QL1706 (anti-PD-1 IgG4/CTLA-4 antibody) plus chemotherapy with or without bevacizumab in advanced non-small cell lung cancer: a multi-cohort, phase II study.

First-line chemoimmunotherapy (with or without bevacizumab) has improved outcomes in advanced non-small cell lung cancer (NSCLC). Here, this open-label, multi-cohort phase II study (NCT05329025) was done to investigate the safety and efficacy of QL1706 (a single bifunctional MabPair product against PD-1 and CTLA-4) and chemotherapy with or without bevacizumab in this population. Patients were enrolled into five different cohorts based on genotype (cohorts 1-4, epidermal growth factor receptor [EGFR] wild-type; cohort 5, EGFR-mutant and progressed on EGFR-tyrosine kinase inhibitors [TKIs]). Between June 11, 2021 and December 29, 2021, 91 patients were enrolled. Most frequent treatment-related adverse events (TRAEs) included decreased appetite (60 [65.9%]), anemia (60 [65.9%]), infusion-related reactions (48 [52.7%]), and pruritus (44 [48.4%]). Grade ≥ 3 TRAEs occurred in 30 (33.0%) patients. Twenty-seven (45%) patients with wild-type EGFR achieved partial response (PR) (objective response rate [ORR] = 45%) and had a median progression-free survival (mPFS) of 6.8 months (95% CI: 5.2-9.7). For 31 patients harboring mutated EGFR, 17 (54.8%) achieved PR (ORR = 54.8%), with an mPFS of 8.5 months (95% CI: 5.72-not evaluable). Overall, QL1706 plus chemotherapy, regardless of having bevacizumab, was generally tolerable and had promising antitumor activity for EGFR wild-type advanced NSCLC in first-line setting. Moreover, QL1706 plus chemotherapy and bevacizumab showed favorable antitumor activity for patients who had EGFR mutated NSCLC but failed in TKI therapy, demonstrating a potential for treating this population.

First-in-human phase I/Ib study of QL1706 (PSB205), a bifunctional PD1/CTLA4 dual blocker, in patients with advanced solid tumors.

BACKGROUND: QL1706 (PSB205) is a single bifunctional MabPair (a novel technical platform) product consisting of two engineered monoclonal antibodies (anti-PD-1 IgG4 and anti-CTLA-4 IgG1), with a shorter elimination half-life (t1/2) for CTLA-4. We report results from a phase I/Ib study of QL1706 in patients with advanced solid tumors who failed standard therapies. METHODS: In the phase I study, QL1706 was administered intravenously once every 3 weeks at one of five doses ranging from 0.3 to 10 mg/kg, and the maximum tolerated dose, recommended phase 2 dose (RP2D), safety, pharmacokinetics (PK), and pharmacodynamics (PD) of QL1706 were investigated. In the phase Ib study, QL1706 was administered at the RP2D intravenously every 3 weeks, and the preliminary efficacies in non-small cell lung cancer (NSCLC), nasopharyngeal carcinoma (NPC), cervical cancer (CC), and other solid tumors were evaluated. RESULTS: Between March 2020 and July 2021, 518 patients with advanced solid tumors were enrolled (phase I, n = 99; phase Ib, n = 419). For all patients, the three most common treatment-related adverse events (TRAEs) were rash (19.7%), hypothyroidism (13.5%), and pruritus (13.3%). The TRAEs and immune-related adverse events (irAEs) of grade ≥ 3 occurred in 16.0% and 8.1% of patients, respectively. In phase I, 2 of 6 patients in the 10mg/kg group experienced dose-limiting toxicities (DLTs) (grade 3 thrombocytopenia and grade 4 immune-mediated nephritis), so the maximum tolerated dose (MTD) was reached at 10 mg/kg. The RP2D was determined to be 5 mg/kg based on comprehensive analysis of tolerability, PK/PD, and efficacy. For all patients who received QL1706 at the RP2D, the objective response rate (ORR) and median duration of response were 16.9% (79/468) and 11.7 months (8.3-not reached [NR]), respectively; and the ORRs were 14.0% (17/121) in NSCLC, 24.5% (27/110) in NPC, 27.3% (15/55) in CC, 7.4% (2/27) in colorectal cancer, 23.1% (6/26) in small cell lung cancer. For immunotherapy-naive patients, QL1706 exhibited promising antitumor activities, especially in NSCLC, NPC, and CC, with ORRs of 24.2%, 38.7%, and 28.3%, respectively. CONCLUSIONS: QL1706 was well tolerated and demonstrated promising antitumor activity in solid tumors, especially in NSCLC, NPC, and CC patients. It is currently being evaluated in randomized phase II (NCT05576272, NCT05179317) and phase III (NCT05446883, NCT05487391) trials. Trial Registration ClinicalTrials.gov Identifier: NCT04296994 and NCT05171790.

The traction force of the pulled limb in hip arthroscopic surgery is determined by stiffness coefficient which is significantly related to muscle volume.

PURPOSE: To verify the relationship between muscle volume, lateral centre-edge angle (LCEA), alpha angle (AA), body mass index (BMI) and Beighton score with stiffness coefficient (SC). To analyse the difference of traction force at different physical states of hip joint capsule. METHODS: Thirty-six patients who underwent hip arthroscopy operation were included. The volumes of some related muscles were measured in MRI images by 3D Slicer. We recorded and tested differences in traction force of five joint capsule physical states, including before (State 1) and after joint capsule puncture (State 2), after the establishment of anterolateral and mid-anterior approaches (State 3) and after incision of the joint capsule through these two approaches (States 4, 5). The correlation between muscle volume, BMI, LCEA, AA and SC was verified by Spearman test. Poisson regression was used to explain confounding variables. RESULTS: The average force at State 1 was 531.8 N. There were significant differences in traction force between these five states (p < 0.001). There was a significant positive correlation between muscle volumes and SC (p < 0.001). BMI had no correlation with SC (n.s.). The preoperative LCEA of the affected side was correlated with SC (p = 0.043). AA and SC were not correlated (n.s.). CONCLUSION: The physical states of the hip joint capsule affected traction force. Muscle volume rather than BMI is an ideal index to estimate preoperative traction force. LCEA affected traction force, whilst AA and Beighton score did not. Measuring the muscle volume can help estimate the most suitable traction force for the patient. LEVELS OF EVIDENCE: IV.

The association between air pollution, meteorological factors, and daily outpatient visits for urticaria in Shijiazhuang, Hebei Province, China: a time series analysis.

The associations of air pollution and meteorological factors with the outpatient visits of urticaria remain poorly studied. This study aimed to assess the association between air pollution, meteorological factors, and daily outpatient visits for urticaria in Shijiazhuang, China, during 2014-2019. Daily recordings of air pollutant concentrations, meteorological data, and outpatient visits data for urticaria were collected during the 6 years. Descriptive research methods were used to describe the distribution characteristics and demographic features of urticaria. A combination of the generalized linear regression model (GLM) and distribution lag nonlinear model (DLNM) was used to evaluate the lag association between environmental factors and daily outpatient visits for urticaria. Stratified analyses by gender (male; female) and age (< 18 years; 18-39 years; > 39 years) were further conducted. The dose-response relationship between daily urticaria visits and CO, NO2, O3, temperature, and relative humidity was nonlinear. High concentrations of CO, NO2, O3, and high temperatures increased the risk of urticaria outpatient visits. The maximum cumulative association of high concentrations of CO, NO2, and O3 was lag 0-14 days (CO: RR = 1.10, 95%CI: 1.06, 1.31; NO2: RR = 1.09, 95%CI: 1.01, 1.08; O3: RR = 1.16, 95%CI: 1.08, 1.25), and high temperatures was lag 0-7 days (RR = 1.27, 95%CI: 1.14, 1.41). Low concentrations of NO2, O3, and high humidity, on the other hand, act as protective factors for urticaria outpatient. The maximum cumulative association of low concentrations of NO2 was the 0-day lag (RR = 0.97, 95%CI: 0.95, 0.99), O3 was lag 0-5 days (RR = 0.94, 95%CI: 0.88, 0.99), and high humidity was lag 0-10 days (RR = 0.93, 95%CI: 0.89, 0.98). Stratified analyses showed that the risk of urticaria outpatient visits was higher for the males and in the < 18 years age group. In conclusion, we found that the development of urticaria in Shijiazhuang has a distinct seasonal and cyclical nature. Air pollutants and meteorological factors had varying degrees of influence on the risk of urticaria outpatient visits. This study provides indirect evidence for a link between air pollution, meteorological factors, and urticaria outpatient visits.

Preoperative systemic chemotherapy does not benefit for appendiceal pseudomyxoma peritonei.

BACKGROUND: Pseudomyxoma peritonei (PMP) is a clinically malignant tumour syndrome mainly derived from mucin-producing appendiceal tumours. This study aimed to explore the effect of preoperative systemic chemotherapy (PSC) before cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) on the safety and postoperative survival in patients with appendiceal PMP. METHODS: We performed a retrospective analysis including consecutive patients with PMP undergoing primary surgery between January, 2008 and December, 2019 in Aerospace Center Hospital. The clinical data and postoperative survival were compared between PSC group and non-PSC group. RESULTS: Seven hundred and fifty patients were included in the study. Significant differences were found between PSC group and non-PSC group on clinicopathological data and perioperative outcomes and the independent risk factor of serious complications was blood loss >1000 mL (P = 0.026). Shorter median overall survival (OS) was found (42 months, 95% CI 31.9-52.1) in PSC group than that (67 months 95% CI 44.5-89.5) in non-PSC group. In the stratified study with PCI < 20, CC 0/1 and low-grade pathological subtype, the OS from non-PSC group was significantly better than that in PSC group (log rank P-values are <0.001, 0.006 and <0.001, respectively). Multivariate survival analysis showed that CC 0/1, HIPEC, PCI < 20 and low-grade pathological subtype were the independent prognostic factors for better OS. CONCLUSIONS: PSC does not increase the risk of major perioperative complications in patients with appendiceal PMP, but it also does not bring postoperative survival benefits to patients either.

Arthroscopic Treatment for Femoroacetabular Impingement Syndrome in Adolescents: A Systematic Review and Meta-Analysis.

OBJECTIVE: The objective of this review was to analyze the effect of arthroscopic surgery for femoroacetabular impingement syndrome (FAI) in adolescents and factors that may influence the revision rate. DESIGN: Systematic review and meta-analysis. SETTING: PubMed, Scopus, Cochrane Library, EMBASE, and MEDLINE were searched from their earliest records to May 2021. PATIENTS: Adolescents who underwent primary arthroscopic treatment for FAI. INTERVENTIONS: Hip arthroscopic treatment. MAIN OUTCOME MEASURES: Patient-reported outcomes (PROs), alpha angle, revision rates, and the rate of complications. RESULTS: A total of 832 hips in 753 patients were included in this study. All PROs improved significantly. The modified Harris Hip Score pooled mean difference was 24.99 (95% CI, 22.88-27.10, P < 0.0001, I2 = 19.9%), Hip Outcome Score (HOS)-Sports-Specific Subscale was 35.88 (95% CI, 33.07-38.68, P < 0.0001, I2 = 0%), HOS-Activities of Daily Living was 23.53 (95% CI, 21.21-25.85, P < 0.0001, I2 = 0%), and the Nonarthritic Hip Score was 22.34 (95% CI, 18.40-26.28, P < 0.0001, I2 = 40.9%). The visual analog scale for pain decreased by 40.39 (44.39-36.40, P < 0.0001, I2 = 0%). The alpha angle decreased by 22.0 degrees from 62.9 degrees to 40.9 degrees after arthroscopic surgery. The rate of complication and revision surgery was 1.2% (10/832) and 3.4% (28/832), respectively, with high postoperative patient satisfaction. CONCLUSIONS: All PROs significantly improved after surgery, with a low rate of complications and reoperation. High postoperative patient satisfaction was also reported.

λ3-Iodane/Lewis Acid Mediated Intramolecular Cross-Nucleophile Coupling of ß-Amino Acrylates: Chemodivergent Syntheses of Indole Alkaloidal Frameworks.

Herein, we report an unprecedented intramolecular cross-nucleophile coupling strategy of indole tethered ß-amino acrylates using a catalyst system combining λ3-iodanes and Lewis acids to achieve the chemodivergent synthesis of three unique alkaloid skeletons. It was worth noting that the acquisition of spiroindolenines and azepino[4,5-b]indoles derivatives was switchable with choice of the Lewis acids. Moreover, the polycyclic spiroindolines containing a lactone fragment could also be accessed for the first time via cross-nucleophile coupling cascade intramolecular condensation sequence.

Association between rs735482 polymorphism and risk of cancer: A meta-analysis of 10 case-control studies.

Several studies have inspected the relationship between rs735482 polymorphism and the risk of some human cancers, but the findings remain controversial. We designed this meta-analysis to validate the association between rs735482 polymorphism and cancer risk. All articles were published before September 1, 2018 and searched in Pubmed, Embase, Web of Science, China National Knowledge Infrastructure, WangFang, and Chinese BioMedical databases, STATA 12.0 software was used for statistical analysis, which provides reasonable data and technical support for this article. A total of 10 studies were included in the meta-analysis, including 2652 cancer cases and 3536 rs735482 polymorphic controls. Data were directly extracted from these studies and odds ratios with 95% confidence intervals were computed to estimate the strength of the association. By pooling all eligible studies, the rs735482 polymorphism showed no significant association with susceptibility of several cancers in all the five genetic models (the allelic model: OR = 1.019, 95% CI: 0.916-1.134, P = .731). In addition, another adjusted OR data showed a significant increased risk between the rs735482 and susceptibility of several cancers (the codominant model BB vs AA: OR = 1.353, 95% CI: 1.033-1.774, P = .028) and the stratification analysis by ethnicity indicated the rs735482 is associated with an increased risk of cancer in Chinese group (BB vs AA, OR = 1.391, 95% CI = 1.054-1.837, P = .020; AB+BB vs AA OR = 1.253, 95% CI = 1.011-1.551, P = .039). However, the ERCC1 rs735482 is associated with a decreased risk of cancer in Italian group (AB vs AA, OR = 0.600, 95% CI = 0.402-0.859, P = .012; AB + BB vs AA, OR = 0.620, 95% CI = 0.424-0.908, P = .014). The results of this meta-analysis do not support the association between rs735482 polymorphism and cancer risk. But stratified analysis showed that rs735482 significantly increased the risk of cancer in Chinese while decreased the risk of cancer in Italian. Because of the limited number of samples, larger and well-designed researches are needed to estimate this association in detail.

Inonotus obliquus and its bioactive compounds alleviate non-alcoholic fatty liver disease via regulating FXR/SHP/SREBP-1c axis.

Non-alcoholic fatty liver disease (NAFLD) is currently the most common chronic liver disease worldwide. However, there is still lack of specific drugs for treating NAFLD in clinic. Inonotus obliquus (IO), a folk medicinal fungus, has long been used to prevent against metabolic syndrome related diseases, such as hypertension and diabetes, etc. However, the study of IO anti-NAFLD effect has been reported rarely. This study aimed to investigate whether IO has an inhibitory effect on NAFLD, identify the active compounds in IO and clarify the underlying mechanisms of its anti-NAFLD effects. The results of Oil Red O(ORO) and Hematoxylin-Eosin (HE) staining, lipid extraction and determination showed that IO and its extracts, including inotodiol (Ino), lanosterol (Lan) and trametenolic acid (TA), could remarkably ameliorate lipid accumulation in MCD diet-induced mouse livers or OA-induced LO2 hepatocytes. Moreover, qPCR analysis revealed that IO and its compounds significantly downregulated the mRNA levels of lipogenic genes, such as SREBP-1c, ACC1 and FASN, and upregulated the mRNA levels of FXR and SHP. We found that the administration of guggulsterone (GS), a FXR inhibitor, abolished the inhibitory effect of Ino on lipid deposition in OA-induced LO2 cells. In conclusion, IO and its compounds attenuate hepatic lipid accumulation in NAFLD by inhibiting liver lipogenesis. The anti-NAFLD effects of Ino, a bioactive compound in IO, are through regulating FXR/SHP/SREBP-1c pathway. Our results suggested that IO and its bioactive compound Ino may become promising drugs to treat NAFLD.