Immune checkpoint inhibitors (ICIs) are among the most prominent immunotherapies for cancer and have been approved as first-line treatments for various tumors. Although some patients experience long-lasting responses, the objective response rate (ORR) of ICIs as monotherapy is relatively low due to the complexity of the tumor microenvironment and the heterogeneity of tumors. Maximizing the benefits of this novel therapeutic approach for a greater number of patients remains a research focus in the field of anticancer treatment. Here, we have investigated a novel Pt/Cu Dual-Atom Nanozyme (Pt/Cu DAzyme) which is engineered by the successive growth of metal-nanocrystals on the assembled surfactant templates. This DAzyme can significantly enhance the intracellular copper ion levels in tumor cells, inducing cuproptosis. Additionally, the Pt/Cu DAzyme exhibits excellent dual enzyme catalytic activity as both glutathione oxidase (GSHOx) and peroxidase (POD) activity, which not only reduces glutathione (GSH) levels in tumors to enhance cuproptosis but also converts intracellular H2O2 into center dot OH to kill tumor cells. Furthermore, the Pt/Cu DAzyme demonstrates a strong photothermal effect, with its enzymatic reactions being enhanced at mildly elevated temperatures. This DAzyme effectively kills tumors and activates the body's robust immune system, reshaping the tumor immune-suppressive microenvironment and significantly increasing the therapeutic response rate to alpha PD-L1. It not only achieves complete ablation of primary tumors but also markedly inhibits the progression of distal tumors and distant metastasis. This study aims to develop new combination therapy strategies to enhance the efficacy of ICIs and promote their advancement in the field of cancer immunotherapy.

Tumor cells can survive when detached from the extracellular matrix or lose cell-to-cell connections, leading to a phenomenon known as anoikis resistance (AR). AR is closely associated with the metastasis and proliferation of tumor cells, enabling them to disseminate, migrate, and invade after detachment. Here, we have investigated a novel composite nanoenzyme comprising mesoporous silica/nano-cerium oxide (MSN-Ce@SP/PEG). This nanoenzyme exhibited satisfactory catalase (CAT) activity, efficiently converting high levels of H2O2 within tumor cells into O2, effectively alleviating tumor hypoxia. Furthermore, MSN-Ce@SP/PEG nanoenzyme demonstrated high peroxidase (POD) activity, elevating reactive oxygen species (ROS) levels and attenuating AR in hepatocellular carcinoma (HCC) cells. The MSN-Ce@SP/PEG nanoenzyme exhibited satisfactory dual bioactivity in CAT and POD and was significantly enhanced under favorable photothermal conditions. Through the synergistic effects of these capabilities, the nanoenzyme disrupted the epithelial-mesenchymal transition (EMT) process in detached HCC cells, ultimately inhibiting the recurrence and metastasis potential of anoikis-resistant HCC cells. This study represents the first report of a novel nanoenzyme based on mesoporous silica/nano-cerium oxide for treating AR in HCC cells, thereby suppressing HCC recurrence and metastasis. The findings of this work offer a pioneering perspective for the development of innovative strategies to prevent the recurrence and metastasis of HCC.

Abstract Background Radical resection is still the most cost-effectiveness curative strategy for intrahepatic cholangiocarcinoma (ICC), but it remains controversial on the survival benefit of anatomic resection (AR). In this study, we sought to compare the oncologic outcomes between AR versus non-AR (NAR) as the primary treatment for early-stage ICC patients. Methods Data of ICC patients who underwent hepatectomy and staged at AJCC I were retrospectively collected from 12 hepatobiliary centers in China between Dec 2012 and Dec 2015. Propensity score matching (PSM) and stabilized inverse probability of treatment weighting (IPTW) analysis were performed to minimize the effect of potential confounders, and the perioperative and long-term outcomes between AR and NAR groups were compared. Results Two hundred seventy-eight ICC patients staged at AJCC I were eligible for this study, including 126 patients receiving AR and 152 patients receiving NAR. Compared to the NAR group, the AR group experienced more intraoperative blood loss before and after PSM or stabilized IPTW (all P > 0.05); AR group also experienced more intraoperative transfusion after stabilized IPTW (P > 0.05). In terms of disease-free survival (DFS) and overall survival (OS), no significant differences were observed between the two groups before and after PSM or stabilized IPTW (all P > 0.05). Multivariable Cox regression analyses found that AR was not an independent prognostic factor for either DFS or OS (all P > 0.05). Further analysis also showed that the survival benefit of AR was not found in any subgroup stratified by Child–Pugh grade (A or B), cirrhosis (presence or absence), tumor diameter (≤ 5 cm or > 5 cm) and pathological type (mass-forming or non-mass-forming) with all P > 0.05. Conclusion Surgical approach does not influence the prognosis of patients with stage I primary ICC, and NAR might be acceptable and oncological safety.

BackgroundThe clinical value of lymph-node dissection (LND) for intrahepatic carcinoma (ICC) patients with clinically negative lymph node metastasis (LNM) remains unclear; hence we conducted a multi-center study to explore it.MethodsPatients who were diagnosed ICC with clinically negative LNM and underwent hepatectomy with or without LND from December 2012 to December 2015 were retrospectively collected from 12 hepatobiliary centers in China. Overall survival (OS) was analyzed using the Kaplan–Meier method, and then subgroup analysis was conducted stratified by variables related to the prognosis.ResultsA total of 380 patients were eligible including 106 (27.9%) in the LND group and 274 (72.1%) in the non-LND group. Median OS in the LND group was slightly longer than that in the non-LND group (24.0 vs. 18.0 months, P = 0.30), but a significant difference was observed between the two groups (24.0 vs. 14.0 months, P = 0.02) after a well-designed 1:1 propensity score matching without increased severe complications. And, LND was identified to be one of the independent risk factors of OS (HR = 0.66, 95%CI = 0.46–0.95, P = 0.025). Subgroup analysis in the matched cohort showed that patients could benefit more from LND if they were male, age <60 years, had no HBV infection, with ECOG score <2, CEA ≤5 ug/L, blood loss ≤400 ml, transfusion, major hepatectomy, resection margin ≥1 cm, tumor size >5 cm, single tumor, mass-forming, no satellite, no MVI, and no perineural invasion (all P < 0.05). Furthermore, only patients with pathologically confirmed positive LNM were found to benefit from postoperative adjuvant therapy (P < 0.001).ConclusionWith the current data, we concluded that LND would benefit the selected ICC patients with clinically negative LNM and might guide the postoperative management.

Background The objective of this study was to investigate the survival outcomes of surgical margin width in intrahepatic cholangiocarcinoma (ICC). Methods Between November 2011 and August 2017, patients who underwent hepatectomy for ICC were collected from 13 major hepatopancreatobiliary centers in China. The survival outcomes for patients who underwent wide margin hepatectomy (WMH) were compared with those who underwent narrow margin hepatectomy (NMH) using the 1:1 propensity score matching (PSM). Results Among 478 included patients, 195 (40.8%) underwent WMH whereas 283 (59.2%) underwent NMH. PSM yielded 79 matched patients with similar baseline characteristics. Patients underwent WMH had a significant better OS and DFS compared with those underwent NMH (before PSM: median OS 27 vs 17 months, P < 0.05; median DFS 15 vs 8 months, P = 0.001, after PSM: median OS 41 vs 22 months, p < 0.05; median DFS 16 vs 10 months, p < 0.05). However, subgroup analysis based on the AJCC staging system, WMH could only improve the survival outcomes in AJCC I ICC patients (Stage I: OS, DFS, P <0.05). Conclusions Surgeons should strive to achieve a wide surgical margin for patients with AJCC I ICC to optimize the long-term outcome.

Objective To investigate the effect of wide surgical margin on the prognosis of patients with single intrahepatic cholangiocarcinoma (ICC) undergoing hepatectomy and the effect of microvascular invasion (MVI) on the treatment of hepatectomy with both wide surgical margin and narrow surgical margin. Methods From December 2011 to December 2017, the clinicopathological data of 302 patients with single ICC who underwent radical resection were retrospectively studied in 13 medical centers. According to the width of surgical margin, there were 126 patients (41.7%) in wide surgical margin group (≥1 cm) and 176 patients (58.3%) in narrow surgical margin group (<1 cm). Overall survival rate and disease-free survival rate of two groups were compared by Kaplan-Meier analysis. Subgroup analysis was conducted to compare the differences in prognosis of patients with different MVI. Results Using 1∶1 propensity score matching(PSM), 83 patients were in both wide surgical margin group and narrow surgical margin group, and there was no statistical difference in baseline data between two groups (all P>0.05). Disease-free survival rate in wide surgical margin group before PSM was significantly higher than that in narrow surgical margin group (P=0.005), while overall survival rate showed no statistically significant difference (P=0.053). After PSM, both overall survival rate and disease-free survival rate in wide surgical margin group were significantly higher than those in narrow surgical margin group (P<0.05). There was no statistically significant difference in both overall survival rate and disease-free survival rate among patients with MVI positive after liver resection with different surgical margins (P>0.05). In MVI negative group, however both overall survival rate and disease-free survival rate were significantly higher in the patients with wide surgical margin hepatectomy than in those with narrow surgical margin (P<0.05). Conclusions Wide surgical margin in hepatectomy can increase overall survival and disease-free survival in patients with single ICC, but does not improve prognosis when patients with MVI.

Although tumor‐specific neoantigen‐based cancer vaccines hold tremendous potential, it still faces low cross‐presentation associated with severe degradation via endocytosis pathway. Herein, a thiolated nano‐vaccine allowing direct cytosolic delivery of neoantigen and Toll like receptor 9 agonist CpG‐ODN is developed. This approach is capable of bypassing the endo‐/lysosome degradation, increasing uptake and local concentration of neoantigen and CpG‐ODN to activate antigen‐presenting cells, significantly strengthening the anti‐cancer T‐cell immunity. In vivo immunization with thiolated nano‐vaccine enhanced the lymph organ homing and promoted the antigen presentation on dendritic cells, effectively inhibited tumor growth, and significantly prolonged the survival of H22‐bearing mice. Strikingly, further combination of the thiolated nano‐vaccine with anti‐programmed cell death protein‐1 antibody ( α PD‐1) could efficiently reverse immunosuppression and enhance response rate of tumors, which led to enhanced tumor elimination, complete prevention of tumor re‐challenge, and long‐term survival above 150 d. Collectively, a versatile methodology to design cancer vaccines for strengthening anti‐cancer T‐cell immunity in solid tumors is presented, which could be further remarkably enhanced by combining with immune checkpoint inhibitors.

On-demand delivery of drug to deep tumor tissues with long-term tumor retention has directly influence on therapeutic efficiency and prognosis of patients, which still remains challenge in cancer therapy. Here we introduce metallo-supramolecular nanoflowers through multi-drugs and metal coordination effect for near-infrared (NIR) or acidic-triggered multi-drugs release, long-term accumulation at tumor tissues and NIR-II fluorescence imaging-guided photo-chemotherapy. The nanoflowers (refer to ICG EDOX) are constructed by (-)-epigallocatechin-3-gallate (EGCG), Cu2+ ions, indocyanine green (ICG) and doxorubicin hydrochloride (DOX) through coordination effect, ox-ox stacking and hydrophobic force. Due to strong intermolecular interaction, the ICG EDOX is superior stable in physiological conditions, while releases DOX/ICG on-demand upon the acidic/NIR laser irradiation. Moreover, ICG EDOX could penetrate deep tumor tissues with ultralong tumor retention (> 8 d) by microvesicle (MVs)-mediated intercellular interaction. Irradiated by 808 nm laser, the higher NIR-II fluorescence signal from ICG EDOX in tumors can effectively guide local phototherapy, and the synergistic therapeutic efficiency of nanoflowers with completely elimination of tumors is achieved in comparison with DOX or DOX/ICG treated 4T1-bearing mice. Overall, the excellent therapeutic effect of nanoflowers may hold great promise for the clinic translation.

BACKGROUND The objective of this study was to investigate the survival outcomes of surgical margin width in intrahepatic cholangiocarcinoma (ICC), and evaluate the efficacy of postoperative adjuvant therapy (p-AT) in ICC patients underwent narrow-margin hepatectomy (NMH).METHODS Between November 2011 and August 2017, patients who underwent hepatectomy for ICC were collected from 13 major hepatopancreatobiliary centers in China. The survival outcomes for patients who underwent wide margin hepatectomy (WMH) were compared with those who underwent NMH using the 1:1 propensity score matching (PSM). For patients who underwent NMH, the relationship between p-AT and overall survival (OS) and disease-free survival (DFS) were analyzed. RESULTS Among 478 included patients, 195(40.8%) underwent WMH whereas 283(59.2%) underwent NMH. PSM yielded 79 matched patients with similar baseline characteristics. Patients underwent WMH had a significant better OS and DFS compared with those underwent NMH (before PSM: Median OS 27 vs. 17 months, P <0.05; Median DFS 15 vs. 8 months, P = 0.001), (after PSM: Median OS 41 vs. 22 months, p <0.05; Median DFS 16 vs. 10 months, p <0.05). However, based on the AJCC staging system, WMH could only improve the survival outcomes in early ICC patients (Stage I: OS, DFS, P <0.05; Stage II: OS, DFS, P >0.05; Stage III: OS, DFS, P >0.05). For patient underwent NMH, p-AT following NMH showed a better OS and RFS when compared to those who underwent NMH alone (OS, P = 0.05; DFS, p <0.05). CONCLUSION With the current data, we suggest surgeons should strive to achieve a wide surgical margin for patients with early ICC to optimize the long-term outcome. The effect of p-AT for the outcome of ICC patients underwent NMH need to be explored further.

The rational design of nanoplatforms to bypass reticuloendothelial system (RES) clearance, enhance spatiotemporal controllability, and boost host immune responses to achieve synergized tumor-targeted therapeutic purpose is highly desired. Herein, a biomimetic nanosystem is developed for tumor-targeted in situ delivery of singlet oxygen (1O2) and carbon monoxide (CO) in response to exogenous stimulus ultrasound (US) and endogenous stimulus hydrogen peroxide (H2O2) in tumor microenvironment, respectively. Taking advantages of tumor homing and RES evasion abilities of the macrophage membrane coating, our designed nanosystem shows excellent accumulation at the tumor site and effective suppression of tumor growth through US/H2O2-generated 1O2 and CO to induce cell apoptosis and mitochondrial dysfunction. Furthermore, our nanosystem can induce significant tumor immunogenic death by 1O2/CO therapy, then can achieve effective immune responses and long-term immune memory through the combination of indoleamin 2,3-dioxygenase (IDO) signal blocking to effectively against tumor rechallenge and prevent lung metastasis. Taken together, the here-presented therapeutic strategy based on sonodynamic/CO therapy and IDO signaling inhibition might provide a promising perspective for synergistically treating cancer in future clinical translations.

目的 分析微血管侵犯(MVI)对肝内胆管癌(ICC)根治性切除病人预后的影响.方法 采用倾向评分匹配(PSM)及回顾性队列研究方法.搜集自2011年12月至2017年12月国内13家医疗中心(海军军医大学东方肝胆外科医院、浙江大学医学院附属第二医院、福建医科大学孟超肝胆医院、陆军军医大学西南医院、中国医学科学院北京协和医学院肿瘤医院、华中科技大学同济医学院附属同济医院、首都医科大学附属北京友谊医院、四川大学华西医院、上海交通大学医学院附属仁济医院、首都医科大学宣武医院、川北医学院附属医院、首都医科大学附属天坛医院、东南大学附属中大医院)收治的初诊为ICC病人的临床病理资料.其中男性202例,女性299例;中位年龄为57 (49 ～ 64)岁,年龄范围为23 ～ 88岁.根据术后病理学诊断是否合并MVI分为MVI组和Non-MVI组,其中MVI组61例、Non-MVI组440例.观察指标:(1)PSM前后两组病人基线资料比较.(2)生存分析:采用Kaplan-Meier法进行总体生存(OS)及无瘤生存(DFS)分析,COX回归分析影响ICC预后的独立危险因素.(3)MVI影响因素分析:Logistic回归分析MVI发生的独立危险因素.结果 (1)共纳入501例ICC根治性切除术后病人,MVI发生率为12.2％.经1:1PSM后,MVI组和Non-MVI组分别获得61例,两组之间基线资料差异无统计学意义(所有P＞ 0.05).(2)PSM前COX多因素分析结果显示:性别、肿瘤最大径、MVI、术后辅助治疗为OS的独立危险因素(HR=0.74,95％ CI 0.58～0.94, P=0.013;HR=1.43,95％ CI 1.11 ～ 1.83, P=0.006;HR=1.87,95％ CI 1.35～2.58,P＜0.01;HR=0.69,95％ CI 0.50～0.97,P=0.031).性别、切缘距离、病理学分型、肿瘤最大径、卫星灶、微血管侵犯为DFS的独立危险因素(HR=0.80,95％ CI 0.64～1.01,P=0.061;HR=1.40, 95％ CI 1.10～1.77,P=0.005;HR=1.51,95％ CI 1.08～2.12, P=0.017;HR=1.35,95％ CI 1.07～1.71, P=0.013;HR=1.74,95％ CI 1.21～2.52,P=0.003;HR=2.36,95％CI 1.73～3.21,P＜0.01).经1:1PSM,COX多因素分析结果显示:Child-Pugh分级、MVI为OS的独立危险因素(HR=1.75,95％ CI 1.03～2.99,P=0.039;HR=1.84,95％CI 1.17～2.90,P=0.008).病理学分型、MVI为DFS的独立危险因素(HR=1.93,95％ CI 1.08～3.44,P=0.027;HR=2.64,95％ CI 1.64～4.24,P＜0.01).(3)Kaplan-Meier分析显示,PSM前后MVI组总存活率和无瘤存活率显著低于Non-MVI组(所有P＜0.05).(4)PSM前,MVI组与Non-MVI组病人的复发率分别为88.5％、62.5％(P＜0.01).PSM后,MVI组与Non-MVI组病人的复发率分别为88.5％和50.8％ (P＜ 0.01).(5) Logistic多因素分析结果显示,ECOG评分＜2分(OR=0.49,95％ CI 0.27～0.87,P=0.014),Child-Pugh分级(OR=0.49,95％ CI 0.25～0.97,P=0.041),肿瘤分化程度(OR=1.85,95％ CI 1.01～3.39,P=0.046),肿瘤最大径(OR=2.19,95％ CI 1.18～4.08,P=0.014)及神经侵犯(OR=2.18,95％ CI 1.03～4.59,P=0.41)是MVI的独立影响因素.结论 MVI与ICC侵袭性特征及肿瘤复发相关,MVI是ICC根治术后预后不良的独立危险因素.

Efficient and cancer cell-targeted delivery of photosensitizer (PS) and therapeutic protein has great potentiality for improving the anticancer effects. Herein, zeolitic imidazolate framework-8 (ZIF-8) nanoparticles, one of the most attractive metal-organic framework materials, were used for coencapsulating the chlorin e6 (Ce6, a potent PS) and cytochrome c (Cyt c, a protein apoptosis inducer); then the nanoparticle was subsequently decorated with the hyaluronic acid (HA) shell to form cancer cell-active targeted nanoplatform (Ce6/Cyt c@ZIF-8/HA). The in vitro and in vivo experiments show the cancer cell targeting capability and pH-responsive decomposition and the release behavior of Ce6/Cyt c@ZIF-8/HA. Upon light irradiation, the released Ce6 produced cytotoxic reactive oxygen species for photodynamic therapy. Meanwhile, the released Cyt c-induced programmed cell death for protein therapy. Furthermore, the Cyt c worked normally under hypoxia conditions and could decompose H2O2 to O2 (with peroxidase-/catalase-like activity), resulting in synergistically improved therapeutic efficiency. These small molecules and protein codelivery nanoplatforms would promote the development of complementary and synergetic modes for biomedical applications.

Objective:To predict the efficacy of biliary drainage stenting (BDS) versus primary duct closure (PDC) alone after laparoscopic common bile duct exploration (LCBDE)using Bayesian network Meta analysis.Methods:Databases including PubMed, MedLine, Embase, the Cochrane Library, Web of Science, CNKI, Wanfang were searched for literatures from January.1st 1990 to January. 31st 2020 with the key words of ( "Choledocholithiasis" OR "common bile duct stone" OR "CBDS" OR "extrahepatic bile duct stone" ) AND ( "laparoscopic common bile duct exploration" OR "LCBDE" ) AND ( "primary duct closure" or "PDC" ) AND ( "T-tube drainage" or "TTD" or "T-tube" ) AND ( "biliary drainage stenting or BDS" ) AND ( "clinical trials" ),胆总管结石,腹腔镜胆总管探查, T管引流,一期缝合,胆道内支架引流. The randomized controlled trials (RCTs) about comparison of efficacy among BDS, PDC alone and T-tube drainage after LCBDE were received and included. BDS group included patients who underwent BDS after LCBDE, PDC group included patients who underwent PDC alone after LCBDE, and T-tube drainage group included patients who underwent T-tube drainage after LCBDE. The primary outcomes were the incidence of postoperative overall complications, bile leakage and residual stones. GeMTC software was used for Meta analysis in the Rstudio environment. This study was conducted using the random effects model in Bayesian network. The Markov Chain Monte Carlo was used for direct evaluation and indirect prediction. The Brooks-Gelman-Rubing graphing method, tracing method and density plotting were used to evaluate the model convergence. No closed loop formed between intervention measures, so there was no need to evaluate consistency. The matrix of rank probabilities in terms of the outcomes were also calculated.Results:(1) Document retrieval: a total of 12 available RCTs were enrolled. There were 982 patients, including 190 in the BDS group, 296 in the PDC group, and 496 in the T-tube drainage group. (2) Results of Bayesian network meta analysis. ① The BDS group and PDC group had lower overall complication rate than T-tube drainage group [ odds ratio ( OR)=0.21, 0.48, 95% confidence interval ( CI): 0.06-0.52, 0.24-0.87, P<0.05]. There was no significant difference in the indirectly predicted overall complication rate between the BDS group and PDC group ( OR=0.43, 95% CI: 0.12-1.30, P>0.05). ② The BDS group had lower incidence of postoperative bile leakage than T-tube drainage group ( OR=0.18, 95% CI: 0.02-0.86, P<0.05). There was no significant difference in the incidence of postoperative bile leakage between the PDC group and T-tube drainage group ( OR=0.70, 95% CI: 0.27-1.70, P>0.05). There was no significant difference in the indirectly predicted incidence of postoperative bile leakage between the BDS group and T-tube drainage group ( OR=0.25, 95% CI: 0.03-1.60, P>0.05). ③ T-tube drainage group had no significant difference in the incidence of postoperative residual stones compared with the BDS group and PDC group ( OR=0.58, 1.40, 95% CI: 0.13-2.40, 0.41-5.50, P>0.05). There was no significant difference in the indirectly predicted incidence of postoperative residual stones between the BDS group and PDC group ( OR=0.39, 95% CI: 0.05-2.70, P>0.05). (3) Ranking of the incidence of postoperative complication among the three groups: for the BDS group, PDC group, and T-tube drainage group, the probability of ranking the first in the incidence of overall complication was 0.08%, 0.98%, 98.94%, the probability of ranking the second was 6.57%, 92.38%, 1.05%, and the probability of ranking the third was 93.36%, 6.64%, 0.01%, respectively, showing the ranking list as T-tube drainage group >PDC group >BDS group in the incidence of overall complication. The probability of ranking the first in the incidence of postoperative bile leakage was 1.25%, 18.93%, 79.82% for the BDS group, PDC group, and T-tube drainage group, the probability of ranking the second was 6.11%, 74.01%, 19.88%, and the probability of ranking the third was 92.64%, 7.06%, 0.30%, respectively, showing the ranking list as T-tube drainage group >PDC group >BDS group in the incidence of postoperative bile leakage. The probability of ranking the first in the incidence of postoperative residual stones was 10.89%, 67.37%, 21.74% for the BDS group, PDC group, and T-tube drainage group, the probability of ranking the second was 16.09%, 21.09%, 62.82%, and the probability of ranking the third was 73.02%, 11.55%, 15.44%, respectively, showing the ranking list as PDC group >T-tube drainage group >BDS group in the incidence of postoperative residual stones. Conclusions:For patients with appropriate choledocholithiasis, BDS would be recommended first after LCBDE, which can reduce duct closure related complications. This study was registered at http: //www.crd.york.ac.uk/ero/, with the registration number of CRD42019137344.

Background and Aims: The prognosis of intrahepatic cholangiocarcinoma (ICC) after radical resection is far from satisfactory, but the effect of postoperative transarterial chemoembolization (p-TACE) remains controversial. This multi-center retrospective study was to evaluate the clinical value of p-TACE and identify the selected patients who would benefit from p-TACE. Methods: Data of ICC patients who underwent radical resection with/without p-TACE therapy was obtained from 12 hepatobiliary centers in China between Jan 2014 and Jan 2017. Overall survival (OS) was set as the primary endpoint, which was analyzed by the Kaplan-Meier method before and after propensity score matching (PSM). Subgroup analysis was conducted based on the established staging system and survival risk stratification. Results: A total of 335 patients were enrolled in this study, including 39 patients in the p-TACE group and 296 patients in the non-TACE group. Median OS in the p-TACE group was longer than that in the non-TACE group (63.0 months vs. 18.0 months, P=0.041), which was confirmed after 1:1 PSM (P=0.009). According to the 8th TNM staging system, patients with stage II and stage III stage would be benefited from p-TACE (P=0.021). Subgroup analysis stratified by risk factors showed that p-TACE could only benefit patients with risk factors <2 (P=0.027). Conclusion: Patients with ICC should be recommended to receive p-TACE following radical resection, especially for those with stage II, stage III or risk factors <2. However, the conclusion deserved further validation.

Immune cold tumor characterized by low immunogenicity, insufficient and exhausted tumor-infiltrating lymphocytes, and immunosuppressive microenvironment is the main bottleneck responsible for low patient response rate of immune checkpoint blockade. Here, we developed biosynthetic functional vesicles (BFVs) to convert immune cold into hot through overcoming hypoxia, inducing immunogenic cell death, and immune checkpoint inhibition. The BFVs present PD1 and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) on the surface, whereas load catalase into their inner core. The TRAIL can specifically induce immunogenic death of cancer cells to initiate immune response, which is further synergistically strengthened by blocking PD1/PDL1 checkpoint signal through ectogenic PD1 proteins on BFVs. The catalase can produce O2 to overcome tumor hypoxia, in turn to increase infiltration of effector T cells while deplete immunosuppressive cells in tumor. The BFVs elicit robust and systematic antitumor immunity, as demonstrated by significant regression of tumor growth, prevention of abscopal tumors, and excellent inhibition of lung metastasis.

AbstractHerein, we propose an aptamer‐equipping strategy to generate specific, universal and permeable (SUPER) NK cells for enhanced immunotherapy in solid tumors. NK cells were chemically equipped with TLS11a aptamer targeting HepG2 cells and PDL1‐specific aptamer without genetic alteration. The dual aptamer‐equipped NK cells exhibited high specificity to tumor cells, resulting in higher cytokine secretion and apoptosis/necrosis compared to parental or single aptamer‐equipped NK cells. Interestingly, dual aptamer‐equipped NK cells induced remarkable upregulation of PDL1 expression in HepG2 cells, enhancing checkpoint blockade. Furthermore, in vivo intravital imaging demonstrated high infiltration of aptamer‐equipped NK cells into deep tumor region, leading to enhanced therapeutic efficacy in solid tumors. This work offers a straightforward chemical strategy to equip NK cells with aptamers, holding considerable potential for enhanced adoptive immunotherapy in solid tumors.

Cancer-associated fibroblasts (CAFs) are crucial for forming the desmoplastic stroma that is associated with chemoresistance in pancreatic ductal adenocarcinoma (PDAC). In the clinic, depleting dense stroma in PDAC tumor tissue is a promising chemotherapeutic strategy. In this study, we report that the local hyperthermia can reduce the number of CAFs in the PDAC PDX mouse mode, which further augments chemotherapeutic efficiency in the PDAC therapy. To achieve this goal, a photothermal-chemotherapeutic agent termed as Abraxane@MoSe2 as a vehicle-saving theranostic probe is prepared by simply mixing an FDA-approved Abraxane and hydrophobic MoSe2 nanosheets via electrostatic and hydrophobic interactions. After labeling with indocyanine green (ICG) dye on the Abraxane@MoSe2, a relatively high fluorescence signal (near infrared second (NIR II)) in PDX tumors can be obtained, which can be precisely imaging-guide local photothermal-chemotherapy upon the 808 nm laser irradiation in vivo. Importantly, the synergy therapeutic efficiency in PDAC is enhanced by the photothermal effect reduction of the number of CAFs, which is confirmed viaα-SMA and vimentin immunofluorescence analysis. This combined therapeutic strategy may provide a new sight for PDAC therapy.

Objective To investigate the clinical value of lymph node dissection (LND) in the radical resection of intrahepatic cholangiocarcinoma (ICC).Methods The propensity score matching and retrospective cohort study was conducted.The clinicopathological data of 448 patients with ICC who were admitted to 12 medical centers from December 2011 to December 2017 were collected,including 279 in the Eastern Hepatobiliary Surgery Hospital of Navy Medical University,32 in the Mengchao Hepatobiliary Hospital of Fujian Medical University,21 in the First Hospital Affiliated to Army Medical University,20 in the Cancer Hospital Chinese Academy of Medical Science and Peking Union Medical College,19 in the West China Hospital of Sichuan University,18 in the Second Hospital Affiliated to Zhejiang University School of Medicine,18 in the Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine,16 in the Beijing Friendship Hospital Affiliated to Capital Medical University,10 in the Xuanwu Hospital Affiliated to Capital Medical University,7 in the Tongji Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology,5 in the Beijing Tiantan Hospital Affiliated to Capital Medical University,and 3 in the Affiliated Hospital of North Sichuan Medical College.There were 281 males and 167 females,aged from 22 to 80 years,with a median age of 57 years.Of the 448 patients,143 with routinely intraoperative LND were divided into LND group and 305 without routinely intraoperative LND were divided into control group,respectively.Observation indicators:(1) the propensity score matching conditions and comparison of general data between the two groups after matching;(2) intraoperative and postoperative situations;(3) follow-up;(4) survival analysis.Patients were followed up by outpatient examinafion,telephone interview and email to detect survival of patients and tumor recurrence up to October 31,2018 or death.Follow-up was conducted once every 3 months within postoperative 1-2 years,once every 6 months within postoperative 2-5 years,and once a year after 5 years.The propensity score matching was realized using the nearest neighbor method with 1∶1 ratio.Measurement data with normal distribution were represented as Mean±SD,and comparison between groups was analyzed using the t test.Measurement data with skewed distribution were represented as M (range),and comparison between groups was analyzed using the Mann-Whitney U test.Count data were described as absolute numbers,and comparison between groups was analyzed using the chi-square test or Fisher exact probability.Kaplan-Meier method was used to calculate survival rates and draw survival curve,and Log-rank test was used to perform survival analysis.Univariate analysis and multivaraiate analysis were conducted using the Log-rank test and COX regression model,respectively.Results (1) The propensity score matching conditions and comparison of general data between the two groups after matching:286 of 448 patients had successful matching,including 143 in each group.The number of males and females,cases with hepatitis,cases with grade A and B of Child-Pugh classification,cases with distance from margin to tumor ＜ 1 cm and ≥ 1 cm,cases with highly,moderately,and poorly differentiated tumor,cases with anatomical hepatectomy and nonanatomical hepatectomy before propensity score matching were 77,66,33,96,47,70,73,105,38,79,64 in the LND group,and 204,101,121,165,140,207,98,251,54,124,181 in the control group,respectively,showing significant differences in the above indices between the two groups (x2 =7.079,11.885,7.098,14.763,5.184,8.362,P＜0.05).After propensity score matching,the above indices were 77,66,33,96,47,70,73,105,38,79,64 in the LND group,and 79,64,29,88,55,71,72,112,31,74,69 in the control group,respectively,showing no significant difference in the above indices between the two groups (x2 =0.056,0.329,2.158,0.014,0.936,1.400,P＞0.05).(2) Intraoperative and postoperative situations:the operation time,volume of intraoperative blood loss,cases with intraoperative blood transfusion,cases with postoperative complications,and duration of postoperative hospital stay were 265 minutes (range,160-371 minutes),300 mL (range,200-500 mL),37,46,12 days (range,9-17 days) for the LND group,and 59 minutes (range,46-250 minutes),200 mL (range,100-400 mL),24,25,9 days (range,7-11 days) for the control group,respectively.There was no significant difference in the volume of intraoperative blood loss or cases with intraoperative blood transfusion between the two groups (Z =1.700,x2 =3.520,P ＞ 0.05).There were significant differences in the operation time,cases with postoperative complications,and duration of postoperative hospital stay (Z=6.520,x2=8.260,Z=4.270,P＜0.05).(3) Follow-up:143 patients in the LND group was followed up for 18-26 months.The 1-,3-,5-year survival rates were 66.9％,32.8％,25.0％,and the median survival time was 22.0 months (range,18.0-26.0 months).In the control group,143 patients were followed up for 11-32 months.The 1-,3-,5-year survival rates were 71.7％,38.0％,31.0％,and the median survival time was 22.0 months (range,11.0-32.0 months).There was no significant difference in the overall survival between the two groups (x2 =0.466,P＞0.05).(4) Survival analysis:results of univariate analysis showed that distance from margin to tumor,tumor diameter,the number of tumors,microvascular tumor thrombus,and lymph node metastasis by pathological examination were related factors for prognosis of patients undergoing radical resection of ICC (x2 =10.662,9.477,16.944,6.520,11.633,P＜0.05).Results of multivariate analysis showed that distance from margin to tumor＜ 1 cm,tumor diameter＞5 cm,multiple tumors,microvascular tumor thrombus,positive lymph node metastasis by pathological examination were independent risk factors for prognosis of patients undergoing radical resection of ICC (hazard ratio =0.600,1.571,1.601,1.750,1.723,95％ confidence interval:0.430-0.837,1.106-2.232,1.115-2.299,1.083-2.829,1.207-2.460,P＜0.05).Conclusion Lymph node metastasis is an independent risk factor affecting the prognosis of ICC patients,and it is necessary to perform LND in radical resection for patients with ICC and lymph node metastasis.