In vivo tumor ultrasound-switchable fluorescence imaging via intravenous injections of size-controlled thermosensitive nanoparticles.

Near-infrared fluorescence imaging has emerged as a noninvasive, inexpensive, and ionizing-radiation-free monitoring tool for assessing tumor growth and treatment efficacy. In particular, ultrasound switchable fluorescence (USF) imaging has been explored with improved imaging sensitivity and spatial resolution in centimeter-deep tissues. This study achieved size control of polymer-based and indocyanine green (ICG) encapsulated USF contrast agents, capable of accumulating at the tumor after intravenous injections. These nanoprobes varied in size from 58 nm to 321 nm. The bioimaging profiles demonstrated that the proposed nanoparticles can efficiently eliminate the background light from normal tissue and show a tumor-specific fluorescence enhancement in the BxPC-3 tumor-bearing mice models possibly via the enhanced permeability and retention effect. In vivo tumor USF imaging further proved that these nanoprobes can effectively be switched 'ON' with enhanced fluorescence in response to a focused ultrasound stimulation in the tumor microenvironment, contributing to the high-resolution USF images. Therefore, our findings suggest that ICG-encapsulated nanoparticles are good candidates for USF imaging of tumors in living animals, indicating their great potential in optical tumor imaging in deep tissue.

Interstitial fluid streaming in deep tissue induced by ultrasound momentum transfer for accelerating nanoagent transport and controlling its distribution.

Objective.This study aims to theoretically investigate the dynamics of ultrasound-induced interstitial fluid streaming and tissue recovery after ultrasound exposure for potentially accelerating nanoagent transport and controlling its distribution in tissue.Approach.Starting from fundamental equations, the dynamics of ultrasound-induced interstitial fluid streaming and tissue relaxation after an ultrasound exposure were modeled, derived and simulated. Also, both ultrasound-induced mechanical and thermal effects were considered in the models.Main results.The proposed new mechanism was named squeezing interstitial fluid via transfer of ultrasound momentum (SIF-TUM). It means that an ultrasound beam can squeeze the tissue in a small focal volume from all the directions, and generate a macroscopic streaming of interstitial fluid and a compression of tissue solid matrix. After the ultrasound is turned off, the solid matrix will recover and can generate a backflow. Rather than the ultrasound pressure itself or intensity, the streaming velocity is determined by the dot product of the ultrasound pressure gradient and its conjugate. Tissue and nanoagent properties also affect the streaming and recovery velocities.Significance.The mobility of therapeutic or diagnostic agents, such as drugs, drug carriers, or imaging contrast agents, in the interstitial space of many diseased tissues, such as tumors, is usually extremely low because of the inefficiency of the natural transport mechanisms. Therefore, the interstitial space is one of the major barriers hindering agent deliveries. The ability to externally accelerate agent transport and control its distribution is highly desirable. Potentially, SIF-TUM can be a powerful technology to accelerate agent transport in deep tissue and control the distribution if appropriate parameters are selected.

Thermo- and pH-sensitive nanoparticles of poly (N-isopropylacrylamide-decenoic acid-1-vinylimidazole) for ultrasound switchable fluorescence imaging.

We herein report the synthesis of poly (9-decenoic acid-1-vinylimidazole-N-isopropylacrylamide) nanoparticles containing indocyanine green (ICG) in one pot and in water phase throughout the reaction. We have shown that copolymers of 9-decenoic acid and 1-vinylimidazole, or 9-decenoic acid alone, have an enhanced sensitivity to pH values between 7.4 and 6.8 and are superior to the widely used acrylic acid. We have also shown that incorporation of acidic comonomers leads to the favorable outcome of a higher fluorescence signal intensity in lower pH values, whereas the opposite is true of basic comonomers, where the fluorescence signal intensity is lower at low pH values. It was shown that to keep the pH response favorable the molar ratio of basic comonomers to acidic comonomers should roughly equal 1:4. We controlled the lower critical solution temperature (LCST) of the nanoparticles from around 30 to 38°C for different applications by adding acrylamide comonomers. Finally, the nanoparticles at varying pH values, when imaged by an ultrasound switchable fluorescence (USF) imaging system, showed pH sensitivity and thermosensitivity at physiological and tumor pH.

Repeat hepatic resection versus percutaneous ablation for the treatment of recurrent hepatocellular carcinoma: meta-analysis.

BACKGROUND: The efficacy of repeat hepatic resection (rHR) in the treatment of recurrent hepatocellular carcinoma compared with radiofrequency or microwave ablation after resection of the primary tumour remains controversial. A systematic review and meta-analysis were performed to compare the safety and efficacy of these procedures. METHODS: PubMed, Embase, Scopus, Cochrane Library, and China National Knowledge Infrastructure databases were systematically searched to identify related studies published before 10 October 2021. Overall and recurrence-free survival after different treatments were compared based on pooled hazard ratios with a random-effects model. RESULTS: Two randomized clinical trials and 28 observational studies were included, involving 1961 and 2787 patients who underwent rHR and ablation respectively. Median perioperative mortality in both groups was zero but patients in the rHR group had higher median morbidity rates (17.0 per cent) than those in the ablation group (3.3 per cent). rHR achieved significantly longer recurrence-free survival than ablation (HR 0.79, 95 per cent c.i. 0.70 to 0.89, P < 0.001), while both groups had similar overall survival (HR 0.93, 95 per cent c.i. 0.83 to 1.04, P = 0.18). CONCLUSION: rHR and ablation based on radio- or microwaves are associated with similar overall survival in patients with recurrent hepatocellular carcinoma after resection of the primary tumour.

Effect of Thoracic Paravertebral Nerve Block on Blood Coagulation in Patients After Thoracoscopic Lobectomy: A Prospective Randomized Controlled Clinical Trial.

PURPOSE: Ultrasound-guided thoracic paravertebral block (TPVB) has become increasingly popular for postoperative analgesia after thoracic surgery. We designed this prospective, randomized, double-blind, placebo-controlled trial to investigate the effect of TPVB on blood coagulation in patients after thoracoscopic lobectomy. PATIENTS AND METHODS: Sixty patients scheduled for thoracoscopic lobectomy were randomly allocated to two groups. Patients underwent ultrasound-guided TPVB with 0.33% ropivacaine (T group) or 0.9% saline (C group) at the end of the surgery under general anesthesia. Patient-controlled intravenous analgesia (PCIA) was administered for both group after the surgery. The primary outcome was the thromboelastogram (TEG) parameters before anesthesia (T0), at the end of operation (T1) and in 1 day (T2) and 2 days (T3) after the operation, the second outcomes were the analgesic effect and the amount of intraoperative opioid consumption, operation time, infusion volume, blood loss and urine volume. RESULTS: The visual analog scale (VAS) scores in group T were lower than group C (P < 0.05). In group T, compared with T0, the R value at T1 and T2 is significantly reduced, and the K value at T1 were significantly shortened, the α-angle and MA value at T1 were significantly increased (P < 0.05). In group C, compared with T0, the R value and K value were significantly shortened, the α-angle and MA value were significantly increased at all postoperative time points (P < 0.05). Compared with group C at the same time point, the R and K values of group T were significantly longer, and the α-angle and MA values were significantly reduced at T2 and T3 points, with statistically significant differences (P<0.05). CONCLUSION: TPVB is beneficial to improve postoperative hypercoagulability and promote postoperative rehabilitation of patients after thoracoscopic lobectomy.

Lower risk of hepatocellular carcinoma with tenofovir than entecavir treatment in subsets of chronic hepatitis B patients: an updated meta-analysis.

BACKGROUND AND AIM: Previous smaller meta-analyses comparing the incidence of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients treated with tenofovir disoproxil fumarate (TDF) versus entecavir (ETV) provided controversial results. This updated meta-analysis aimed to reliably identify any difference in the HCC incidence between TDF-treated or ETV-treated CHB patients in general or in specific subgroups. METHODS: PubMed, EMBASE, Web of Science, and Cochrane Library were systematically searched for relevant studies with hazard ratios (HRs) for HCC between TDF-treated and ETV-treated CHB patients. Retrieved dates ranged from January 2009 to October 2021. HRs with or without adjustment were pooled with random-effects model. RESULTS: Twenty-four comparative studies involving 37 771 CHB patients treated with TDF and 72 094 treated with ETV were included. TDF was associated with lower risk of HCC compared with ETV, with pooled unadjusted HR of 0.76 (95% confidence interval [CI]: 0.67-0.86) (24 studies) and adjusted HR of 0.81 (95% CI: 0.72-0.91) (21 studies). In propensity score matching cohorts, the TDF superiority was confirmed for unadjusted HR 0.83 (95% CI: 0.71-0.97) (14 studies) and was close to significance for adjusted HR (0.78, 95% CI: 0.58-1.04) (8 studies). Subgroup analyses showed that TDF was associated with lower HCC risk than ETV treatment in CHB patients who were from Asia (adjusted HR: 0.76, 95% CI: 0.66-0.87; 15 studies) or nucleos(t)ide naïve (adjusted HR:0.74, 95% CI: 0.65-0.84; 18 studies). CONCLUSION: Current evidence from a sizable population suggests that TDF is associated with significantly lower HCC risk compared with ETV treatment in patients who are from Asia and/or nucleos(t)ide naïve.

Calcium Channel Protein ORAI1 Mediates TGF-ß Induced Epithelial-to-Mesenchymal Transition in Colorectal Cancer Cells.

Accumulating evidence suggested that calcium release-activated calcium modulator 1(ORAI1), a key calcium channel pore-forming protein-mediated store-operated Ca2+ entry (SOCE), is associated with human cancer. However, its role in colorectal cancer (CRC) progression has not been well studied. Epithelial-mesenchymal transition (EMT) is a multistep process that occurs during the progression of cancers and is necessary for metastasis of epithelial cancer. Transforming growth factor-ß (TGF-ß) is a pleiotropic cytokine that has been shown to induce EMT. In this study, we are aimed at exploring the effects of ORAI1 on TGF-ß1-induced EMT process in CRC cells. Herein, we confirmed ORAI1 expression was higher in CRC tissues than in adjacent non-cancerous tissues by using immunohistochemical staining and Western blot analysis. Higher ORAI1 expression was associated with more advanced clinical stage, higher incidence of metastasis and shorter overall survival. We compared ORAI1 expression in SW480 and SW620 cells, two CRC cell lines with the same genetic background, but different metastatic potential. We found ORAI1 expression was significantly higher in SW620 cells which exhibited higher EMT characteristics. Furthermore, knockdown of ORAI1 suppressed the EMT of SW620 Cells. After induced the EMT process in SW480 cells with TGF-ß1, we found treatment of TGF-ß1 showed a significant increase in cell migration along with the loss of E-cadherin and an increase in N-cadherin and Vimentin protein levels. Also, TGF-ß1 treatment increased ORAI1 expression and was closely associated with the increase of SOCE. Silencing ORAI1 significantly suppressed Ca2+ entry, reversed the changes of EMT-relevant marks expression induced by TGF-ß1, and inhibited TGF-ß1-mediated calpain activation and cell migration. Finally, we blocked SOCE with 2-APB (2-Aminoethyl diphenylborinate), a pharmacological inhibitor. Interestingly, 2-APB and sh-ORAI1 both exhibited similar inhibition effects to the SW480 cells. In conclusion, our results demonstrated that ORAI1 could mediate TGF-ß-Induced EMT by promoting Ca2+ entry and calpain activity in Colorectal Cancer Cells.

Improving sensitivity and imaging depth of ultrasound-switchable fluorescence via an EMCCD-gain-controlled system and a liposome-based contrast agent.

BACKGROUND: The ultrasound-switchable fluorescence (USF) technique was recently developed to achieve high-resolution fluorescence imaging in centimeters-deep tissue. This study introduced strategies to significantly improve imaging sensitivity and depth using an electron multiplying charge-coupled device (EMCCD) camera-based USF imaging system and a newly developed USF contrast agent of indocyanine green (ICG)-encapsulated liposomes. For a quantitative study, a phantom of a sub-millimeter silicone tube embedded in centimeter-thick chicken breast tissue was adopted in this study as a model. METHODS: The synthesized ICG-liposome was characterized and compared with the previously reported ICG-nanogel. The exposure of the EMCCD camera was controlled via the MATLAB (The MathWorks, Inc. USA), instead of an external hardware trigger. The stability of the electron multiplying (EM) gain of the EMCCD camera was compared between two trigger modes: the MATLAB trigger mode and the external hardware trigger mode. The signal-to-noise ratio (SNR) of the USF imaging with different EM gain in various thick tissue was studied. RESULTS: The hydrodynamic size of the ICG-liposome was ~181 nm. The ICG-liposome had a sharper temperature switching curve and a better USF performance than the previously reported ICG-nanogel. The EM gain was more stable in MATLAB trigger mode than the external hardware trigger mode. Although, as usual, the SNR decreased quickly with the increase of the tissue thickness, the proposed strategies improved the SNR and the imaging depth significantly by adopting the novel contrast agent and controlling the EM gain. CONCLUSIONS: We successfully imaged the sub-millimeter silicone tube with an inner diameter of 0.76 mm and an outer diameter of 1.65 mm in 5.5 cm-thick chicken breast tissue using 808 nm excitation light with a low intensity of 28.35 mW/cm2, the improved EMCCD camera-based USF imaging system and the novel ICG-liposomes.

Near-infrared temperature-switchable fluorescence nanoparticles.

BACKGROUND: Near infrared (NIR) environment-sensitive fluorophores are highly desired for many biomedical applications because of its non-invasive operation, high sensitivity and specificity, non-ionizing radiation and deep penetration in biological tissue. When the fluorophores are appropriately encapsulated in or conjugated with some thermal-sensitive polymers, they could work as excellent temperature-sensing probes. METHODS: In this study, we synthesized and characterized a series of NIR temperature-switchable nanoparticles based on two series of NIR fluorophores aza-BODIPY (ADP is used for abbreviation in this work) and Zinc phthalocyanine (ZnPc) and four pluronic polymers (F127, F98, F68 and F38). Encapsulating the fluorophores in the polymers by sonication, we synthesized the nanoparticles that showed switch-like functions of the fluorescence intensity (and/or lifetime) as the temperature, with high switch on-to-off ratio. We also investigated various factors that might change the temperature thresholds (Tth) of the switch functions, in order to control Tth during synthesis. RESULTS: These nanoparticles showed excellent temperature-switchable properties of fluorescence intensity and/or lifetime. Meanwhile, some factors (i.e., pluronic categories and nanoparticles' concentration) significantly affected the nanoparticles' Tths while other (i.e., fluorophore categories) that weakly affected Tths. CONCLUSIONS: By selecting appropriate pluronic categories and adjusting the nanoparticle's concentration, we can synthesize the nanoparticles with a wide range of Tths. These temperature-switchable fluorescence nanoparticles can be used for biomedical imaging and in vivo tissue temperature sensing/imaging.

In vivo ultrasound-switchable fluorescence imaging using a camera-based system.

Ultrasound-switchable fluorescence (USF) is a novel imaging technique that provides high spatial resolution fluorescence images in centimeter-deep biological tissue. Recently, we successfully demonstrated the feasibility of in vivo USF imaging using a frequency-domain photomultiplier tube-based system. In this work, for the first time we carried out in vivo USF imaging via a camera-based USF imaging system. The system acquires a USF signal on a two-dimensional (2D) plane, which facilitates the image acquisition because the USF scanning area can be planned based on the 2D image and provides high USF photon collection efficiency. We demonstrated in vivo USF imaging in the mouse's glioblastoma tumor with multiple targets via local injection. In addition, we designed the USF contrast agents with different particle sizes (70 nm and 330 nm) so that they could bio-distribute to various organs (spleen, liver, and kidney) via intravenous (IV) injections. The results showed that the contrast agents retained stable USF properties in tumors and some organs (spleen and liver). We successfully achieved in vivo USF imaging of the mouse's spleen and liver via IV injections. The USF imaging results were compared with the images acquired from a commercial X-ray micro computed tomography (micro-CT) system.

Recruitment of endogenous progenitor cells by erythropoietin loaded particles for in situ cartilage regeneration.

Cartilage injury affects millions of people throughout the world, and at this time there is no cure. While transplantation of stem cells has shown some success in the treatment of injured cartilage, such treatment is limited by limited cell sources and safety concerns. To overcome these drawbacks, a microscaffolds system was developed capable of targeting, reducing the inflammatory response and recruiting endogenous progenitor cells to cartilage-defect. Erythropoietin (EPO)-loaded-hyaluronic acid (HA) microscaffolds (HA + EPO) were fabricated and characterized. HA-microscaffolds showed good cell-compatibility and could target chondrocytes via CD44 receptors. HA + EPO was designed to slowly release EPO while recruiting progenitor cells. Finally, the ability of HA + EPO to repair cartilage-defects was assessed using a rabbit model of full-thickness cartilage-defect. Our results showed that the intra-articular administration of EPO, HA, and EPO + HA reduced the number of inflammatory cells inside the synovial-fluid, while EPO + HA had the greatest anti-inflammatory effects. Furthermore, among all groups, EPO + HA achieved the greatest progenitor cell recruitment and subsequent chondrogenesis. The results of this work support that, by targeting and localizing the release of growth-factors, HA + EPO can reduce inflammatory responses and promote progenitor cells responses. This new platform represents an alternative treatment to stem-cell transplantation for the treatment of cartilage injury.

In vivo ultrasound-switchable fluorescence imaging.

The conventional fluorescence imaging has limited spatial resolution in centimeter-deep tissue because of the tissue's high scattering property. Ultrasound-switchable fluorescence (USF) imaging, a new imaging technique, was recently proposed to realize high-resolution fluorescence imaging in centimeter-deep tissue. However, in vivo USF imaging has not been achieved so far because of the lack of stable near-infrared contrast agents in a biological environment and the lack of data about their biodistributions. In this study, for the first time, we achieved in vivo USF imaging successfully in mice with high resolution. USF imaging in porcine heart tissue and mouse breast tumor via local injections were studied and demonstrated. In vivo and ex vivo USF imaging of the mouse spleen via intravenous injections was also successfully achieved. The results showed that the USF contrast agent adopted in this study was very stable in a biological environment, and it was mainly accumulated into the spleen of the mice. By comparing the results of CT imaging and the results of USF imaging, the accuracy of USF imaging was proved.

Interleukin-33 regulates hematopoietic stem cell regeneration after radiation injury.

BACKGROUND: IL-33 is a pleiotropic cytokine of the IL-1 family, which has been reported to implicate in both innate and adaptive immune responses. Recent studies suggest IL-33 is crucial for regulation of myelopoiesis and myeloid cell activity. Here, we explore the potential effect of IL-33 against hematopoietic injury after total body irradiation (TBI). METHODS: C57BL/6 mice were irradiated with a sublethal dose of radiation (600 cGy) and treated with IL-33 at a dose of 3 µg/dose i.p. once a day for seven consecutive days. H&E staining was used to determine the bone marrow cellularity. A flow cytometer was used to quantify the hematopoietic stem cell (HSC) population, cell proliferation, and apoptosis. The colony-forming assay was used to evaluate the clonogenic function of HSCs. RT-qPCR was used to determine the expression of apoptosis-associated genes. RESULTS: Bone marrow HSCs from wild-type mice expressed functional IL-33 receptor (ST2), and treatment with IL-33 promoted the recovery of the HSC pool in vivo and improved the survival of mice after TBI. Conversely, mice with ST2 deficiency showed decreased HSC regeneration and mouse survival after TBI. Of note, IL-33 reduced radiation-induced apoptosis of HSCs and mediated this effect through repression of the p53-PUMA pathway. CONCLUSIONS: IL-33 regulates HSC regeneration after myelosuppressive injury through protecting HSCs from apoptosis and enhancing proliferation of the surviving HSCs.

Perioperative entecavir for patients with HBV-related hepatocellular carcinoma and low levels of viral DNA: analysis using propensity score matching.

The safety and efficacy of perioperative antiviral therapy for patients with hepatitis B virus related hepatocellular carcinoma and low serum levels of hepatitis B virus DNA are unknown. This retrospective study compared serum levels of hepatitis B virus DNA, liver function, morbidity, and length of hospital stay between patients who underwent hepatic resection alone and patients who received entecavir therapy before and after resection (n = 44 in each group). Propensity score matching was used to reduce confounding due to baseline differences between the groups. Hepatitis B virus reactivation during follow-up, which lasted a median of 6.1 months, occurred in one patient in the entecavir group (2.3%) and 11 patients in the resection-only group (25%; P = 0.02). Liver function, especially alanine aminotransferase levels, recovered much faster in the entecavir group. This group also showed a slightly lower rate of morbidity (P = 0.081) as well as significantly shorter overall hospital stay (20.1 ± 4.9 vs 24.9 ± 13.2 days; P = 0.028) and postoperative hospital stay (11.4 ± 1.9 vs 16.8 ± 13.1 days; P = 0.008). These results from this pilot study suggest that patients with hepatitis B virus related hepatocellular carcinoma and low levels of hepatitis B virus DNA are at risk of hepatitis B virus reactivation following resection, and that perioperative entecavir therapy can safely and effectively reduce this risk. Such therapy also appears to improve liver function and shorten hospitalization.

Modulation of ultrasound-switchable fluorescence for improving signal-to-noise ratio.

Simultaneously achieving high signal-to-noise ratio (SNR) (or sensitivity) and high resolution is desired in biomedical imaging. However, conventional imaging modality has a tradeoff between SNR (or sensitivity) and resolution. We developed a method to simultaneously achieve high SNR (or sensitivity) and high resolution for fluorescence imaging in deep tissue. We first introduce a recently developed deep-tissue high-resolution imaging technique termed as ultrasound-switchable fluorescence (USF). An approach of modulating ultrasound exposure time is adopted to increase the detectability of the USF signal. The control parameters of modulation of ultrasound­such as (1) frequency, (2) duty cycle, and (3) exposure duration­are varied to study their influence on the USF signal and SNR. We conclude that high SNR can be achieved by modulating ultrasound exposure without sacrificing the spatial resolution. This is important for future fluorescence molecular imaging of cancer in deep tissue.

IL-33 improves wound healing through enhanced M2 macrophage polarization in diabetic mice.

IL-33 is a newly discovered member of the IL-1 family and has been identified as a potent inducer of Th2 type immunity. Emerging evidence imply that IL-33 may also act as an alarm to alert the immune system when released by epithelial barrier tissues during trauma or infection. In this study, we further investigate the potential efficacy of IL-33 on dermal wound healing in streptozotocin-induced diabetic mice. A full-thickness skin wound was generated on the back of diabetic mice and treated with IL-33 or vehicle topically. Our data showed that IL-33 delivery contributed to diabetic wound closure with wounds gaping narrower and exhibiting elevated re-epithelialization. IL-33 promoted the new extracellular matrix (ECM) deposition and angiogenesis formation, which indicates an important role of IL-33 on matrix synthesis and neovascularization. Meanwhile, IL-33 accelerated the development of M2 macrophages in wound sites in vivo, and amplified IL-13-induced polarization of bone marrow-derived macrophages toward a M2 phenotype in vitro. Furthermore, IL-33-amplified M2 macrophages augmented the proliferation of fibroblasts and ECM deposition. All together, these results strongly suggest manipulation of IL-33-mediated signal might be a potential therapeutic approach for diabetic skin wounds.

Treatment of hepatocellular carcinoma with portal vein tumor thrombus: advances and challenges.

Portal vein tumor thrombus is a frequent, challenging complication in hepatocellular carcinoma. Hepatocellular carcinoma patients with portal vein tumor thrombus may show worse liver function, less treatment tolerance and worse prognosis than patients without portal vein tumor thrombus, and they may be at higher risk of comorbidity related to portal hypertension. Western and some Asian guidelines stratify hepatocellular carcinoma with portal vein tumor thrombus together with metastatic hepatocellular carcinoma and therefore recommend only palliative treatment with sorafenib or other systemic agents. In recent years, more treatment options have become available for hepatocellular carcinoma patients with portal vein tumor thrombus, and an evidence-based approach to optimizing disease management and treatment has become more widespread. Nevertheless, consensus policies for managing hepatocellular carcinoma with portal vein tumor thrombus have not been established. This comprehensive literature review, drawing primarily on studies published after 2010, examines currently available management options for patients with hepatocellular carcinoma and portal vein tumor thrombus.

Timely meta-analysis on the efficacy of adoptive immunotherapy for hepatocellular carcinoma patients after curative therapy.

AIMS: The role of adoptive immunotherapy (AIT) for patients with hepatocellular carcinoma (HCC) who have received curative therapy is still not well illustrated. This timely meta-analysis aims to update the current evidence on efficacy and safety of AIT for patients with HCC who have received curative therapy. METHODS: We searched PubMed, EMBASE, Scopus and the Cochrane Library Through January 2017 for relevant studies. Mortality and tumor recurrence were compared between patients with or without adjuvant AIT. The meta-analysis was performed using Review Manager 5.3. RESULTS: Eight studies involving 1861 patients met the eligibility criteria and were meta-analyzed. Adjuvant AIT was associated with significantly lower mortality at 1 year (RR 0.64, 95%CI 0.52-0.79), 3 years (RR 0.73, 95%CI 0.65-0.81) and 5 years (RR 0.86, 95%CI 0.79-0.94). Similarly, adjuvant AIT was associated with significantly lower recurrence rate than curative therapies alone at 1 year (RR 0.64, 95%CI 0.49-0.82), 3 years (RR 0.85, 95%CI 0.79-0.91) and 5 years (RR 0.90, 95%CI 0.85-0.95). Short-term outcomes were confirmed in sensitivity analyses based on randomized trials or choice of random- or fixed-effect meta-analysis model. None of the included patients experienced grade 4 adverse events. CONCLUSIONS: This timely meta-analysis confirms the evidence that adjuvant AIT for patients with HCC after curative treatment lowers risk of mortality and tumor recurrence.