Heat stress hinders the growth and productivity of sweetpotato plants,predominantly through oxidative damage to cellular membranes.Therefore,the development of efficient approaches for mitigating heat-related impairme...Heat stress hinders the growth and productivity of sweetpotato plants,predominantly through oxidative damage to cellular membranes.Therefore,the development of efficient approaches for mitigating heat-related impairments is essential for the long-term production of sweetpotatoes.Melatonin has been recognised for its capacity to assist plants in dealing with abiotic stress conditions.This research aimed to investigate how different doses of exogenous melatonin influence heat damage in sweetpotato plants.Heat stress drastically affected shoot and root fresh weight by 31.8 and 44.5%,respectively.This reduction resulted in oxidative stress characterised by increased formation of hydrogen peroxide(H_(2)O_(2))by 804.4%,superoxide ion(O_(2)^(·-))by 211.5%and malondialdehyde(MDA)by 234.2%.Heat stress also reduced chlorophyll concentration,photosystemⅡefficiency(F_v/F_m)by 15.3%and gaseous exchange.However,pre-treatment with 100μmol L^(-1)melatonin increased growth and reduced oxidative damage to sweetpotato plants under heat stress.In particular,melatonin decreased H_(2)O_(2),O_(2)^(·-)and MDA by 64.8%,42.7%and 38.2%,respectively.Melatonin also mitigated the decline in chlorophyll levels and improved stomatal traits,gaseous exchange and F_(v)/F_(m)(13%).Results suggested that the favorable outcomes of melatonin treatment can be associated with elevated antioxidant enzyme activity and an increase in non-enzymatic antioxidants and osmo-protectants.Overall,these findings indicate that exogenous melatonin can improve heat stress tolerance in sweetpotatoes.This stu dy will assist re searchers in further investigating how melatonin makes sweetpotatoes more resistant to heat stress.展开更多
免疫检查点抑制剂(immune checkpoint inhibitors,ICIs)的应用改写了很多恶性肿瘤的治疗策略,成为肿瘤治疗的又一个里程碑。ICIs作用原理可以理解为“刹车理论”,在“松开刹车”后会带来一系列的全身性毒副反应,其中部分可能为危重和难...免疫检查点抑制剂(immune checkpoint inhibitors,ICIs)的应用改写了很多恶性肿瘤的治疗策略,成为肿瘤治疗的又一个里程碑。ICIs作用原理可以理解为“刹车理论”,在“松开刹车”后会带来一系列的全身性毒副反应,其中部分可能为危重和难治性,甚至具有潜在致死性。本文对免疫相关不良事件(immune-related adverse effects,irAEs)相关的最新国内外指南及共识中关于3度-4度irAEs的诊治建议进行了汇总,包括欧洲肿瘤内科学会年会(European Society for Medical Oncology,ESMO)、美国国立综合癌症网络(National Comprehensive Cancer Network,NCCN)/美国临床肿瘤学会(American Society of Clinical Oncology,ASCO)、肿瘤免疫治疗学会(Society for Immunotherapy of Cancer,SITC)和中国临床肿瘤学会(Chinese Society of Clinical Oncology,CSCO)指南,并复习了2019年5月20日前公开发表的关于irAEs的个案报告和相关的综述文献后,对以上指南和共识中尚未纳入的3级-4级irAEs的诊治建议进行补充,重点介绍了特异性免疫抑制药物在不同的irAEs中成功应用的情况,包括抗白介素6(interleukin 6,IL-6)阻断、抗CD20单抗、抗肿瘤坏死因子α(tumor necrosis factor-α,TNFα)单抗、抗整合素4单抗、Janus激酶抑制剂、血小板生成素受体激动剂和抗胸腺细胞球蛋白(antithymocyte globulin,ATG).本文对于类固醇激素在irAEs中超大剂量使用和升级使用及反复使用提出质疑,并强调应同时关注激素继发的感染、肿瘤进展和无法满足ICIs再挑战的等问题。本文提出对于危重和难治性irAEs的“降阶梯治疗”原则,建议应尽早使用细胞因子靶向药物这些特异性免疫抑制药物。免疫治疗时代诸多的irAEs是传统化疗及小分子靶向治疗时代不曾有过的,不断地挑战肿瘤科大夫的知识储备和临床基本技能。因此,建立肿瘤多学科讨论体系对于肿瘤患者的治疗管理极为重要。展开更多
Next-generation sequencing(NGS) technology is capable of sequencing millions or billions of DNA molecules simultaneously.Therefore, it represents a promising tool for the analysis of molecular targets for the initial ...Next-generation sequencing(NGS) technology is capable of sequencing millions or billions of DNA molecules simultaneously.Therefore, it represents a promising tool for the analysis of molecular targets for the initial diagnosis of disease, monitoring of disease progression, and identifying the mechanism of drug resistance. On behalf of the Tumor Biomarker Committee of the Chinese Society of Clinical Oncology(CSCO) and the China Actionable Genome Consortium(CAGC), the present expert group hereby proposes advisory guidelines on clinical applications of NGS technology for the analysis of cancer driver genes for precision cancer therapy. This group comprises an assembly of laboratory cancer geneticists, clinical oncologists, bioinformaticians,pathologists, and other professionals. After multiple rounds of discussions and revisions, the expert group has reached a preliminary consensus on the need of NGS in clinical diagnosis, its regulation, and compliance standards in clinical sample collection. Moreover, it has prepared NGS criteria, the sequencing standard operation procedure(SOP), data analysis, report, and NGS platform certification and validation.展开更多
Chemotherapy-induced neutropenia(CIN)is a potentially fatal and common complication in myelosuppressive chemotherapy.The timing and grade of CIN may play prognostic and predictive roles in cancer therapy.CIN is associ...Chemotherapy-induced neutropenia(CIN)is a potentially fatal and common complication in myelosuppressive chemotherapy.The timing and grade of CIN may play prognostic and predictive roles in cancer therapy.CIN is associated with older age,poor functional and nutritional status,the presence of significant comorbidities,the type of cancer,previous chemotherapy cycles,the stage of the disease,specific chemotherapy regimens,and combined therapies.There are many key points and new challenges in the management of CIN in adults including:(1)Genetic risk factors to evaluate the patient’s risk for CIN remain unclear.However,these risk factors urgently need to be identified.(2)Febrile neutropenia(FN)remains one of the most common reasons for oncological emergency.No consensus nomogram for FN risk assessment has been established.(3)Different assessment tools[e.g.,Multinational Association for Supportive Care in Cancer(MASCC),the Clinical Index of Stable Febrile Neutropenia(CISNE)score model,and other tools]have been suggested to help stratify the risk of complications in patients with FN.However,current tools have limitations.The CISNE score model is useful to support decision-making,especially for patients with stable FN.(4)There are still some challenges,including the benefits of granulocyte colony stimulating factor treatment and the optimal antibiotic regimen in emergency management of FN.In view of the current reports,our group discusses the key points,new challenges,and management of CIN.展开更多
Objective: Crizotinib has demonstrated promising efficacy in patients with anaplastic lymphoma kinase(ALK)-positive non-small-cell lung cancer(NSCLC) in clinical trials. We conducted this retrospective multicenter stu...Objective: Crizotinib has demonstrated promising efficacy in patients with anaplastic lymphoma kinase(ALK)-positive non-small-cell lung cancer(NSCLC) in clinical trials. We conducted this retrospective multicenter study to assess the outcomes of crizotinib therapy in, to our knowledge, a large sample cohort of patients with ALKpositive advanced NSCLC.Methods: We reviewed the medical records of 484 unselected ALK-positive NSCLC patients treated with crizotinib at 5 cancer centers in China from January 2013 to November 2017. Clinical data were collected from the initiation of crizotinib therapy to Response Evaluation Criteria in Solid Tumors(RECIST)-defined progressive disease(PD).Results: A total of 428 eligible ALK-positive NSCLC patients were enrolled, 273(63.8%) of whom received crizotinib as first-line treatment. The median progression-free survival(PFS) and overall survival(OS) from the initiation of crizotinib treatment were 14.4 [95% confidence interval(95% CI), 12.4-16.4] months and 53.4(95%CI, 33.7-73.1) months, respectively. In subgroup analyses, patients who received crizotinib as first-line treatment showed a higher disease control rate(DCR) and a longer median OS compared with second-/later-line crizotinib treatment(94.8% and OS not reached vs. 89.0% and 40.5 months, respectively). For 261 patients with RECISTdefined PD, multivariate Cox analysis revealed that in patients who received first-line crizotinib therapy, continued crizotinib beyond progressive disease(CBPD) and next-generation ALK inhibitors after crizotinib failure were associated with improved survival.Conclusions: This study has demonstrated the clinically meaningful benefit of crizotinib treatment in a large cohort of Chinese ALK-positive NSCLC patients. CBPD and next-generation ALK inhibitor treatment may provide improved survival after RECIST-defined progression on crizotinib.展开更多
Objective BAG3-related myopathy is a rare condition so far reported in twenty patients worldwide.The purpose of this study was to draw attention to this rare disease and to the fact that BAG3-related myopathy should b...Objective BAG3-related myopathy is a rare condition so far reported in twenty patients worldwide.The purpose of this study was to draw attention to this rare disease and to the fact that BAG3-related myopathy should be considered as a rare differential diagnosis of hypercapnia.Methods We report a sporadic case of a 14-year-old Chinese girl with a de novo p.Pro209 Leu mutation in BAG3 and reviewed the literatures for reported cases related to this mutation.Results We described a 14-year-old Chinese girl who presented with gradually appearing symptoms of hypercapnia that required assisted ventilation.The muscle biopsy and the blood whole-exome sequencing results confirmed the diagnosis of myofibrillar myopathy with a de novo p.Pro209 Leu mutation in BAG3.Totally twentyone patients from twenty families with a confirmed diagnosis of BAG3-related myopathy were reported to date,including this patient and literature review.The male to female ratio was 11:10 and most showed initial symptoms in the first decade of life.Most patients presented toe/clumsy walking or running as the onset symptom,followed by muscle weakness or atrophy.Creatine kinase levels were elevated in fourteen patients and were normal in three.Eighteen patients developed respiratory insufficiency during the disease course and thirteen(one could not tolerate non-invasive assisted ventilation)required non-invasive assisted ventilation for treatment.Except for one not reported,heart involvement was found in seventeen patients during the disease course and seven underwent heart transplantation.Z-disk streaming and aggregation could be observed in most of the patients’muscle histology.In the long-term follow-up,five patients died of cardiac or respiratory failure.Conclusion BAG3-associated myopathy is a rare type of myofibrillar myopathy.It should be considered as a rare differential diagnosis of hypercapnia.展开更多
Programmed death-1(PD-1)targeted immunotherapy has revolutionized cancer treatment but fails to induce durable responses in many patients,mainly due to restricted reversal of CD8^(+)T cell exhaustion.In cancer and chr...Programmed death-1(PD-1)targeted immunotherapy has revolutionized cancer treatment but fails to induce durable responses in many patients,mainly due to restricted reversal of CD8^(+)T cell exhaustion.In cancer and chronic infections,persistent antigens hinder effective immune clearance,leading CD8^(+)T cells into a dysfunctional and epigenetically stable state of"exhaustion"(Fig.1a)[1].展开更多
Background:This study aimed to investigate programmed death-ligand 1 tumor proportion score in predicting the safety and efficacy of PD-1/PD-L1 antibody-based therapy in treating patients with advanced non-small cell ...Background:This study aimed to investigate programmed death-ligand 1 tumor proportion score in predicting the safety and efficacy of PD-1/PD-L1 antibody-based therapy in treating patients with advanced non-small cell lung cancer(NSCLC)in a real-world setting.Methods:This retrospective,multicenter,observational study enrolled adult patients who received PD-1/PD-L1 antibody-based therapy in China and met the following criteria:(1)had pathologically confirmed,unresectable stage III–IV NSCLC;(2)had a baseline PD-L1 tumor proportion score(TPS);and(3)had confirmed efficacy evaluation results after PD-1/PD-L1 treatment.Logistic regression,Kaplan–Meier analysis,and Cox regression were used to assess the progression-free survival(PFS),overall survival(OS),and immune-related adverse events(irAEs)as appropriate.Results:A total of 409 patients,65.0%(n=266)with a positive PD-L1 TPS(≥1%)and 32.8%(n=134)with PD-L1 TPS≥50%,were included in this study.Cox regression confirmed that patients with a PD-L1 TPS≥1%had significantly improved PFS(hazard ratio[HR]0.747,95%confidence interval[CI]0.573–0.975,P=0.032).A total of 160(39.1%)patients experienced 206 irAEs,and 27(6.6%)patients experienced 31 grade 3–5 irAEs.The organs most frequently associated with irAEs were the skin(52/409,12.7%),thyroid(40/409,9.8%),and lung(34/409,8.3%).Multivariate logistic regression revealed that a PD-L1 TPS≥1%(odds ratio[OR]1.713,95%CI 1.054–2.784,P=0.030)was an independent risk factor for irAEs.Other risk factors for irAEs included pretreatment absolute lymphocyte count>2.5×10^(9)/L(OR 3.772,95%CI 1.377–10.329,P=0.010)and pretreatment absolute eosinophil count>0.2×109/L(OR 2.006,95%CI 1.219–3.302,P=0.006).Moreover,patients who developed irAEs demonstrated improved PFS(13.7 months vs.8.4 months,P<0.001)and OS(28.0 months vs.18.0 months,P=0.007)compared with patients without irAEs.Conclusions:A positive PD-L1 TPS(≥1%)was associated with improved PFS and an increased risk of irAEs in a real-world setting.The onset of irAEs was associated with improved PFS and OS in patients with advanced NSCLC receiving PD-1/PD-L1-based therapy.展开更多
Immune checkpoint inhibitors(ICIs)have revolutionized the treatment landscape for various malignancies by demonstrating exceptional antitumor effects and significant improvement in patient survival.Despite their overt...Immune checkpoint inhibitors(ICIs)have revolutionized the treatment landscape for various malignancies by demonstrating exceptional antitumor effects and significant improvement in patient survival.Despite their overt therapeutic advantages,ICIs also induce immune-related adverse events(irAEs).Of these,checkpoint inhibitor pneumonitis(CIP)represents a prominent manifestation of pulmonary toxicity following ICI therapy,with inci-dence rates ranging from 2.7%to 20.0%.Notably,a substantial proportion of CIP cases show severe manifesta-tions,often leading to life-threatening complications,which emphasizes its clinical significance.Understanding the risk factors and potential pathogenetic mechanisms of CIP,combined with vigilant monitoring during im-munotherapy,is pivotal for early detection and management of this condition.Proactive strategies for the timely identification,accurate diagnosis,and effective management of CIP are essential to optimize patient outcomes.However,several challenges persist in CIP management,including management of severe and refractory cases,determining the timing of ICI rechallenge after CIP,management of long-term chronic CIP,and mitigating sec-ondary infections.In order to manage this potentially life-threatening irAE effectively,it is urgent to establish multi-disciplinary treatment(MDT)management,precision CIP management,and practical surveillance systems for CIP monitoring,diagnosis,and management and to call for prospective multi-center clinical trials.展开更多
Background:Treatment options for Chinese patients with locally advanced or metastatic squamous-cell non-small-cell lung cancer(sqNSCLC)after failure of first-line chemotherapy are limited.This study(ORIENT-3)aimed to ...Background:Treatment options for Chinese patients with locally advanced or metastatic squamous-cell non-small-cell lung cancer(sqNSCLC)after failure of first-line chemotherapy are limited.This study(ORIENT-3)aimed to evaluate the efficacy and safety of sintilimab versus docetaxel as second-line treatment in patients with locally advanced or metastatic sqNSCLC.Methods:ORIENT-3 was an open-label,multicenter,randomized controlled phase 3 trial that recruited patients with stage IIIB/IIIC/IV sqNSCLC after failure with first-line platinum-based chemotherapy.Patients were randomized in a 1:1 ratio to receive either 200 mg of sintilimab or 75 mg/m^(2) of docetaxel intravenously every 3 weeks,stratified by the Eastern Cooperative Oncology Group performance status.The primary endpoint was overall survival(OS)in the full analysis set(FAS).Secondary endpoints included progression-free survival(PFS),objective response rate(ORR),disease control rate(DCR),duration of response(DoR)and safety.Results:Between August 25,2017,and November 7,2018,290 patients were randomized.For FAS,10 patients fromthe docetaxel armwere excluded.Themedian OS was 11.79(n=145;95%confidence interval[CI],10.28-15.57)months with sintilimab versus 8.25(n=135;95%CI,6.47-9.82)months with docetaxel(hazard ratio[HR]:0.74;95%CI,0.56-0.96;P=0.025).Sintilimab treatment significantly prolonged PFS(median 4.30 vs.2.79 months;HR:0.52;95%CI,0.39-0.68;P<0.001)and showed higher ORR(25.50%vs.2.20%,P<0.001)and DCR(65.50%vs.37.80%,P<0.001)than the docetaxel arm.The median DoRwas 12.45(95%CI,4.86-25.33)months in the sintilimab arm and 4.14(95%CI,1.41-7.23)months in the docetaxel arm(P=0.045).Treatment-related adverse events of grade≥3were reported in 26(18.1%)patients in the sintilimab arm and 47(36.2%)patients in the docetaxel arm.Exploratory biomarker analysis showed potential predictive values of expression levels of two transcription factors,including OVOL2(HR:0.35;P<0.001)and CTCF(HR:3.50;P<0.001),for sintilimab treatment.Conclusions:Compared with docetaxel,sintilimab significantly improved the OS,PFS,and ORR of Chinese patients with previously treated locally advanced or metastatic sqNSCLC.展开更多
Dear Editor,The application of immune checkpoint inhibitors(ICIs),anti-tumor immunotherapy unleashing the host immune system to eradicate tumor cells,has revolutionized the treatment of various advanced cancers and sh...Dear Editor,The application of immune checkpoint inhibitors(ICIs),anti-tumor immunotherapy unleashing the host immune system to eradicate tumor cells,has revolutionized the treatment of various advanced cancers and showed remarkable anti-tumor effects[1].However,emphasis must be placed on fatal immune-related adverse events(irAEs),especially some fulminant irAEs like ICI-related cardiovascular AEs[2,3].However,due to the low rate of cardiovascular AEs,little is known about the effective methods for evaluating the risk of catastrophic cardiac events in ICI-associated myocarditis and its management[4,5].展开更多
Lung cancer has the highest risk of brain metastasis(BM)among all solid carcinomas.The emergence of BM has a significant impact on the selection of oncologic treatment for patients.Immune checkpoint inhibitors(ICIs)ar...Lung cancer has the highest risk of brain metastasis(BM)among all solid carcinomas.The emergence of BM has a significant impact on the selection of oncologic treatment for patients.Immune checkpoint inhibitors(ICIs)are the most promising treatment option for patients without druggable mutations and have been shown to improve survival in patients with non-small cell lung cancer(NSCLC)BM in clinical trials with good safety.Moreover,ICI has shown certain effects in NSCLC BM,and the overall intracranial efficacy is comparable to extracranial efficacy.However,a proportion of patients showed discordant responses in primary and metastatic lesions,suggesting that multiple mechanisms may exist underlying ICI activity in BM.According to studies pertaining to tumor immune microenvironments,ICIs may be capable of provoking immunity in situ.Meanwhile,systematic immune cells activated by ICIs can migrate into the central nervous system and exert antitumor effects.This review summarizes the present evidence for ICI treatment efficacy in NSCLC BM and proposes the possible mechanisms of ICI treatment for NSCLC BMs based on existing evidence.展开更多
The phosphosphatidylinositol-3-kinase(PI3K)signaling pathway is one of the most important intracellular signal transduction pathways affecting cell functions,such as apoptosis,translation,metabolism,and angiogenesis.L...The phosphosphatidylinositol-3-kinase(PI3K)signaling pathway is one of the most important intracellular signal transduction pathways affecting cell functions,such as apoptosis,translation,metabolism,and angiogenesis.Lung cancer is a malignant tumor with the highest morbidity and mortality rates in the world.It can be divided into two groups,non-small cell lung cancer(NSCLC)and small cell lung cancer(SCLC).NSCLC accounts for>85%of all lung cancers.There are currently many clinical treatment options for NSCLC;however,traditional methods such as surgery,chemotherapy,and radiotherapy have not been able to provide patients with good survival benefits.The emergence of molecular target therapy has improved the survival and prognosis of patients with NSCLC.In recent years,there have been an increasing number of studies on NSCLC and PI3K signaling pathways.Inhibitors of various parts of the PI3K pathway have appeared in various phases of clinical trials with NSCLC as an indication.This article focuses on the role of the PI3K signaling pathway in the occurrence and development of NSCLC and summarizes the current clinical research progress and possible development strategies.展开更多
基金supported jointly by the earmarked fund for CARS-10-GW2the key research and development program of Hainan Province(Grant No.ZDYF2020226)+1 种基金Collaborative innovation center of Nanfan and high-efficiency tropical agriculture,Hainan University(Grant No.XTCX2022NYC21)funding of Hainan University[Grant No.KYQD(ZR)22123]。
文摘Heat stress hinders the growth and productivity of sweetpotato plants,predominantly through oxidative damage to cellular membranes.Therefore,the development of efficient approaches for mitigating heat-related impairments is essential for the long-term production of sweetpotatoes.Melatonin has been recognised for its capacity to assist plants in dealing with abiotic stress conditions.This research aimed to investigate how different doses of exogenous melatonin influence heat damage in sweetpotato plants.Heat stress drastically affected shoot and root fresh weight by 31.8 and 44.5%,respectively.This reduction resulted in oxidative stress characterised by increased formation of hydrogen peroxide(H_(2)O_(2))by 804.4%,superoxide ion(O_(2)^(·-))by 211.5%and malondialdehyde(MDA)by 234.2%.Heat stress also reduced chlorophyll concentration,photosystemⅡefficiency(F_v/F_m)by 15.3%and gaseous exchange.However,pre-treatment with 100μmol L^(-1)melatonin increased growth and reduced oxidative damage to sweetpotato plants under heat stress.In particular,melatonin decreased H_(2)O_(2),O_(2)^(·-)and MDA by 64.8%,42.7%and 38.2%,respectively.Melatonin also mitigated the decline in chlorophyll levels and improved stomatal traits,gaseous exchange and F_(v)/F_(m)(13%).Results suggested that the favorable outcomes of melatonin treatment can be associated with elevated antioxidant enzyme activity and an increase in non-enzymatic antioxidants and osmo-protectants.Overall,these findings indicate that exogenous melatonin can improve heat stress tolerance in sweetpotatoes.This stu dy will assist re searchers in further investigating how melatonin makes sweetpotatoes more resistant to heat stress.
文摘免疫检查点抑制剂(immune checkpoint inhibitors,ICIs)的应用改写了很多恶性肿瘤的治疗策略,成为肿瘤治疗的又一个里程碑。ICIs作用原理可以理解为“刹车理论”,在“松开刹车”后会带来一系列的全身性毒副反应,其中部分可能为危重和难治性,甚至具有潜在致死性。本文对免疫相关不良事件(immune-related adverse effects,irAEs)相关的最新国内外指南及共识中关于3度-4度irAEs的诊治建议进行了汇总,包括欧洲肿瘤内科学会年会(European Society for Medical Oncology,ESMO)、美国国立综合癌症网络(National Comprehensive Cancer Network,NCCN)/美国临床肿瘤学会(American Society of Clinical Oncology,ASCO)、肿瘤免疫治疗学会(Society for Immunotherapy of Cancer,SITC)和中国临床肿瘤学会(Chinese Society of Clinical Oncology,CSCO)指南,并复习了2019年5月20日前公开发表的关于irAEs的个案报告和相关的综述文献后,对以上指南和共识中尚未纳入的3级-4级irAEs的诊治建议进行补充,重点介绍了特异性免疫抑制药物在不同的irAEs中成功应用的情况,包括抗白介素6(interleukin 6,IL-6)阻断、抗CD20单抗、抗肿瘤坏死因子α(tumor necrosis factor-α,TNFα)单抗、抗整合素4单抗、Janus激酶抑制剂、血小板生成素受体激动剂和抗胸腺细胞球蛋白(antithymocyte globulin,ATG).本文对于类固醇激素在irAEs中超大剂量使用和升级使用及反复使用提出质疑,并强调应同时关注激素继发的感染、肿瘤进展和无法满足ICIs再挑战的等问题。本文提出对于危重和难治性irAEs的“降阶梯治疗”原则,建议应尽早使用细胞因子靶向药物这些特异性免疫抑制药物。免疫治疗时代诸多的irAEs是传统化疗及小分子靶向治疗时代不曾有过的,不断地挑战肿瘤科大夫的知识储备和临床基本技能。因此,建立肿瘤多学科讨论体系对于肿瘤患者的治疗管理极为重要。
基金supported by grants from Guangdong Provincial Key Lab of Translational Medicine in Lung Cancer (Grant No. 2017B030314120)General Research Project of Guangzhou Science and Technology Bureau (Grant No. 201607010391)+1 种基金National Key Research and Development Program of China (Grant No. 2016YFC1303800)Guangdong Provincial Applied S&T R&D Program (Grant No. 2016B020237006)
文摘Next-generation sequencing(NGS) technology is capable of sequencing millions or billions of DNA molecules simultaneously.Therefore, it represents a promising tool for the analysis of molecular targets for the initial diagnosis of disease, monitoring of disease progression, and identifying the mechanism of drug resistance. On behalf of the Tumor Biomarker Committee of the Chinese Society of Clinical Oncology(CSCO) and the China Actionable Genome Consortium(CAGC), the present expert group hereby proposes advisory guidelines on clinical applications of NGS technology for the analysis of cancer driver genes for precision cancer therapy. This group comprises an assembly of laboratory cancer geneticists, clinical oncologists, bioinformaticians,pathologists, and other professionals. After multiple rounds of discussions and revisions, the expert group has reached a preliminary consensus on the need of NGS in clinical diagnosis, its regulation, and compliance standards in clinical sample collection. Moreover, it has prepared NGS criteria, the sequencing standard operation procedure(SOP), data analysis, report, and NGS platform certification and validation.
基金supported by grants from the Demonstrative Research Platform of Clinical Evaluation Technology for New Anticancer Drugs(Grant Nos.18ZX09201-015 and 2017ZX09304015)the Innovation Fund for Medical Sciences of the Chinese Academy of Medical Sciences(Grant No.CIFMS,2016-I2M-1-001)。
文摘Chemotherapy-induced neutropenia(CIN)is a potentially fatal and common complication in myelosuppressive chemotherapy.The timing and grade of CIN may play prognostic and predictive roles in cancer therapy.CIN is associated with older age,poor functional and nutritional status,the presence of significant comorbidities,the type of cancer,previous chemotherapy cycles,the stage of the disease,specific chemotherapy regimens,and combined therapies.There are many key points and new challenges in the management of CIN in adults including:(1)Genetic risk factors to evaluate the patient’s risk for CIN remain unclear.However,these risk factors urgently need to be identified.(2)Febrile neutropenia(FN)remains one of the most common reasons for oncological emergency.No consensus nomogram for FN risk assessment has been established.(3)Different assessment tools[e.g.,Multinational Association for Supportive Care in Cancer(MASCC),the Clinical Index of Stable Febrile Neutropenia(CISNE)score model,and other tools]have been suggested to help stratify the risk of complications in patients with FN.However,current tools have limitations.The CISNE score model is useful to support decision-making,especially for patients with stable FN.(4)There are still some challenges,including the benefits of granulocyte colony stimulating factor treatment and the optimal antibiotic regimen in emergency management of FN.In view of the current reports,our group discusses the key points,new challenges,and management of CIN.
文摘Objective: Crizotinib has demonstrated promising efficacy in patients with anaplastic lymphoma kinase(ALK)-positive non-small-cell lung cancer(NSCLC) in clinical trials. We conducted this retrospective multicenter study to assess the outcomes of crizotinib therapy in, to our knowledge, a large sample cohort of patients with ALKpositive advanced NSCLC.Methods: We reviewed the medical records of 484 unselected ALK-positive NSCLC patients treated with crizotinib at 5 cancer centers in China from January 2013 to November 2017. Clinical data were collected from the initiation of crizotinib therapy to Response Evaluation Criteria in Solid Tumors(RECIST)-defined progressive disease(PD).Results: A total of 428 eligible ALK-positive NSCLC patients were enrolled, 273(63.8%) of whom received crizotinib as first-line treatment. The median progression-free survival(PFS) and overall survival(OS) from the initiation of crizotinib treatment were 14.4 [95% confidence interval(95% CI), 12.4-16.4] months and 53.4(95%CI, 33.7-73.1) months, respectively. In subgroup analyses, patients who received crizotinib as first-line treatment showed a higher disease control rate(DCR) and a longer median OS compared with second-/later-line crizotinib treatment(94.8% and OS not reached vs. 89.0% and 40.5 months, respectively). For 261 patients with RECISTdefined PD, multivariate Cox analysis revealed that in patients who received first-line crizotinib therapy, continued crizotinib beyond progressive disease(CBPD) and next-generation ALK inhibitors after crizotinib failure were associated with improved survival.Conclusions: This study has demonstrated the clinically meaningful benefit of crizotinib treatment in a large cohort of Chinese ALK-positive NSCLC patients. CBPD and next-generation ALK inhibitor treatment may provide improved survival after RECIST-defined progression on crizotinib.
基金supported by the Youth Program of National Natural Science Foundation of China(Grant No.82003309)the National Key Research and Development Program of China(Grant 2020YFB1313700)。
文摘Objective BAG3-related myopathy is a rare condition so far reported in twenty patients worldwide.The purpose of this study was to draw attention to this rare disease and to the fact that BAG3-related myopathy should be considered as a rare differential diagnosis of hypercapnia.Methods We report a sporadic case of a 14-year-old Chinese girl with a de novo p.Pro209 Leu mutation in BAG3 and reviewed the literatures for reported cases related to this mutation.Results We described a 14-year-old Chinese girl who presented with gradually appearing symptoms of hypercapnia that required assisted ventilation.The muscle biopsy and the blood whole-exome sequencing results confirmed the diagnosis of myofibrillar myopathy with a de novo p.Pro209 Leu mutation in BAG3.Totally twentyone patients from twenty families with a confirmed diagnosis of BAG3-related myopathy were reported to date,including this patient and literature review.The male to female ratio was 11:10 and most showed initial symptoms in the first decade of life.Most patients presented toe/clumsy walking or running as the onset symptom,followed by muscle weakness or atrophy.Creatine kinase levels were elevated in fourteen patients and were normal in three.Eighteen patients developed respiratory insufficiency during the disease course and thirteen(one could not tolerate non-invasive assisted ventilation)required non-invasive assisted ventilation for treatment.Except for one not reported,heart involvement was found in seventeen patients during the disease course and seven underwent heart transplantation.Z-disk streaming and aggregation could be observed in most of the patients’muscle histology.In the long-term follow-up,five patients died of cardiac or respiratory failure.Conclusion BAG3-associated myopathy is a rare type of myofibrillar myopathy.It should be considered as a rare differential diagnosis of hypercapnia.
基金supported by the Beijing Natural Science Foundation(7252108)the National Science and Technology Major Project(2023ZD0502804)the Beijing Nova Program(20220484).
文摘Programmed death-1(PD-1)targeted immunotherapy has revolutionized cancer treatment but fails to induce durable responses in many patients,mainly due to restricted reversal of CD8^(+)T cell exhaustion.In cancer and chronic infections,persistent antigens hinder effective immune clearance,leading CD8^(+)T cells into a dysfunctional and epigenetically stable state of"exhaustion"(Fig.1a)[1].
基金This study is funded by a grant from the National High Level Hospital Clinical Research Funding to Wei Zhong,grant number 2022-PUMCH-C-054.
文摘Background:This study aimed to investigate programmed death-ligand 1 tumor proportion score in predicting the safety and efficacy of PD-1/PD-L1 antibody-based therapy in treating patients with advanced non-small cell lung cancer(NSCLC)in a real-world setting.Methods:This retrospective,multicenter,observational study enrolled adult patients who received PD-1/PD-L1 antibody-based therapy in China and met the following criteria:(1)had pathologically confirmed,unresectable stage III–IV NSCLC;(2)had a baseline PD-L1 tumor proportion score(TPS);and(3)had confirmed efficacy evaluation results after PD-1/PD-L1 treatment.Logistic regression,Kaplan–Meier analysis,and Cox regression were used to assess the progression-free survival(PFS),overall survival(OS),and immune-related adverse events(irAEs)as appropriate.Results:A total of 409 patients,65.0%(n=266)with a positive PD-L1 TPS(≥1%)and 32.8%(n=134)with PD-L1 TPS≥50%,were included in this study.Cox regression confirmed that patients with a PD-L1 TPS≥1%had significantly improved PFS(hazard ratio[HR]0.747,95%confidence interval[CI]0.573–0.975,P=0.032).A total of 160(39.1%)patients experienced 206 irAEs,and 27(6.6%)patients experienced 31 grade 3–5 irAEs.The organs most frequently associated with irAEs were the skin(52/409,12.7%),thyroid(40/409,9.8%),and lung(34/409,8.3%).Multivariate logistic regression revealed that a PD-L1 TPS≥1%(odds ratio[OR]1.713,95%CI 1.054–2.784,P=0.030)was an independent risk factor for irAEs.Other risk factors for irAEs included pretreatment absolute lymphocyte count>2.5×10^(9)/L(OR 3.772,95%CI 1.377–10.329,P=0.010)and pretreatment absolute eosinophil count>0.2×109/L(OR 2.006,95%CI 1.219–3.302,P=0.006).Moreover,patients who developed irAEs demonstrated improved PFS(13.7 months vs.8.4 months,P<0.001)and OS(28.0 months vs.18.0 months,P=0.007)compared with patients without irAEs.Conclusions:A positive PD-L1 TPS(≥1%)was associated with improved PFS and an increased risk of irAEs in a real-world setting.The onset of irAEs was associated with improved PFS and OS in patients with advanced NSCLC receiving PD-1/PD-L1-based therapy.
基金support from the National High Level Hospital Clinical Research(No.2022-PUMCH–C-054).
文摘Immune checkpoint inhibitors(ICIs)have revolutionized the treatment landscape for various malignancies by demonstrating exceptional antitumor effects and significant improvement in patient survival.Despite their overt therapeutic advantages,ICIs also induce immune-related adverse events(irAEs).Of these,checkpoint inhibitor pneumonitis(CIP)represents a prominent manifestation of pulmonary toxicity following ICI therapy,with inci-dence rates ranging from 2.7%to 20.0%.Notably,a substantial proportion of CIP cases show severe manifesta-tions,often leading to life-threatening complications,which emphasizes its clinical significance.Understanding the risk factors and potential pathogenetic mechanisms of CIP,combined with vigilant monitoring during im-munotherapy,is pivotal for early detection and management of this condition.Proactive strategies for the timely identification,accurate diagnosis,and effective management of CIP are essential to optimize patient outcomes.However,several challenges persist in CIP management,including management of severe and refractory cases,determining the timing of ICI rechallenge after CIP,management of long-term chronic CIP,and mitigating sec-ondary infections.In order to manage this potentially life-threatening irAE effectively,it is urgent to establish multi-disciplinary treatment(MDT)management,precision CIP management,and practical surveillance systems for CIP monitoring,diagnosis,and management and to call for prospective multi-center clinical trials.
基金funded by Innovent biologics,Inc.Eli Lilly and Companypartly supported by China National Major Project for New Drug Innovation(2017ZX09304015).
文摘Background:Treatment options for Chinese patients with locally advanced or metastatic squamous-cell non-small-cell lung cancer(sqNSCLC)after failure of first-line chemotherapy are limited.This study(ORIENT-3)aimed to evaluate the efficacy and safety of sintilimab versus docetaxel as second-line treatment in patients with locally advanced or metastatic sqNSCLC.Methods:ORIENT-3 was an open-label,multicenter,randomized controlled phase 3 trial that recruited patients with stage IIIB/IIIC/IV sqNSCLC after failure with first-line platinum-based chemotherapy.Patients were randomized in a 1:1 ratio to receive either 200 mg of sintilimab or 75 mg/m^(2) of docetaxel intravenously every 3 weeks,stratified by the Eastern Cooperative Oncology Group performance status.The primary endpoint was overall survival(OS)in the full analysis set(FAS).Secondary endpoints included progression-free survival(PFS),objective response rate(ORR),disease control rate(DCR),duration of response(DoR)and safety.Results:Between August 25,2017,and November 7,2018,290 patients were randomized.For FAS,10 patients fromthe docetaxel armwere excluded.Themedian OS was 11.79(n=145;95%confidence interval[CI],10.28-15.57)months with sintilimab versus 8.25(n=135;95%CI,6.47-9.82)months with docetaxel(hazard ratio[HR]:0.74;95%CI,0.56-0.96;P=0.025).Sintilimab treatment significantly prolonged PFS(median 4.30 vs.2.79 months;HR:0.52;95%CI,0.39-0.68;P<0.001)and showed higher ORR(25.50%vs.2.20%,P<0.001)and DCR(65.50%vs.37.80%,P<0.001)than the docetaxel arm.The median DoRwas 12.45(95%CI,4.86-25.33)months in the sintilimab arm and 4.14(95%CI,1.41-7.23)months in the docetaxel arm(P=0.045).Treatment-related adverse events of grade≥3were reported in 26(18.1%)patients in the sintilimab arm and 47(36.2%)patients in the docetaxel arm.Exploratory biomarker analysis showed potential predictive values of expression levels of two transcription factors,including OVOL2(HR:0.35;P<0.001)and CTCF(HR:3.50;P<0.001),for sintilimab treatment.Conclusions:Compared with docetaxel,sintilimab significantly improved the OS,PFS,and ORR of Chinese patients with previously treated locally advanced or metastatic sqNSCLC.
基金the Youth Program of National Natural Science Foundation of China(to YX)(82003309)the National Key Research and Development Program of China(to WW)(2016YFC0905102)CAMS Innovation Fund for Medical Sciences(to WW)(CIFMS)(2017-I2M-2-002).
文摘Dear Editor,The application of immune checkpoint inhibitors(ICIs),anti-tumor immunotherapy unleashing the host immune system to eradicate tumor cells,has revolutionized the treatment of various advanced cancers and showed remarkable anti-tumor effects[1].However,emphasis must be placed on fatal immune-related adverse events(irAEs),especially some fulminant irAEs like ICI-related cardiovascular AEs[2,3].However,due to the low rate of cardiovascular AEs,little is known about the effective methods for evaluating the risk of catastrophic cardiac events in ICI-associated myocarditis and its management[4,5].
基金Youth Program of the National Natural Science Foundation of China(No.82003309)
文摘Lung cancer has the highest risk of brain metastasis(BM)among all solid carcinomas.The emergence of BM has a significant impact on the selection of oncologic treatment for patients.Immune checkpoint inhibitors(ICIs)are the most promising treatment option for patients without druggable mutations and have been shown to improve survival in patients with non-small cell lung cancer(NSCLC)BM in clinical trials with good safety.Moreover,ICI has shown certain effects in NSCLC BM,and the overall intracranial efficacy is comparable to extracranial efficacy.However,a proportion of patients showed discordant responses in primary and metastatic lesions,suggesting that multiple mechanisms may exist underlying ICI activity in BM.According to studies pertaining to tumor immune microenvironments,ICIs may be capable of provoking immunity in situ.Meanwhile,systematic immune cells activated by ICIs can migrate into the central nervous system and exert antitumor effects.This review summarizes the present evidence for ICI treatment efficacy in NSCLC BM and proposes the possible mechanisms of ICI treatment for NSCLC BMs based on existing evidence.
基金Youth Program of the National Natural Science Foundation of China (to YX)(No. 82003309)
文摘The phosphosphatidylinositol-3-kinase(PI3K)signaling pathway is one of the most important intracellular signal transduction pathways affecting cell functions,such as apoptosis,translation,metabolism,and angiogenesis.Lung cancer is a malignant tumor with the highest morbidity and mortality rates in the world.It can be divided into two groups,non-small cell lung cancer(NSCLC)and small cell lung cancer(SCLC).NSCLC accounts for>85%of all lung cancers.There are currently many clinical treatment options for NSCLC;however,traditional methods such as surgery,chemotherapy,and radiotherapy have not been able to provide patients with good survival benefits.The emergence of molecular target therapy has improved the survival and prognosis of patients with NSCLC.In recent years,there have been an increasing number of studies on NSCLC and PI3K signaling pathways.Inhibitors of various parts of the PI3K pathway have appeared in various phases of clinical trials with NSCLC as an indication.This article focuses on the role of the PI3K signaling pathway in the occurrence and development of NSCLC and summarizes the current clinical research progress and possible development strategies.
