Anatomic versus non-anatomic resection for early-stage intrahepatic cholangiocarcinoma: a propensity score matching and stabilized inverse probability of treatment weighting analysis.

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.

Impact of surgical margin width on long-term outcomes for intrahepatic cholangiocarcinoma: a multicenter study.

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.

Prognostic Value of Lymph Node Dissection for Intrahepatic Cholangiocarcinoma Patients With Clinically Negative Lymph Node Metastasis: A Multi-Center Study From China.

BACKGROUND: The 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. METHODS: Patients 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. RESULTS: A 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). CONCLUSION: With the current data, we concluded that LND would benefit the selected ICC patients with clinically negative LNM and might guide the postoperative management.

Cytosolic Delivery of Thiolated Neoantigen Nano-Vaccine Combined with Immune Checkpoint Blockade to Boost Anti-Cancer T Cell Immunity.

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 (αPD-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.

Cancer Cell-Targeted Photosensitizer and Therapeutic Protein Co-Delivery Nanoplatform Based on a Metal-Organic Framework for Enhanced Synergistic Photodynamic and Protein Therapy.

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.

Converting Immune Cold into Hot by Biosynthetic Functional Vesicles to Boost Systematic Antitumor Immunity.

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.

Ultrasound-Driven Biomimetic Nanosystem Suppresses Tumor Growth and Metastasis through Sonodynamic Therapy, CO Therapy, and Indoleamine 2,3-Dioxygenase Inhibition.

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.

Adjuvant transarterial chemoembolization following radical resection for intrahepatic cholangiocarcinoma: A multi-center retrospective study.

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.

Photothermal augment stromal disrupting effects for enhanced Abraxane synergy chemotherapy in pancreatic cancer PDX mode.

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.

Equipping Natural Killer Cells with Specific Targeting and Checkpoint Blocking Aptamers for Enhanced Adoptive Immunotherapy in Solid Tumors.

Herein, 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.

Artificial Engineered Natural Killer Cells Combined with Antiheat Endurance as a Powerful Strategy for Enhancing Photothermal-Immunotherapy Efficiency of Solid Tumors.

Although photothermal therapy (PTT) is preclinically applied in solid tumor treatment, incomplete tumor removal of PTT and heat endurance of tumor cells induces significant tumor relapse after treatment, therefore lowering the therapeutic efficiency of PTT. Herein, a programmable therapeutic strategy that integrates photothermal therapeutic agents (PTAs), DNAzymes, and artificial engineered natural killer (A-NK) cells for immunotherapy of hepatocellular carcinoma (HCC) is designed. The novel PTAs, termed as Mn-CONASHs, with 2D structure are synthesized by the coordination of tetrahydroxyanthraquinone and Mn2+ ions. By further adsorbing polyetherimide/DNAzymes on the surface, the DNAzymes@Mn-CONASHs exhibit excellent light-to-heat conversion ability, tumor microenvironment enhanced T1 -MRI guiding ability, and antiheat endurance ability. Furthermore, the artificial engineered NK cells with HCC specific targeting TLS11a-aptamer decoration are constructed for specifically eliminating any possible residual tumor cells after PTT, to systematically enhance the therapeutic efficacy of PTT and avoid tumor relapse. Taken together, the potential of A-NK cells combined with antiheat endurance as a powerful strategy for immuno-enhancing photothermal therapy efficiency of solid tumors is highlighted, and the current strategy might provide promising prospects for cancer therapy.

Photocatalysis Enhancement for Programmable Killing of Hepatocellular Carcinoma through Self-Compensation Mechanisms Based on Black Phosphorus Quantum-Dot-Hybridized Nanocatalysts.

Recently reported black phosphorus quantum dots (BPQDs) possess unique photocatalysis activities. However, the environmental instability accompanied by a hypoxic tumor microenvironment (TME) seriously hindered the bioapplications of BPQDs, especially in oxygen-dependent photodynamic therapy (PDT). Here, we construct a hepatocellular carcinoma (HCC)-specific targeting aptamer "TLS11a"-decorated BPQDs-hybridized nanocatalyst, which can specifically target HCC tumor cells and self-compensate oxygen (O2) into hypoxic TME for enhancing PDT efficiency. The BPQD-hybridized mesoporous silica framework (BMSF) with in situ synthesized Pt nanoparticles (PtNPs) in the BMSF is simply prepared. After being decorated by TLS11a aptamer/Mal-PEG-NHS, the resultant nanosystem (refer as Apt-BMSF@Pt) exhibits excellent environmental stability, active targeting ability to HCC cells, and self-compensation ability of oxygen. Compared with the PEG-BMSF@Pt without H2O2 incubation, the PEG-BMSF@Pt nanocatalyst exhibits 4.2-folds O2 and 1.6-folds 1O2 generation ability in a mimetic closed-system in the presence of both H2O2 and near-infrared laser. In a mouse model, the Apt-BMSF@Pt can effectively accumulate into tumor sites, and the core of BMSF subsequently can act as a photosensitizer to generate reactive oxygen species, while the PtNPs can serve as a catalyst to convert H2O2 into O2 for enhancing PDT through self-compensation mechanisms in hypoxic TME. By comparison of the tumor volume/weight, H&E, and immunohistochemical analysis, the excellent antitumor effects with minimized side effects of our Apt-BMSF@Pt could be demonstrated in vivo. Taken together, the current study suggests that our Apt-BMSF@Pt could act as an active targeting nanocatalyst for programmable killing of cancer cells in hypoxic TME.

Ultrasound-induced reactive oxygen species generation and mitochondria-specific damage by sonodynamic agent/metal ion-doped mesoporous silica.

Designing tumor microenvironment (TME)-specific active nanoparticles with minimum side effects for synergistic cancer therapy has become a hot topic in the recent decades. Aiming at further enhancing the therapeutic efficacy, an in situ-induced mitochondrial dysfunction is a very promising strategy. To achieve these goals, a nano-sono-chemodynamic agent denoted as TPP-Cu@HMS, which integrated hematoporphyrin monomethyl ether (HMME), mPEG-NHS, triphenylphosphonium (TPP)-decorated mesoporous silica (MS) and coordinatively bound Cu2+ ions for mitochondria-specific sonodynamic-chemodynamic therapy (SDT-CDT) of cancer, was designed. Upon the ultrasound (US) treatment, TPP-Cu@HMS can specifically target mitochondria and in situ generate 1O2 against cancer cells. Specifically, to overcome the short lifespan of 1O2, the released Cu2+ ions from TPP-Cu@HMS could act as a Fenton-like agent to convert endogenous H2O2 to ·OH in the acidic environment of cancer cells, disrupt the mitochondrial membrane potential and lead to mitochondrial disintegration, which could systematically enhance the therapeutic efficiency of SDT. Therefore, we highlight the current strategy as a promising prospect for cancer therapy.