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Genetic insights into thymic carcinomas and thymic neuroendocrine neoplasms denote prognosis signatures and pathways

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Chinese Medical Journal 2023年第22期136卷 2712-2721页

作者： Shuyuan Wang Zhitao Gu Lei Zhu Yuchen han Hong Yu Wentao Fang baohui han Department of Respiratory and Critical Care Medicine Shanghai Chest HospitalShanghai Jiao Tong University School of MedicineShanghai 200030China Department of Thoracic Surgery Shanghai Chest HospitalShanghai Jiao Tong University School of MedicineShanghai 200030China Department of Pathology Shanghai Chest HospitalShanghai Jiao Tong University School of MedicineShanghai 200030China Department of Radiology Shanghai Chest HospitalShanghai Jiao Tong University School of MedicineShanghai 200030China

Background:Thymic carcinomas(TCs)and thymic neuroendocrine neoplasms(TNENs)are two aggressive subtypes of thymic malignancy.Traditional therapy for advanced TCs and TNENs has limited outcome.New genomic profiling of TCs and TNENs might provide insights that contribute to the development of new treatment approaches.Methods:We used gene panel sequencing technologies to investigate the genetic aberrations of 32 TC patients and 15 TNEN patients who underwent surgery at Shanghai Chest Hospital between 2015 and 2017.Patient samples were sequenced using a 324-gene platform with licensed technologies.In this study,we focused on clinically relevant genomic alterations(CRGAs),which are previously proven to be pathogenic alterations,to identify the pathology-specific mutational patterns,prognostic signatures of TCs and TNENs.Results:The mutational profiles between TCs and TNENs were diverse.The genetic alterations that ranked highest in TCs were in CDKN2A,TP53,ASXL1,CDKN2B,PIK3C2G,PTCH1,and ROS1,while those in TNENs were in MEN1,MLL2,APC,RB1,and TSC2.Prognostic analysis showed that mutations of ROS1,CDKN2A,CDKN2B,BRAF,and BAP1 were significantly associated with worse outcomes in TC patients,and that mutation of ERBB2 indicated shortened disease-free survival(DFS)and overall survival(OS)in TNEN patients.Further investigation found that the prognosis-related genes were focused on signal pathways of cell cycle control,chromatin remodeling/DNA methylation,phosphoinositide 3-kinases(PI3K)/protein kinase B(AKT)/mammalian target of rapamycin(mTOR),and receptor tyrosine kinase(RTK)/RAS/mitogen-activated protein kinase(MAPK)signaling.Conclusion:We profiled the mutational features of 47 Chinese patients with thymic malignancy of diverse pathologic phenotypes to uncover the integrated genomic landscape of these rare tumors,and identified the pathology-specific mutational patterns,prognostic signatures,and potential therapeutic targets for TCs and TNENs.

关键词： Mutational profile Thymic carcinomas Thymic neuroendocrine neoplasms Pathologic subtypes Prognosis Thymic malignancy

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Identification of FUT7 hypomethylation as the blood biomarker in the prediction of early-stage lung cancer

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遗传学报:英文版 2023年第8期50卷 573-581页

作者： Rong Qiao Feifei Di Jun Wang Yujie Wei Tian Xu Liping Dai Wanjian Gu baohui han Rongxi Yang Department of Pulmonary Medicine Shanghai Chest HospitalShanghai Jiaotong UniversityShanghai 200030China Nanjing TANTICA Biotechnology Co.Ltd NanjingJiangsu 210061China Department of Clinical Laboratory Jiangsu Province Hospital of Chinese MedicineNanjingJiangsu 210029China Henan Institute of Medical and Pharmaceutical Sciences Academy of Medical ScienceZhengzhou UniversityZhengzhouHenan 450001China Department of Epidemiology and Biostatistics School of Public HealthNanjing Medical UniversityNanjingJiangsu 211166China Department of Environmental Genomics Jiangsu Key Laboratory of Cancer BiomarkersPrevention and TreatmentCollaborative Innovation Center for Cancer Personalized MedicineNanjing Medical UniversityNanjingJiangsu 211166China Department of Genetic Toxicology The Key Laboratory of Modern Toxicology of Ministry of EducationCenter for Global HealthSchool of Public HealthNanjing Medical UniversityNanjingJiangsu 211166China

Early detection of lung cancer (LC) is vital for reducing LC-related mortality. However, noninvasive diagnostic tools remain a great challenge. We aim to identify blood-based biomarkers for the early detection of LC. Here, LC-associated hypomethylation in alpha-1,3-fucosyltransferase VII (FUT7) is identified via the Illumina 850K array in a discovery study and validated by mass spectrometry in two independent casecontrol studies with blood samples from 1720 LC patients (86.8% LC at stage I, blood is collected before surgery and treatment) and 3143 healthy controls. Compared to the controls, blood-based FUT7 hypomethylation is identified in LC patients at stage I, and even in LC patients with malignant nodules ≤1 cm and in patients with adenocarcinoma in situ. Gender plays a role in the LC-associated FUT7 hypomethylation in blood, which is more significant in males than in females. We also reveal that FUT7 hypomethylation in LC could be enhanced by the advanced stage of cancer, involvement of lymph nodes, and larger tumor size. Based on a large sample size and semi-quantitative methods, our study reveals a strong association between blood-based FUT7 hypomethylation and LC, suggesting that methylation signatures in blood may be a group of potential biomarkers for detection of early-stage LC.

关键词： Lung cancer Early detection DNA methylation FUT7 Mass spectrometry

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Anlotinib as third- or further-line therapy for short-term relapsed small-cell lung cancer: subgroup analysis of a randomized phase 2 study (ALTER1202)

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Frontiers of Medicine 2022年第5期16卷 766-772页

作者： Jianhua Shi Ying Cheng Qiming Wang Kai Li Lin Wu baohui han Gongyan Chen Jianxing He Jie Wang Haifeng Qin Xiaoling Li Department of Medical Oncology Linyi Cancer HospitalLinyi 276002China Department of Thoracic Medical Oncology Jilin Cancer HospitalChangchun 130012China Department of Internal Medicine Affiliated Cancer Hospital of Zhengzhou UniversityHenan Cancer HospitalZhengzhou 450003China Department of Pulmonary Oncology Tianjin Medical University Cancer Institute and HospitalTianjin 300060China Department of Thoracic Medical Oncology The Affiliated Cancer Hospital of Xiangya School of MedicineCentral South University(Hunan Cancer Hospital)Changsha 410031China Department of Respiratory Medicine Shanghai Chest HospitalShanghai Jiao Tong UniversityShanghai 200030China Department of Respiratory Medicine Harbin Medical University Cancer HospitalHarbin 150081China Department of Thoracic Surgery The First Affiliated Hospital of Guangzhou Medical UniversityGuangzhou 510120China National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China Department of Pulmonary Oncology The Fifth Medical Centre of Chinese PLA General HospitalBeijing 100039China Department of Medical Oncology Liaoning Cancer HospitalShenyang 110042China

Patients with small-cell lung cancer (SCLC) relapse within months after completing previous therapies. This study aimed to investigate the efficacy and safety of anlotinib as third- or further-line therapy in patients with short-term relapsed SCLC from ALTER1202. Patients with short-term relapsed SCLC (disease progression within 3 months after completing ≥ two lines of chemotherapy) in the anlotinib (n = 67) and placebo (n = 34) groups were analyzed. The primary endpoint was progression-free survival (PFS). The secondary endpoints included overall survival, objective response rate (ORR), disease control rate, and safety. Anlotinib significantly improved median PFS/OS (4.0 vs. 0.7 months, P han that in the placebo group (73.1% vs. 11.8%, P < 0.001). The most common adverse events (AEs) were hypertension (38.8%), loss of appetite (28.4%), and fatigue (22.4%) in the anlotinib group and gamma-glutamyl transpeptidase elevation (20.6%) in the placebo group. No grade 5 AEs occurred. For patients with short-term relapsed SCLC, third- or further-line anlotinib treatment was associated with improved survival benefit. Further studies are warranted in this regard.

关键词： anlotinib chemotherapy short-term relapsed small-cell lung cancer

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Equivalent efficacy assessment of QL1101 and bevacizumab in nonsquamous non-small cell lung cancer patients:A two-year follow-up data update

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Chinese Journal of Cancer Research 2022年第1期34卷 28-39页

作者： Jun Lu Tianqing Chu Hongyu Liu Minjuan Hu Yuqing Lou Yanwei Zhang Zhiqiang Gao Wei Zhang Xueyan Zhang Huimin Wang Hua Zhong baohui han Department of Pulmonary Medicine Shanghai Chest HospitalShanghai Jiao Tong UniversityShanghai 200030China Shanghai Institute of Thoracic Oncology Shanghai Chest HospitalShanghai Jiao Tong UniversityShanghai 200030China Translational Medical Research Platform for Thoracic Oncology Shanghai Chest HospitalShanghai Jiao Tong UniversityShanghai 200030China Department of Bio-bank Shanghai Chest HospitalShanghai Jiao Tong UniversityShanghai 200030China

Objective: Anti-vascular endothelial growth factor(VEGF) monoclonal antibodies are an effective means of treating non-small cell lung cancer(NSCLC). Here, we aim to update the equivalent efficacy assessment between QL1101 and bevacizumab based on two-year follow-up data.Methods: In total, 535 eligible NSCLC patients were enrolled in this randomized controlled trial. Patients were randomly assigned 1:1 to the QL1101 group and the bevacizumab group. The full end time of this study was defined as 24 months after the last enrolled patient was randomized. The primary endpoint was the objective response rate(ORR);equivalence was confirmed if the two-sided 90% confidence interval(90% CI) of the relative risk was within the range of 0.75-1.33. The secondary endpoints were progression-free survival(PFS) and overall survival(OS).Results: The two-year updated data showed similar ORR(QL1101 vs. bevacizumab: 53.1% vs. 54.3%;relative risk=0.977;90% CI: 0.838-1.144), PFS(235 d vs. 254 d, log-rank P=0.311), and OS(577 d vs. 641 d, log-rank P=0.099) results between the QL1101 group and the bevacizumab group. The mean shrinkage ratio of targeted lesions was also similar between the QL1101 group and the bevacizumab group(22.5% vs. 23.5%). For patients who received QL1101 maintenance therapy, similar results were shown between the QL1101 group(n=157) and the bevacizumab group(n=148)(PFS: 253 d vs. 272 d, log-rank P=0.387;OS: 673 d vs. 790 d, log-rank P=0.101;mean tumor shrinkage rate: 26.6% vs. 27.5%).Conclusions: This study reported that QL1101 had similar efficacy in treating nonsquamous NSCLC in terms of ORR, PFS and OS based on two-year updated data, providing a basis for the clinical application of QL1101.

关键词： QL1101 biosimilar non-small cell lung cancer bevacizumab VEGF

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Third-line or above anlotinib in relapsed and refractory small cell lung cancer patients with brain metastases:A post hoc analysis of ALTER1202,a randomized,double-blind phase 2 study

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Cancer Innovation 2023年第3期2卷 181-190页

作者： Ying Cheng Qiming Wang Kai Li Jianhua Shi baohui han Lin Wu Gongyan Chen Jianxing He Jie Wang Haifeng Qin Xiaoling Li Department of Thoracic Medical Oncology Jilin Cancer HospitalChangchunChina Department of Internal Medicine Affiliated Cancer Hospital of Zhengzhou UniversityHenan Cancer HospitalZhengzhouChina Department of Pulmonary Oncology Tianjin Medical University Cancer HospitalTianjinChina Department of Medical Oncology Linyi Cancer HospitalLinyiChina Department of Respiratory Medicine Shanghai Chest HospitalShanghai Jiaotong UniversityShanghaiChina Department of Thoracic Medical Oncology Hunan Cancer HospitalChangshaChina Department of Respiratory Medicine Harbin Medical University Cancer HospitalHarbinChina Department of Thoracic Surgery The First Affiliated Hospital of Guangzhou Medical UniversityGuangzhouChina Department of Thoracic Medical Oncology Cancer Hospital Chinese Academy of Medical SciencesBeijingChina Department of Pulmonary Oncology The Fifth Medical Centre of Chinese PLA General HospitalBeijingChina Department of Medical Oncology Liaoning Cancer Hospital and InstituteShenyangChina

Background:The prognosis of patients with small cell lung cancer(SCLC)and brain metastases(BM)was poor.This study aimed to explore the efficacy and safety of anlotinib as third-line or above treatment in SCLC with BM.Methods:This was a subgroup analysis of the ALTER1202 trial,which was a randomized,placebo-controlled trial aimed to evaluate the role of anlotinib as third-line treatment or above in patients with SCLC.This study included patients with BM at baseline.The efficacy and safety outcomes included progression-free survival(PFS),overall survival(OS),central nervous system(CNS),objective response rate(ORR),CNS disease control rate(DCR),time to CNS progression,and adverse events(AEs).Results:Twenty-one and nine patients with BM were included in the anlotinib and placebo groups,respectively.The median PFS and OS were 3.8 months(95%confidence interval[CI]:1.8-6.1)and 6.1 months(95%CI:4.1-8.0)in the anlotinib group.Anlotinib was associated with a significant improvement in PFS(hazard ratio[HR]=0.15,95%CI:0.04-0.51,p=0.0005)and OS(HR=0.26,95%CI:0.09-0.73,p=0.0061)than placebo.Anlotinib significantly prolonged the time to CNS progression(phan placebo(95.2%vs.22.2%,p=0.0001).The most common grade 3 or higher AEs were increased lipase(19.0%),hypertension(14.3%),and hyponatremia(14.3%)in the anlotinib group.Conclusions:Anlotinib proved to have potential CNS activity and a manageable toxicity profile in patients with SCLC and BM,significantly delaying CNS progression.

关键词： anlotinib angiogenesis inhibitors brain metastasis advanced small cell lung cancer safety

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Efficacy and safety evaluation of icotinib in patients with advanced non-small cell lung cancer

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Chinese Journal of Cancer Research 2013年第1期25卷 90-94页

作者： Aiqin Gu Chunlei Shi Liwen Xiong Tianqing Chu Jun Pei baohui han Department of pulmonary medicine Shanghai Chest Hospital Shanghai Jiao Tong University

Objective： To evaluate the efficacy and safety of icotinib hydrochloride in patients with advanced non-small cell lung cancer （NSCLC）. Methods： A total of 89 patients with stage IIIB or IV NSCLC received icotinib at a dose of 125 mg administered 3 times a day. Icotinib treatment was continued until disease progression or development of unacceptable toxicity. Results： A total of 89 patients were assessable. In patients treated with icotinib, the overall response rate （RR） was 36.0% （32/89）, and the disease control rate （DCR） was 69.7% （62/89）. RR and DCR were significantly improved in patients with adenocarcinoma versus non-adenocarcinoma （P〈0.05）. The symptom improvement rate was 57.3% （51/89）, and the main symptoms improved were cough, pain, chest distress, dyspnea, and Eastern Cooperative Oncology Group performance status. The main toxic effects were rash [30/89 （33.7%）] and diarrhea [15/89 （16.9%）]. The level of toxicity was typically low. Conclusions： The use of icofinib hydrochloride in the treatment of advanced NSCLC is efficacious and safe, and its toxic effects are tolerable.

关键词： Icotinib non-small cell lung cancer （NSCLC） targeted therapy

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基于多头概率稀疏自注意力模型的综合能源系统多元负荷短期预测

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电力建设 2024年第2期45卷 127-136页

作者：韩宝慧陆玲霞包哲静于淼浙江大学电气工程学院杭州市310027

精准的多元负荷短期预测是综合能源系统调度和运行的基础。综合能源系统中的多种负荷之间存在较强的耦合作用,目前已有的单一负荷预测难以挖掘不同负荷之间复杂的内在联系。对此,提出一种基于多头概率稀疏自注意力模型的多元负荷短期预... 详细信息

精准的多元负荷短期预测是综合能源系统调度和运行的基础。综合能源系统中的多种负荷之间存在较强的耦合作用,目前已有的单一负荷预测难以挖掘不同负荷之间复杂的内在联系。对此,提出一种基于多头概率稀疏自注意力模型的多元负荷短期预测方法。首先,采用皮尔逊相关系数分析多元负荷之间的相关性,并提取多元负荷之间的耦合特征;然后,使用改进位置编码的多头概率稀疏自注意力机制学习长序列输入的依赖关系,并且采用多元预测任务的参数软共享机制,通过不同子任务对共享特征的差异化选择,实现多元负荷的联合预测;最后,在亚利桑那州立大学Tempe校区的多元负荷数据集上对所提模型的性能进行验证,结果表明所提预测方法相较于其他预测模型能够有效提高预测精度。

关键词：综合能源系统多元负荷预测多头概率稀疏自注意力模型位置编码

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Advances in Lung Cancer and Treatment Research

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Journal of Cancer Therapy 2013年第8期4卷 36-43页

作者： Xiaofei Wang baohui han Shanghai Chest Hospital Shanghai Jiao Tong University Shanghai China

With the advances in surgery, chemotherapy, and radiotherapy over the last decades, the treatment strategies of lung cancer has been largely changed. In this review, we summarize recent advances in lung cancer and treatment research. We discuss current clinical management, highlight stage-specific therapy approaches, chemotherapy options for advanced-stage of non-small-cell lung cancer (NSCLC) patients, along with new agents such as epidermal growth factor receptor (EGFR)-targeting tyrosine kinase inhibitors erlotinib and gefitinib, and the anaplastic lymphoma kinase (ALK) inhibitor crizotinib. We also give an outlook into NSCLC disease biology, focuse on the importance of EGFR activating mutations and the role of the tumor-microenvironment. Finally we summarize the new recommendations in treating small-cell-lung cancer (SCLC).

关键词： NSCLC EGFR-Targeting Tyrosine Kinase

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Equivalent efficacy study of QL1101 and bevacizumab on untreated advanced non-squamous non-small cell lung cancer patients: a phase 3 randomized, double-blind clinical trial

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Cancer Biology & Medicine 2021年第3期18卷 816-824页

作者： Tianqing Chu Jun Lu Minghong Bi Helong Zhang Wu Zhuang Yan Yu Jianhua Shi Zhendong Chen Xiaochun Zhang Qisen Guo Quan Liu Huijuan Wu Jian Fang Yi Hu Xiuwen Wang Cuicui han Kai Li baohui han Department of Pulmonary Medicine Shanghai Chest HospitalShanghai Jiao Tong UniversitySha nghai 200030China Department of Oncology The First Affiliated Hospital of Bengbu Medical CollegeBengbu 233004China Department of Oncology Tangdu HospitalAir Force Medical University of PLAXi'an 710038China Department of Medical Thoracic Oncology Fujian Cancer HospitalFujian Medical University Cancer HospitalFuzhou 350014China Department of Oncology Harbin Medical University Cancer HospitalHarbin 150081China Department of Oncology Linyi Cancer HospitalLinyi 276000China Department of Oncology The Second Hospital of Anhui Medical UniversityHefei 230601China Department of Oncology The Affiliated Hospital of Qingdao UniversityQingdao 266071China Department of Internal Medicine Shandong Cancer Hospital Affiliated to Shandong UniversityJinan 250117China Department of Oncology Affiliated Hospital of Jiang Nan UniversityWuxi 214122China Department of Internal Medicine Henan Province Tumor HospitalZhengzhou UniversityZhengzhou 450008China Department of Thoracic OncologyⅡ Peking University Cancer Hospital and InstituteBeijing 100142China Department of Oncology Chinese PLA General HospitalBeijing 100039China Department of Oncology Qilu Hospital of Shandong UniversityJinan 250012China Department of Clinical Research Centre Qilu Pharmaceutical Co.LtdJinan 250101China Department of Thoracic Oncology Tianjin Medical University Cancer Institute and HospitalNational Clinical Research Center for CancerKey Laboratory of Cancer Prevention and TherapyTianjinTianjin’s Clinical Research Center for CancerTianjin 300060China

Objective:This phase 3 study aimed to test equivalence in efficacy and safety for QL1101,a bevacizumab analogue in Chinese patients with untreated locally advanced non-squamous non-small cell lung cancer(NSCLC).Methods:Eligible patients were randomly assigned 1:1 to receive carboplatin and paclitaxel in combination with either QL1101 or bevacizumab,15 mg/kg every 3-week for 6 cycles.This was followed by maintenance treatment with single agent QL1101 every 3-week.The primary end-point was objective response rate(ORR),with secondary end-points being progression-free survival(PFS),overall survival(OS),disease control rate(DCR),and adverse events(AEs).Results:Of 675 patients,535 eligible patients were randomized to the QL1101 group(n=269)and bevacizumab group(n=266).ORRs were 52.8%and 56.8%,respectively,for the QL1101 and bevacizumab groups,with an ORR hazard ratio 0.93(95%confidence interval:0.8-0131.1).The PFS,OS,DCR,and AEs were comparable between the 2 groups,which remained the same after stratification according to epidermal growth factor receptor mutation or smoking history.Conclusions:QL1101 showed similar efficacy and safety profiles as compared to bevacizumab among Chinese patients with untreated locally advanced non-squamous NSCLC.

关键词： Biosimilar bevacizumab equivalence non-squamous NSCLC clinical efficacy

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Prognostic factors of refractory NSCLC patients receiving anlotinib hydrochloride as the third-or further-line treatment

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Cancer Biology & Medicine 2018年第4期15卷 443-451页

作者： Jing Wang Yizhuo Zhao Qiming Wang Li Zhang Jianhua Shi Zhehai Wang Ying Cheng Jianxing He Yuankai Shi Hao Yu Yang Zhao Weiqiang Chen Yi Luo Xiuwen Wang Kejun Nan Faguang Jin Jian Dong Baolan Li Zhujun Liu baohui han Kai Li Department of Pulmonary Oncology Tianjin Medical University Cancer Institute and Hospital Department of Respiratory Medicine Shanghai Chest Hospital Department of Medical Oncology Henan Province Tumor Hospital Department of Respiratory Medicine Peking Union Medical College Hospital Department of Medical Oncology Linyi Cancer Hospital Department of Internal Medicine Shandong Cancer Hospital Department of Thoracic Oncology Jilin Cancer Hospital Department of Thoracic Surgery The First Affiliated Hospital of Guangzhou Medical University Department of Medical Oncology Cancer Hospital Chinese Academy of Medical Sciences Department of Biostatistics School of Public Health Nanjing Medical University Department of Respiratory Medicine Lanzhou Military General Hospital Department of Head and Neck Oncology Hunan Cancer Hospital Department of Chemotherapy Qilu Hospital of Shandong University Department of Medical Oncology The First Affiliated Hospital of Xi'an Jiaotong University Department of Respiratory and Critical Diseases Tang Du Hospital Department of Oncology Yunnan Cancer Hospital General Department Capital Medical University Beijing Chest Hospital

Objective:Anlotinib hydrochloride is a multitarget tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor,fibroblast growth factor receptor,platelet-derived growth factor receptor,c-Kit,and c-MET;therefore,it exhibits both antitumor and anti-angiogenetic activities.A phase III trial has shown that anlotinib improved progression-free survival(PFS)and overall survival(OS)in patients with advanced non-small cell lung cancer(NSCLC),who presented with progressive disease or intolerance after standard chemotherapy.This study aimed to analyze the characteristics of patients receiving anlotinib treatment to determine the dominant populations who are fit for the treatment.Methods:Data were collected from March 2015 to January 2017 from a randomized,double-blind,placebo-controlled,multicenter,phase III trial of anlotinib(ALTER0303).A total of 437 patients were enrolled and randomly allocated(2:1)to the anlotinib and placebo groups.Kaplan–Meier analysis and log-rank test were performed to compare PFS and OS.Cox proportional hazards model was adopted for multivariate prognostic analysis.Results:Multivariate analysis indicated that high post-therapeutic peripheral blood granulocyte/lymphocyte ratio and elevated alkaline phosphatase levels were independent risk factors for PFS.Meanwhile,elevated thyroid-stimulating hormone,blood glucose,and triglyceride levels;hypertension;and hand–foot syndrome were independent protective factors of PFS.High posttherapeutic peripheral blood granulocyte/lymphocyte ratio,an Eastern Cooperative Oncology Group(ECOG)score≥2,and the sum of the maximal target lesion length at baseline were independent risk factors of OS,and hypertriglyceridemia was an independent protective factor of OS.Conclusions:This study preliminarily explored the possible factors that affected PFS and OS after anlotinib treatment in patients with advanced refractory NSCLC,and the baseline characteristics of the therapeutically dominant populations were then identified.

关键词： Non-small cell lung cancer anlotinib third- or further-line therapy prognostic factor analysis

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