Safety, efficacy and pharmacokinetics of BPI-9016M in c-MET overexpression or MET exon 14 skipping mutation patients with locally advanced or metastatic non-small-cell lung cancer: a phase Ib study.

BACKGROUND: As a potential target receptor tyrosine kinase, mesenchymal-epithelial transition factor (MET) exhibits high aberrant expression across various tumors. This study aimed to evaluated the safety, tolerability, efficacy and pharmacokinetics (PK) of BPI-9016M, a novel tyrosine kinase inhibitor (TKI) targeting c-MET, in c-MET overexpression or MET exon 14 skipping mutation patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC). METHODS/DESIGN: In this two-part multicenter phase Ib study, eligible patients with locally advanced or metastatic NSCLC harboring c-MET overexpression or MET exon 14 skipping mutation were enrolled into Part A (tested positive for c-MET overexpression [immunohistochemical staining score ≥ 2+]; 300 mg quaque die [QD], 450 mg QD and 600 mg QD cohorts) or Part B (tested positive for MET exon 14 skipping mutation; 400 mg bis in die [BID] cohort), respectively. The primary endpoints were safety, objective response rate (ORR) and disease control rate (DCR), the second endpoints were PK parameters, progression-free survival (PFS) and overall survival (OS). RESULTS: Between March 15, 2017 and September 18, 2021, 38 patients were enrolled (Part A, n = 34; Part B, n = 4). Of 38 patients, 32 (84.2%) patients completed the treatment protocol. As of the data cut-off date on January 27, 2022, all patients reported at least one treatment-emergent adverse event (TEAE). Ninety-two point one percent (35/38) of patients experienced treatment-related adverse events (TRAEs), and grade ≥ 3 TRAEs were observed in 11 (28.9%) patients. The most common TRAEs were elevated alanine aminotransferase (ALT, 14/38, 36.8%) and elevated aspartate aminotransferase (AST, 11/38, 28.9%). Only one (2.6%) patient had treatment-related serious adverse event (SAE) in 600 mg QD cohort due to thrombocytopenia. PK analysis showed BPI-9016M and its main metabolites (M1 and M2-2) reached steady state after seven days of continuous administration. At the dose of 300 mg QD and 450 mg QD, the exposure of BPI-9016M increased with increasing dose. Exposure of BPI-9016M was similar at 450 mg QD and 600 mg QD, which may exhibit a saturation trend. In all patients, ORR and DCR were 2.6% (1/38, 95% confidence interval [CI] 0.1-13.8%) and 42.1% (16/38, 95% CI 26.3-59.2%), respectively. Only one partial response (PR) patient was observed at a dose of 600 mg QD in Part A. In Part B, DCR was 75.0% (3/4, 95% CI 19.4-99.4%). The median PFS and OS in all 38 patients were 1.9 months (95% CI 1.9-3.7) and 10.3 months (95% CI 7.3-not evaluable [NE]), respectively. CONCLUSION: BPI-9016M showed manageable safety profile in c-MET overexpression or MET exon 14 skipping mutation patients with locally advanced or metastatic NSCLC, but showed limited efficacy. TRIAL REGISTRATION: Clinicaltrials.gov NCT02929290 (11/10/2016).

Effects of Blood Flow Restriction Combined with Low-Intensity Resistance Training on Lower-Limb Muscle Strength and Mass in Post-Middle-Aged Adults: A Systematic Review and Meta-Analysis.

We studied the effect of blood flow restriction (BFR) combined with low-intensity resistance training (LIRT) on lower-limb muscle strength and mass in post-middle-aged adults. The PubMed, OVID, ProQuest, Cochrane Library, EMBASE, Web of Science, and Scopus databases were used to obtain randomized controlled trials, and the effects of BFR and LIRT (BFRt) on muscle strength and mass in adults were examined. The Cochrane risk of bias tool assessed bias in the included trials. The combined effects of BFR and LIRT (BFRt) were calculated by meta-analysis, the association between muscle strength/mass and interventions was determined by meta-regression, and beneficial variables of intervention were explored by subgroup analysis. A total of 11 articles were included in the meta-analysis. The combined effects showed that BFRt significantly improved lower extremity muscle strength but not muscle mass gain. Meta-regression analysis indicated that the effect of BFRt on changes in muscle strength was correlated with frequency of the intervention. Subgroup analysis revealed that BFRt achieved greater muscle strength gains than normal activity, LIRT, and similar muscle strength gains compared to high-intensity resistance training. The increased muscle strength after BFRt was noticed with a frequency of three times a week, but not with a frequency of two times a week, and the difference between these subgroups was statistically significant. Our findings indicate that BFRt can increase lower-limb muscle strength in post-middle-aged adults. Frequency of intervention is a key variable; particularly, a schedule of three times a week is effective in improving muscle strength.

Cross-sectional and longitudinal associations of serum Cysteine-rich 61 with severity and prognosis among community-acquired pneumonia patients in China.

Background: Cysteine-rich 61 (CYR61) is implicated in many pulmonary diseases. However, the relationship between CYR61 and community-acquired pneumonia (CAP) patients was unknown. This research aimed to estimate the correlations of serum CYR61 with severity and prognosis in CAP patients through a prospective cohort study. Methods: All 541 CAP patients were enrolled in this study. Fasting venous blood was collected. Clinical characteristics and demographic information were obtained. CYR61 and inflammatory cytokines were detected in serum using ELISA. Results: Serum CYR61 was gradually increased in parallel with severity scores in CAP patients. Correlative analysis indicated that serum CYR61 was strongly associated with many clinical parameters in CAP patients. Moreover, mixed logistic and linear regression models found that there were positive correlations between serum CYR61 and CAP severity scores after adjusted for age, BMI, and respiratory rate. Stratified analyses suggested that age affected the associations between serum CYR61 and severity scores. On admission, higher serum CYR61 levels elevated the risks of mechanical ventilation, vasoactive agent, ICU admission, death, and longer hospital stays during hospitalization. Moreover, serum CYR61 in combination with severity scores upregulated the predictive capacities for severity and death than single serum CYR61 or severity scores in CAP patients. Conclusion: There are significantly positive dose-response associations of serum CYR61 on admission with the severity and adverse prognostic outcomes, demonstrating that CYR61 is involved in the pathophysiology of CAP. Serum CYR61 may be used as a potential biomarker for the diagnosis and prognosis in CAP patients.

Value of CT Radiomics Combined with Clinical Features in the Diagnosis of Allergic Bronchopulmonary Aspergillosis.

Objective: Early diagnosis of allergic bronchopulmonary aspergillosis (ABPA) and targeted treatment can block the process of the disease. This study explores the diagnostic value of CT radiomics combined with clinical features in allergic ABPA. Methods: A total of 40 patients with ABPA were studied retrospectively, divided into training set (n = 28) and test set (n = 12). Based on CT imaging, the radiomics features are extracted and combined with clinical features to build a diagnostic model. The diagnosis model was based on support vector machine algorithm. The receiver operating characteristic curve (ROC) and area under the curve (AUC) were used to evaluate the diagnostic efficiency of the model. Results: There was no significant difference in general information and clinical data between the training and test sets (P > 0.05). The AUC of the training set and the test set is 0.896 (95% CI: 0.836-0.963) and 0.886 (95% CI: 0.821-0.952), respectively. Conclusion: Based on the CT radiomics model combined with clinical data, it has high efficiency in the diagnosis of ABPA.