Common Causes of Poor Efficacy of Immune Checkpoint Inhibitors in Special Populations

doi:10.12114/j.issn.1007-9572.2019.00.041

Abstract

Abstract: Recently，treatment with immune checkpoint blockers （ICB） for advanced non-small cell lung cancer （NSCLC） has progressed very rapidly.It is one of the most popular cancer treatments，and has even been listed as a first-line treatment in the latest NCCN guidelines for driver gene mutation negative patients.The recent approval of ICB by China Food and Drug Administration has brought a new treatment concept for cancer treatment and new hopes for lung cancer patients，indicating that it has a broad prospect of clinical use.However，clinical use of ICB faces many problems，such as the associations of response to ICB with steroid hormones used before ICB treatment，cumulative antibiotic use，brain metastases in NSCLC，and tobacco exposure，and efficacy of ICB in combination with local-brain radiation therapy.Along with these problems being solved successively，anti-PD-1/PD-L1 monoclonal antibodies will bring survival benefits to more special populations.

Key words: Carcinoma, non-small-cell lung；Immune checkpoint inhibitors；Programmed cell death 1 receptor；Treatment outcome

摘要： 近年来，免疫检查点抑制剂（ICB）在晚期非小细胞肺癌（NSCLC）的治疗中进展非常迅速，也是目前最热门的肿瘤治疗手段之一。尤其是对于驱动基因突变阴性的患者，在最新的美国国立综合癌症网络（NCCN）指南中甚至提到了一线治疗的地位。前不久国家食品药品监督管理总局（CFDA）对于ICB的批准给肿瘤治疗带来了全新的治疗理念，为肺癌患者带来了新的希望，ICB具有广阔的临床应用前景。但是，临床上仍存在许多问题有待解决，如基线使用类固醇激素是否影响ICB疗效，抗生素的累积使用对ICB疗效如何，脑转移人群ICB疗效是否不佳，ICB结合局部脑照射是否获益，烟草暴露状态是否影响免疫应答，随着这些问题的相继解决，抗程序性死亡分子1（PD-1）/PD-1配体（PD-L1）单抗将会使更多特殊人群在生存上获益。

关键词: 癌, 非小细胞肺；免疫检查点抑制剂；程序性细胞死亡受体1；治疗结果

ZHU Yue,SUN Gengyun. Common Causes of Poor Efficacy of Immune Checkpoint Inhibitors in Special Populations　[J]. Chinese General Practice, 2019, 22(17): 2099-2105. DOI: 10.12114/j.issn.1007-9572.2019.00.041.
朱悦,孙耕耘. 特殊人群免疫检查点抑制剂疗效不佳的常见原因[J]. 中国全科医学, 2019, 22(17): 2099-2105. DOI: 10.12114/j.issn.1007-9572.2019.00.041.

References

［1］SIEGEL R L，MILLER K D，JEMAL A，et al．Cancer statistics［J］.CA Cancer J Clin，2017，67（1）：7-30.DOI：10.3322/caac.21387.
［2］MALVEZZI M，CARIOLI G，BERTUCCIO P，et al．European cancer mortality predictions for the year 2016 with focus on leukaemias［J］.Ann Oncol，2016，27（4）：725-731.DOI：10.1093/annonc/mdw022.
［3］黄志煜，李晖，范云.抗PD-1/PD-L1单抗治疗肺癌临床研究进展［J］.中国肺癌杂志，2015，18（11）：706-713.DOI：10.3779/j.issn.1009-3419.2015.11.09.
HUANG Z Y，LI H，FAN Y.Clinical research progress of anti PD-1/PD-L1 monoclonal antibody in the treatment of lung cancer［J］.Chinese Journal of Lung Cancer，2015，18（11）：706-713.DOI：10.3779/j.issn.1009-3419.2015.11.09.
［4］曾玉兰，刘洋洋，梁金燕，等．免疫检查点抑制剂耐药机制及耐药后治疗策略的研究进展［J］.实用肿瘤学杂志，2017，31（4）：353-358.DOI：10.11904/j.issn.1002-3070.2017.04.012.
ZENG Y L，LIU Y Y，LIANG J Y，et al．Advances in drug resistance mechanism of immunological checkpoint inhibitors and post-drug resistant therapeutic strategy［J］.Practical Oncology Journal，2017，31（4）：353-358.DOI：10.11904/j.issn.1002-3070.2017.04.012.
［5］GETTINGER S，HORN L，JACKMAN D，et al．Five-year follow-up of nivolumab in previously treated advanced non-small-cell lung cancer：results from the CA209-003 study［J］.J Clin Oncol，2018，36（17）：1675-1684.DOI：10.1200/JCO.2017.77.0412.
［6］CRITTENDEN M R，ZEBERTAVAGE L，KRAMER G，et al．Tumor cure by radiation therapy and checkpoint inhibitors depends on pre-existing immunity［J］.Sci Rep，2018，8（1）：7012.DOI：10.1038/s41598-018-25482-w.
［7］WEHLER T，THOMAS M，SCHUMANN C，et al．A randomized，phase 2 evaluation of the CHK1 inhibitor，LY2603618，administered in combination with pemetrexed and cisplatin in patients with advanced nonsquamous non-small cell lung cancer［J］.Lung Cancer，2017，108：212-216.DOI：10.1016/j.lungcan.2017.03.001.
［8］TABCHI S，KOURIE H R，KATTAN J.Adding checkpoint inhibitors to tyrosine kinase inhibitors targeting EGFR/ALK in non-small cell lung cancer：a new therapeutic strategy［J］.Invest New Drugs，2016，34（6）：794-796.DOI：10.1007/s10637-016-0383-2.
［9］HELWICK C.Experts consider the new immunotherapy paradigm in advanced lung cancer［C］.American：ASCO Annual Meeting，2016.
［10］ARBOUR K C，MEZQUITA L，LONG N，et al．Impact of baseline steroids on efficacy of programmed cell death-1 and programmed death-ligand 1 blockade in patients with non-small-cell lung cancer［J］.J Clin Oncol，2018，36（28）：2872-2878.DOI：10.1200/JCO.2018.79.0006.
［11］RYKEN T C，MCDERMOTT M，ROBINSON P D，et al．The role of steroids in the management of brain metastases：a systematic review and evidence-based clinical practice guideline［J］.J Neurooncol，2010，96（1）：103-114.DOI：10.1007/s11060-009-0057-4.
［12］PAULSEN O，KLEPSTAD P，ROSLAND J H，et al．Efficacy of methylprednisolone on pain，fatigue，and appetite loss in patients with advanced cancer using opioids：a randomized，placebo-controlled，double-blind trial［J］.J Clin Oncol，2014，32（29）：3221-3228.DOI：10.1200/JCO.2013.54.3926.
［13］YENNURAJALINGAM S，FRISBEE-HUME S，PALMER J L，et al．Reduction of cancer-related fatigue with dexamethasone：a double-blind，randomized，placebo-controlled trial in patients with advanced cancer［J］.J Clin Oncol，2013，31（25）：3076-3082.DOI：10.1200/JCO.2012.44.4661.
［14］BEN-AHARON I，GAFTER-GVILI A，LEIBOVICI L，et al．Interventions for alleviating cancer-related dyspnea：a systematic review and meta-analysis［J］.Acta Oncol，2012，51（8）：996-1008.DOI：10.3109/0284186X.2012.709638.
［15］LIN R J，ADELMAN R D，MEHTA S S.Dyspnea in palliative care：expanding the role of corticosteroids［J］.J Palliat Med，2012，15（7）：834-837.DOI：10.1089/jpm.2011.0260.
［16］LIBERT C，DEJAGER L.How steroids steer T cells［J］.Cell Rep，2014，7（4）：938-939.DOI：10.1016/j.celrep.2014.04.041.
［17］BIANCHI M，MENG C，IVASHKIV L B.Inhibition of IL-2-induced Jak-STAT signaling by glucocorticoids［J］.Proc Natl Acad Sci USA，2000，97（17）：9573-9578.DOI：10.1073/pnas.160099797.
［18］CHEN X，MURAKAMI T，OPPENHEIM J J，et al．Differential response of murine CD4+CD25+ and CD4+CD25- T cells to dexamethasone-induced cell death［J］.Eur J Immunol，2004，34（3）：859-869.DOI：10.1002/eji.200324506.
［19］CHEN X，OPPENHEIM J J，WINKLER-PICKETT R T，et al．Glucocorticoid amplifies IL-2-dependent expansion of functional FoxP3（+）CD4（+）CD25（+） T regulatory cells in vivo and enhances their capacity to suppress EAE［J］.Eur J Immunol，2006，36（8）：2139-2149.DOI：10.1002/eji.200635873.
［20］IM S J，HASHIMOTO M，GERNER M Y，et al．Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy［J］.Nature，2016，537（7620）：417-421.DOI：10.1038/nature19330.
［21］VETIZOU M，PITT J M，DAILLERE R，et al．Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota［J］.Science，2015，350（6264）：1079-1084.DOI：10.1126/science.aad1329.
［22］SIVAN A，CORRALES L，HUBERT N，et al．Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy［J］.Science，2015，350（6264）：1084-1089.DOI：10.1126/science.aac4255.
［23］SCHELENZ S，GILES D，ABDALLAH S.Epidemiology，management and economic impact of febrile neutropenia in oncology patients receiving routine care at a regional UK cancer centre［J］.Ann Oncol，2012，23（7）：1889-1893.DOI：10.1093/annonc/mdr520.
［24］JERNBERG C，LOFMARK S，EDLUND C，et al．Long-term impacts of antibiotic exposure on the human intestinal microbiota［J］.Microbiology，2010，156（Pt 11）：3216-3223.DOI：10.1099/mic.0.040618-0.
［25］LANGE K，BUERGER M，STALLMACH A，et al．Effects of antibiotics on gut microbiota［J］.Dig Dis，2016，34（3）：260-268.DOI：10.1159/000443360.
［26］JAKOBSSON H E，JERNBERG C，ANDERSSON A F，et al．Short-term antibiotic treatment has differing long-term impacts on the human throat and gut microbiome［J］.PLoS One，2010，5（3）：e9836.DOI：10.1371/journal.pone.0009836.
［27］CECILIA ARBOUR K.Deleterious effect of baseline steroids on efficacy of PD-（L）1 blockade in patients with NSCLC［C］.America：ASCO Annual Meeting，2018.
［28］PAVLAKIS N.Association between progression-free survival （PFS） rate （PFSR） and overall survival （OS） in LUME-Meso，a study of nintedanib （N） vs.placebo （P） in combination with first-line pemetrexed/cisplatin （PEM/CIS） in patients （pts） with malignant pleural mesothelioma （MPM）［C］.America：ASCO Annual Meeting，2018.
［29］DEROSA L，HELLMANN M D，SPAZIANO M，et al．Negative association of antibiotics on clinical activity of immune checkpoint inhibitors in patients with advanced renal cell and non-small-cell lung cancer［J］.Ann Oncol，2018，29（6）：1437-1444.DOI：10.1093/annonc/mdy103.
［30］AHMED J，KUMAR A，PARIKH K，et al．Use of broad-spectrum antibiotics impacts outcome in patients treated with immune checkpoint inhibitors［J］.Oncoimmunology，2018，7（11）：e1507670.DOI：10.1080/2162402X.2018.1507670.
［31］HUEMER F，RINNERTHALER G，WESTPHAL T，et al．Impact of antibiotic treatment on immune-checkpoint blockade efficacy in advanced non-squamous non-small cell lung cancer［J］.Oncotarget，2018，9（23）：16512-16520.DOI：10.18632/oncotarget.24751.
［32］ARVOLD N D，LEE E Q，MEHTA M P，et al．Updates in the management of brain metastases［J］.Neuro Oncol，2016，18（8）：1043-1065.DOI：10.1093/neuonc/now127.
［33］NAYAK L，LEE E Q，WEN P Y.Epidemiology of brain metastases［J］.Curr Oncol Rep，2012，14（1）：48-54.DOI：10.1007/s11912-011-0203-y.
［34］KHASRAW M，POSNER J B.Neurological complications of systemic cancer［J］.Lancet Neurol，2010，9（12）：1214-1227.DOI：10.1016/S1474-4422（10）70220-9.
［35］YANG H，LU S Q.Advances and strategy of up-to-date treatment of brain metastases［J］.Biomed Research International，2010，2014（1）：93-100.DOI：10.1155/2014/484161.
［36］AMELOT A，TERRIER L M，MATHON B，et al．Can anticancer chemotherapy promote the progression of brain metastases?［J］.Med Oncol，2018，35（3）：35.DOI：10.1007/s12032-018-1097-4.
［37］AKAMATSU H，KATAKAMI N，OKAMOTO I，et al．Osimertinib in Japanese patients with EGFR T790M mutation-positive advanced non-small-cell lung cancer：AURA3 trial［J］.Cancer Sci，2018，109（6）：1930-1938.DOI：10.1111/cas.13623.
［38］VANSTEENKISTE J，REUNGWETWATTANA T，NAKAGAWA K，et al．CNS response to osimertinib vs standard of care （SoC） EGFR-TKI as first-line therapy in patients （pts） with EGFR-TKI sensitising mutation （EGFRm）-positive advanced non-small cell lung cancer （NSCLC）：data from the FLAURA study［J］.Ann Oncol，2017，28（suppl 10）：x7.DOI：10.1093/annonc/mdx782.
［39］WEBER J S，AMIN A，MINOR D，et al．Safety and clinical activity of ipilimumab in melanoma patients with brain metastases：retrospective analysis of data from a phase 2 trial［J］.Melanoma Res，2011，21（6）：530-534.DOI：10.1097/CMR.0b013e32834d3d88.
［40］LONG G V，ATKINSON V，LO S，et al．Combination nivolumab and ipilimumab or nivolumab alone in melanoma brain metastases：a multicentre randomised phase 2 study［J］.Lancet Oncol，2018，19（5）：672-681.DOI：10.1016/S1470-2045（18）30139-6.
［41］BORDONI R，CIARDIELLO F，VON PAWEL J，et al．Patient-reported outcomes in OAK：a phase Ⅲ study of atezolizumab versus docetaxel in advanced non-small-cell lung cancer［J］.Clin Lung Cancer，2018，19（5）：441-449.e4.DOI：10.1016/j.cllc.2018.05.011.
［42］BARLESI F，STEINS M，HORN L，et al．Long-term outcomes with nivolumab vs docetaxel in patients with advanced NSCLC：CheckMate 017 and CheckMate 057 2-y update［C］.Denmark：Esmo Congress，2016.
［43］RIZVI N A，MAZIERES J，PLANCHARD D，et al．Activity and safety of nivolumab，an anti-PD-1 immune checkpoint inhibitor，for patients with advanced，refractory squamous non-small-cell lung cancer （CheckMate 063）：a phase 2，single-arm trial［J］.Lancet Oncol，2015，16（3）：257-265.DOI：10.1016/S1470-2045（15）70054-9.
［44］KAMATH S D，KUMTHEKAR P U.Immune checkpoint inhibitors for the treatment of entral nervous system （CNS） metastatic disease［J］.Front Oncol，2018，8：414.DOI：10.3389/fonc.2018.00414.
［45］GIANNONI P，BADAUT J，DARGAZANLI C，et al．The pericyte-glia interface at the blood-brain barrier［J］.Clin Sci，2018，132（3）：361-374.DOI：10.1042/CS20171634.
［46］PARDOLL D M.The blockade of immune checkpoints in cancer immunotherapy［J］.Nat Rev Cancer，2012，12（4）：252-264.DOI：10.1038/nrc3239.
［47］BRASTIANOS P K，CARTER S L，SANTAGATA S，et al．Genomic characterization of brain metastases reveals branched evolution and potential therapeutic targets［J］.Cancer Discov，2015，5（11）：1164-1177.DOI：10.1158/2159-8290.CD-15-0369.
［48］FIDLER I J.The biology of brain metastasis：challenges for therapy［J］.Cancer J，2015，21（4）：284-293.DOI：10.1097/PPO.0000000000000126.
［49］HENDRIKS L.Impact of central nervous system （CNS） involvement in advanced non-small cell lung cancer （NSCLC） patients （pts） treated with immune checkpoint inhibitors （ICI）［C］.America：ASCO Annual Meeting，2018.
［50］DALY M E，MONJAZEB A M，KELLY K.Clinical trials integrating immunotherapy and radiation for non-small-cell lung cancer［J］.J Thorac Oncol，2015，10（12）：1685-1693.DOI：10.1097/JTO.0000000000000686.
［51］REYNDERS K，ILLIDGE T，SIVA S，et al．The abscopal effect of local radiotherapy：using immunotherapy to make a rare event clinically relevant［J］.Cancer Treat Rev，2015，41（6）：503-510.DOI：10.1016/j.ctrv.2015.03.011.
［52］DENG L，LIANG H，BURNETTE B，et al．Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice［J］.J Clin Invest，2014，124（2）：687-695.DOI：10.1172/JCI67313.
［53］VATNER R E，COOPER B T，VANPOUILLE-BOX C，et al．Combinations of immunotherapy and radiation in cancer therapy［J］.Front Oncol，2014，4：325.DOI：10.3389/fonc.2014.00325.
［54］TOMASINI P，GREILLIER L，BOYER A，et al．Durvalumab after chemoradiotherapy in stage Ⅲ non-small cell lung cancer［J］.J Thorac Dis，2018，10（Suppl 9）：S1032-1036.DOI：10.21037/jtd.2018.04.61.
［55］KIRKPATRICK J P，KELSEY C R，PALTA M，et al．Stereotactic body radiotherapy：a critical review for nonradiation oncologists［J］.Cancer，2014，120（7）：942-954.DOI：10.1002/cncr.28515.
［56］SCHAUE D，RATIKAN J A，IWAMOTO K S，et al．Maximizing tumor immunity with fractionated radiation［J］.Int J Radiat Oncol Biol Phys，2012，83（4）：1306-1310.DOI：10.1016/j.ijrobp.2011.09.049.
［57］LEE Y，AUH S L，WANG Y，et al．Therapeutic effects of ablative radiation on local tumor require CD8+ T cells：changing strategies for cancer treatment［J］.Blood，2009，114（3）：589-595.DOI：10.1182/blood-2009-02-206870.
［58］CHEN D S，MELLMAN I.Elements of cancer immunity and the cancer-immune set point［J］.Nature，2017，541（7637）：321-330.DOI：10.1038/nature21349.
［59］LUKE J J，LEMONS J M，KARRISON T G，et al．Safety and clinical activity of pembrolizumab and multisite stereotactic body radiotherapy in patients with advanced solid tumors［J］.J Clin Oncol，2018，36（16）：1611-1618.DOI：10.1200/JCO.2017.76.2229.
［60］KLUG F，PRAKASH H，HUBER P E，et al．Low-dose irradiation programs macrophage differentiation to an iNOS+/M1 phenotype that orchestrates effective T cell immunotherapy［J］.Cancer Cell，2013，24（5）：589-602.DOI：10.1016/j.ccr.2013.09.014.
［61］DEMARIA S，FORMENTI S C.Radiation as an immunological adjuvant：current evidence on dose and fractionation［J］.Front Oncol，2012，2：153.DOI：10.3389/fonc.2012.00153.
［62］Cancer Genome Atlas Research Network.Comprehensive genomic characterization of squamous cell lung cancers［J］.Nature，2012，489（7417）：519-525.DOI：10.1038/nature11404.
［63］BRAHMER J，RECKAMP K L，BAAS P，et al．Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer［J］.N Engl J Med，2015，373（2）：123-135.DOI：10.1056/NEJMoa1504627.
［64］GAINOR J F.Response and durability of anti-PD-（L）1 therapy in never- or light-smokers with non-small cell lung cancer （NSCLC） and high PD-L1 expression［C］.America：ASCO Annual Meeting，2018.
［65］CHAMPIAT S，FERTE C，LEBEL-BINAY S，et al．Exomics and immunogenics：bridging mutational load and immune checkpoints efficacy［J］.Oncoimmunology，2014，3（1）：e27817.DOI：10.4161/onci.27817.
［66］RIZVI N A，HELLMANN M D，SNYDER A，et al．Cancer immunology.Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer［J］.Science，2015，348（6230）：124-128.DOI：10.1126/science.aaa1348.
［67］INAMURA K，YOKOUCHI Y，KOBAYASHI M，et al．WITHDRAWN：tumor B7-H3 （CD276） expression and smoking history in relation to lung adenocarcinoma prognosis［J］.Lung Cancer，2016，243（1）：21-28.DOI：10.1016/j.lungcan.2016.09.016.
［68］LAWRENCE M S，STOJANOV P，POLAK P，et al．Mutational heterogeneity in cancer and the search for new cancer-associated genes［J］.Nature，2013，499（7457）：214-218.DOI：10.1038/nature12213.
［69］GOVINDAN R，DING L，GRIFFITH M，et al．Genomic landscape of non-small cell lung cancer in smokers and never-smokers［J］.Cell，2012，150（6）：1121-1134.DOI：10.1016/j.cell.2012.08.024.
［70］TAKADA K，TOYOKAWA G，OKAMOTO T，et al．A comprehensive analysis of programmed cell death ligand-1 expression with the clone SP142 antibody in non-small-cell lung cancer patients［J］.Clin Lung Cancer，2017，18（5）：572-582.e1.DOI：10.1016/j.cllc.2017.02.004.
［71］LAWRENCE M S，STOJANOV P，POLAK P，et al．Mutational heterogeneity in cancer and the search for new cancer-associated genes［J］.Nature，2013，499（7457）：214-218.DOI：10.1038/nature12213.
［72］SNYDER A，MAKAROV V，MERGHOUB T，et al．Genetic basis for clinical response to CTLA-4 blockade in melanoma［J］.N Engl J Med，2014，371（23）：2189-2199.DOI：10.1056/NEJMoa1406498.
［73］ROONEY M S，SHUKLA S A，WU C J，et al．Molecular and genetic properties of tumors associated with local immune cytolytic activity［J］.Cell，2015，160（1/2）：48-61.DOI：10.1016/j.cell.2014.12.033.
［74］STRICKLAND K C，HOWITT B E，SHUKLA S A，et al．Association and prognostic significance of BRCA1/2-mutation status with neoantigen load，number of tumor-infiltrating lymphocytes and expression of PD-1/PD-L1 in high grade serous ovarian cancer［J］.Oncotarget，2016，7（12）：13587-13598.DOI：10.18632/oncotarget.7277.
［75］GIBBONS D L，BYERS L A，KURIE J M.Smoking，p53 mutation，and lung cancer［J］.Mol Cancer Res，2014，12：3-13.DOI：10.1158/1541-7786.MCR-13-0539.
［76］RIZVI H，SANCHEZ-VEGA F，LA K，et al．Molecular determinants of response to anti-programmed cell death （PD）-1 and anti-programmed death-ligand 1 （PD-L1） blockade in patients with non-small-cell lung cancer profiled with targeted next-generation sequencing［J］.J Clin Oncol，2018，36（7）：633-641.DOI：10.1200/JCO.2017.75.3384.
［77］HELLMANN M D，CIULEANU T E，PLUZANSKI A，et al．Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden［J］.N Engl J Med，2018，378（22）：2093-2104.DOI：10.1056/NEJMoa1801946.
［78］WU Y L，LU S，CHENG Y，et al．Nivolumab versus docetaxel in a predominantly Chinese patient population with previously treated advanced non-small cell lung cancer （NSCLC）：results of the phase 3 CheckMate 078 study［J］.Cancer Res，2018，78（13）：14-18.DOI：10.1158/1538-7445.

[1]	FENG Yuxi, WANG Jinjin, CAI Yi, ZHU Runzhi, ZHU Qin. Research Progress on Protein Lactylation in Kidney Diseases [J]. Chinese General Practice, 2026, 29(21): 3056-3063.
[2]	ZHANG Shiya, MIAO Tongguo, LOU Xianzhe, ZHANG Yunjing, MA Dong, NAN Yuemin. Predictive Value of Serum HDL-C in the Occurrence of PVTT in Patients with NBNC-HCC [J]. Chinese General Practice, 2026, 29(11): 1441-1447.
[3]	ZHOU Hongmei, HE Lin, XU Hui, WANG Ning. A Systematic Review of Fatigue Assessment Tools for Cancer Patients Based on the COSMIN Guidelines [J]. Chinese General Practice, 2026, 29(08): 965-973.
[4]	YANG Haifei, SUN Wu, WU Cheng, REN Wei, LI Rutian. Analysis of Predictors for Immune-related Adverse Events and the Correlation with Efficacy in Progressive Esophageal Squamous Cell Carcinoma [J]. Chinese General Practice, 2026, 29(06): 710-717.
[5]	ZHANG Shujing, SUN Lixin, CAO Yuqing. Comparative Study on the Clinicopathological Features and Prognostic between HPV-related and Non-HPV-related Cervical Adenocarcinoma [J]. Chinese General Practice, 2025, 28(14): 1758-1764.
[6]	YUAN Xiaorui, TAN Yanlin, FU Chun. Construction of the Predictive Model for Lymph Node Metastasis in Patients with Epithelial Ovarian Cancer: Based on ¹⁸F-FDG PET/CT Radiomics Technology [J]. Chinese General Practice, 2025, 28(12): 1465-1472.
[7]	ZHANG Yushuang, WU Zhongbing, HUANG Ming, JIA Lei, GAO Shuang, ZHAO Weipeng, LI Jing. Study on Metabolic Characteristics in Esophageal Squamous Cell Carcinoma Patients with TCM Differentiation of Deficiency of Fluid and Blood Based on Non Target Metabolomics [J]. Chinese General Practice, 2025, 28(12): 1513-1519.
[8]	LOU Xianzhe, MIAO Tongguo, ZHANG Shiya, MA Dong, NAN Yuemin. The Impact of the Monocyte-to-High-Density Lipoprotein Cholesterol Ratio on the Prognosis of Patients with Non-Viral, Non-Alcoholic Hepatocellular Carcinoma: a Retrospective Cohort Study [J]. Chinese General Practice, 2025, 28(09): 1092-1099.
[9]	MA Xiaoxuan, WANG Rongqi. Research Progress in Metabolomics for HCC Diagnosis and Treatment [J]. Chinese General Practice, 2025, 28(08): 1017-1022.
[10]	SONG Fenfen, LI Shengmian. Real-World Study of Camrelizumab-based Regimen for Locally Advanced and Metastatic Esophageal Cancer [J]. Chinese General Practice, 2025, 28(07): 844-852.
[11]	ZHANG Jin, SUN Di, WANG Hao, SHI Cong, ZHAO Yihan, PAN Yijin, MU Zhuanzhuan, DING Zhiguo, LIN Yansong. Factors Influencing Biochemical Progression in Distant Metastatic Papillary Thyroid Carcinoma [J]. Chinese General Practice, 2024, 27(36): 4546-4553.
[12]	YANG Anyin, LIU Hongli, CHEN Miaoyang, ZHENG Yufeng, XU Zhiyuan, YANG Yongfeng. Mechanism and in Vitro Experiment of Wogonin in Treatment of Hepatocellular Carcinoma Based on Network Pharmacology [J]. Chinese General Practice, 2024, 27(32): 4040-4049.
[13]	CHEN Chao, CHEN Tianxiang, LIU Qianwei, ZHANG Zhi, WANG Huanhuan, WU Pingping, GAO Lei, YU Zhaoxiang. Analysis and Identification of Hub Genes in Hepatocellular Carcinoma Based on Weighted Gene Co-expression Network and Cancer Genome Atlas Clinical Data [J]. Chinese General Practice, 2024, 27(32): 4050-4059.
[14]	MAIERHABA· Maimaitiaili, ZHANG Kainan, ZHAO Hui, YAKUFU· Tuoheti, YE Jianwei, LYU Guodong. Investigating Serum PARP2 as a Potential Diagnostic Biomarker for Hepatocellular Carcinoma [J]. Chinese General Practice, 2024, 27(32): 4060-4065.
[15]	HU Lingxi, LI Mei, FU Yiwei, LU Lixia, MA Xiaoxuan, WANG Rongqi, NAN Yuemin. The Value of Serum VEGF in Evaluating the Clinical Efficacy of TACE Alone or Combined with Target Immunotherapy in Advanced Hepatocellular Carcinoma [J]. Chinese General Practice, 2024, 27(32): 4033-4039.