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  • BMJ  (18)
  • 1
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    Lenvatinib plus anti-PD-1 antibodies as conversion therapy for patients with unresectable intermediate-advanced hepatocellular carcinoma: a single-arm, phase II trial
    BMJ ; 2023
    In:  Journal for ImmunoTherapy of Cancer Vol. 11, No. 9 ( 2023-09), p. e007366-
    Details
    In: Journal for ImmunoTherapy of Cancer, BMJ, Vol. 11, No. 9 ( 2023-09), p. e007366-
    Abstract: Over 70% of the patients with hepatocellular carcinoma (HCC) are diagnosed at an advanced stage and lose the opportunity for radical surgery. Combination therapy of tyrosine kinase inhibitors (TKIs) and anti-programmed cell death protein-1 (PD-1) antibodies has achieved a high tumor response rate in both the first-line and second-line treatment of advanced HCC. However, few studies have prospectively evaluated whether TKIs plus anti-PD-1 antibodies could convert unresectable intermediate-advanced HCC into resectable disease. Methods This single-arm, phase II study enrolled systemic therapy-naïve adult patients with unresectable Barcelona Clinic Liver Cancer stage B or C HCC. Patients received oral lenvatinib one time per day plus intravenous anti-PD-1 agents every 3 weeks (one cycle). Tumor response and resectability were evaluated before the fourth cycle, then every two cycles. The primary endpoint was conversion success rate by investigator assessment. Secondary endpoints included objective response rate (ORR) by independent imaging review (IIR) assessment per modified RECIST (mRECIST) and Response Evaluation Criteria in Solid Tumors, V.1.1 (RECIST 1.1), progression-free survival (PFS) and 12-month recurrence-free survival (RFS) rate by IIR per mRECIST, R0 resection rate, overall survival (OS), and safety. Biomarkers were assessed as exploratory objectives. Results Of the 56 eligible patients enrolled, 53 (94.6%) had macrovascular invasion, and 16 (28.6%) had extrahepatic metastasis. The median follow-up was 23.5 months. The primary endpoint showed a conversion success rate of 55.4% (31/56). ORR was 53.6% per mRECIST and 44.6% per RECIST 1.1. Median PFS was 8.9 months, and median OS was 23.9 months. Among the 31 successful conversion patients, 21 underwent surgery with an R0 resection rate of 85.7%, a pathological complete response rate of 38.1%, and a 12-month RFS rate of 47.6%. Grade ≥3 treatment-related adverse events were observed in 42.9% of patients. Tumor immune microenvironment analysis of pretreatment samples displayed significant enrichment of CD8 + T cells (p=0.03) in responders versus non-responders. Conclusion Lenvatinib plus anti-PD-1 antibodies demonstrate promising efficacy and tolerable safety as conversion therapy in unresectable HCC. Pre-existing CD8 + cells are identified as a promising biomarker for response to this regimen. Trial registration number Chinese Clinical Trial Registry, ChiCTR1900023914.
    Type of Medium: Online Resource
    ISSN: 2051-1426
    URL: Article
    DOI: 10.1136/jitc-2023-007366
    Language: English
    Publisher: BMJ
    Publication Date: 2023
    detail.hit.zdb_id: 2719863-7
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  • 2
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    Safety and efficacy of tranexamic acid in paediatric cardiac surgery: study protocol for a double-blind randomised controlled trial
    BMJ ; 2019
    In:  BMJ Open Vol. 9, No. 11 ( 2019-11), p. e032642-
    Details
    In: BMJ Open, BMJ, Vol. 9, No. 11 ( 2019-11), p. e032642-
    Abstract: An initial retrospective study suggested that tranexamic acid (TXA) administration increased the incidence of seizures in paediatric patients undergoing cardiac surgery. However, the efficacy of TXA in paediatric cardiac surgery remains unclear owing to the small sample sizes of the studies. Therefore, this study will investigate the efficacy and safety of TXA in paediatric patients undergoing cardiac surgery. We hypothesised that TXA may increase the incidence of postoperative seizures with no effect on postoperative allogeneic transfusion in paediatric patients undergoing cardiac surgery. The pragmatic study will provide important implications for paediatric cardiac surgery. Methods and analysis This will be a single-centre prospective, double-blind randomised controlled trial. The plan is to enrol in the study 2090 paediatric patients aged 31 days to 7 years who will be undergoing cardiac surgery with cardiopulmonary bypass (CPB). All eligible participants will be randomly assigned to either the TXA or placebo group by using a Web-based randomisation service in a 1:1 ratio. The primary safety end point will be postoperative seizures until hospital discharge, and the primary efficacy end point will be the volume of allogeneic red blood cell transfusion after termination of CPB. All patients will be followed up for 1 year postdischarge. All data will be analysed in accordance with the intention-to-treat principle. Ethics and dissemination This study was approved by the institutional review board of Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (No 20191195). Written informed consent will be obtained from the parents/legal guardian of each patient because all participants will be 〈 18 years of age. The results of the trial will be published in an international peer-reviewed journal. Trial registration number Chinese Clinical Trial Register (ChiCTR1900024131).
    Type of Medium: Online Resource
    ISSN: 2044-6055 , 2044-6055
    URL: Article
    DOI: 10.1136/bmjopen-2019-032642
    Language: English
    Publisher: BMJ
    Publication Date: 2019
    detail.hit.zdb_id: 2599832-8
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  • 3
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    Exome-wide association study identifies four novel loci for systemic lupus erythematosus in Han Chinese population
    BMJ ; 2018
    In:  Annals of the Rheumatic Diseases Vol. 77, No. 3 ( 2018-03), p. 417-417
    Details
    In: Annals of the Rheumatic Diseases, BMJ, Vol. 77, No. 3 ( 2018-03), p. 417-417
    Abstract: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease of considerable genetic predisposition. Genome-wide association studies have identified tens of common variants for SLE. However, the majority of them reside in non-coding sequences. The contributions of coding variants have not yet been systematically evaluated. Methods We performed a large-scale exome-wide study in 5004 SLE cases and 8179 healthy controls in a Han Chinese population using a custom exome array, and then genotyped 32 variants with suggestive evidence in an independent cohort of 13 246 samples. We further explored the regulatory effect of one novel non-coding single nucleotide polymorphism (SNP) in ex vivo experiments. Results We discovered four novel SLE gene regions ( LCT , TPCN2 , AHNAK2 and TNFRSF13B ) encompassing three novel missense variants (XP_016859577.1:p.Asn1639Ser, XP_016859577.1:p.Val219Phe and XP_005267356.1:p.Thr4664Ala) and two non-coding variants (rs10750836 and rs4792801) with genome-wide significance (p meta 〈 5.00×10 −8 ). These variants are enriched in several chromatin states of primary B cells. The novel intergenic variant rs10750836 exhibited an expression quantitative trait locus effect on the TPCN2 gene in immune cells. Clones containing this novel SNP exhibited gene promoter activity for TPCN2 (P=1.38×10 −3 ) whose expression level was reduced significantly in patients with SLE (P 〈 2.53×10 −2 ) and was suggested to be further modulated by rs10750836 in CD19+ B cells (P=7.57×10 −5 ) in ex vivo experiments. Conclusions This study identified three novel coding variants and four new susceptibility gene regions for SLE. The results provide insights into the biological mechanism of SLE.
    Type of Medium: Online Resource
    ISSN: 0003-4967 , 1468-2060
    URL: Article
    URL: Article
    DOI: 10.1136/annrheumdis-2017-211823
    DOI: 10.1136/annrheumdis-2017-211823.supp1
    RVK:
    XA 10000
    Language: English
    Publisher: BMJ
    Publication Date: 2018
    detail.hit.zdb_id: 1481557-6
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  • 4
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    Comparison of novel oncology drugs that received dual approval from the US accelerated approval and EU conditional marketing authorisation pathways, 2006–2021: a cross-sectional study
    BMJ ; 2023
    In:  BMJ Open Vol. 13, No. 6 ( 2023-06), p. e069132-
    Details
    In: BMJ Open, BMJ, Vol. 13, No. 6 ( 2023-06), p. e069132-
    Abstract: We aimed to provide insight into differences in drug review decisions made by the US Food and Drug Administration’s (FDA) accelerated approval (AA) pathway and the European Medicines Agency’s (EMA) conditional marketing authorisation (CMA) pathway, and to add to the current knowledge base of drug approval processes. Design, setting, participants This cross-sectional study thoroughly examines novel oncology drugs with dual approval through FDA AA and EMA CMA between 2006 and 2021. Statistical analysis was performed from June to July 2022. Primary and secondary outcome measures The study examined the regulatory differences between regions for dually approved novel oncology drugs, including approval decisions, pivotal efficacy clinical trials, speed of review and postmarketing obligations. Results During this time period, there was a difference in the use of the FDA AA and the EMA CMA (FDA: EMA: 41.2%: 70.0%, p 〈 0.05). Of the 25 drugs approved by both the FDA AA and the EMA CMA, 22 (88.0%) of the regulatory decisions were based on the same pivotal clinical trials. But there were more differences in the requirements for postmarketing obligations, with the EMA’s postmarketing obligations focusing on the efficacy and safety of the drug (EMA: FDA: 63.0%: 27.0%, p＜0.05) and the FDA’s postmarketing obligations focusing more on the efficacy (FDA: EMA: 73.0%: 23.9%, p＜0.05). In addition, both the USA and EU had some postmarketing obligations completed beyond the schedule (30.4% and 19.2% in the USA and EU, respectively), with the longest delays lasting 3.7 years (0.2–3.7 years) and 3.3 years (0.04–3.3 years) in the USA and EU, respectively. Conclusions The FDA and EMA have different orientations and benefit–risk balance considerations in the use of AA or CMA. It is also the case that the shortcomings in the design and implementation of postmarketing studies have made it a challenge to obtain the evidence needed to confirm a drug’s benefits.
    Type of Medium: Online Resource
    ISSN: 2044-6055 , 2044-6055
    URL: Article
    URL: Article
    DOI: 10.1136/bmjopen-2022-069132
    DOI: 10.1136/bmjopen-2022-069132.supp1
    Language: English
    Publisher: BMJ
    Publication Date: 2023
    detail.hit.zdb_id: 2599832-8
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  • 5
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    Prevalence, risk factors, and mortality of COPD in young people in the USA: results from a population-based retrospective cohort
    BMJ ; 2023
    In:  BMJ Open Respiratory Research Vol. 10, No. 1 ( 2023-07), p. e001550-
    Details
    In: BMJ Open Respiratory Research, BMJ, Vol. 10, No. 1 ( 2023-07), p. e001550-
    Abstract: Chronic obstructive pulmonary disease (COPD) has been considered a disease of the elderly, but it could also occur in young people aged 20–50 years. However, the characteristics and prognosis of COPD in such young people remain unclear. Methods Our retrospective cohort study was based on the National Health and Nutrition Examination Survey (NHANES). Participants who 20–50 years old at baseline and completed the pulmonary function test were enrolled in our study cohort. These participants were followed up to 31 December 2019. The sample weight and Taylor Linearization Procedures were adapted to make representative estimations of prevalence and baseline characteristics. The weighted logistic regression model was used to assess the risk factors. The propensity score method and Cox proportional hazard models were applied to calculate the risk of mortality. Results The weighted prevalence of COPD in young people in the USA was 1.64% and it increased with age, with a higher prevalence in males than females (2.59% vs 0.72%, p 〈 0.001). The proportion of Global Initiative for COPD 1–2 was 96.7%. Males (OR=4.56, 95% CI: 2.74 to 7.61), non-Hispanic black (OR=2.77; 95% CI: 1.14 to 6.75), non-Hispanic white (OR=4.93; 95% CI: 2.16 to 11.28) and smoking (current smoking, OR=2.36; 95% CI: 1.40 to 3.98; ever smoking, OR=1.92; 95% CI: 1.05 to 3.51; passive smoking, OR=2.12; 95% CI: 1.41 to 3.20) were shown to be independent risk factors for COPD in young people. Compared with those matched by sex, age and race, the young people with COPD had a higher risk of all-cause death (HR=3.314, p 〈 0.001). Conclusion COPD in young people has a low prevalence in the USA and its independent risk factors included male, race (non-Hispanic black and non-Hispanic white) and smoking. Young COPD has a higher risk of all-cause mortality than the matched non-COPD.
    Type of Medium: Online Resource
    ISSN: 2052-4439
    URL: Article
    DOI: 10.1136/bmjresp-2022-001550
    Language: English
    Publisher: BMJ
    Publication Date: 2023
    detail.hit.zdb_id: 2736454-9
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  • 6
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    Community-based stroke system of care improves patient outcomes in Chinese rural areas
    BMJ ; 2018
    In:  Journal of Epidemiology and Community Health Vol. 72, No. 7 ( 2018-07), p. 630-635
    Details
    In: Journal of Epidemiology and Community Health, BMJ, Vol. 72, No. 7 ( 2018-07), p. 630-635
    Abstract: Building effective and efficient stroke care systems is a key step in improving prevention, treatment and rehabilitation of stroke. The aim of this study was to evaluate the effectiveness of this stroke system of care on stroke management during a 2-year follow-up. Methods A stroke system of care was developed from November 2009 to November 2010 in three townships in Ganyu County. Additional three matched townships were invited as controls. We first investigated the stroke incidence of these populations. Subsequently, this stroke system of care and an educational campaign in the three intervention townships were implemented and the effectiveness of the system was evaluated in the next 2 years. Results At postintervention, more patients in the intervention communities obtained stroke knowledge and then the proportion of patients with stroke who were admitted within 3 hours of onset markedly increased in 2012 (12.0% vs 8.1%, p=0.044) and in 2013 (15.2% vs 9.7%, p=0.008) compared with those in the control communities. In the intervention communities, this proportion of patients with acute ischaemic stroke who received thrombolytic treatment was markedly raised from 2.1% in 2012 to 3.0% in 2013. More importantly, the fatality rate substantially decreased in 2013 in the intervention communities compared with that in the control communities (6.1% vs 9.7%, p=0.032). Similarly, the disability rate significantly decreased in 2013 (45.3% vs 51.5%, p=0.045). Conclusions The community-based stroke system of care was effective and practical for optimising stroke treatments and improving patient outcomes. Trial registration number ChiCTR-RCH-13003408, Post-results.
    Type of Medium: Online Resource
    ISSN: 0143-005X , 1470-2738
    URL: Article
    URL: Article
    DOI: 10.1136/jech-2017-210185
    DOI: 10.1136/jech-2017-210185.supp1
    Language: English
    Publisher: BMJ
    Publication Date: 2018
    detail.hit.zdb_id: 2015405-7
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  • 7
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    Exome sequencing identifies SLC17A9 pathogenic gene in two Chinese pedigrees with disseminated superficial actinic porokeratosis
    BMJ ; 2014
    In:  Journal of Medical Genetics Vol. 51, No. 10 ( 2014-10), p. 699-704
    Details
    In: Journal of Medical Genetics, BMJ, Vol. 51, No. 10 ( 2014-10), p. 699-704
    Type of Medium: Online Resource
    ISSN: 0022-2593 , 1468-6244
    URL: Article
    DOI: 10.1136/jmedgenet-2014-102486
    RVK:
    WA 15000
    Language: English
    Publisher: BMJ
    Publication Date: 2014
    detail.hit.zdb_id: 2009590-9
    SSG: 12
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  • 8
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    Generation of a safe and efficacious llama single-domain antibody fragment (vHH) targeting the membrane-proximal region of 4-1BB for engineering therapeutic bispecific antibodies for cancer
    BMJ ; 2021
    In:  Journal for ImmunoTherapy of Cancer Vol. 9, No. 6 ( 2021-06), p. e002131-
    Details
    In: Journal for ImmunoTherapy of Cancer, BMJ, Vol. 9, No. 6 ( 2021-06), p. e002131-
    Abstract: The discovery of checkpoint inhibitors towards cytotoxic T-lymphocyte protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) has been revolutionary for the treatment of cancers. These therapies have only offered an average of 20%–30% response rates across the tumor spectrum and the combination of agonists towards the tumor-necrosis superfamily members, such as 4-1BB and CD40, has shown potent efficacy in preclinical studies; however, these agonists have exhibited high degrees of toxicity with limited efficacy in human trials. In this study, we have generated a single-domain antibody towards a unique epitope of 4-1BB that limits its potential on-target toxicity while maintaining sufficient potency. This 4-1BB binder is ideal for use in the engineering of multispecific antibodies to localize 4-1BB activation within the tumor microenvironment, as shown here by a anti-PD-L1/4-1BB bispecific candidate (PM1003). Methods To determine the functional activity of the 4-1BB- and PD-L1-binding elements of PM1003, in vitro luciferase reporter and primary cell assays were used to test the potency of programmed cell death 1 ligand 1 (PD-L1) blockade and PD-L1-mediated 4-1BB activation via cross-bridging. X-ray crystallography was conducted to resolve the binding epitopes of the respective binding arms, and accurate binding kinetics were determined using standard affinity measurement techniques. Human 4-1BB and/or PD-L1 knock-in mice were used in cancer models for testing the in vivo antitumor efficacy of PM1003, and safety was evaluated further. Results PM1003 shows potent activation of 4-1BB and blockade of PD-L1 in cell-based assays. 4-1BB activation was exerted through the bridging of PD-L1 on target cells and 4-1BB on effector cells. No PD-L1-independent activation of 4-1BB was observed. Through X-ray crystallography, a unique binding epitope in the cysteine-rich domain 4 (CRD4) region was resolved that provides high potency and potentially low on-target toxicity as determined by primary immune cell assays and toxicity evaluation in vivo . Conclusions A unique single-domain antibody was discovered that binds to the CRD4 domain of 4-1BB. When incorporated into a 4-1BB/PD-L1 bispecific (PM1003), we have shown the potent inhibition of PD-L1 activity with 4-1BB agonism upon cross-bridging with PD-L1 in vitro . Antitumor activity with minimal toxicity was found in vivo . Thus, PM1003 is a uniquely differentiating and next generation therapeutic agent for cancer therapy.
    Type of Medium: Online Resource
    ISSN: 2051-1426
    URL: Article
    DOI: 10.1136/jitc-2020-002131
    Language: English
    Publisher: BMJ
    Publication Date: 2021
    detail.hit.zdb_id: 2719863-7
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  • 9
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    Combination of AKT1 and CDH1 mutations predicts primary resistance to immunotherapy in dMMR/MSI-H gastrointestinal cancer
    BMJ ; 2022
    In:  Journal for ImmunoTherapy of Cancer Vol. 10, No. 6 ( 2022-06), p. e004703-
    Details
    In: Journal for ImmunoTherapy of Cancer, BMJ, Vol. 10, No. 6 ( 2022-06), p. e004703-
    Abstract: Gastrointestinal (GI) cancer is the second most common cancer type with mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) phenotype that is expected to respond to immune-checkpoint inhibitors (ICIs). However, approximately half of the patients with dMMR/MSI-H GI cancer derive no benefit from ICIs. We sought to identify the predictors of primary resistance to ICIs in dMMR/MSI-H GI cancer. Methods Three independent cohorts were included: (1) the discovery cohort (65 patients with dMMR/MSI-H GI cancer) with ICI efficacy data and pre-ICIs tissue samples for genomic profile and tumor immune infiltration; (2) the validation cohort (22 patients with dMMR/MSI-H GI cancer) with ICI efficacy data and pre-ICIs plasma samples for genomic profile; and (3) the TCGA (The Cancer Genome Atlas) cohort not receiving ICIs (152 patients with MSI-H GI cancer) with genomic profile and survival data. Results AKT1 and CDH1 mutations were identified as independent predictors of poor progression-free survival (PFS) and primary resistance to ICIs in dMMR/MSI-H GI cancer. We combined these two genes as an immuno-oncology therapy predictor (IOpred), which could recognize 52.4% (11/21) of dMMR/MSI-H patients with primary resistance to ICIs with a positive predictive value (PPV) of 91.7% (11/12). Receiver operating characteristic analysis demonstrated IOpred with a good performance in predicting primary resistance (area under the curve 0.751). Patients with IOpred-Mut (mutant AKT1 or CDH1) GI cancer had significantly shorter PFS (HR=8.36, p 〈 0.001) and overall survival (OS, HR=5.17, p 〈 0.001) than IOpred-WT (wild-type for both AKT1 and CDH1) cases upon ICI treatment. The validation cohort also confirmed the correlation between IOpred-mutation and poorer prognosis (PFS, HR=4.68, p=0.004; OS, HR=15.98, p 〈 0.001) in dMMR/MSI-H patients after ICIs. The PPV of IOpred in identifying primary resistance to ICIs was 80% (4/5) in the validation cohort. Additionally, IOpred-WT patients could be further stratified by tumor mutational burden (TMB), wherein TMB-low patients (TMB ≤26.19 mutations per megabase (Mb)) had a significantly higher primary resistance rate to ICIs (34.8% vs 6.7%, p=0.014) and poorer PFS (HR=3.46, p=0.008) and OS (HR=4.42, p=0.047) than TMB-high patients (TMB 〉 26.19 mutations/Mb). Conclusions IOpred was identified as a powerful predictor of primary resistance to ICIs in dMMR/MSI-H GI cancer, which might serve as a promising biomarker to help guide immunotherapy decision-making.
    Type of Medium: Online Resource
    ISSN: 2051-1426
    URL: Article
    DOI: 10.1136/jitc-2022-004703
    Language: English
    Publisher: BMJ
    Publication Date: 2022
    detail.hit.zdb_id: 2719863-7
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  • 10
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    ADCOMS: a composite clinical outcome for prodromal Alzheimer's disease trials
    BMJ ; 2016
    In:  Journal of Neurology, Neurosurgery & Psychiatry Vol. 87, No. 9 ( 2016-09), p. 993-999
    Details
    In: Journal of Neurology, Neurosurgery & Psychiatry, BMJ, Vol. 87, No. 9 ( 2016-09), p. 993-999
    Type of Medium: Online Resource
    ISSN: 0022-3050 , 1468-330X
    URL: Article
    DOI: 10.1136/jnnp-2015-312383
    RVK:
    XA 10000
    Language: English
    Publisher: BMJ
    Publication Date: 2016
    detail.hit.zdb_id: 1480429-3
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