Three novel rare TP53 fusion mutations in a patient with multiple primary cancers:a case report

As survival rates improve and detection technologies advance,the occurrence of multiple primary cancers(MPCs)has been increasing.Approximately 16%of cancer survivors develop a subsequent malignancy,with lung cancer often developing after esophageal cancer due to potential“field cancerization”effects.Despite this observation,the genetic heterogeneity underlying MPCs remains understudied.However,the recent emergence of genetic testing has expanded the scope of investigations into MPCs to investigate signatures underlying cancer predisposition.This report reveals 3 unprecedented TP53 fusion mutations in a Chinese patient afflicted by MPCs,namely,AP1M2–TP53(A1;T11)fusion,TP53–ILF3(T10;I13)fusion,and SLC44A2–TP53(S5;T11)fusion.This patient exhibited an extended period of survival after diagnosis of extensive-stage small cell lung cancer,which occurred 6 years after the diagnosis of esophageal squamous cell cancer.This unique reportmay provide supplementary data that enhance our understanding of the genetic landscape ofMPCs.

Purifi cation and identification of anti-inflammatory peptides from sturgeon (Acipenser schrenckii) cartilage

Cartilage is a nonedible byproduct with little saleable value.However,previous studies have proposed the possibility of producing peptides from cartilage with immune function modulation potential.The current study aimed to investigate the potential anti-inflammatory activity of peptides derived from sturgeon(Acipenser schrenckii)cartilage in lipopolysaccharide(LPS)-stimulated RAW264.7 macrophages.Five peptide sequences,including four novel peptides,were identified from ethanol-soluble cartilage hydrolysates.Among these five peptides,LTGP,LLLE,LLEL and VGPAGPAGP reduced the production of nitric oxide(NO)and interleukin-6(IL-6)while increasing interleukin-10(IL-10)excretion.Transcriptome analysis suggested the inhibition of activated mitogen-activated protein kinase(MAPK)and interleukin-17(IL-17)signaling pathways after LLEL intervention.MAPK,which is involved in the IL-17 signaling pathway,was further proved to be blocked by downregulating the phosphorylation of p38,extracellular-signal regulated protein kinase(ERK),and c-jun N-terminal kinase(JNK).This novel peptide offers an attractive approach to develop functional foods.

中国非小细胞肺癌免疫检查点抑制剂治疗专家共识(2020年版)

非小细胞肺癌(non-small cell lung cancer,NSCLC)是肺癌最常见的病理类型。晚期NSCLC的系统性抗肿瘤治疗经历了化疗、靶向治疗及免疫治疗的变革,患者总体生存时间不断延长。免疫检查点抑制剂(immune checkpoint inhibitors,ICIs),尤其是程序性死亡分子-1(programmed cell death protein 1,PD-1)/程序性死亡分子配体-1(programmed death-ligand 1,PD-L1)抗体已成为表皮生长因子受体(epidermal growth factor receptor,EGFR)/间变性淋巴瘤激酶(anaplastic lymphoma kinase,ALK)阴性晚期NSCLC一线及二线的标准治疗和局部晚期NSCLC同步放化疗后标准治疗,并在辅助/新辅助治疗中显示出可喜的结果,改变了NSCLC整体治疗格局。随着越来越多的ICIs在国内获批肺癌适应证,中国临床肿瘤学会(Chinese Society of Clinical Oncology,CSCO)NSCLC专家委员会牵头,组织该领域的专家,结合2019年版专家共识,参考最新国内外文献、临床研究数据及系统评价,在专家共同讨论的基础上,达成统一意见并制定、更新本共识,为国内同行更好地应用ICIs治疗NSCLC提供参考意见。

放疗联合免疫治疗非小细胞肺癌:前沿学术问题专家交流共识

肺癌是目前导致全球和中国癌症患者死亡的主要瘤种。多年来,常规的肿瘤治疗方法,如手术、化疗和放疗一直主导着非小细胞肺癌(non-small cell lung cancer,NSCLC)治疗领域。临床实践中引入免疫疗法使肺癌的治疗与其他实体瘤一样发生了根本性转变。最新临床前和临床数据表明,放疗可以通过诱导免疫原性细胞死亡和重新编程肿瘤微环境促进抗肿瘤免疫反应。研究者开始重新审视放疗作为免疫治疗的联合疗法,导致研究其潜在协同作用的临床试验数量呈指数级增长。放疗联合免疫治疗的临床试验引起了医疗界的广泛关注,会议邀请专家交流前沿及争议学术问题:①放疗联合免疫检查点抑制剂治疗NSCLC最新进展;②放疗联合免疫治疗是否显著增加毒性;③免疫检查点抑制剂治疗后出现的混合反应及局部治疗的干预价值;④放疗联合免疫治疗脑转移瘤的机制和进展。

Investigation of quality of life in patients with lung cancer by the EORTC QLQ-C30(V3.0) Chinese version

Objective To explore quality of life(QOL) and its influencing factors in patients with lung cancer.Methods A QOL questionnaire(European Organization for Research and Treatment of Cancer [EORTC] Quality of Life Questionnaire-Core 30 [QLQ-C30] Chinese version) was used with 138 patients with lung cancer participating in the study. A statistical description of the general characteristics of the patients with lung cancer was performed. The patients' QLQ-C30 scores were compared with the reference value for each dimension. To analyze the influence of QOL in different genders, age groups, and cancer stages, ttests and rank sum tests were used to compare the differences in QOL using a 5% significance level. Results The QLQ-C30 function scores in PF(physical functioning), EF(emotional functioning), SF(social functioning), and GH(global functioning), and symptom scales in NV(nausea and vomiting), DY(dyspnea), SL(insomnia), and FI(financial difficulties) were significantly different(P < 0.05) in comparison to the reference values. Female patients were worse than males(P < 0.05) in EF, NV, and DI(diarrhea). The later the stage of lung cancer, the worse the quality of life became; the functional scales in RF(role functioning), EF, CF, SF, and GH, and symptom scales in PA(pain), AP(appetite), and SL differences were statistically significant(P < 0.05). Conclusion This study aids understanding of the status of the quality of life of Chinese patients with cancer and might be useful for clinical work, theory research, and health policymakers.

Prevalence and clinical significance of pathogenic germline BRCA1/2 mutations in Chinese non-small cell lung cancer patients

Objective: Germline alterations in the breast cancer susceptibility genes type 1 and 2, BRCA1 and BRCA2, predispose individuals to hereditary cancers, including breast, ovarian, prostate, pancreatic, and stomach cancers.Accumulating evidence suggests inherited genetic susceptibility to lung cancer.The present study aimed to survey the prevalence of pathogenic germline BRCA mutations(gBRCAm) and explore the potential association between gBRCAm and disease onset in Chinese advanced non-small cell lung cancer(NSCLC) patients.Methods: A total of 6,220 NSCLC patients were screened using capture-based ultra-deep targeted sequencing to identify patients harboring germline BRCA1/2 mutations.Results: Out of the 6,220 patients screened, 1.03%(64/6,220) of the patients harbored the pathogenic gB RCAm, with BRCA2 mutations being the most predominant mutations(49/64, 76.5%).Patients who developed NSCLC before 50 years of age were more likely to carry gBRCAm(P = 0.036).Among the patients harboring classic lung cancer driver mutations, those with concurrent gBRCAm were significantly younger than those harboring the wild-type gBRCA(P = 0.029).By contrast, the age of patients with or without concurrent gBRCAm was comparable to those of patients without the driver mutations(P = 0.972).In addition, we identified EGFR-mutant patients with concurrent gBRCAm who showed comparable progression-free survival but significantly longer overall survival(P = 0.002) compared to EGFR-mutant patients with wild-type germline BRCA.Conclusions: Overall, our study is the largest survey of the prevalence of pathogenic gBRCAm in advanced Chinese NSCLC patients.Results suggested a lack of association between germline BRCA status and treatment outcome of EGFR-TKI.In addition,results showed a positive correlation between pathogenic gB RCAm and an early onset of NSCLC.

Deficiency of Tfh Cells and Germinal Center in Deceased COVID-19 Patients

Summary:The COVID-19 pandemic caused by SARS-CoV2 is characterized by a remarkable variation in clinical severity ranging from a mild illness to a fatal multi-organ disease.Understanding the dysregulated human immune responses in the fatal subjects is critical for management of COVID-19 patients and the pandemic.In this study,we examined the immune cell compositions in the lung tissues and hilar lymph nodes using immunohistochemistry on 6 deceased COVID-19 patients and 4 focal organizing pneumonia(FOP)patients who underwent lung surgery and served as controls.We found a dominant presence of macrophages and a general deficiency of T cells and B cells in the lung tissues from deceased COVID-19 patients.In contrast to the FOP patients,Tfh cells and germinal center formation were largely absent in the draining hilar lymph nodes in the deceased COVID-19 patients.This was correlated with reduced IgM and IgG levels compared to convalescent COVID-19 patients.In summary,our data highlight a defect of germinal center structure in deceased COVID-19 patients leading to an impaired humoral immunity.Understanding the mechanisms of this deficiency will be one of the key points for the management of this epidemic.

Erratum to Prevalence and clinical significance of pathogenic germline BRCA1/2 mutations in Chinese non-small cell lung cancer patients

In the published article1,the affiliation for the first author,Xingshcng Hu,is"Department of Medical Oncology,Cancer Hospital,Chinese Academy of Medical Sciences",we would like to update it to"Department of Medical Oncology,National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing,100021,China".We apologize for the errors and for any confusion it may have caused.

乳腺浸润性导管癌组织中HMGB1表达的临床意义(英文)

Objective: Exploring the clinical signification of high-mobility group box 1 protein(HMGB1) expression in infiltrating ductal carcinoma(IDC) breast tissue. Methods: The expression of HMGB1 protein in IDC breast tissue was detected by immunohistochemistry, and the relations among size of tumour, lymph node metastasis, clinical staging, estrogen receptor(ER), progesterone receptor(PR) and human epidermal growth factor receptor 2(HER-2) were also analyzed. Results: Fortysix cases out of 60 cases of IDC breast tissue showed positive or strong positive HMGB1 expression(76.67%), statistical significance was observed between HMGB1 expression with clinical staging(P < 0.01), lymph node metastasis(P < 0.01), breast cancer ER(P < 0.05) and HER-2(P < 0.05), however same conclusion can not be drawn between HMGB1 with either size of tumour or PR expression(P > 0.05) in IDC breast tissue. Spearman analysis showed negative correlation between HMGB1 expression and ER, and positive correlation between HMGB1 expression and clinical staging, lymph node metastasis together with HER-2. Conclusion: It's promising that HMGB1 expression in IDC tissue can be one of biological indicators of poor prognosis.

Combined targeting of CCL7 and Flt3L to promote the expansion and infiltration of cDC1s in tumors enhances T-cell activation and anti-PD-1 therapy effectiveness in NSCLC

mmune checkpoint inhibitors(ICIs),represented by anti-PD-1/PD-L1 antibodies,have been widely applied in various cancers,and the efficacy of ICIs is closely associated with the tumor immune microenvironment(TIME)[1,2].We previously demonstrated that the alveolar macrophage-derived chemokine CCL7 recruited conventional type 1 dendritic cells(cDC1s)to remodel the TIME,thereby promoting the expansion of T cells to inhibit non-small cell lung cancer(NSCLC)progression in KrasLSL-G12D/+Tp53fl/fl(KP)and KrasLSL-G12D/+Lkb1fl/fl(KL)mouse models[3].Here,we showed that the fusion protein PD-1Ab7,in which CCL7 was fused with the single-chain variable fragment region(scFv)of an anti-PD-1 antibody(PD-1Ab),exhibited antitumor activity superior to that of PD-1Ab in a manner dependent on cDC1s.In addition,Fms-like tyrosine kinase 3 ligand(Flt3L)synergized with PD-1Ab7 to inhibit NSCLC progression in both the KP and the KL mouse models.Mechanistically,Flt3L promoted the generation and proliferation of cDC1s,whereas PD-1Ab7 increased the infiltration and migration of cDC1s in the TIME to potentiate the activation and proliferation of T cells.These findings not only highlight the essential roles of the PD-1Ab-based chemokine fusion strategy in targeting cDC1s and T cells to potentiate the efficacy of ICIs for cancer prevention but also provide therapeutic lead molecules for antitumor therapy.

Targeting tumor microenvironment for non-small cell lung cancer immunotherapy

The tumor microenvironment(TME)is composed of different cellular and non-cellular elements.Constant inter-actions between tumor cells and the TME are responsible for tumor initiation,tumor progression,and responses to therapies.Immune cells in the TME can be classified into two broad categories,namely adaptive and innate immunity.Targeting these immune cells has attracted substantial research and clinical interest.Current research focuses on identifying key molecular players and developing targeted therapies.These approaches may offer more efficient ways of treating different cancers.In this review,we explore the heterogeneity of the TME in non-small cell lung cancer,summarize progress made in targeting the TME in preclinical and clinical studies,discuss the potential predictive value of the TME in immunotherapy,and highlight the promising effects of bispecific antibodies in the era of immunotherapy.

Notch signaling pathway:architecture,disease,and therapeutics

The NOTCH gene was identified approximately 110 years ago.Classical studies have revealed that NOTCH signaling is an evolutionarily conserved pathway.NOTCH receptors undergo three cleavages and translocate into the nucleus to regulate the transcription of target genes.NOTCH signaling deeply participates in the development and homeostasis of multiple tissues and organs,the aberration of which results in cancerous and noncancerous diseases.However,recent studies indicate that the outcomes of NOTCH signaling are changeable and highly dependent on context.In terms of cancers,NOTCH signaling can both promote and inhibit tumor development in various types of cancer.The overall performance of NOTCH-targeted therapies in clinical trials has failed to meet expectations.Additionally,NOTCH mutation has been proposed as a predictive biomarker for immune checkpoint blockade therapy in many cancers.Collectively,the NOTCH pathway needs to be integrally assessed with new perspectives to inspire discoveries and applications.In this review,we focus on both classical and the latest findings related to NOTCH signaling to illustrate the history,architecture,regulatory mechanisms,contributions to physiological development,related diseases,and therapeutic applications of the NOTCH pathway.The contributions of NOTCH signaling to the tumor immune microenvironment and cancer immunotherapy are also highlighted.We hope this review will help not only beginners but also experts to systematically and thoroughly understand the NOTCH signaling pathway.

Clinical outcomes of coronavirus disease 2019 (COVID-19) in cancer patients with prior exposure to immune checkpoint inhibitors

Dear Editor,The coronavirus disease 2019(COVID-19)pandemic has affected over 6,000,000 people globally[1].Patients with COVID-19 manifest with symptoms of fever,dry cough,dyspnea,and present with radiological changes that are consistent with atypical pneumonia[2].Pathogenetic mechanisms for these abnormalities involve the systemic immune response that is associated with the hyperactivation of peripheral CD8+and CD4+T cells,and a cytokine storm[3].Globally,the reported prevalence of patients with COVID-19 and cancer ranges from 0.5%to 6.0%in the different case series[4].

Characteristics of immune and inflammatory responses among different age groups of pediatric patients with COVID-19 in China

Background Severe cases of coronavirus disease 2019(COVID-19)among pediatric patients are more common in children less than 1 year of age.Our aim is to address the underlying role of immunity and inflammation conditions among different age groups of pediatric patients.Methods We recruited pediatric patients confirmed of moderate COVID-19 symptoms,admitted to Wuhan Children's Hospital from January 28th to April 1st in 2020.Patients were divided into four age groups(≤1,1–6,7–10,and 11–15 years).Demographic information,clinical characteristics,laboratory results of lymphocyte subsets test,immune and inflammation related markers were all evaluated.Results Analysis included 217/241(90.0%)of patients with moderate clinical stage disease.Average recovery time of children more than 6 years old was significantly shorter than of children younger than 6 years(P=0.001).Reduced neutrophils and increased lymphocytes were significantly most observed among patients under 1 year old(P<0.01).CD19+B cells were the only significantly elevated immune cells,especially among patients under 1 year old(cell proportion:n=12,30.0%,P<0.001;cell count:n=13,32.5%,P<0.001).While,low levels of immune related makers,such as immunoglobulin(Ig)G(P<0.001),IgA(P<0.001),IgM(P<0.001)and serum complement C3c(P<0.001),were also mostly found among patients under 1 year old,together with elevated levels of inflammation related markers,such as tumor necrosis factor γ (P=0.007),interleukin(IL)-10(P=0.011),IL-6(P=0.008),lactate dehydrogenase(P<0.001),and procalcitonin(P=0.007).Conclusion The higher rate of severe cases and long course of COVID-19 among children under 1 year old may be due to the lower production of antibodies and serum complements of in this age group.

Hollow-core fiber-based Raman probe extension kit for in situ and sensitive ultramicro-analysis

A metal-lined hollow-core fiber-based Raman probe extension kit is proposed in this Letter for in situ and sensitive ultramicro-analysis. A hollow-core fiber can confine light and fluid samples in its hollow core, with enhanced light–sample interaction. By using a homemade light coupling device with a glass window for liquid isolation, a 3.5-cm-long hollow-core fiber could mount on and connect to a Raman probe, with perfect light coupling efficiency. After full filling the hollow-core fiber chamber with a volume of 13 μL by using a syringe pump, it can act as an extension kit for an ordinary Raman probe and be used as a ultramicro-analysis tool for the sample of microfluidic chips. In order to enhance its sensitivity, a gold film coated fiber tip is inserted into the capillary, which can double the Raman signal received by reflecting pump light and Raman light. Finally, a detection limit of 5% for ethanol solution and an enhancement factor of two compared with direct detection of bulk sample volume are demonstrated. Above all, our device can be utilized as a Raman probe extension kit, which is suitable for rapid, sensitive, and in situ measurements for a few microliter level samples.

The role of gut microbiota in immune checkpoint inhibitor therapy

It has been well established that the gut microbiota has a substantial influence on the host immune system.By crosstalk between specific microorganism-associated molecular patterns and the immune system,in addition to bacterial metabolic activity,gut microbiota regulates local or systemic inflammation(1).Recently,the composition of gut microbiota has been presumed to be one of the factors affecting the cancer-immune set point of cancer patients,which subsequently determines the efficacy of immune checkpoint inhibitor(ICI)treatment(2).