PhI(OAc)2/Pd(OAc)2 promoted the formation of 8-hydroxyquinoline derivatives from benzoxazoles and alcohols.

A PhI(OAc)2/Pd(OAc)2 system that synergistically promotes the formation of 8-hydroxyquinoline derivatives from benzoxazoles and alcohols has been developed. The reaction proceeded smoothly with a range of benzoxazoles and alcohols to give the corresponding 8-hydroxyquinoline derivatives in moderate yields.

Anaphylactic shock in a small cell lung cancer patient receiving atezolizumab therapy: a rare but potentially fatal complication.

Immunotherapy has been a revolutionary innovation in cancer therapy in recent years, but it is accompanied by various unique immune-related adverse events (irAEs). Among these irAEs, anaphylactic shock is very rare. Here, we report a case of a patient who developed anaphylactic shock after receiving one dose of atezolizumab. A 74-year-old male patient with small cell lung cancer experienced recurrence 10 years after surgery. After one cycle of treatment, the patient developed a grade 2 rash and recovered after receiving oral methylprednisolone tablets. In the second cycle, atezolizumab was discontinued. Then, the patient was scheduled to receive atezolizumab plus carboplatin and etoposide again after three weeks, but approximately three minutes after an intravenous infusion of atezolizumab, the patient developed signs and symptoms of anaphylactic shock, such as dyspnea, cold limbs, and loss of consciousness. At this point, the infusion was immediately stopped, and a normal saline infusion was administered. Meanwhile, ECG monitoring, supplemental humidified high-flow supplemental 100% oxygen, epinephrine, dopamine, hormone treatment with methylprednisolone, and other anti-shock treatments were carried out. For better recuperation, this patient was transferred to the intensive care unit for further treatment and was discharged two days later. Anaphylactic shock develops rapidly and is also a very severe complication. Prompt detection, diagnosis, and therapeutic intervention are the basics for survival.

Association analysis of GmMAPKs and functional characterization of GmMMK1 to salt stress response in soybean.

Salinity is one of the major abiotic constraints affecting the growth and yield of plants including soybean. In this context, the previous studies have documented the role of the mitogen-activated protein kinase (MAPK) cascade in the regulation of salt signaling in model plants. However, there is not a systematic analysis of salt-related MAPKs in soybean. Hence, in this study, we identified a total of 32 GmMAPKs via., genome-wide reanalysis of the MAPK family using the soybean genome v4.0. Based on the transcriptome datasets in the public database, we observed that GmMAPKs are induced by different abiotic stresses, especially salt stress. Furthermore, based on the candidate gene association mapping and haplotype analysis of the GmMAPKs, we identified a salt-related MAPK member, GmMMK1. GmMMK1 possesses significant sequence variations, which affect salt tolerance in soybean at the germination stage. Besides, the overexpression of the GmMMK1 in soybean hairy roots has a significant negative effect on the root growth, leading to increased sensitivity of the GmMMK1-OE plants to salt stress. Moreover, the heterologous expression of the GmMMK1 in Arabidopsis has been also observed to have a negative effect on the germination and root growth under salt stress. The transcriptome analysis and yeast two-hybrid screening showed that hormone signaling and the homeostasis of reactive oxygen species are involved in the GmMMK1 regulation network. In conclusion, the results of this work demonstrated that GmMMK1 is an important negative regulator of the salt stress response, and provides better insights for understanding the role of the MAPKs in soybean salt signaling.

Mediating Effects of Maternal Blood Triglycerides on the Relationship between Prepregnancy Body Mass Index and Fetal Macrosomia.

OBJECTIVE: To examine whether the association of prepregnancy body mass index (BMI) with fetal macrosomia is mediated through maternal circulating lipid concentrations during pregnancy. STUDY DESIGN: In this prospective cohort, 3011 eligible pregnant women were enrolled. Information on demographic characteristics were collected using questionnaires, and anthropometrics and laboratory tests were performed at 24 weeks of gestation and before delivery. Macrosomia was defined as birth weight ≥4000 g. Logistic regression and multivariable linear regression, adjusted for age, fetal sex, education, gestational weight gain, fasting blood glucose, gestational diabetes, gestational hypertension, gestational age at delivery, delivery mode, and parity, were used to assess the mediation path between prepregnancy BMI, maternal serum lipids, and fetal macrosomia. RESULTS: A total of 2454 participants with completed records were included in the final analyses. Among the maternal circulating lipid biomarkers, only triglyceride was significantly associated with both prepregnancy BMI and fetal macrosomia risk, adjusting for potential confounders. Mediation analyses demonstrated that the direct effect of prepregnancy BMI on fetal macrosomia was 0.0085 (95% CI, 0.0003-0.018; P < .05), the indirect effect mediated through maternal serum triglycerides was 0.0016 (95% CI, 0.0007-0.0029; P < .001), and the estimated proportion of mediated effect was 15.7% (P < .05). CONCLUSIONS: Maternal circulating triglycerides mediate the association of prepregnancy BMI with the risk of fetal macrosomia.

Clinical evaluation of plasma coagulation parameters in patients with advanced-stage non-small cell lung cancer treated with palliative chemotherapy in China.

AIMS OF THE STUDY: Blood coagulation parameters are colossally important for clinical evaluation of palliative chemotherapy; however, this niche was not explored earlier for advanced-stage non-small cell lung cancer (NSCLC). Study focuses to explore the clinical relevancy of Coagulation parameters; prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), fibrinogen (FIB), D-dimer and international normalised ratio (INR) and their response to palliative chemotherapy in advanced-stage NSCLC. METHODS: A retrospective study was conducted between 2013 and 2019 in Jiangsu Cancer hospital, Nanjing, PR. China. Medical records of 5445 patients were succinctly reviewed and classified accordingly to the inclusion and exclusion criteria. A total of 216 advanced NSCLC patients who used a first-line chemotherapy and antiangiogenic therapy regimen were enrolled in this study under ethical approval (JSCH-2020C-009). Blood samples were collected from these patients to measure the response levels of these coagulation parameters at time of admission to hospital and at the beginning of 4 cycles of Palliative therapy. We find the clinical value of all these coagulation parameters by using SPSS 24. Univariate Cox regression and Multivariate Cox regression models were used to identify the factors that were associated with progression-free survival (PFS) and the response to palliative chemotherapy. RESULTS: In the Kaplan-Meier survival analysis for overall median (95% CI) survival of high pre-treatment coagulation parameters showed shorter PFS compared with normal pre-treatment except TT and their overall median (95% CI) follow-up was 3.3 (3.12-3.47). Coagulation parameters have showed clinical relevance as a potential independent prognostic factor of PFS in the Univariate Cox regression. In multivariable model, Age (≥60 years vs < 60 years), cancer differentiation (Unknown vs Poor), PT (High vs Normal) range, FIB (High vs Normal) range and D-dimer (High vs Normal) range, (P = .025, P = .045, P = .029, P = .049 and P = .011, respectively) were associated as a prognostic factor of PFS in NSCLC. Patients on 3-drugs regimen found to have better PFS compared with the ones taking the 2-drugs treatment regimen (P = .043). CONCLUSION: The high range of PT, FIB and D-dimers was associated with poor prognosis of advanced-stage NSCLC. Our findings also confirmed that patients on 3-drugs regimen showed longer PFS compared with 2-drugs regimen.

Phase I dose escalation and pharmacokinetic study on the nanoparticle formulation of polymeric micellar paclitaxel for injection in patients with advanced solid malignancies.

Background Polymeric micellar paclitaxel (PM-paclitaxel) is a novel Cremophor EL-free, nanoparticle-encapsulated paclitaxel formulation administered through intravenous injection. The primary objective of this phase I trial was to determine the first cycle dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of PM-paclitaxel. Secondary objectives included the evaluation of the safety, antitumor activity, and pharmacokinetic (PK) profile of PM-paclitaxel in patients with advanced malignancies. Methods The PM-paclitaxel dose was escalated from 175 mg/m2 (level 1) to 435 mg/m2 (level 5). PM-paclitaxel was intravenously administered to patients for 3 h without premedication on day 1 of a 21-day cycle. Results Eighteen patients with confirmed advanced malignancies received PM-paclitaxel. DLT included grade 4 neutropenia (four patients) and grade 3 numbness (one patient), which occurred in one of the six patients who received 300 mg/m2 (level 3) PM-paclitaxel and all three patients who were treated with 435 mg/m2 PM-paclitaxel. Thus, the MTD of PM-paclitaxel was determined as 390 mg/m2 (level 4). Acute hypersensitive reactions were not observed. Partial response was observed in six of 18 patients (33.3%), three of whom had prior exposure to paclitaxel chemotherapy. The peak concentration and area under the curve values of paclitaxel increased with increasing dosage, indicating that PM-paclitaxel exhibits linear PKs. Conclusions PM-paclitaxel showed high MTD without additional toxicity, and exhibited desirable antitumor activity. The recommended dose of PM paclitaxel for phase II study is 300 mg/m2.

Phase III study of dulanermin (recombinant human tumor necrosis factor-related apoptosis-inducing ligand/Apo2 ligand) combined with vinorelbine and cisplatin in patients with advanced non-small-cell lung cancer.

Background Dulanermin is a recombinant soluble human Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) that activates apoptotic pathways by binding to proapoptotic death receptor (DR) 4 and DR5. The purpose of this study was to evaluate the efficacy and safety of dulanermin combined with vinorelbine and cisplatin (NP) as the first-line treatment for patients with advanced non-small-cell lung cancer (NSCLC). Experimental design Patients were randomly assigned to receive NP chemotherapy (vinorelbine 25 mg/m2 on days 1 and 8 and cisplatin 30 mg/m2 on days 2 to 4) for up to six cycles plus dulanermin (75 µg/kg on days 1 to 14) or placebo every three weeks until disease progression, intolerable toxicity, or withdrawal of consent. The primary end point was progression-free survival (PFS), and the secondary end points included objective response rate (ORR), overall survival (OS), and safety evaluation. Results Between October 2009 and June 2012, 452 untreated patients with stage IIIB to IV NSCLC were randomly assigned to receive dulanermin plus NP (n = 342) and placebo plus NP (n = 110). Median PFS was 6.4 months in the dulanermin arm versus 3.5 months in the placebo arm (hazard ratio (HR), 0.4034; 95% CI, 0.3181 to 0.5117, p < 0.0001). ORR was 46.78% in the dulanermin arm versus 30.00% in the placebo arm (p = 0.0019). Median OS was 14.6 months in the dulanermin arm versus 13.9 months in the placebo arm (HR, 0.94; 95% CI, 0.74 to 1.21, p = 0.64). The most common grade ≥ 3 adverse events (AEs) were oligochromemia, leukopenia, neutropenia, and oligocythemia. Overall incidence of AEs, grade ≥ 3 AEs, and serious AEs were similar across the two arms. Conclusion Addition of dulanermin to the NP regimen significantly improved PFS and ORR. However, our results showed that the combination of dulanermin with chemotherapy had a synergic activity and favorable toxic profile in the treatment of patients with advanced NSCLC.

Corrigendum: Identification and validation of differentially expressed genes for targeted therapy in NSCLC using integrated bioinformatics analysis.

[This corrects the article DOI: 10.3389/fonc.2023.1206768.].

Clinical Significance of Disulfidptosis-related Genes and Functional Analysis in Gastric Cancer.

Background: Worldwide, gastric cancer (GC) remains intractable due to its poor prognosis and high morbidity and mortality. Disulfidptosis is a novel kind of cell death mediated by abnormal accumulation of intracellular disulphides. The correlation between disulfidptosis and GC is still unknown. Therefore, it is necessary to elucidate the pathogenesis and mechanism of disulfidptosis and GC for clinical diagnosis and intervention. Methods: RNA-sequencing data from several public data portals and clinical samples were collected. We compared the expression levels of four key genes of disulfidptosis, including SLC7A11, SLC3A2, RPN1, and NCKAP1, in GC and selected prognostic genes to build a novel GC prognosis-related nomogram model. The biological functions and immune landscape of the identified prognostic genes were explored. Results: Overexpressed NCKAP1 and SLC7A11 were prognostic disulfidptosis-related genes in GC. We combined these genes and several clinicopathological factors to build a prognostic nomogram model for GC. Meanwhile, the ROC curves showed that NCKAP1 and SLC7A11 were promising biomarkers for GC screening. The biological and cellular functions were focused on actin activities, GTPase and immunoreaction. The tumour immune microenvironment and immune therapy targets were identified. Competing endogenous RNA network was built to explore the downstream regulatory mechanisms. Finally, the elevated NCKAP1 and SLC7A11 expression in GC was validated via qRT-PCR in a cell line and tissue line. Conclusion: In conclusion, NCKAP1 and SLC7A11 are promising prognostic and diagnostic biomarkers for GC that correlate with the activities of actin, energy metabolism of GTPase, immune infiltration and immunotherapy.

Cross-Sectional and Prospective Association of Serum 25-Hydroxyvitamin D with Gut Mycobiota during Pregnancy among Women with Gestational Diabetes.

SCOPE: Little is known about the effect of blood vitamin D status on the gut mycobiota (i.e., fungi), a crucial component of the gut microbial ecosystem. The study aims to explore the association between 25-hydroxyvitamin D [25(OH)D] and gut mycobiota and to investigate the link between the identified mycobial features and blood glycemic traits. METHODS AND RESULTS: The study examines the association between serum 25(OH)D levels and the gut mycobiota in the Westlake Precision Birth Cohort, which includes pregnant women with gestational diabetes mellitus (GDM). The study develops a genetic risk score (GRS) for 25(OH)D to validate the observational results. In both the prospective and cross-sectional analyses, the vitamin D is associated with gut mycobiota diversity. Specifically, the abundance of Saccharomyces is significantly lower in the vitamin D-sufficient group than in the vitamin D-deficient group. The GRS of 25(OH)D is inversely associated with the abundance of Saccharomyces. Moreover, the Saccharomyces is positively associated with blood glucose levels. CONCLUSION: Blood vitamin D status is associated with the diversity and composition of gut mycobiota in women with GDM, which may provide new insights into the mechanistic understanding of the relationship between vitamin D levels and metabolic health.

Identification and validation of differentially expressed genes for targeted therapy in NSCLC using integrated bioinformatics analysis.

Background: Despite the high prevalence of lung cancer, with a five-year survival rate of only 23%, the underlying molecular mechanisms of non-small cell lung cancer (NSCLC) remain unknown. There is a great need to identify reliable candidate biomarker genes for early diagnosis and targeted therapeutic strategies to prevent cancer progression. Methods: In this study, four datasets obtained from the Gene Expression Omnibus were evaluated for NSCLC- associated differentially expressed genes (DEGs) using bioinformatics analysis. About 10 common significant DEGs were shortlisted based on their p-value and FDR (DOCK4, ID2, SASH1, NPR1, GJA4, TBX2, CD24, HBEGF, GATA3, and DDR1). The expression of significant genes was validated using experimental data obtained from TCGA and the Human Protein Atlas database. The human proteomic data for post- translational modifications was used to interpret the mutations in these genes. Results: Validation of DEGs revealed a significant difference in the expression of hub genes in normal and tumor tissues. Mutation analysis revealed 22.69%, 48.95%, and 47.21% sequence predicted disordered regions of DOCK4, GJA4, and HBEGF, respectively. The gene-gene and drug-gene network analysis revealed important interactions between genes and chemicals suggesting they could act as probable drug targets. The system-level network showed important interactions between these genes, and the drug interaction network showed that these genes are affected by several types of chemicals that could serve as potential drug targets. Conclusions: The study demonstrates the importance of systemic genetics in identifying potential drug- targeted therapies for NSCLC. The integrative system- level approach should contribute to a better understanding of disease etiology and may accelerate drug discovery for many cancer types.

Study on synergistic catalytic degradation of wastewater containing polyacrylamide catalyzed by low-temperature plasma-H2O2.

The degradation behavior of polyacrylamide (PAM) solution by low-temperature plasma was investigated, and the effect of some factors that might affect the degradation process was further examined. The PAM solution was treated with low-temperature plasma generated by dielectric barrier discharge (DBD) combined with H2O2 and a Mn + Cu/AC composite catalyst. The optimal conditions for the oxidation degradation of a PAM solution using low-temperature plasma-H2O2-Mn + Cu/AC were determined as follows: initial concentration of 1000 mg/L, discharge voltage of 18 kV, H2O2 addition of 2%, and catalyst addition of 810 mg. The results indicated that the degradation rate increased with the increase of the catalyst dosage at the same discharge time. The degradation rate of 180 min increases from 90 to 97.6% with an increase in voltage from 16 to 18 kV, and the molecular weight decreases from 2,720,204.23 to 1,370,815.54. The degradation effect caused by the change of H2O2 addition was considerable compared with other factors. When the discharge time was 180 min, the degradation rate increased 26.3% with the increase of 1.6% H2O2 addition. Under the optimal process conditions, the addition of the catalyst resulted in a more rapid initial decrease in the pH value of the solution compared to the system without the catalyst.

Co-Occurring EGFR S645C and EGFR L858R in a Patient with Lung Adenocarcinoma Induced Primary Resistance to Osimertinib.

Approximately 10-20% of patients demonstrate primary resistance to EGFR-TKIs, and different EGFR mutations vary in sensitivity to EGFR-TKIs. We report a case of a 78-year-old male with lung adenocarcinoma that EGFR L858R (AF = 1.32%) coexisting with EGFR S645C (AF = 7.13%) in his diagnosed tissues analyzed by NGS. The patient was primarily resistant to first-line osimertinib and rapidly progressed after pembrolizumab in combination with pemetrexed and bevacizumab, as demonstrated by persistently elevated CEA levels during treatment. ctDNA-based NGS analysis revealed loss of EGFR L858R while persistence of highly abundant EGFR S645C in the pleural fluid and plasma after treatment, suggesting that EGFR L858R may be a subclone. We provide the first clinical evidence of the primary resistance of EGFR S645C to osimertinib and emphasize the importance of identifying clones and subclones. Our patient did not respond to immunotherapy either, and preclinical studies have shown that EGFR S645C activates the MEK signaling pathway, the combination of EGFR-TKIs and MEK inhibitors may be effective.

Real world experience with camrelizumab in patients with advanced non-small cell lung cancer: a prospective multicenter cohort study (NOAH-LC-101).

Background: Camrelizumab has shown promising survival benefits in treatment-naïve advanced non-small cell lung cancer (NSCLC) patients when used in combination with chemotherapy. However, its effectiveness and safety outside the clinical trial setting are largely unknown. Therefore, we conducted NOAH-LC-101, a prospective multicenter cohort study, to investigate the real-world effectiveness and safety of camrelizumab on a large cohort of advanced NSCLC patients in daily clinical practice. Methods: All consecutive patients aged ≥18 years with confirmed advanced NSCLC scheduled for camrelizumab treatment were screened for inclusion at 43 hospitals in China. The primary outcome was progression-free survival (PFS). The secondary outcomes included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety. Results: Between August 2019 and February 2021, 403 patients were included. The median age of participants was 65 years (range, 27-87 years). There were 57 (14.1%) participants with an Eastern Cooperative Oncology Group performance status (ECOG PS) of ≥2. Most participants received camrelizumab in the second or later lines (68.7%) and plus chemotherapy (64.8%). The median PFS was 12.6 [95% confidence interval (CI): 10.7-17.0] months and median OS was 22.3 months [95% CI: 19.3-not reached (NR)]. The ORR was 28.8% (95% CI: 24.4-33.5%) and DCR was 79.9% (95% CI: 75.7-83.7%). Adverse events of any grade occurred in 348 (86.4%) participants. No new safety signals were identified. Reactive cutaneous capillary endothelial proliferation was observed in 75 (18.6%) patients, all of which were grade 1-2. Conclusions: This study demonstrates the effectiveness and safety of camrelizumab in a large sample of real-world NSCLC patients. The results are generally consistent with those previously reported in pivotal clinical trials. This study supports the clinical use of camrelizumab in a broader patient population (ChiCTR1900026089).

Efficacy and safety of NAHAO® hydrogel in amelioration of chemoradiotherapy-induced oral mucositis: An preliminary clinical study (ChiCTR2200064766).

OBJECTIVE: To evaluate the efficacy of NAHAO® oral mucosal antibacterial care solution (NAHAO® spray) on attenuating oral mucositis (OM) symptoms and related mechanisms investigation. MATERIAL AND METHODS: Experimental OM models were established by acetic acid and 5-fluorouracil combined with mechanical trauma. We investigated spontaneous pain of conscious OM rats after using NAHAO®. The expression of NF-κB in affected trigeminal ganglion was measured by western blot. In clinical study, 60 patients who developed post-treatment OM of grade 2 or above or persistent mucosal pain with a score equal to or greater than 4 points were selected. All patients were required to receive NAHAO® spray 8 times a day and were examined for OM degrees and oral mucosal pain scores before and after application. RESULTS: Experimental data from experimental model suggested that clinical efficacy of NAHAO® spray was involved in inflammation inhibition via NF-κB pathway. The results of clinical study showed that NAHAO® spray improved the symptoms of OM, there is statistically significant difference in oral mucosal pain scores after treated with NAHAO, and the dietary restrictions were also improved. CONCLUSION: NAHAO® spray alleviates pain and improves the diet situation in OM patients, which is partly mediated through the inhibition of NF-κB pathway.

Continuous glucose monitoring-derived glycemic metrics and adverse pregnancy outcomes among women with gestational diabetes: a prospective cohort study.

Background: Continuous glucose monitoring (CGM) has shown potential in improving maternal and neonatal outcomes in individuals with type 1/2 diabetes, but data in gestational diabetes mellitus (GDM) is limited. We aimed to explore the relationship between CGM-derived metrics during pregnancy and pregnancy outcomes among women with GDM. Methods: We recruited 1302 pregnant women with GDM at a mean gestational age of 26.0 weeks and followed them until delivery. Participants underwent a 14-day CGM measurement upon recruitment. The primary outcome was any adverse pregnancy outcome, defined as having at least one of the outcomes: preterm birth, large-for-gestational-age (LGA) birth, fetal distress, premature rupture of membranes, and neonatal intensive care unit (NICU) admission. The individual outcomes included in the primary outcome were considered as secondary outcomes. We conducted multivariable logistic regression to evaluate the association of CGM-derived metrics with these outcomes. Findings: Per 1-SD difference in time above range (TAR), glucose area under the curve (AUC), nighttime mean blood glucose (MBG), daytime MBG, and daily MBG was associated with higher risk of any adverse pregnancy outcome, with odds ratio: 1.22 (95% CI 1.08-1.36), 1.22 (95% CI 1.09-1.37), 1.18 (95% CI 1.05-1.32), 1.21 (95% CI 1.07-1.35), and 1.22 (95% CI 1.09-1.37), respectively. Time in range, TAR, AUC, nighttime MBG, daytime MBG, daily MBG, and mean amplitude of glucose excursions were positively associated, while time blow range was inversely associated with the risk of LGA. Additionally, higher value for TAR was associated with higher risk of NICU admission. We further summarized the potential thresholds of TAR (2.5%) and daily MBG (4.8 mmol/L) to distinguish individuals with and without any adverse pregnancy outcome. Interpretation: The CGM-derived metrics may help identify individuals at higher risk of adverse pregnancy outcomes. These CGM biomarkers could serve as potential new intervention targets to maintain a healthy pregnancy status among women with GDM. Funding: National Key R&D Program of China, National Natural Science Foundation of China, and Westlake Laboratory of Life Sciences and Biomedicine.

Genome-wide genotype-serum proteome mapping provides insights into the cross-ancestry differences in cardiometabolic disease susceptibility.

Identification of protein quantitative trait loci (pQTL) helps understand the underlying mechanisms of diseases and discover promising targets for pharmacological intervention. For most important class of drug targets, genetic evidence needs to be generalizable to diverse populations. Given that the majority of the previous studies were conducted in European ancestry populations, little is known about the protein-associated genetic variants in East Asians. Based on data-independent acquisition mass spectrometry technique, we conduct genome-wide association analyses for 304 unique proteins in 2,958 Han Chinese participants. We identify 195 genetic variant-protein associations. Colocalization and Mendelian randomization analyses highlight 60 gene-protein-phenotype associations, 45 of which (75%) have not been prioritized in Europeans previously. Further cross-ancestry analyses uncover key proteins that contributed to the differences in the obesity-induced diabetes and coronary artery disease susceptibility. These findings provide novel druggable proteins as well as a unique resource for the trans-ancestry evaluation of protein-targeted drug discovery.

Gumarontinib in patients with non-small-cell lung cancer harbouring MET exon 14 skipping mutations: a multicentre, single-arm, open-label, phase 1b/2 trial.

Background: Approximately 3-4% of patients with non-small-cell lung cancer (NSCLC) have MET exon 14 (METex14) skipping mutations. We report primary results from the phase 2 stage of a phase 1b/2 study of gumarontinib, a selective, potent, oral MET inhibitor, in patients with METex14 skipping mutation-positive (METex14-positive) NSCLC. Methods: The single-arm, multicentre, open-label, phase 2 stage of the GLORY study was conducted at 42 centres across China and Japan. Adults with locally advanced or metastatic METex14-positive NSCLC received oral gumarontinib 300 mg once daily in continuous 21-day cycles until disease progression, intolerable toxicity, or withdrawal of consent. Eligible patients had failed one or two prior lines of therapy (not including a MET inhibitor), were ineligible for/refused chemotherapy, and had no genetic alterations targetable with standard therapies. The primary endpoint was objective response rate in patients with a valid baseline tumour assessment, by blinded independent review. The study was registered at ClinicalTrials.gov (NCT04270591). Findings: Between Aug 2, 2019 and Apr 28, 2021, 84 patients were enrolled and received gumarontinib (median follow-up 13.5 months [IQR 8.7-17.1]), at data cut-off (Apr 28, 2022) five patients whose METex14 status could not be confirmed by a central laboratory were excluded from the efficacy analysis. The objective response rate was 66% (95% CI 54-76) overall (n = 79), 71% (95% CI 55-83) in treatment-naïve patients (n = 44), and 60% (95% CI 42-76) in previously-treated patients (n = 35). The most common treatment-related adverse events (any grade) were oedema (67/84 patients, 80%) and hypoalbuminuria (32/84, 38%). Grade ≥3 treatment-emergent adverse events occurred in 45 (54%) patients. Treatment-related adverse events leading to permanent discontinuation occurred in 8% (7/84) of patients. Interpretation: Gumarontinib monotherapy had durable antitumour activity with manageable toxicity in patients with locally advanced or metastatic METex14-positive NSCLC when used in first line or later. Funding: Haihe Biopharma Co., Ltd. Supported in part by grants from the National Science and Technology Major Project of China for "Clinical Research of Gumarontinib, a highly selective MET inhibitor" (2018ZX09711002-011-003); the National Natural Science Foundation of China (82030045 to S.L. and 82172633 to YF.Y); Shanghai Municipal Science & Technology Commission Research Project (19411950500 to S.L.); Shanghai Shenkang Action Plan (16CR3005A to S.L.) and Shanghai Chest Hospital Project of Collaborative Innovation (YJXT20190105 to S.L.).

Toripalimab Plus Chemotherapy for Patients With Treatment-Naive Advanced Non-Small-Cell Lung Cancer: A Multicenter Randomized Phase III Trial (CHOICE-01).

PURPOSE: The CHOICE-01 study investigated the efficacy and safety of toripalimab in combination with chemotherapy as a first-line treatment for advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients (N = 465) with treatment-naive, advanced NSCLC without EGFR/ALK mutations were randomly assigned 2:1 to receive toripalimab 240 mg (n = 309) or placebo (n = 156) once every 3 weeks in combination with chemotherapy for 4-6 cycles, followed by the maintenance of toripalimab or placebo once every 3 weeks plus standard care. Stratification factors included programmed death ligand-1 expression status, histology, and smoking status. The primary end point was progression-free survival (PFS) by investigator per RECIST v1.1. Secondary end points included overall survival and safety. RESULTS: At the final PFS analysis, PFS was significantly longer in the toripalimab arm than in the placebo arm (median PFS, 8.4 v 5.6 months, hazard ratio = 0.49; 95% CI, 0.39 to 0.61; two-sided P < .0001). At the interim OS analysis, the toripalimab arm had a significantly longer OS than the placebo arm (median OS not reached v 17.1 months, hazard ratio = 0.69; 95% CI, 0.53 to 0.92; two-sided P = .0099). The incidence of grade ≥ 3 adverse events was similar between the two arms. Treatment effects were similar regardless of programmed death ligand-1 status. Genomic analysis using whole-exome sequencing from 394 available tumor samples revealed that patients with high tumor mutational burden were associated with significantly better PFS in the toripalimab arm (median PFS 13.1 v 5.5 months, interaction P = .026). Notably, patients with mutations in the focal adhesion-PI3K-Akt signaling pathway achieved significantly better PFS and OS in the toripalimab arm (interaction P values ≤ .001). CONCLUSION: Toripalimab plus chemotherapy significantly improves PFS and OS in patients with treatment-naive advanced NSCLC while having a manageable safety profile. Subgroup analysis showed the OS benefit was mainly driven by the nonsquamous subpopulation.

Immunotherapy for bilateral multiple ground glass opacities: An exploratory study for synchronous multiple primary lung cancer.

Background: Bilateral multiple ground glass opacities (GGOs) are observed in quite a part of patients with early-stage lung adenocarcinoma. For this so-called synchronous multiple primary lung cancer (sMPLC), targeting immune checkpoint is a favorable option in addition to surgical resection. The purpose of this study is to reveal the safety and efficacy of performing immune checkpoint inhibitors (ICIs) on patients with sMPLC and to explore the biomarkers of the efficacy. Methods: A total of 21 patients with sMPLC were enrolled and all included cases were pathologically confirmed adenocarcinoma after conducting surgical treatment for unilateral GGOs. ICIs of Sintilimab were then used to target programmed death 1 (200mg i.v., Q3W) for up to 10 cycles. Seven patients of them received the other surgery for contralateral GGOs, and multiomics assessments, including neoantigens, somatic mutations, and methylated loci, were further performed to investigate potential biomarkers. Results: Grade 1 or 2 treatment-related adverse events (AEs) occurred in most of the patients (12/21, 57.1%), and one subject withdrawn for grade 3 AEs. For the seven patients underwent twice surgeries, twelve and thirteen GGOs were achieved before and after the use of ICIs separately, and a favorable efficacy was observed among six lesions after immunotherapy (> 50% pathologic tumor regression). Tumor infiltration T-cell and B-cell were further shown to be associated with the biological activity of ICIs. According to mechanism-based multiomics analyses, MUC19- and PCDHB5- mutations were indicated to correlate with a favorable prognosis of sMPLC underwent immunotherapy, and our results suggested that immunogenetic mutation and associated promoter methylation could provide a quantitative explanation for the pathologic response of GGOs. Conclusion: Our study provides evidence that the use of ICIs contributed favorable efficacy and safety to patients with sMPLC. Immune infiltration and immunogenic biomarkers are revealed to be implications of performing ICIs on sMPLC. These preliminary findings exhibit the prospects in performing neoadjuvant or adjuvant immunotherapies on patients with sMPLC. Clinical Trial Registration: https://www.chictr.org.cn/showproj.aspx?proj=36878, identifier ChiCTR1900022159.