李涛医生的科普号

肝细胞癌(HCC)是最常见的原发性肝癌，也是全世界癌症相关死亡的主要原因。近年来，HCC的系统治疗格局发生了迅速变化，免疫检查点抑制剂(ICI)已成为晚期肝癌一线治疗方案的基石。在以免疫检查点抑制剂(ICI)为基础的一线治疗晚期肝细胞癌(HCC)进展后进行二线免疫治疗仍然是一个挑战，因为在免疫治疗一线治疗的患者中没有研究可用的二线免疫治疗方案。特别是ICI二线使用在HCC患者中的作用尚不清楚，肝癌一线免疫治疗后肿瘤进展的病人二线治疗继续使用免疫治疗病人是否获益目前仍缺乏前瞻性试验的数据。发表于2023年5月著名肝脏病杂志JHEPreports的一项回顾性、国际、多中心研究中调查了基于ICI的治疗方案对免疫治疗预处理的HCC患者的疗效和安全性。在这项国际回顾性多中心研究中，研究了来自奥地利、德国、意大利、瑞士、英国和美国14个机构接受ICI疗法的994名肝癌患者，其中有58名患者接受了ICI一线和二线治疗，其中大多数患者因病情进展而停用一线ICI治疗。研究发现，这些患者接受ICI一线治疗的客观缓解率为22%，接受ICI二线治疗的客观缓解率为26%。ICI一线治疗和二线治疗的中位进展时间分别为5.4(95%CI3.0-7.7)个月和5.2(95%CI3.3-7.0)个月。ICI一线治疗和二线治疗相关严重不良事件分别在9名(16%)和10名(17%)患者中观察到。从这个研究可以发现在ICI一线治疗疾病进展后二线使用ICI是安全的，并且对HCC患者带来了治疗益处。这些数据为一线免疫治疗进展的肝癌患者接受二线ICI治疗提供了理论依据。免疫治疗作为二线治疗对一线免疫治疗进展的肝癌患者仍然是有效和安全的。https://www.jhep-reports.eu/article/S2589-5559(22)00192-6/fulltext

目前，免疫检查点抑制剂（ICI）已成为多种晚期实体瘤的一线治疗方案。但是接受ICI治疗的患者通常因为免疫治疗不良反应或者疾病进展而中断治疗。据文献报道，接受免疫治疗的患者中所有级别免疫相关不良事件（irAEs）的发生率为64.4%~86.8%，严重irAEs的发生率为15.1%~28.6%，成为阻碍晚期肿瘤患者获得长期生存的重要因素。此外，接受基于ICI的一线联合治疗方案治疗的肿瘤患者中，约20-40%对免疫治疗产生原发性耐药或者获得性耐药（初始出现客观反应或疾病稳定后进展），导致免疫治疗效果不佳。根据NCCN指南，≤2级irAEs可以考虑恢复免疫治疗，而免疫治疗引起严重（≥3级）irAEs，通常需要永久停止同类型的免疫治疗，但是永久停药往往会导致肿瘤进展，因此患有严重irAEs的患者在不良反应痊愈后是否可以重新接受ICI治疗值得进一步探索。此外，因肿瘤进展而停止ICI治疗的肿瘤患者是重新开始ICI治疗生存是否有获益尚不明确。为了解决以上两个问题，更好的指导肿瘤患者免疫治疗，从而获得长期生存，齐鲁医院肝胆外科李涛教授团队系统回顾分析全球36项临床研究，共计2026例肿瘤患者接受ICI免疫治疗的数据，发现对于因免疫治疗不良反应停药的患者，与初始ICI治疗相比，停药后再次使用ICI治疗总不良反应和严重不良反应的发生率显着降低，而治疗效果与初次ICI治疗效果相当。因此对于因irAEs停止ICI治疗的肿瘤患者来说，再次使用ICI可能是一种可行且有效的策略，与初始治疗相比，irAEs复发的风险降低、同时具有相似的疗效和改善的生存结果。但是在因为疾病进展而停药的患者中，再次使用ICI可能会导致严重不良反应的发生率升高，同时具有更差的疗效，对于此类病人再次使用ICI治疗应慎重。李涛教授团队还发现，再次使用ICI治疗的患者中，如果使用的与初次免疫治疗不同的ICI，患者不良反应并不会增加而疗效可能更好。相比于永久停止ICI免疫治疗的患者，再次使用ICI治疗患者的无进展生存时间和总生存时间都显著延长。 相关研究成果发表于2024年6月肿瘤学的著名期刊oncologisthttps://academic.oup.com/oncolo/advance-article/doi/10.1093/oncolo/oyae134/7701003

????门诊经常遇到胆囊结石或胆囊息肉的病人，他们的病情本来应该做胆囊切除，可是病人往往受到网上一些错误信息的误导，不敢做胆囊切除手术，导致病情发展恶化，甚至胆囊癌变。门诊遇到病人忧虑最多的就是网上误传的所谓胆囊切除会增加结直肠癌的发生率，甚至一些莆田系医院也借此吓唬病人，忽悠不适合做保胆手术的病人去做保胆手术。难道胆囊切除真的会引起肠癌发生率增加吗？最新最权威的研究证实胆囊切除与肠癌发生没有因果关系。????2012年，世界外科学最权威的期刊《外科年鉴》（AnnSurg2012;256:1068-1072）发表了迄今为止规模最大研究结果，该研究以1998年到2008年300万英格兰人群为研究对象，其中因胆囊炎或胆囊结石接受胆囊切除手术病人327460人，患有胆囊疾病但并未接受胆囊切除手术病人133114人，比较胆囊切除术组、胆囊疾病未切除胆囊组、正常健康人群的癌症比率。结果胆囊切除病人术后的第1年小肠癌、结肠癌、直肠癌的癌症比率分别为4.6（95％置信区间3.9-5.5）、2.0（1.9-2.1）、1.7（1.6-1.9），此后，癌症的发生率随时间增加而减少，胆囊切除术后8至10年，小肠癌、结肠癌或直肠癌的比率分别降为与健康人群类似的2.47（0.82-6.28）、0.99（0.70-1.36）、0.85（0.52-1.33）。而在未做胆囊切除手术的胆结石患者中，这些癌症的发生率却很高，诊断后第一年的癌症发生率小肠癌为7.86（6.42-9.57）、结肠癌为2.95（2.75-3.15）、直肠癌为2.08（1.88-2.30），高于胆囊切除病人肠癌发生率。结论：小肠癌、结肠癌或直肠癌发生率增高与胆结石有关，而与胆囊切除无关。胆囊切除术后小肠癌、结肠癌或直肠癌的患病风险逐年降低至与健康人群一致。胆囊切除术和肠癌之间的不存在因果关系，不是胆囊切除增加了肠癌的发生率，而是胆结石增加了肠癌的发生率，胆囊切除能将胆结石引起的肠癌风险逐年降低至正常人群水平。????英国的这项研究很明确的说明了，为什么胆囊切除会有引起肠癌风险的错觉，因为胆囊切除的病人是因为胆囊结石而做手术，胆囊结石导致肠癌发生率增加，即使切除了胆囊，因为之前存在胆囊结石的缘故，肠癌的发生率也比健康人群增加，但是胆囊切除后，胆囊结石也去除了，肠癌的患病率逐年下降，说明肠癌的发生与胆囊切除无关，否侧胆囊切除后时间越长，肠癌的发生率应该越高，而实际上胆囊切除术后肠癌发病率是越来越低。????下面附上这篇文章的英文全文，以便英语好的患者参考。（版权所有，转载请标明出处）。

越来越多的证据表明肿瘤免疫与表观遗传调控之间存在密切关联。组蛋白赖氨酸N-甲基转移酶2(KMT2)家族在组蛋白H3赖氨酸甲基化中发挥着至关重要的作用。通过影响染色质结构和DNA可及性，这种修饰成为肿瘤的关键调节因子影响各种肿瘤的进展和免疫耐受。这些发现凸显了其潜在意义KMT2家族在确定对免疫检查点抑制剂(ICI)治疗的反应时需要进一步研究探索。在这项研究中，我们整合了10种癌症类型和癌症的4个ICI治疗队列(n=2069)基因组图谱全癌队列并进行了全面的临床和生物信息学分析。我们的研究表明KMT2家族基因突变患者总体上从ICI治疗中受益更多生存期(P＜0.001，风险比[HR]=0.733[95%置信区间(CI):0.632–0.850])，无进展生存期(P=0.002，HR=0.669[95%CI:0.518–0.864])，持久的临床获益(P＜0.001，54.1%vs.32.6%)和客观答复率(P＜0.001，40.6%vs.22.0%)。通过对肿瘤微环境的综合分析在不同的KMT2突变状态下，我们观察到携带KMT2突变的肿瘤表现出增强免疫原性、免疫细胞浸润增加以及免疫细胞细胞毒性的水平升高表明倾向于“热肿瘤”表型。因此，我们的研究表明KMT2突变和ICI治疗的反应两者之间存在潜在的关联，KMT2突变肿瘤患者从ICI免疫治疗获益更大。组蛋白甲基化是一种常见的DNA修饰，在基因转录的调节中发挥着关键作用。这种修饰主要发生在组蛋白N末端的赖氨酸残基上，并由称为组蛋白-赖氨酸N-甲基转移酶(KMT)的酶家族催化[1]。组蛋白-赖氨酸N-甲基转移酶2(KMT2)家族的成员包括几个亚型，包括KMT2A、KMT2B、KMT2C和KMT2D，它们对细胞在各个阶段的增殖、生长、发育和分化等过程发挥显着作用。新出现的研究表明，KMT2基因的突变或异常表达在各种肿瘤中经常观察到。这些改变会破坏组蛋白甲基化，导致DNA损伤修复、基因表达和染色体结构失调，最终影响它们的正常功能[2]。因此，这些异常直接导致基因组不稳定性的积累，增加基因突变和染色体畸变的风险，从而促进肿瘤的发生和进展。此外，肿瘤细胞中的基因组不稳定性增强了肿瘤免疫原性，有可能提高对免疫检查点抑制剂(ICI)治疗的敏感性[3]。因此，人们对研究KMT2基因在肿瘤免疫治疗中的作用越来越感兴趣。在结直肠癌中，KMT2家族突变与较高的肿瘤突变负担(TMB)和微卫星不稳定性相关，这与结直肠癌患者预后改善相关[1，4]。在非小细胞肺癌(NSCLC)中，不同的遗传改变与不同水平的程序性死亡配体1表达和TMB相关[5]。TP53/KMT2C突变的共发生可以有效预测对ICI治疗的反应。总的来说，这些发现强调了了解KMT2基因对肿瘤免疫治疗的影响的重要性，为靶向治疗和个性化治疗策略提供了潜在途径。然而，目前的研究主要集中在KMT2家族内或特定癌症类型的个体基因上，缺乏对整个KMT2家族的全身影响及其对肿瘤免疫微环境的影响的全面研究[6]。因此，使用多个免疫疗法队列和全癌症数据库进行系统分析至关重要，这些数据库可以提供广泛的基因分析特征[7，8，9，10]。本研究旨在探索KMT2突变肿瘤对ICI治疗的反应以及跨各个维度的内在生物学联系，包括免疫治疗功效和肿瘤免疫微环境。通过检查多种特征，本研究旨在提供有关KMT2改变与肿瘤免疫治疗之间关系的有力证据，从而可能促进该领域的进步。这项研究表明，KMT2突变患者在OS、PFS、DCB和ORR方面从ICI治疗中获益匪浅。KMT2突变肿瘤被认为是“热肿瘤”，含有对ICI治疗更具反应性的肿瘤微环境，免疫治疗效果更佳。因此，KMT2家族突变状态可以作为肿瘤患者ICI治疗效果的有效预测因子，指导肿瘤患者的个性化治疗。https://www.researchgate.net/publication/377407231_Mutation_status_of_the_KMT2_family_associated_with_immune_checkpoint_inhibitors_ICIs_therapy_and_implicating_diverse_tumor_microenvironmentshttps://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-023-01930-8

ClinicalSurgicalOncology杂志2023年12月在线发表了山东大学齐鲁医院肝胆外科李涛教授团队的研究结果，该团队对54名最初无法切除的晚期HCC患者进行了以免疫为主的联合治疗，取得了良好的效果.https://www.sciencedirect.com/science/article/pii/S2773160X2300017X联合免疫疗法已逐渐成为晚期肝细胞癌(HCC)系统治疗的主要手段，但术前免疫疗法是否有可能降低肿瘤活动度、提高切除率、改善预后仍不清楚。本研究旨在探讨术前联合免疫疗法对最初无法切除的HCC患者的疗效和安全性。方法：这项回顾性、现实世界的研究涉及最初无法切除的HCC患者，在手术前接受基于PD-1/L1阻断的联合免疫疗法。评估肿瘤治疗反应、术后标本的病理表现和总生存期(OS)。治疗相关不良事件(AE)根据国家癌症研究所不良事件通用术语标准(NCICTCAE，4.0版)进行评估。结果：该研究连续纳入了54名最初无法切除的HCC患者，并评估了34名患者的安全性、有效性和随后进行根治性手术的可能性。在这些接受手术切除的患者中，57.1%(n=8)在手术前接受联合免疫治疗，取得了部分缓解(PR)。术后标本的病理评估证实，21.4%(n=3)获得完全缓解，78.6%(n=11)获得PR。28.6%(4/14)患者遇到3级或4级AE。主要AE包括疲劳(n=11;78.6%)，白细胞减少症(n=8;57.1%)和天冬氨酸转氨酶(AST)升高(n=6;42.9%)。结论：联合免疫疗法后，应全面评估患者是否符合手术切除的标准。联合免疫疗法后的手术切除可能有效且安全地控制肿瘤进展，并且至少可以改善一些最初无法切除的HCC患者的预后。ClinicalSurgicalOncologyVolume2,Issue4,December2023,100025OriginalArticleSalvagesurgeryaftercombinationimmunotherapyforinitiallyunresectableormetastastichepatocellularcarcinoma:AretrospectiveclinicalstudyAuthorlinksopenoverlaypanelJun-ShuaiXue,HuiLiu,Rui-ZheLi,Si-YuTan,Yu-ChuanYan,Zhao-RuDong,Jian-GuoHong,En-YuLiu,Qiang-BoZhang,Zhi-QiangChen,Dong-XuWang,TaoLiShowmoreAddtoMendeleyShareCitehttps://doi.org/10.1016/j.cson.2023.100025GetrightsandcontentUnderaCreativeCommonslicenseopenaccessAbstractBackgroundCombinationimmunotherapyhasgraduallybecomethemainstayofsystematictherapyforadvancedhepatocellularcarcinoma(HCC),however,whetherpreoperativeimmunotherapyhasthepotentialtoreducetumoractivity,increasetheresectionrateandimproveprognosisremainsunclear.ThisstudyaimedtoinvestigatetheefficacyandsafetyofpreoperativecombinedimmunotherapiesforpatientswithinitiallyunresectableHCC.MethodsThisretrospective,real-worldstudyinvolvedpatientswithinitiallyunresectableHCCreceivingcombinedimmunotherapiesbasedonPD-1/L1blockadebeforesurgery.Tumortreatmentresponses,pathologicalmanifestationsinpostoperativespecimensandoverallsurvival(OS)wereevaluated.Treatmentrelatedadverseevents(AEs)wereassessedaccordingtotheNationalCancerInstituteCommonTerminologyCriteriaforAdverseEvents(NCICTCAE,version4.0).ResultsThestudyconsecutivelyincluded54initiallyunresectableHCCpatientsand34patientswereevaluatedforthesafety,efficacy,andpossibilityofsubsequentradicalsurgery.Amongthesepatientswithsurgicalresection,57.1%(n=8)receivingcombinationimmunotherapybeforesurgeryachievedapartialresponse(PR).Pathologicalevaluationofpostoperativespecimensconfirmedthat21.4%(n=3)achievedcompleteresponses,and78.6%(n=11)achievedPR.28.6%(4/14)patientsencounteredgrade3or4AEs.ThemainAEsincludedfatigue(n=11;78.6%),leukocytopenia(n=8;57.1%)andaspartateaminotransferase(AST)elevation(n=6;42.9%).ConclusionsAftercombinationimmunotherapy,patientsshouldbecomprehensivelyevaluatedwhethertheymeetthecriteriaforsurgicalresection.SurgicalresectionfollowingcombinationimmunotherapymighteffectivelyandsafelycontroltumorprogressionandcouldimprovetheprognosisatleastforsomepatientswithinitiallyunresectableHCC.PreviousarticleinissueNextarticleinissueKeywordsHepatocellularcarcinomaCombinationimmunotherapyImmunecheckpointinhibitorConversiontherapy1.IntroductionPrimarylivercancer(PLC)ranksthesixthmostcommonmalignancyandisthethirdleadingcauseofcancerdeath,withapproximately906,000newcasesand830,000deathseachyear(Sungetal.,2021).Hepatocellularcarcinoma(HCC)accountsfor85–90%ofallPLCs.ThoughtherapeuticregimensforHCChavegraduallyprogressed,surgicalresectionremainsoneofthemosteffectivetreatmentstogetlongtermsurvival(Petrowskyetal.,2020).However,HCCisoftendiagnosedatanadvancedstageandlosestheopportunityforradicalsurgery.Meanwhile,almost70%HCCpatients,especiallythosewithportalveininvasionorlargetumorsize,havetoexperiencediseaserecurrenceat5yearsevenafterundergoingradicalresection(Yangetal.,2019).Therefore,increasingsurgicalresectionrateandreducingpostoperativerecurrencehavealwaysbeenthecriticalmeasurestosignificantlyimprovetheprognosisofpatients(Villanueva,2019).Withthedevelopmentoftumorgenomicsandimmunology,combinationimmunotherapybasedonimmunecheckpointinhibitorssuchasPD-1/PD-L1(programmedcelldeathprotein1/ligand1)playsakeyroleintheoveralltreatmentofHCCandwillbecomethemainstayofsystematictreatmentofHCC(Villanueva,2019;Forneretal.,2018).Currently,theregimensofcombinationimmunotherapymainlyincludePD-1blockadecombiningwithanti-CTLA4,antiangiogenictargetedtherapy,cytotoxicchemotherapyorlocoregionaltherapy,whichisaimedatachievingsynergistickillingoftumorcells(Wangetal.,2019).Neoadjuvantoradjuvantimmunotherapybasedoncombinationimmunotherapycanbeeffectiveinreducingtumoractivity,potentiallyprovidinganeffectiveapproachforreducingtumorrecurrence.InHCC,tworecentstudieshavefoundthatprovidingPD-1/L1basedimmunotherapiesduringtheperioperativeperiodcaneffectivelyreducetumorcellactivity,whichwilldecreasethelikelihoodofpostoperativerecurrence(Marronetal.,2022;Kasebetal.,2022).Inothertypesofcancer,neoadjuvantPD-1antibodycouldinduceamajorpathologicalresponsein45%resectablelungcanceranddidnotdelayorprecludesurgery(Fordeetal.,2018);andformuscle-invasivebladdercarcinoma,neoadjuvantpembrolizumabresultedin42%ofpatientswithpT0andcouldbeaworthwhileneoadjuvanttherapy(Necchietal.,2018).Foradvancedgastriccancer,28.0%and76.0%ofpatientsreceivingneoadjuvantPD-1blockadepluschemotherapyachievedpathologicalcompleteresponse(pCR)andpost-therapypathologicaldownstaging,respectively.Postoperativespecimensalsoshowedmoreanti-tumorimmuneinfiltration(Tangetal.,2022).Althoughneoadjuvantimmunotherapycanpotentiallydriveimmediateinductionoftumor-cellkillingandinducedurableimmuneresponse(Shindohetal.,2013),itstillfacesunfavorableconditionssuchassevereadverseeventsandtumorhyper-progression.AsforinitiallyunresectableHCC,itcanbecategorizedassurgicallyunresectableandbiologicallyunresectable,theformerreferstothatthepatient‘ssystemicconditionorhepaticfunctioncannottoleratesurgeryaswellasthevolumeoftheremainingliverisinsufficient,andthelatterreferstotechnicallyresectablebuttheresultafterresectionisnotbetterthannon-surgery.Resultsfrommultiplerandomizedcontrolledtrials(RCT)confirmedthatcombinationimmunotherapysubstantiallyincreasestheobjectiveresponserate(ORR)comparedtoconventionallocoregionalandsystemictherapy,whichmeansthataconsiderablenumberofpatients(between9.5%and36%)canachieve30%tumorshrinkage(PR,partialresponse)afterreceivingimmunecheckpointinhibitors(ICIs)basedcombinationtherapy(Finnetal.,2020;Abou-Alfaetal.,2022;Sangroetal.,2021).Theshrinkageofthetumorisaccompaniedbythegrowthoftheresidualliver,whichfacilitatesthere-evaluationofthepatient‘sconditiontoconsiderthepossibilityofsurgery.Therefore,basedonthecurrentpreclinicalandclinicalstudies,severalcohortstudiesandcasereportshaveconfirmedthatsomepatientswithinitiallyunresectableHCCcanundergosurgicalresectionafterreceivingimmunotherapy,whichisassociatedwithfavorableprognosis(Yangetal.,2021;Kasebetal.,2019).Nevertheless,radicalsurgeryaftercombinedtherapybasedonimmunedrugsisanewfieldforHCC,andincreasedstudiesarestillneededtoprovideexperienceandsupport(Wangetal.,2022;Yinetal.,2022).Inthepresentstudy,weretrospectivelyreportedacohortofpatientswithinitiallyunresectableHCCundergoingsurgicalresectionaftercombinationimmunotherapy,andthenanalyzedthetreatmentcharacteristicsofthesepatientsindetail,aswellasthesafetyandefficacyoftheoperation,inordertopromotethedevelopmentofthisfield.2.Methods2.1.PatientsandstudydesignThiswasaretrospective,singleinstitutionclinicalstudy,designedtosummarizetheefficacyandsafetyofpreoperativelyprescribedcombinedimmunotherapiesbasedonPD-1/L1blockadeforpatientswithinitiallyunresectableHCC.WefirstretrospectivelycollectedallthepatientswithunresectableHCCduring1stJanuary2020and1stAugust2022.Aftertheinitialdiagnosis,thecliniciansadopteddifferenttreatmentplansaccordingtothepatient‘stumorcondition.Duringtheperiodoftreatment,clinicalphysiciansevaluatedtheefficacyandadjustedthetherapyregimenaccordingthetumorconditionofpatients.Amongthesepatientswithinitiallyunresectabletumor,weincludedthepatientswhoreceivedtheregimensofcombinationimmunotherapy.Finally,patientswhounderwentfurthersalvagesurgeryaftercombinationimmunotherapywereretrospectivelyanalyzed.Allpatientsprovidedwritteninformedconsentbeforeparticipatinginthisstudy.Accordingtotheobjectivesofresearch,weformulatedtheinclusionandexclusioncriteriatoremovepotentialinterferingfactors.Theprimaryinclusioncriteriawerepatientsolderthan18yearswitheitherpathologicallyorclinicallyconfirmedHCCdiagnosis.Patientshadtobephysicallytolerant,withEasternCooperativeOncologyGroupperformancestatus(ECOG-PS)0or1,andChild-PughliverfunctionclassificationAorB(≤7points).PatientsalsohadatleastonemeasurabletumorlesionatbaselinepertheResponseEvaluationCriteriainSolidTumors,version1.1(RECISTv1.1).AllthepatientshadreceivedatleastonedoseofcombinedimmunotherapiesbasedonPD-1/L1blockadebeforeperformingthesurgicalresection.Exclusioncriteriaincludedpatientswithhistologicallyconfirmedintrahepaticcholangiocarcinoma(ICC)orothertypesofprimarylivercancer.Patientssufferingfromco-morbidautoimmunediseasesthatcouldpotentiallyaffectefficacyevaluationduringtreatmentwerealsoexcluded.AcompletelistofinclusionandexclusioncriteriaisavailableintheSupplement-1.Baselineinformation,imagingevaluation,laboratorytestsanddetailsofimmunotherapyandsurgerywererecorded.Thestudyprotocol,includingtreatmentregimensanddatacollection,adheredtotheprinciplesoftheDeclarationofHelsinkiandwasapprovedbytheInstitutionalReviewBoardandEthicsCommitteeofQiluhospitalofShandonguniversity.2.2.TreatmentregimensTheprotocolisfocusedonICIs-basedcombinationtherapyanddoesnotlimitthetypesofPD-1/L1blockadeandthespecificsystemicorlocoregionaltherapy.AllthepatientswereadministratedICIsplustyrosinekinaseinhibitors(TKIs)oralocoregionaltherapy.ICIswereintravenouslyadministratedeverythreeweeks.TKIswereadministratedorallyonceaday.Inthisstudy,locoregionaltherapymainlyinvolvedtranscatheterarterialchemoembolization(TACE)andhepaticarteryinfusionchemotherapy(HAIC).ThespecifictreatmentregimenwasattachedatSupplement-2.Fromtheinitiationofimmunotherapy,patientswereassessedbyimagingexaminationevery4–8weeks.Duringthecourseoftreatment,themultidisciplinaryteam(MDT)adjustedthetreatmentplanbasedonthepatient‘sconditionandevaluatedthenextstepinthetreatmentplan,includingpotentialsurgery.Thebaselinecharacteristicsofallthepatientsundergoingsurgeryshouldmeetthefollowingconditions:Child-PughofA-B;ECOGPSscore≤1;residualliverfunction＞30%inpatientswithoutcirrhosisand＞40%inpatientswithcirrhosis;tumordiameterreductionaccordingtomodifiedRECIST(mRECIST),andpatient‘swillingnesstosurgery.Surgicalfactorsincludingsurgicaltype,timeofsurgery,plasmaorredbloodcelltransfusion,infusionvolume,urinevolumeandpostoperativehospitalizationdayswererecordedforfurtheranalysis.2.3.AssessmentofefficacyandtreatmentrelatedadverseeventsChangeintumorsizewasassessedusingenhancedcomputedtomography(CT),magneticresonanceimaging(MRI)orotheravailableimagingtechnologiesatbaselineandevery4–8weeks.Beforesurgery,RECISTv1.1andmRECISTcriteriawereusedtoassessthetherapeuticefficacywhichincludedORRanddiseasecontrolrate(DCR)(Eisenhaueretal.,2009;LencioniandLlovet,2010).Aftersurgery,specimensweresurgicallyremovedforpathologicalexaminationbytwopathologistswhowereblindedtothetreatment.pCRandpathologicalpartialresponse(pPR)wasdefinedastheabsenceofresidualviabletumorcellsandmorethan50%tumornecrosisonsurgicallyresectedspecimens,respectively.Duringtheperioperativeperiod,tolerabilityandtoxicityofthecombinationimmunotherapywasassessedaccordingtotheNationalCancerInstituteCommonTerminologyCriteriaforAdverseEventsversion4.0(NCICTCAE4.0).Thecut-offfollow-uptimewas1stAugust2022.Overallsurvivalisdefinedastheintervalfromthestartdateoftherapytothedateofdeathofthepatientorthedeadlineoffollow-up.2.4.StatisticalanalysisBaselinecharacteristicsincludingage,gender,hepatitisinfectionstatus,ECOGperformance,Chinalivercancer(CNLC)stage,Barcelonacliniclivercancer(BCLC)stage,alpha-fetoprotein(AFP)levelandsizeoftargetlesionwerecalculatedandpresentedasmedianswithcorrespondinginterquartilerangesorassimplenumbersandpercentages.Tocomparevariablesbetweengroups,X2test,Fisher‘stest,independentsamplest-test,nonparametricranksumtest,Coxregression,Logisticregression,Kaplan-Meier(KM)survivalcurvesandlogranksurvivalanalysiswerecalculated.Factorswithpvalues＜0.10forunivariateLogisticandCoxregressionswereincludedinthemultivariateregression.Pvalues＜0.05wereconsideredsignificant.AllstatisticalanalysesandgraphswereperformedusingIBMSPSS25.0,GraphPadPrism(version8.0.1)andRsoftware(version4.1.1).3.Results3.1.BaselinecharacteristicsofthestudypopulationInthepresentstudy,weconsecutivelyassessedatotalof54initiallyunresectableHCCpatientstreatedwithcombinedimmunotherapies.Accordingtotheinclusioncriteria,20patientswereexcludedbecause8patientshadinsufficientliverfunctionstoundergoresection,6patientsdidnothavemeasurablelesionsorevaluablematerials,4patientswerecomplicatedwithotherseriousdiseases,whichmighthaveaffectedtherapeuticefficacy,and2patientswithdrewconsentaftertreatment.Finally,34patientswereincludedtoevaluatethesafetyandefficacyandthepossibilityofsubsequentradicalsurgery.Ofthesepatients,20patientscontinuedtoadoptcombinedimmunotherapytocontrolthedisease,andtheother14patientsreceivedradicalsurgicalresection(Fig.1).Download:Downloadhigh-resimage(528KB)Download:Downloadfull-sizeimageFig.1.Theflowchartofeligiblepatients.BaselinecharacteristicsforallincludedpatientshasbeensummarizedinTable1.Amongthesepatientswhounderwentradicalsurgery,10patientswereatCNLCstageIIb/IIIa/IIIb.Theremaining4patientswereatCNLCstageIbbeforetreatmentandcouldnotreceiveone-stageresectionbecauseofthelargesizeofthetumorandinsufficientresidualliver.ThemediantimefromthelasttherapeuticadministrationtosurgeryforTKIswas8.5days(range6–192),andICIswas19days(range13–203).Thecharacteristicsofthe14patientswhoreceivedradicalsurgeryhavebeenprovidedinTable2andFig.2.Table1.Patientbaselinedemographicsanddiseasecharacteristics.ParametersPatientswhounderwentsurgery(n=14)Patientswhodidnotundergosurgery(n=20)P-valuesAge,years(median,IQR)54.5(47.8–62.0)56.0(47.0–68.0)0.429Gender(female:male)4:102:180.202Hepatitis(HBV)infection,n(%)10(71.4%)16(80.0%)0.660ECOGperformance,n(%)0.16309(64.3%)8(40.0%)15(35.7%)12(60.0%)20(0)0(0)Child-Pughstage,n(%)0.501A14(100%)18(90.0%)B0(0)2(10.0%)CNLCstage,n(%)0.005Ia0(0)0(0)Ib4(28.6%)0(0)IIa0(0)0(0)IIb4(28.6%)2(10.0%)IIIa5(35.7%)8(40.0%)IIIb1(7.1%)10(50.0%)BCLCstage,n(%)0.007A4(28.6%)0(0)B4(28.6%)2(10.0%)C6(42.9%)18(90.0%)Vascularinvasion,n(%)5(35.7%)18(90.0%)0.002Extentofdisease,n(%)Metastatic1(7.1%)7(35.0%)0.102Recurrent0(0.0%)5(25.0%)0.063Previoustreatmentregimens,n(%)0.133Surgery0(0)4(20.0%)Systemictherapy3(21.4%)2(10.0%)Ragionalradiotherapyorablation0(0)3(15.0%)Transarterialchemoembolization6(42.9%)8(40.0%)Hepaticarterialinfusionchemotherapy4(28.6%)0(0)BaselineAFP,ng/mL(median,IQR)1758.00(7.67–24200.00)149.80(5.37–18329.95)0.592BaselineAFP≥400​ng/mL,n(%)7(50.0%)7(35.0%)0.382Sizeoftargetlesion,cm(median,IQR)11.55(9.45–13.75)8.75(3.98–12.83)0.034Abbreviation:ECOG,EasternCooperativeOncologyGroup;BCLC,BarcelonaClinicLiverCancer;CNLC,ChinaLiverCancer;HBV,HepatitistypeBvirus;AFP,Alpha-fetoprotein;IQR,Interquartilerange.Table2.Thecharacteristicsofthecombinationimmunotherapyforpatientswithhepatocellularcarcinoma.PatientsDaysformcombinationimmunotherapytosurgeryTKIswithdrawaldaysbeforesurgeryICIswithdrawaldaysbeforesurgeryCombinationimmunotherapylineBCLCstageCNLCstagePretreatmenttumorsize,cmPreoperativetumorsize,cmTumorresponse,byRECISTv1.1Tumorresponse,bymRECISTPathologicalevaluation01717211BIIb7.67.4SDPRpPR023712161AIb11.511.0SDPRpPR031267201AIb11.010.5SDSDpPR04357181BIIb13.512.5SDPRpPR05456181AIb13.011.8SDPRpPR06517151AIb12.111SDPRpPR071207162CIIIb11.67.7PRCRpCR084638362CIIIa10.76.9PRPRpPR094261922031CIIIa14.59.1PRPRpPR1021315161CIIIa16.410.2PRCRpCR1146815221CIIIa9.35.5PRPRpPR121609202BIIb9.55.5PRPRpPR133961441651CIIIa19.010.0PRCRpCR1424713131BIIb6.63.3PRPRpPRAbbreviation:TKIs,Tyrosinekinaseinhibitors;ICIs,Immunecheckpointinhibitors;BCLC,Barcelonacliniclivercancer;CNLC,Chinalivercancer;RECIST,ResponseEvaluationCriteriainSolidTumors;CR,Completeresponse;PR,Partialresponse;SD,Stabledisease;pCR,Pathologicalcompleteresponse;pPR,Pathologicalpartialresponse.Download:Downloadhigh-resimage(128KB)Download:Downloadfull-sizeimageFig.2.Theoverviewofthecombinationimmunotherapy.X-axisrepresentsdifferentpatientsandy-axisrepresentstreatmentduration.TACE,Transarterialchemotherapyandembolization;HAIC,Hepaticarterialinfusionchemotherapy;PVE,Portalveinembolization.Therewerestatisticallysignificantdifferencesbetweenthetwogroupsregardingtumorstage(p,0.005;p,0.007),vascularinvasion(p,0.002)andtumorsize(p,0.034).Furthermore,patientswithmetastasis(n​=​7;35.0%)andrecurrence(n​=​5;25.0%)weremorelikelytobeobservedinnon-surgerygroup.LogisticregressionanalysisoftheincludedbaselinecharacteristicsrevealedthatCNLCstageofpatientandvascularinvasionwerefactorspotentiallyinfluencingsurgeryaftercombinationimmunotherapy.TheCoxregressionanalysisregardingthesurvivalshowednostatisticalsignificance(Supplement-2).3.2.EfficacyofcombinationimmunotherapyduringperioperationForpatientswithsurgicalresection,treatmentresponseswereassessedbasedonpretreatmentandpreoperativeimaging.AccordingtoRECISTv1.1,8patientsreachedPRand6patientsreachedstabledisease(SD).ORRandDCRwere57.1%and100.0%,respectively.WhileusingthemRECISTtoevaluatedtheefficacy,theresultsshowedthattherewere3patientswithCR,10patientswithPRand1patientwithSDaftertreatment.ORRandDCRwere92.9%and100.0%,respectively.Fromapathologicalpointofview,21.4%(n​=​3)achievedpCRand78.6%(n​=​11)patientsachievedpPR(Table4andFig.3).Duringthecombinedimmunotherapystage,patientsexhibitedvaryingdegreesofchangeintumorbiomarkers.TheAFPof11patientsshowedadownwardtrendaftertreatment,andtheotherswereinastateoffluctuation(Supplement-3).Thedetailsof4representativepatientswereshowninFig.4.Download:Downloadhigh-resimage(421KB)Download:Downloadfull-sizeimageFig.3.ThetreatmentwasevaluatedbasedonRECISTv1.1criteria(A),mRECISTcriteria(B)andpathology(C).RECISTv1.1,Responseevaluationcriteriainsolidtumorsversion1.1;mRECIST,modifiedRECIST.Download:Downloadhigh-resimage(881KB)Download:Downloadfull-sizeimageFig.4.Thecharacteristicsofrepresentativepatientsduringcombinationimmunotherapy,includingpretreatmentandpreoperativeimaging,alpha-fetoproteinchange,tumorimageandpostoperativepathology.AsshowninTable2,Table3,themediantimefromcombinationimmunotherapytosurgerywas143days(range35–468).9patientsunderwentopensurgeryand5underwentlaparoscopicsurgery.Themediansurgerytimewas205​min(interquartilerange[IQR],144-288).Themedianposthospitaldaywas9days(IQR,8-11).Inaddition,1patientdevelopedpostoperativebleedingcomplicationandwasdischargedaftersymptomatictreatment.Table3.Surgicalsettingandpathologicalconditions.ParametersAll(n=14)Surgicaltype,n(%)Open9(64.3%)Laparoscopic5(35.7%)Timeofsurgery,mins(median,IQR)205(144–288)RBCtransfusion,mL(median,IQR)0(0–500)Plasmatransfusion,mL(median,IQR)0(0–320)transfusionvolume,mL(median,IQR)2000(2000–2500)urinevolume,mL(median,IQR)375(200–725)Postoperativehospitalday,days(median,IQR)9(8–11)Differentiatedhistology,n(%)Poor4(28.6%)Moderate-poor5(35.7%)Moderate2(14.3%)Moderate-high3(21.4%)PathologicalevaluationpCR3(21.4%)pPR11(78.6%)MVI,n(%)M07(50.0%)M17(50.0%)Abbreviation:RBC,Redbloodcell;MVI,Microvascularinvasion;pCR,Pathologicalcompleteresponse;pPRPathologicalpartialresponse;IQR,Interquartilerange.3.3.Treatmentrelatedadverseeventsandfollow-upDuringtheclinicalobservationperiod,allpatientsexperiencedatleastonekindofadverseevent,andgrade3or4AEsoccurredin28.5%(n​=​4)of14patients.Amongthegrade≥3adverseevents,1patientoccurredtocerebralhemorrhageduetoseverethrombopeniainsurgerygroup.Theremainingcouldreturntonormalafteractivetreatment.However,innon-surgerygroup,6patientsdiscontinuedbecausethetumorsprogressedandthepatientswereinextremelypoorcondition(Supplement-4).Insurgerygroup,themostcommonAEsofanygradewerefatigue(n​=​11,78.6%),leukocytopenia(n​=​8,57.1%)andaspartateaminotransferase(AST)elevation(n​=​6,42.9%).Hypertensionandthrombopeniawerealsocommoninbothgroups(Table5).Table4.EfficacyofperioperativecombinationimmunotherapyinHCCpatients.InvestigatorreviewRECISTv1.1mRECISTPathologicalevaluationObjectiveresponserate,n(%,95%CI)8(57.1%,29.7–81.2)13(92.9%,64.2–99.6)14(100.0%,73.2–100.0)Completeresponse,n(%)03(21.4%)3(21.4%)Partialresponse,n(%)8(57.1%)10(71.5%)11(78.6%)Stabledisease,n(%)6(42.9%)1(7.1%)0Progressivedisease,n(%)000Diseasecontrolrate,n(%,95%CI)14(100.0%,73.2–100.0)14(100.0%,73.2–100.0)14(100.0%,73.2–100.0)Medianfollow-uptime(months,95%CI)13.5(9.7–19.9)Medianoverallsurvival(months,95%CI)NAAbbreviation:RECISTv1.1,Responseevaluationcriteriainsolidtumorsversion1.1;NA,Notavailable.Table5.Drugssafetyassessmentbetweensurgerygroupandnon-surgerygroup.Adverseevents(AEs)Patientswhounderwentsurgery(n=14)Patientswhodidnotundergosurgery(n=20)Anygrade,n(%)Grade≥3,n(%)Anygrade,n(%)Grade≥3,n(%)Fatigue11(78.6%)0(0)16(80.0%)6(30.0%)Leukocytopenia8(57.1%)0(0)7(35.0%)6(30.0%)ASTelevation6(42.9%)0(0)12(60.0%)6(30.0%)Hypertension5(35.7%)2(14.3%)6(30.0%)0(0)Thrombopenia5(35.7%)1(7.1%)11(55.0%)7(35.0%)ALTelevation4(28.6%)0(0)11(55.0%)6(30.0%)Skinrash4(28.6%)1(7.1%)2(10.0%)0(0)Abdominalpain4(28.6%)0(0)7(35.0%)2(10.0%)Decreasedappetite3(21.4%)0(0)8(40.0%)6(30.0%)Anaemia3(21.4%)0(0)8(40.0%)6(30.0%)Vomiting2(14.3%)2(14.3%)6(30.0%)1(5.0%)Diarrhoea2(14.3%)2(14.3%)1(5.0%)0(0)Hypothyroidism2(14.3%)0(0)1(5.0%)0(0)Hand-footsyndrome2(14.3%)0(0)1(5.0%)0(0)Asthma0(0)0(0)0(0)0(0)Abbreviation:ALT,Alanineaminotransferase;AST,Aspartateaminotransferase.Atthedatacut-offof1stAugust2022,afteramedianfollow-upof13.5months(95%confidenceinterval[CI]9.7–19.9),allpatientswhounderwentsurgeryaftercombinationimmunotherapyweresurvivalwithonepatienthadtumorrecurred.Uptothefollow-uptime,themediansurvivaltimeofthepatientwithradicalresectionhasnotyetbeenreached.Asforthepatientswithoutradicalresection,medianOStimewas14.0months(95%CI12.0–16.0)(Fig.5).Download:Downloadhigh-resimage(174KB)Download:Downloadfull-sizeimageFig.5.TheKaplan-Meieranalysisofoverallsurvivalbetweensurgeryandnon-surgerygroupduringcombinationimmunotherapy.4.DiscussionThissingle-center,retrospectivestudywasconductedtoinvestigatetheefficacyandsafetyofpreoperativecombinationimmunotherapyforinitiallyunresectableHCCpatients.AccordingtotheRECISTv1.1,57.1%(n​=​8)ofthosewhoreceivedcombinedimmunotherapybeforesurgeryachievedPR,whichindicateda30%reductionintumorsize.Pathologicevaluationsofpostoperativespecimensconfirmedthat21.4%(n​=​3)achievedpCRand78.6%(n​=​11)achievedpPR.Althoughallpatientsexperiencedatleastonekindofadverseevent,grade3or4AEsoccurredin28.6%(n​=​4)of14patients.Themaintreatmentrelatedadverseeventsincludedfatigue,leukocytopeniaandaminotransferaseelevation,whichcanberelievedafteractivesymptomatictreatment.Atpresent,preoperativeimmunotherapyisarelativelynewresearchfield,andtherearegenerallytwoformsofpreoperativeimmunotherapyforHCC:neoadjuvantimmunotherapyforpatientswithearlyresectabletumorandconversionordown-stagetreatmentforpatientswithinitiallyunresectabletumor(Pinatoetal.,2021;Suetal.,2021).Althoughstudiesintumors,suchaslungcancerandbladdercancer,haveshownthatneoadjuvanttherapywithappropriatecyclesdoesnotdelaysurgery(Fordeetal.,2018;Necchietal.,2018),preoperativeimmunotherapystillfaceadverseconditionssuchaspotentialtoxicsideeffectsandtumorhyperprogression(Sangroetal.,2021).Inaddition,althoughtheefficacyofcombinationimmunotherapymaybebetterthanimmunemonotherapyinthesettingofneoadjuvanttherapy,patientswiththeadditionofdrugsorothertreatmentsaremorelikelytohavethetreatmentrelatedadverseevents,suchashepatotoxicity,andfacetheriskofdelayedsurgeryandincreasedthedifficultiesofsurgicaloperation(Ahernetal.,2021).ConversiontherapyregardingpatientswithunresectableHCCdoesnotfacetheriskofdelayingtheoperation,butthechoiceoftreatmentneedstobetreatedmorecarefully.Becausenotallpatientsrespondtocombinationimmunotherapy,meanwhile,excessivepursuitofsurgicalresectionmaybringovertreatmenttopatientswithoutsurvivalbenefits.Fromapreclinicalperspective,combinedimmunotherapyhasasynergisticanti-tumoreffect.Notonlycantheyregulatethetumormicroenvironment,butalsoviasignaltransductiondirectlyactonimmunecells,suchasTcellsandtumor-associatedmacrophages(TAMs),whichhasalsobeenconfirmedinseveralanimalmodelstudies(KhanandKerbel,2018;Shigetaetal.,2020;Torrensetal.,2021).Inclinicalstudies,Zhuetal.screened10patientsfrom63patientswithunresectableHCCwhoweresystematicallytreatedfortumordownstagingtosurgicalresectionaftertherapy.TheresultsshowedanORRof60%andapCRof9.5%(6/63)or60%(6/10)(Zhuetal.,2021).Yangetal.alsoanalyzed9advancedHCCpatientswithextrahepaticmetastaseswhounderwentsurgeryaftercombinedtherapyandfoundthattheORRandDCRwere55.6%and100%,respectively,withapostoperativepCRof33%(Yangetal.,2021).Inaddition,Zhangetal.included10advancedHCCpatientswithmacrovascularinvasionwhometthecriteriaforsuccessfulconversionaftercombinationtherapy,and8patientsunderwentsurgery.Inthepreoperativeevaluation,ORRaswellasDCRwere100%,andpostoperativepathologyshowedpCRinonepatient(12.5%),pPRin5patients(62.5%)(Zhangetal.,2021).Inthepresentstudy,althoughthedurationofcombinationimmunotherapywasdifferentineachpatient,postoperativepathologicalresultsdemonstratedthattheactivityoftumorcellsinpatientswithsurgicalresectionwasinhibitedtoacertainextent(pCR:3/10;pPR:7/10).Forpatientswithlargetumorburden,insufficientresiduallivervolumeistheprimaryreasonwhichhindersradicalresection(Pandeyetal.,2007).Furthermore,somestudieshavereportedthattheincreaseoftumorsizewasassociatedwithincreaseofAFPandmicrovascularinvasion(MVI),whichmayindicateworseprognosisofpatients(Liuetal.,2020).ThehigherORRofcombinationimmunotherapymeansthatagreatnumberofpatientscanreducethetumorburdenandincreasethenormallivervolumethroughimmunotherapy.Thisundoubtedlyprovidesanopportunityforpatientstore-evaluateradicalsurgery.Inthisstudy,theaveragetumordiameterofpatientswhounderwentradicalresectionreached11.90​cm.Therefore,basedonthesefactors,severalprospectiveclinicalstudiesfocusingonunresectableHCCarecurrentlyunderway.Duringtheperiodoffollow-up,allpatientsweresurvivalandonlyonepatientencounteredrecurrence.Ofnote,twoofthethreepatientswithpCRreceivedalongcycleofimmunotherapyincombinationwithlocoregionaltherapy.AretrospectivestudyalsoshowedthatLenvatinibcombinedwithTislelizumabandHAICresultedinahigherORRcomparedtosingle-agentofLenvatinib(RECISTv1.1:59.2%versus9.3%,p​＜​0.001;mRECIST:67.6%versus16.3%,p​＜​0.001)(Heetal.,2021).Regardingthetolerabilityoftreatment,adverseeventsoccurredinalmostallpatients.Themostcommonadverseeventwasfatigue(78.6%),followedbyleukocytopeniaandASTelevation(57.1%and42.9%).Thrombopeniaandhypertensionalsoneededtobenoted.Mostoftheseadverseeventsweregrade1-2andcanbeeffectivelycontrolledwithmedication,butitwasequallycriticaltobealerttograde3-4adverseevents.Asdiscussedabove,surgicalresectionaftercombinationimmunotherapyisanewfield,andtherearemanyproblemsthatneedtobestudied.Well-designedprospectiveclinicalstudiescanmoreaccuratelyevaluatetheefficacyofpatients,andthencalculatetheproportionofpatientswhocanundergosurgery,butpotentiallyfacetheproblemofover-treatmentcausedbytheadministrationofimmunedrugs.Incontrast,thisretrospectivestudyavoidstheproblemsofprospectiveclinicaltrials,buthasapotentialtreatmentbias.Atthesametime,thelargecohortstudyneedstobecarriedoutafterafullunderstandingoftherisksandbenefits.Ourresearchcertainlycannotprovidewhatthelargecohortstudyhasconfirmed.Wecanonlyprovidewhatweobserve,andfromthecurrentpointofviewprovidethereferencecontenttoimproveprogressinthisfield.Secondly,althoughthereareavarietyofanti-PD-1drugsandtheregimensofcombinedtherapy,butallofthemaremainlyforthepurposeofsynergism.Thepresentstudydoesnotlimitthespecificregimens,whichmaybebeneficialtotheapplicabilityoftheconclusion,butaccuratedrugadministeringismoreconducivetothestabilityoftheconclusion.Inaddition,thegoldstandardofanytreatmentisthesurvivalbenefit.Onthebasisofincreasingthenumberofpatients,afollow-upperiodof3yearsoreven5yearsisworthcarryingout.Inconclusion,thestudyshowsthatforinitiallyunresectableHCC,aftertheapplicationofcombinationimmunotherapy,patientsshouldbecomprehensivelyevaluatedwhethertheymeetthecriteriaforsurgicalresection.Surgicalresectionfollowingcombinationimmunotherapyhasacertainsafetyandefficacyandwouldimprovesurvivalbenefitforsomepatients.EthicsapprovalandconsenttoparticipateThestudyprotocol,includingtreatmentprotocolanddatacollection,wasinaccordancewiththeDeclarationoftheHelsinkiAssociationofWorldMedicalEthicsGuidelines.ApprovedbytheResearchEthicsCommitteeofQiluhospitalofShandonguniversity.DataavailabilitystatementTheoriginaldatapresentedinthisstudyareincludedinthearticleorsupplementmaterials,additionalinformationcanbeobtainedfromthecorrespondingauthors.DisclosurestatementThisworkwassupportedbytheNationalNaturalScienceFoundationofChina(GrantNo.82073200＆81874178＆82203000),MajorbasicresearchofShandongProvincialNaturalScienceFoundation(GrantNo.ZR2021ZD26),FoundsforIndependentCultivationofInnovativeTeamfromUniversitiesinJinan(GrantNo.2020GXRC023),theTaishanScholarsProgramofShandongProvince(tstp20221158,tsqnz20221164),andShandongProvincialNaturalScienceFoundation(ZR202111120102).AuthorcontributionsJSX,DXWandTLwereresponsiblefordesigningthestudy.JSX,HL,RZL,SYT,YCY,ZRD,JGH,EYL,QBZ,ZQCandDXWprimarilyperformedthequalityassessmentaswellassupervision.JSXanalyzed,interpretedthedata,anddraftedthemanuscript.DXWandTLrevisedthemanuscript.Alldataandmaterialanalyzedduringthisstudywereincludedinthisarticle.Allauthorshavereadandapprovedthefinalversionofthemanuscript.DeclarationofcompetinginterestTheauthorsdeclarethattheyhavenoknowncompetingfinancialinterestsorpersonalrelationshipsthatcouldhaveappearedtoinfluencetheworkreportedinthispaper.AbbreviationDownloadallsupplementaryfilesincludedwiththisarticleWhat’sthis?PLCPrimarylivercancerHCCHepatocellularcarcinomaPD-1/PD-L1Programmedcelldeathprotein1/ligand1RCTRandomizedcontrolledtrialICCIntrahepaticcholangiocarcinomaTKIsTyrosinekinaseinhibitorsICIsImmunecheckpointinhibitorsMDTMultidisciplinaryteamORRObjectiveresponserateDCRDiseasecontrolrateOSOverallsurvivalAEsAdverseeventsNCICTCAENationalCancerInstituteCommonTerminologyCriteriaforAdverseEventsRECISTv1.1ResponseEvaluationCriteriainSolidTumorsversion1.1mRECISTmodifiedRECISTPRPartialresponseSDStablediseasepCRPathologicalcompleteresponsepPRPathologicalpartialresponseCIConfidenceintervalTACETranscatheterarterialchemoembolizationHAICHepaticarteryinfusionchemotherapyBCLCBarcelonacliniclivercancerCNLCChinalivercancerECOGPSEasternCooperativeOncologyGroupperformancestatusMRIMagneticresonanceimagingCTComputedtomographyKMKaplan-MeierAFPAlpha-fetoproteinMVIMicrovascularinvasionASTAspartateaminotransferaseTAMsTumor-associatedmacrophagesAppendixA.SupplementarydataThefollowingaretheSupplementarydatatothisarticle:Download:DownloadWorddocument(4MB)Multimediacomponent1.Download:DownloadWorddocument(19KB)Multimediacomponent2.Download:DownloadWorddocument(34KB)Multimediacomponent3.Download:DownloadWorddocument(24KB)Multimediacomponent4.ReferencesAbou-Alfaetal.,2022G.K.Abou-Alfa,G.Lau,M.Kudo,S.L.Chan,R.K.Kelley,J.Furuse,etal.TremelimumabplusdurvalumabinunresectablehepatocellularcarcinomaNEJMEvidence(2022),ArticleEVIDoa2100070GoogleScholarAhernetal.,2021E.Ahern,B.J.Solomon,R.Hui,N.Pavlakis,K.O‘Byrne,B.G.HughesNeoadjuvantimmunotherapyfornon-smallcelllungcancer:rightdrugs,rightpatient,righttime?Journalforimmunotherapyofcancer,9(2021)GoogleScholarEisenhaueretal.,2009E.A.Eisenhauer,P.Therasse,J.Bogaerts,L.H.Schwartz,D.Sargent,R.Ford,etal.NewResponseEvaluationCriteriainSolidTumours:RevisedRECISTGuideline(Version1.1),vol.45,Europeanjournalofcancer(Oxford,England:1990)(2009),pp.228-247,10.1016/j.ejca.2008.10.026ViewPDFViewarticleViewinScopusGoogleScholarFinnetal.,2020R.S.Finn,S.Qin,M.Ikeda,P.R.Galle,M.Ducreux,T.-Y.Kim,etal.AtezolizumabplusbevacizumabinunresectablehepatocellularcarcinomaN.Engl.J.Med.,382(2020),pp.1894-1905,10.1056/NEJMoa1915745ViewinScopusGoogleScholarFordeetal.,2018P.M.Forde,J.E.Chaft,K.N.Smith,V.Anagnostou,T.R.Cottrell,M.D.Hellmann,etal.NeoadjuvantPD-1blockadeinresectablelungcancerN.Engl.J.Med.,378(2018),pp.1976-1986,10.1056/NEJMoa1716078ViewinScopusGoogleScholarForneretal.,2018A.Forner,M.Reig,J.BruixHepatocellularcarcinomaLancet(London,England),391(2018),pp.1301-1314,10.1016/s0140-6736(18)30010-2ViewPDFViewarticleViewinScopusGoogleScholarHeetal.,2021M.K.He,R.B.Liang,Y.Zhao,Y.J.Xu,H.W.Chen,Y.M.Zhou,etal.Lenvatinib,toripalimab,plushepaticarterialinfusionchemotherapyversuslenvatinibaloneforadvancedhepatocellularcarcinomaTherAdvMedOncol,13(2021),Article17588359211002720,10.1177/17588359211002720GoogleScholarKasebetal.,2019A.O.Kaseb,L.Vence,J.Blando,S.S.Yadav,N.Ikoma,R.C.Pestana,etal.ImmunologiccorrelatesofpathologiccompleteresponsetopreoperativeimmunotherapyinhepatocellularcarcinomaCancerImmunol.Res.,7(2019),pp.1390-1395,10.1158/2326-6066.Cir-18-0605ViewinScopusGoogleScholarKasebetal.,2022A.O.Kaseb,E.Hasanov,H.S.T.Cao,L.Xiao,J.N.Vauthey,S.S.Lee,etal.Perioperativenivolumabmonotherapyversusnivolumabplusipilimumabinresectablehepatocellularcarcinoma:arandomised,open-label,phase2trialLancetGastroenterolHepatol,7(2022),pp.208-218,10.1016/s2468-1253(21)00427-1ViewPDFViewarticleViewinScopusGoogleScholarKhanandKerbel,2018K.A.Khan,R.S.KerbelImprovingimmunotherapyoutcomeswithanti-angiogenictreatmentsandviceversaNat.Rev.Clin.Oncol.,15(2018),pp.310-324,10.1038/nrclinonc.2018.9ViewinScopusGoogleScholarLencioniandLlovet,2010R.Lencioni,J.M.LlovetModifiedRECIST(mRECIST)assessmentforhepatocellularcarcinomaSemin.LiverDis.,30(2010),pp.52-60,10.1055/s-0030-1247132ViewinScopusGoogleScholarLiuetal.,2020H.Liu,Y.Yang,C.Chen,L.Wang,Q.Huang,J.Zeng,etal.ReclassificationoftumorsizeforsolitaryHBV-relatedhepatocellularcarcinomabyminimumpvaluemethod:alargeretrospectivestudyWorldJ.Surg.Oncol.,18(2020),p.185,10.1186/s12957-020-01963-zViewPDFViewarticleGoogleScholarMarronetal.,2022T.U.Marron,M.I.Fiel,P.Hamon,N.Fiaschi,E.Kim,S.C.Ward,etal.Neoadjuvantcemiplimabforresectablehepatocellularcarcinoma:asingle-arm,open-label,phase2trialLancetGastroenterolHepatol,7(2022),pp.219-229,10.1016/s2468-1253(21)00385-xViewPDFViewarticleViewinScopusGoogleScholarNecchietal.,2018A.Necchi,A.Anichini,D.Raggi,A.Briganti,S.Massa,R.Lucianò,etal.Pembrolizumabasneoadjuvanttherapybeforeradicalcystectomyinpatientswithmuscle-invasiveurothelialbladdercarcinoma(PURE-01):anopen-label,single-arm,phaseIIstudyJ.Clin.Oncol.,36(2018),pp.3353-3360,10.1200/jco.18.01148ViewinScopusGoogleScholarPandeyetal.,2007D.Pandey,K.H.Lee,C.T.Wai,G.Wagholikar,K.C.TanLongtermoutcomeandprognosticfactorsforlargehepatocellularcarcinoma(10cmormore)aftersurgicalresectionAnn.SurgOncol.,14(2007),pp.2817-2823,10.1245/s10434-007-9518-1ViewinScopusGoogleScholarPetrowskyetal.,2020H.Petrowsky,R.Fritsch,M.Guckenberger,M.L.DeOliveira,P.Dutkowski,P.A.ClavienModerntherapeuticapproachesforthetreatmentofmalignantlivertumoursNat.Rev.Gastroenterol.Hepatol.,17(2020),pp.755-772,10.1038/s41575-020-0314-8ViewinScopusGoogleScholarPinatoetal.,2021D.J.Pinato,P.Fessas,G.Sapisochin,T.U.MarronPerspectivesontheneoadjuvantuseofimmunotherapyinhepatocellularcarcinomaHepatology,74(2021),pp.483-490CrossRefViewinScopusGoogleScholarSangroetal.,2021B.Sangro,P.Sarobe,S.Hervás-Stubbs,I.MeleroAdvancesinimmunotherapyforhepatocellularcarcinomaNat.Rev.Gastroenterol.Hepatol.,18(2021),pp.525-543,10.1038/s41575-021-00438-0ViewinScopusGoogleScholarShigetaetal.,2020K.Shigeta,A.Matsui,H.Kikuchi,S.Klein,E.Mamessier,I.X.Chen,etal.RegorafenibcombinedwithPD1blockadeincreasesCD8T-cellinfiltrationbyinducingCXCL10expressioninhepatocellularcarcinomaJImmunotherCancer,8(2020),10.1136/jitc-2020-001435GoogleScholarShindohetal.,2013J.Shindoh,K.Hasegawa,Y.Inoue,T.Ishizawa,R.Nagata,T.Aoki,etal.Riskfactorsofpost-operativerecurrenceandadequatesurgicalapproachtoimprovelong-termoutcomesofhepatocellularcarcinomaHPB:theofficialjournaloftheInternationalHepatoPancreatoBiliaryAssociation,15(2013),pp.31-39,10.1111/j.1477-2574.2012.00552.xViewPDFViewarticleViewinScopusGoogleScholarSuetal.,2021Y.Y.Su,C.C.Li,Y.J.Lin,C.HsuAdjuvantversusneoadjuvantimmunotherapyforhepatocellularcarcinoma:clinicalandimmunologicperspectivesSemin.LiverDis.,41(2021),pp.263-276,10.1055/s-0041-1730949ViewinScopusGoogleScholarSungetal.,2021H.Sung,J.Ferlay,R.L.Siegel,M.Laversanne,I.Soerjomataram,A.Jemal,etal.Globalcancerstatistics2020:GLOBOCANestimatesofincidenceandmortalityworldwidefor36cancersin185countriesCa-CancerJ.Clin.,71(2021),pp.209-249,10.3322/caac.21660GoogleScholarTangetal.,2022X.Tang,M.Li,X.Wu,T.Guo,L.Zhang,L.Tang,etal.NeoadjuvantPD-1blockadepluschemotherapyinducesahighpathologicalcompleteresponserateandanti-tumorimmunesubsetsinclinicalstageIIIgastriccancerOncoImmunology,11(2022),Article2135819,10.1080/2162402x.2022.2135819ViewinScopusGoogleScholarTorrensetal.,2021L.Torrens,C.Montironi,M.Puigvehí,A.Mesropian,J.Leslie,P.K.Haber,etal.Immunomodulatoryeffectsoflenvatinibplusanti-programmedcelldeathprotein1inmiceandrationaleforpatientenrichmentinhepatocellularcarcinomaHepatology,74(2021),pp.2652-2669,10.1002/hep.32023ViewinScopusGoogleScholarVillanueva,2019A.VillanuevaHepatocellularcarcinomaN.Engl.J.Med.,380(2019),pp.1450-1462,10.1056/NEJMra1713263ViewinScopusGoogleScholarWangetal.,2019D.Wang,J.Lin,X.Yang,J.Long,Y.Bai,X.Yang,etal.CombinationregimenswithPD-1/PD-L1immunecheckpointinhibitorsforgastrointestinalmalignanciesJ.Hematol.Oncol.,12(2019),pp.1-21GoogleScholarWangetal.,2022J.Wang,Z.Zheng,T.Wu,W.Li,J.Wang,Y.Pan,etal.Hepaticarterialinfusionchemotherapyasatimingstrategyforconversionsurgerytotreathepatocellularcarcinoma:asingle-centerreal-worldstudyJ.Hepatocell.Carcinoma,9(2022),pp.999-1010,10.2147/jhc.S379326ViewinScopusGoogleScholarYangetal.,2019J.D.Yang,P.Hainaut,G.J.Gores,A.Amadou,A.Plymoth,L.R.RobertsAglobalviewofhepatocellularcarcinoma:trends,risk,preventionandmanagementNat.Rev.Gastroenterol.Hepatol.,16(2019),pp.589-604GoogleScholarYangetal.,2021X.Yang,H.Xu,B.Zuo,X.Yang,J.Bian,J.Long,etal.DownstagingandresectionofhepatocellularcarcinomainpatientswithextrahepaticmetastasesafterstereotactictherapyHepatobiliarySurg.Nutr.,10(2021),pp.434-442,10.21037/hbsn-21-188GoogleScholarYinetal.,2022Z.Yin,D.Chen,S.Liang,X.LiNeoadjuvanttherapyforhepatocellularcarcinomaJ.Hepatocell.Carcinoma,9(2022),pp.929-946,10.2147/jhc.S357313GoogleScholarZhangetal.,2021W.Zhang,B.Hu,J.Han,Z.Wang,G.Ma,H.Ye,etal.SurgeryafterconversiontherapywithPD-1inhibitorsplustyrosinekinaseinhibitorsareeffectiveandsafeforadvancedhepatocellularcarcinoma:apilotstudyoftenpatientsFront.Oncol.,11(2021),Article747950,10.3389/fonc.2021.747950ViewinScopusGoogleScholarZhuetal.,2021X.D.Zhu,C.Huang,Y.H.Shen,Y.Ji,N.L.Ge,X.D.Qu,etal.Downstagingandresectionofinitiallyunresectablehepatocellularcarcinomawithtyrosinekinaseinhibitorandanti-PD-1antibodycombinationsLiverCancer,10(2021),pp.320-329,10.1159/000514313ViewinScopusGoogleScholar

抑郁症和癌症都是全世界普遍存在的疾病。许多癌症患者在恶性肿瘤的预后不佳后会经历心理疾病，尤其是抑郁症。尽管一些研究表明咖啡因可能可以预防抑郁症状，但目前尚不清楚咖啡因与癌症患者之间的关系。NutritionResearch杂志2023年12月发表了山东大学齐鲁医院肝胆外科李涛教授团队的研究结果：在非癌症人群中，每日摄入适量咖啡因可以减轻抑郁症状，而在癌症人群中，咖啡因摄入并不能减轻癌症患者的抑郁症状。https://www.sciencedirect.com/science/article/pii/S0271531723000647数据是从2007年至2016年美国国家健康和营养检查调查中提取和合并的。在控制了潜在的混杂因素后，使用相互作用效应分析来阐明咖啡因和癌症对抑郁症状的相互作用。使用线性回归分析和限制三次样条进一步分析癌症和非癌症人群中咖啡因与抑郁之间的关系。共有24145名参与者纳入分析。在非癌症人群中，四分位数3组的咖啡因摄入量与患者健康问卷9(PHQ-9)评分之间呈负相关(β=–0.23，95%置信区间，–0.45至–0.01;P=.041)。在癌症人群中没有观察到咖啡因摄入量与PHQ-9评分之间存在关联。在癌症和非癌症人群中，限制型三次样条表明咖啡因和PHQ-9评分之间存在非线性趋势，当咖啡因摄入量为119.52mg时，PHQ-9评分最低。在非癌症人群中，每日摄入适量咖啡因(第3四分位组;范围(119.5-236.5mg)与抑郁症状减轻相关，而在癌症人群中，没有发现咖啡因摄入量与抑郁之间存在关联

2023年3月7日，山东大学齐鲁医院肝胆外科李涛教授团队在《Europeanjournalofcancer》上发表题为“Anthropometricindicatorsofadiposityandriskofprimarylivercancer:asystematicreviewanddose-responsemeta-analysis”的研究论文，研究表明中心性肥胖的人群比一般肥胖性肥胖的人群更容易患肝癌。对于肥胖人群来说，腰围（WC）比BMI更能准确预测患肝癌的风险。肥胖是原发性肝癌发病的风险因素，与原发性肝癌（PLC）的风险增加有关。BMI(身体质量指数)作为最常用的肥胖指标，在反映体内脂肪分布存在局限性，其预测肝癌发病风险的作用常受到质疑。本研究旨在通过考虑潜在的非线性关联来研究不同人体测量指标在识别PLC风险中的作用。在研究中，李涛教授团队通过分析69项研究中超过3000万人群的数据，全面探究了五种肥胖相关测量指标(腰围身高比、腰臀围比、BMI、腰围、臀围)在预测肝癌发病风险中的作用，明确腰围（WC)所反映的向心性肥胖人群的肝癌发病风险比BMI所反映的一般性肥胖人群的发病风险更高;该研究阐明了体内脂肪分布在肝癌发病中的重要性，明确了腰围是更有价值的肝癌发病风险的预测指标，提出促进体重和体型管理的公共卫生干预有助于肝癌的一级预防，为肝癌预防策略提供了新思路。

使用微信预约挂号很方便，先将流程介绍一下，方便广大患者预约就医（微信预约挂号后就不用到医院现场排队缴费挂号，节省时间，方便就诊。因为在好大夫网站加号后还需要到齐鲁医院门诊挂号就诊或者用微信在齐鲁医院官网预约挂号就诊，因此关闭好大夫网站加号，患者可每周三到齐鲁医院门诊挂号后或者微信预约挂号后到外科门诊4-2诊室就诊）第一步 微信搜索山东大学齐鲁医院，关注山东大学齐鲁医院微信公众号后点击进入公众号第二步进入公众号后点击左下角“就医服务”，从下一个界面选择“预约挂号”第三步用手机号或微信号注册登录第四步登录后点击“我已阅读并同意”第五步：进入后点击“专家号“选择科室和医生进行预约，或者在搜索栏输入您想预约挂号的医生的名字后点击即可显示医生预约界面。例如周一门诊，可逐级点击”专家号“，然后点击“外科”， “普外科”“肝胆外科”，就可以选择“李涛”医生预约挂号，或者直接搜索“李涛”后预约挂号。第六步点击医生名字可浏览医生的介绍第七步 点击预约即可选择就诊时间（就诊当天可根据门诊情况灵活就诊，比如预约就诊时间是上午10点，也可以提前或延后就诊）

2021年5月15日，在全国肿瘤规范化诊疗工作会议暨肿瘤多学科诊治及转化研究高峰论坛上，全国肿瘤单病种质控工作全面启动，我国肿瘤诊治逐步进入规范化、个体化和精准化的多学科综合治疗新时代。此次大会上，赫捷院士还公布了国家肿瘤质控中心确定的肺癌、肝癌、食管癌、宫颈癌、卵巢癌5个质控专家委员会名单，截至目前，国家肿瘤质控中心共成立包括乳腺癌、结直肠癌等在内的7个国家级肿瘤质控专委会，并由多名院士牵头担任主委和副主委。接下来国家癌症中心和国家肿瘤质控中心将从提升质控管理水平、开展抗肿瘤药物临床应用监测和落实肿瘤单病种质量控制工作方案等方面发力，进一步规范各级医疗机构诊疗活动，全面提高我国肿瘤诊疗水平。 肝癌是严重危害我国人民健康的恶性肿瘤，虽然近年来我国肝癌的诊治水平有了明显的提高，但总的五年生存率仍明显低于日本、韩国、美国等国家。提高我国肝癌诊治工作的规范化和同质化水平，是改善我国肝癌患者预后的重要手段和途径。国家癌症中心委托樊嘉院士担任主任委员的“国家癌症中心肝癌质控专家委员会”已于2021 年5 月15 日在北京正式成立，肝癌质控专委会将在国家癌症中心的领导下，团结全国从事肝癌诊治工作的各位同道，秉承“单病种、多学科”的质控原则，逐步构建和完善肝癌规范化诊疗的质控指标、标准和体系，将肝癌的多学科综合治疗与科学、合理的个体化方案有机结合，进一步提升我国肝癌的整体规范化诊疗水平和疗效。