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Paired box 5 increases the chemosensitivity of esophageal squamous cell cancer cells by promoting p53 signaling activity

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Chinese Medical Journal 2022年第5期135卷 606-618页

作者： Weiwei Zhang Wenji Yan Niansong Qian Quanli Han Weitao Zhang guanghai dai Chinese People’s Liberation Army Medical School Beijing 100853China Department of the Third Health Care The Second Medical CenterChinese People’s Liberation Army General HospitalBeijing 100853China Department of Oncology The First Medical CenterChinese People’s Liberation Army General HospitalBeijing 100853China Department of Oncology The Hainan Medical CenterChinese People’s Liberation Army General HospitalSanya 572022China Cancer Center Beijing Tongren Hospital Affiliated to Capital Medical UniversityEconomic and Technological Development ZoneBeijing 100176China

Background:Gene promoter methylation is a major epigenetic change in cancers,which plays critical roles in carcinogenesis.As a crucial regulator in the early stages of B-cell differentiation and embryonic neurodevelopment,the paired box 5(PAX5)gene is downregulated by methylation in several kinds of tumors and the role of this downregulation in esophageal squamous cell carcinoma(ESCC)pathogenesis remains unclear.Methods:To elucidate the role of PAX5 in ESCC,eight ESCC cell lines,51 primary ESCC tissue samples,and eight normal esophageal mucosa samples were studied and The Cancer Genome Atlas(TCGA)was queried.PAX5 expression was examined by reverse transcription-polymerase chain reaction and western blotting.Cell apoptosis,proliferation,and chemosensitivity were detected by flow cytometry,colony formation assays,and 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide assays in ESCC cell lines with PAX5 overexpression or silencing.Tumor xenograft models were established for in vivo verification.Results:PAX5 methylation was found in 37.3%(19/51)of primary ESCC samples,which was significantly associated with age(P=0.007)and tumor-node-metastasis stage(P=0.014).TCGA data analysis indicated that PAX5 expression was inversely correlated with promoter region methylation(r=-0.189,P=0.011 for cg00464519 and r=-0.228,P=0.002 for cg02538199).Restoration of PAX5 expression suppressed cell proliferation,promoted apoptosis,and inhibited tumor growth of ESCC cell lines,which was verified in xenografted mice.Ectopic PAX5 expression significantly increased p53 reporter luciferase activity and increased p53 messenger RNA and protein levels.A direct interaction of PAX5 with the p53 promoter region was confirmed by chromatin immunoprecipitation assays.Re-expression of PAX5 sensitized ESCC cell lines KYSE150 and KYSE30 to fluorouracil and docetaxel.Silencing of PAX5 induced resistance of KYSE450 cells to these drugs.Conclusions:As a tumor suppressor gene regulated by promoter region methylation in human ESCC,PAX5 inhibit

关键词： PAX5 DNA methylation Esophageal cancer p53 signaling Chemosensitivity

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The model of cytokine release syndrome in CAR T-cell treatment for B-cell non-Hodgkin lymphoma

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Signal Transduction and Targeted Therapy 2020年第1期5卷 1295-1303页

作者： Jianshu Wei Yang Liu Chunmeng Wang Yajing Zhang Chuan Tong guanghai dai Wei Wang John E.J.Rasko J.Joseph Melenhorst Wenbin Qian Aibin Liang Weidong Han Department of Bio-therapeutic the First Medical CenterChinese PLA General Hospital100853 BeijingChina Department of Oncology the first Medical CenterChinese PLA General Hospital100853 BeijingChina State Key Laboratory of Biotherapy and Cancer Center West China HospitalSichuan UniversityChengdu 610041China Collaborative Innovation Center for Biotherapy Chengdu 610041China Department of Cell and Molecular Therapies Royal Prince Alfred HospitalSydneyNSW 2006Australia Gene and Stem Cell Therapy Program Centenary InstituteUniversity of SydneySydneyNSW 2006Australia Central Clinical School Faculty of Medicine and HealthThe University of SydneyCamperdownNSW 2050Australia Department of Pathology and Laboratory Medicine Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPA 19104-515USA Department of Hematology The Second Affiliated HospitalCollege of MedicineZhejiang UniversityHangzhou 310009China Department of Hematology Shanghai Tongji HospitalTongji University School of MedicineShanghai 200065China State Key Laboratory of Kidney Diseases National Clinical Research Center for Kidney Diseases100853 BeijingChina

Chimeric antigen receptor T(CAR T)cell therapy has demonstrated efficacy in the treatment of haematologic malignancies.However,the accompanying adverse events,the most common of which is cytokine release syndrome(CRS),substantially limit its wide application.Due to its unique physiological characteristics,CRS in CAR T-cell treatment for B-cell non-Hodgkin lymphoma(BNHL)may exhibit some special features.Although existing guidelines had greatly promoted the recognition and management of CRS,many recommendations are not fully applicable to B-NHL.Therefore,it is imperative to identify responses that are specific to CRS observed following CAR T treatment for B-NHL.Based on underlying biological processes and known pathophysiological mechanisms,we tentatively propose a new model to illustrate the occurrence and evolution of CAR T-cell-therapy-related CRS in BNHL.In this model,tumour burden and bone marrow suppression are considered determinants of CRS.Novel phenomena after CAR T-cell infusion(such as local inflammatory response)are further identified.The proposed model will help us better understand the basic biology of CRS and recognize and manage it more rationally.

关键词： cytokine lymphoma treatment

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Dietary organic acids ameliorate high stocking density stress-induced intestinal inflammation through the restoration of intestinal microbiota in broilers

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Journal of Animal Science and Biotechnology 2023年第2期14卷 745-759页

作者： Dong dai guanghai Qi Jing Wang Haijun Zhang Kai Qiu Yanming Han Yuanyuan Wu Shugeng Wu Laboratory of Quality and Safety Risk Assessment for Animal Products on Feed Hazards(Beijing)of the Ministry of Agriculture and Rural Affairs Institute of Feed ResearchChinese Academy of Agricultural SciencesNo.12 Zhongguancun South St.Haidian districtBeijingChina Trouw Nutrition Research&Development Centers AmersfoortNetherlands.

Background:High stocking density(HSD)stress has detrimental effects on growth performance,intestinal barrier function,and intestinal microbiota in intensive animal production.Organic acids(OA)are widely used as feed addi-tives for their ability to improve growth performance and intestinal health in poultry.However,whether dietary OA can ameliorate HSD stress-induced impaired intestinal barrier in broilers remains elusive.In this study,a total of 528 one-day-old male Arbor Acres broilers were randomly allocated into 3 treatments with 12 replicates per treatment including 10 birds for normal stocking density and 17 birds for HSD.The dietary treatments were as follows:1)Normal stocking density+basal diet;2)HSD+basal diets;3)HSD+OA.Results:HSD stress can induce increased levels of serum corticosterone,lipopolysaccharides,interleukin-1β,tumor necrosis factor-α,and down-regulated mRNA expression of ZO-1,resulting in compromised growth performance of broilers(P<0.05).Dietary OA could significantly reduce levels of serum corticosterone,lipopolysaccharides,interleukin-1β,and tumor necrosis factor-α,which were accompanied by up-regulated interleukin-10,mRNA expres-sion of ZO-1,and growth performance(P<0.05).Moreover,OA could down-regulate the mRNA expression of TLR4 and MyD88 to inhibit the NF-κB signaling pathway(P<0.05).Additionally,HSD stress significantly decreased the abundance of Bacteroidetes and disturbed the balance of microbial ecosystems,whereas OA significantly increased the abundance of Bacteroidetes and restored the disordered gut microbiota by reducing competitive and exploita-tive interactions in microbial communities(P<0.05).Meanwhile,OA significantly increased the content of acetic and butyric acids,which showed significant correlations with intestinal inflammation indicators(P<0.05).Conclusions:Dietary OA ameliorated intestinal inflammation and growth performance of broilers through restor-ing the disordered gut microbial compositions and interactions induced by HSD and elevating short-chain fatty acid p

关键词： Broiler High stocking density Intestinal inflammation Intestinal microbiota Organic acid Short-chain fatty acid

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Efficacy and safety of chemotherapy combined with bevacizumab in Chinese patients with metastatic colorectal cancer:A prospective,multicenter,observational,non-interventional phaseⅣtrial

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Chinese Journal of Cancer Research 2021年第4期33卷 490-499页

作者： Fenghua Wang guanghai dai Yanhong Deng Yong Tang Wei Wang Zuoxing Niu Feng Bi Liangjun Zhu Zengqing Guo Jin Yan Bing Hu Min Tao Shujun Yang Suzhan Zhang Lu Wen Ruihua Xu Department of Medical Oncology Sun Yat-sen University Cancer CenterGuangzhou 510060China Department of Medical Oncology Chinese PLA General HospitalBeijing 100853China Department of Medical Oncology the Sixth Affiliated HospitalSun Yat-sen UniversityGuangzhou 510655China Department of Medical Oncology Xinjiang Medical University Cancer HospitalUrumqi 830000China Department of Medical Oncology Foshan First People’s HospitalFoshan 528010China Department of Medical Oncology Shandong Cancer HospitalJinan 250117China Department of Medical Oncology West China Hospital of Sichuan UniversityChengdu 610041China Department of Medical Oncology Jiangsu Cancer HospitalNanjing 210009China Department of Medical Oncology Fujian Cancer HospitalFuzhou 350014China Department of Surgical Oncology Sichuan Cancer HospitalChengdu 610041China Department of Medical Oncology Anhui Provincial HospitalHefei 230001China Department of Medical Oncology the First Affiliated Hospital of Soochow UniversitySuzhou 215006China Department of Medical Oncology Henan Cancer HospitalZhengzhou 450003China Department of Medical Oncology the Second Affiliated Hospital of Zhejiang University School of MedicineHangzhou 310009China Department of Medical Oncology Shanxi Provincial Cancer HospitalTaiyuan 030009China

Objective:Bevacizumab has an important and evolving role in improving outcomes in patients with metastatic colorectal cancer(mCRC)worldwide and was approved in China in 2010.However,there are limited real-world data on the efficacy and safety of chemotherapy regimens combined with bevacizumab in Chinese patients with mCRC.This observational,phase IV trial study aimed to obtain more experience on the efficacy and safety of bevacizumab combined with chemotherapy in Chinese mCRC patients.Methods:Between September 2013 and November 2016,patients with histologically confirmed mCRC were enrolled in a prospective,multicenter,observational,non-interventional phase IV trial at 26 centers across China.Eligible patients received different chemotherapeutic regimens combined with bevacizumab.The efficacy and safety data in the intention-to-treat study population were analyzed.Results:A total of 611 patients were included in the efficacy analysis.The median overall survival and median progression-free survival was 18.00 and 10.05 months,respectively.The objective response rate was 21.00%and disease control rate was 89.40%.In subgroup analyses,the survival differences were observed according to metastatic status,duration of treatment and elevation in blood pressure.A total of 613 patients were evaluable for safety assessments.And 569(92.82%)patients reported at least one adverse event(AE),and 151(24.63%)experienced grade 3 or higher AEs.The incidence of bevacizumab-associated AEs of special interest was reported in 31(5.06%)patients with hypertension(n=12),abscesses and fistulae(n=7),bleeding(n=6),proteinuria(n=3),gastrointestinal perforation(n=2)and venous thrombotic events(n=1).Conclusions:This observational phase IV trial broadens our experience and knowledge of bevacizumab in the Chinese population and provides a good indication of its overall efficacy and safety.Bevacizumab in combination with chemotherapy offers clinical benefits to Chinese patients with mCRC and has an acceptable and manageable safety profile.

关键词： Metastatic colorectal cancer bevacizumab chemotherapy efficacy safety

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Efficacy and safety of a novel anti-HER2 therapeutic antibody RC48 in patients with HER2-overexpressing,locally advanced or metastatic gastric or gastroesophageal junction cancer:a single-arm phase II study

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Cancer Communications 2021年第11期41卷 1173-1182页

作者： Zhi Peng Tianshu Liu Jia Wei Airong Wang Yifu He Liuzhong Yang Xizhi Zhang Nanfeng Fan Suxia Luo Zhen Li Kangsheng Gu Jianwei Lu Jianming Xu Qingxia Fan Ruihua Xu Liangming Zhang Enxiao Li Yuping Sun Guohua Yu Chunmei Bai Yong Liu Jiangzheng Zeng Jieer Ying Xinjun Liang Nong Xu Chao Gao Yongqian Shu Dong Ma guanghai dai Shengmian Li Ting Deng Yuehong Cui Jianmin Fang Yi Ba Lin Shen Department of Gastrointestinal Oncology Key Laboratory of Cancinogenesis and Translational Research(Ministry of Education)Peking University Cancer Hospital&InstituteBeijing 100142P.R.China Department of Gastrointestinal Oncology Affiliated Zhongshan Hospital of Fudan UniversityShanghai 200032P.R.China Department of Oncology Nanjing Drum Tower Hospitalthe Affiliated Hospital of Nanjing University Medical SchoolNanjingJiangsu 210008P.R.China Department of Oncology Weihai Municipal HospitalWeihaiShandong 264299P.R.China Department of Oncology Anhui Provincial Cancer HospitalHefeiAnhui 230031P.R.China Department of Oncology The First Affiliated Hospital of Xinxiang Medical CollegeXinxiangHenan 453100P.R.China Department of Oncology Subei People’s HospitalYangzhouJiangsu 225009P.R.China Department of Abdominal Oncology Fujian Provincial Cancer HospitalFuzhouFujian 350014P.R.China Department of Gastrointestinal Oncology Henan Cancer HospitalZhengzhouHenan 450003P.R.China Department of Oncology Linyi Cancer HospitalLinyiShandong 276002P.R.China Department of Oncology The First Affiliated Hospital of Anhui Medical UniversityHefeiAnhui 230022P.R.China Department of Oncology Jiangsu Cancer HospitalNanjingJiangsu 210009P.R.China Department of Oncology The Fifth Medical Center of PLA General HospitalBeijing 100039P.R.China Department of Oncology The First Affiliated Hospital of ZhengzhouZhengzhouHenan 450099P.R.China Department of Oncology Sun Yat-sen University Cancer CenterGuangzhouGuangdong 510060P.R.China Department of Oncology Yantai Yuhuangding HospitalYantaiShandong 264099P.R.China Department of Oncology The First Affiliated Hospital of Xi’an Jiaotong UniversityXi’anShanxi 710061P.R.China Department of Oncology Jinan Central HospitalJinanShandong 250013P.R.China Department of Oncology Weifang People’s HospitalWeifangShandong 261041P.R.China Department of Oncology Peking Union Medical College HospitalBeijing 100005P.R.China Department of Oncology Xuzhou Central

Background:Current treatment options for human epidermal growth factor receptor 2(HER2)-overexpressing gastric cancer at third-line have shown limited clinical benefit.Further,there is no specific treatment for HER2 immunohistochemistry(IHC)2+and fluorescence in-situ hybridization-negative patients.Here,we report the efficacy and safety of a novel anti-HER2 antibody RC48 for patients with HER2-overexpressing,advanced gastric or gastroesophageal junction cancer.Methods:Patients with HER2-overexpressing(IHC 2+or 3+),locally advanced or metastatic gastric or gastroesophageal junction cancer who were under at least second-line therapy were eligible and received RC482.5 mg/kg alone every 2 weeks.The primary endpoint was the objective response rate(ORR)assessed by an independent review committee.Secondary endpoints included progressionfree survival(PFS),overall survival(OS),duration of response,time to progression,disease control rate,and safety.Results:Of 179 patients screened,125 were eligible and received RC48 treatment.The ORR was 24.8%(95%confidence interval[CI]:17.5%-33.3%).The median PFS and OS were 4.1 months(95%CI:3.7-4.9 months)and 7.9 months(95%CI:6.7-9.9 months),respectively.The most frequently reported adverse events were decreased white blood cell count(53.6%),asthenia(53.6%),hair loss(53.6%),decreased neutrophil count(52.0%),anemia(49.6%),and increased aspartate aminotransferase level(43.2%).Serious adverse events(SAEs)occurred in 45(36.0%)patients,and RC48-related SAEs were mainly decreased neutrophil count(3.2%).Seven patients had adverse events that led to death were not RC48-related.Conclusions:RC48 showed promising activity with manageable safety,suggesting potential application in patients with HER2-overexpressing,advanced gastric or gastroesophageal junction cancer who have previously received at least two lines of chemotherapy.

关键词： antibody-drug conjugate gastric cancer HER2-overexpressing phase II clinical trial RC48 third-line therapy

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Randomized Double-Blind Clinical Comparison of Sodium Ibandronate and Pamidronate Disodium for Treatment of 141 Patients with Malignant Tumor Ostealgia

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Chinese Journal of Clinical Oncology 2007年第2期4卷 103-108页

作者： guanghai dai Shunchang Jiao Junlan Yang Shaohao Jiang Donggang Liu Department of Medical Oncology Genera Hospital of the PLA Beijing 100853 China

OBJECTIVE To evaluate the therapeuticeffect and potential adverse ef- fects of sodium ibandronate(SI)in patients with malignant tumor ostealgia. METHODS Patients were randomly classified into two groups.Group A(SI)of 68 patients who received 4 mg SI i.v.,and 73 patients in Group B (pamidronate disodium[PD])who received 60 mg PD i.v.A randomized, double-blind method,with PD as a positive drug control,was used to assess changes in bone pain and adverse effects over a three-week period. RESULTS A total of 141 patients were enrol ed in the study,with 136 cases of appraisable efficacy.The effective rate was 72.3%(47/65)in Group A,and 63.4%(45/71)in Group B.There was no significant difference in ef- ficacy or adverse effects between the 2 groups. CONCLUSION The SI injection,with a pronounced effect,can relieve bone pain caused by osseous metastasis from a malignant tumor.The cura- tive and adverse effects were similar compared to PD.

关键词：恶性癌性骨痛治疗伊班膦酸钠帕米膦酸二钠随机双盲临床对照

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HIF诱导EMT在肿瘤侵袭转移中的作用

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中南大学学报（医学版） 2016年第8期41卷 872-878页

作者：陈杨石燕戴广海解放军总医院肿瘤内二科北京100853

缺氧是肿瘤微环境的主要特点,通过缺氧诱导因子(hypoxia-inducible factor,HIF)激活众多靶基因,从而影响肿瘤的代谢、增殖、凋亡、侵袭转移、耐药等多个方面。上皮细胞间质化(epithelial to mesenchymal transition,EMT)是肿瘤发生侵袭... 详细信息

缺氧是肿瘤微环境的主要特点,通过缺氧诱导因子(hypoxia-inducible factor,HIF)激活众多靶基因,从而影响肿瘤的代谢、增殖、凋亡、侵袭转移、耐药等多个方面。上皮细胞间质化(epithelial to mesenchymal transition,EMT)是肿瘤发生侵袭转移的重要起始过程,缺氧亦是EMT的诱发因素之一并可通过多条信号转导通路包括TGF-β,Notch,Wnt/β-catenin等调节EMT。研究缺氧诱导EMT的机制并阻断其进程,可成为治疗肿瘤的新靶点。

关键词：缺氧诱导因子上皮细胞间质化侵袭转移肿瘤

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融合事故表征和CBR的特种设备事故预测研究

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计算机工程与应用 2022年第1期58卷 255-267页

作者：谷梦瑶李光海戴之希中国计量大学质量与安全工程学院杭州310018 中国特种设备检测研究院北京100029

为了更好地预测特种设备事故,提出了融合事故表征和CBR(case-based reasoning)的特种设备事故预测研究。详细说明了面向全类特种设备的通用型事故表征技术,包括事故表征信息的结构模型、规范化方法和编码规则。介绍了融合事故表征和CBR... 详细信息

为了更好地预测特种设备事故,提出了融合事故表征和CBR(case-based reasoning)的特种设备事故预测研究。详细说明了面向全类特种设备的通用型事故表征技术,包括事故表征信息的结构模型、规范化方法和编码规则。介绍了融合事故表征和CBR的特种设备事故预测方法,其中为了更精准地检索相似案例,提出了针对不同属性类型的属性相似度计算方法、基于专家置信度的改进型AHP法、考虑时间衰减效应的案例相似度计算方法以及案例相似度阈值确定函数。通过上海某公司的汽车起重机案例验证了该方法。结果表明该方法不但能根据事故前兆信息,给出特种设备的事故原因故障树,以了解事故发展趋势,还能提供如事故特征、事故发生部位等事故表征信息的发生概率,以及应采取的预防措施。

关键词：特种设备事故表征事故预测案例推理

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Ras Raf Mek Erk信号传导通路在肝细胞癌发生中的作用机制及在靶向治疗中的应用

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中国肿瘤临床 2008年第23期35卷 1377-1380页

作者：蒋成英戴广海中国人民解放军总医院肿瘤内科北京市100853

肝细胞癌(HCC)是我国原发性肝癌最常见的一种类型,也是全球癌性死亡中最重要的一个因素。因此,研究肿瘤生长的细胞机制对于探索新的有效治疗方法非常重要。目前已知,所有真核细胞中均存在Ras/Raf/Mek/Erk这一高度保守的细胞信号传导通路... 详细信息

肝细胞癌(HCC)是我国原发性肝癌最常见的一种类型,也是全球癌性死亡中最重要的一个因素。因此,研究肿瘤生长的细胞机制对于探索新的有效治疗方法非常重要。目前已知,所有真核细胞中均存在Ras/Raf/Mek/Erk这一高度保守的细胞信号传导通路,这一信号传导通路广泛参与细胞的生长、增殖、分化、凋亡、转移等过程。Ras/Raf/Mek/Erk信号传导通路是"MAPK"众多通路中的一个,它在多种致瘤性疾病中通常是上调的。同样,该信号传导通路的异常激活与肝细胞癌的发生及恶性进展密切相关。Ras基因的突变,EGF、VEGF、PDGF等生长因子及相应的膜受体过度表达均可使其激活,诱导肝癌细胞异常增殖,侵袭生长和转移,从而参与和促进肝细胞癌的发生、发展。因此,抑制Ras/Raf/Mek/Erk信号通路的传导将成为肝细胞癌的一种有效治疗方法。

关键词： Ras Raf Mek Erk肝细胞癌

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交界可切除胰腺癌新辅助化疗联合免疫治疗的回顾性临床分析

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中华肝胆外科杂志 2022年第8期28卷 587-591页

作者：邓国超贾茹王治宽司海燕张楠戴广海解放军总医院第五医学中心肿瘤学部北京100081

目的探讨新辅助化疗联合免疫治疗在交界可切除胰腺癌患者中的应用价值。方法回顾性分析2019年1月至2021年6月在解放军总医院第五医学中心就诊的拟行围手术期治疗及手术治疗的胰腺癌患者的临床资料。共纳入22例胰腺癌患者,其中男性10例,... 详细信息

目的探讨新辅助化疗联合免疫治疗在交界可切除胰腺癌患者中的应用价值。方法回顾性分析2019年1月至2021年6月在解放军总医院第五医学中心就诊的拟行围手术期治疗及手术治疗的胰腺癌患者的临床资料。共纳入22例胰腺癌患者,其中男性10例,女性12例,年龄(56.0±10.2)岁。术前接受白蛋白结合型紫杉醇联合替吉奥(AS)方案新辅助化疗联合程序性死亡蛋白-1(PD-1)单抗治疗。对患者的治疗效果、手术病理及预后情况进行分析。结果22例新辅助化疗联合PD-1单抗治疗的患者中,11例(50%)患者肿瘤位于胰腺头颈部及钩突部。疗效评价中有1例患者影像学评估达到完全缓解(4.5%,1/22),9例达到部分缓解(40.9%,9/22),11例达到疾病稳定(50.0%,11/22)。所有患者均行R0切除。术后pTNM分期中91%(20/22)患者为IA~IIB期,pT2患者占31.8%(7/22),N0患者占63.6%(14/22)。1例化疗联合免疫治疗的患者达到病理完全缓解。13例(54.2%,13/22)患者接受术后辅助治疗。患者中位无复发生存期(RFS)和中位疾病进展时间(TTP)分别为6.4和12.8个月。患者的中位生存时间未达到。术后病理TNM分期IIA~III期(HR=3.63,95%CI:1.18~11.20,P=0.025)、术后病理T2~3分期(HR=2.02,95%CI:1.01~5.05,P=0.049)与RFS相关。术后病理TNM分期IIA~III期(HR=2.39,95%CI:1.04~5.50,P=0.041)和术后病理T2~3分期(HR=2.53,95%CI:1.26~5.09,P=0.009)与TTP相关。结论AS联合PD-1单抗在交界可切除胰腺癌患者的新辅助治疗中具有较好的有效率。

关键词：胰腺肿瘤交界可切除免疫治疗新辅助治疗有效率

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