using a well-established mouse model of pulmonary fibrosis induced by bleomycin (BLM). The antifibrotic effects of scutellarein on histopathologic manifestations and fibrotic marker expression levels were examined. The effects of scutellarein on fibroblast differentiation, proliferation, and apoptosis and on related signaling pathways were next investigated to demonstrate the underlying mechanisms. RESULTS: In the present study, we found that scutellarein alleviated BLM-induced pulmonary fibrosis, as indicated by histopathologic manifestations and the expression levels of fibrotic markers. Further data demonstrated that the ability of fibroblasts to differentiate into myofibroblasts was attenuated in scutellarein-treated mice model. In addition, we obtained in vitro evidence that scutellarein inhibited fibroblast-to-myofibroblast differentiation by repressing TGF-ß/Smad signaling, inhibited cellular proliferation by repressing PI3K/Akt signaling, and increased apoptosis of fibroblasts by affecting Bax/Bcl2 signaling. DISCUSSION: In general, scutellarein might exert therapeutic effects on pulmonary fibrosis by altering the differentiation, proliferation, and apoptosis of fibroblasts. Although scutellarein has been demonstrated to be safe in mice, further studies are required to investigate the efficacy of scutellarein in patients with IPF.

A crucial role of endoplasmic reticulum stress in cellular responses during pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH), a chronic and progressive disease of the lung vascular system, is characterized by vasculopathy in the pulmonary arterioles, especially in endothelial cells and pulmonary vascular smooth cells. Several mechanisms are involved in PAH occurrence and development, and all are characterized by excessive pulmonary vasoconstriction and abnormal vascular remodeling, which leads to a progressive resistance to blood flow and an increase in pulmonary artery pressure. Recent studies have shown that endoplasmic reticulum (ER) stress is implicated in the pathophysiology of PAH. In this review, we highlight the effect of ER stress on the proliferation and apoptosis of endothelial cells and pulmonary vascular smooth muscle cells, and discuss the feasibility of targeting unfolded protein response components as a strategy to reverse or alleviate the progression of PAH.

Update on the role of endoplasmic reticulum stress in asthma.

Asthma has long attracted extensive attention because of its recurring symptoms of reversible airflow obstruction, airway hyperresponsiveness (AHR) and airway inflammation. Although accumulating evidence has enabled gradual increases in understanding of the pathogenesis of asthma, many questions regarding the mechanisms underlying asthma onset and progression remain unanswered. Recent advances delineating the potential functions of endoplasmic reticulum (ER) stress in meeting the need for an airway hypersensitivity response have revealed critical roles of unfolded protein response (UPR) pathways in asthma. In this review, we highlight the roles of ER stress and UPR activation in the etiology, pathogenesis and treatment of asthma and discuss whether the related mechanisms could be targets for therapeutic strategies.

Curdione ameliorates bleomycin-induced pulmonary fibrosis by repressing TGF-ß-induced fibroblast to myofibroblast differentiation.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive and irreversible disease characterized by excessive fibroblast to myofibroblast differentiation with limited therapeutic options. Curdione, a sesquiterpene compound extracted from the essential oil of Curcuma aromatica Salisb, has anti-inflammatory and anti-tumor effects. However, the role of curdione in IPF is still unclear. METHODS: The effects of curdione were evaluated in a bleomycin (BLM)-induced pulmonary fibrosis mouse model. C57BL/6 mice were treated with BLM on day 0 by intratracheal injection and intraperitoneal administered curdione or vehicle. In vitro study, expression of fibrotic protein was examined and the transforming growth factor (TGF)-ß-related signaling was evaluated in human pulmonary fibroblasts (HPFs) treated with curdione following TGF-ß1 stimulation. RESULTS: Histological and immunofluorescent examination showed that curdione alleviated BLM-induced lung injury and fibrosis. Specifically, curdione significantly attenuated fibroblast to myofibroblast differentiation in the lung in BLM induced mice. Furthermore, curdione also decreased TGF-ß1 induced fibroblast to myofibroblast differentiation in vitro, as evidenced by low expression of α-SMA, collagen 1 and fibronectin in a dose dependent manner. Mechanistically, curdione suppressed the phosphorylation of Smad3 following TGF-ß1 treatment, thereby inhibiting fibroblast differentiation. CONCLUSIONS: Overall, curdione exerted therapeutic effects against pulmonary fibrosis via attenuating fibroblast to myofibroblast differentiation. As curdione had been shown to be safe and well-tolerated in BLM-induced mouse model, curdione might be useful for developing novel therapeutics for IPF.

Fabrication of Cu(I)-Functionalized MIL-101(Cr) for Adsorptive Desulfurization: Low-Temperature Controllable Conversion of Cu(II) via Vapor-Induced Reduction.

Because of their nontoxicity, economic applicability, and excellent performance on adsorptive desulfurization, the fabrication of Cu(I) sites onto porous supports has drawn much attention. However, high temperatures (usually ≥700 °C) are required for the formation of Cu(I) sites from Cu(II) species through the traditional autoreduction method, which is unworkable for thermolabile metal-organic frameworks (MOFs). Here, we report a strategy named vapor-induced reduction (VIR) to convert Cu(II) species to Cu(I) in MIL-101(Cr), in which ethanol is used as an environmentally benign reductant. The entire formation of Cu(I) from Cu(II) with more than 96% selectivity is allowed, at a relatively low temperature of 200 °C, and well-maintains the structure of the MOF. Moreover, the generated Cu(I) sites exhibit good performances in adsorption desulfurization with regard to both activity and reusability.