Selective internal radiation therapy with yttrium-90 resin microspheres followed by anatomical hepatectomy: A potential curative strategy in advanced hepatocellular carcinoma.

About 80% of hepatocellular carcinoma (HCC) patients are in advanced stages and ineligible for curative surgery. Palliative treatments just maintained limited survival, thus an effective downstaging therapy is badly needed. Here we report an initially unresectable patient who underwent radical hepatectomy after successful downstaging with selective internal radiation therapy (SIRT). A 34-year-old man was diagnosed with China Liver Cancer Staging (CNLC) IIIa HCC. Due to insufficient future liver remnant and vascular involvement, the patient was suggested to be unresectable. SIRT with yttrium-90 resin microspheres was given. At three months post-SIRT, a complete response was achieved. The tumor was downstaged to CNLC Ia stage. The patient underwent anatomical hepatectomy 5 months after SIRT. Histopathological examination of the resected specimen showed 4% viable tumor cells inside a necrotic mass. To our knowledge, this is the first case who underwent SIRT with yttrium-90 resin microspheres in China mainland. The success of the downstaging in this case renders a possible cure to be achieved in an initially unresectable patient. In addition, the nearly complete tumor necrosis in the resected specimen indicates a good prognosis post-surgery. This is the first case who underwent SIRT with yttrium-90 resin microspheres in China mainland. SIRT followed by anatomical hepatectomy is a potentially curative strategy for unresectable HCC, which deserves a confirmative trial in the future.

Detection and subtyping of hepatic echinococcosis from plain CT images with deep learning: a retrospective, multicentre study.

BACKGROUND: Hepatic echinococcosis is a severe endemic disease in some underdeveloped rural areas worldwide. Qualified physicians are in short supply in such areas, resulting in low rates of accurate diagnosis of this condition. In this study, we aimed to develop and evaluate an artificial intelligence (AI) system for automated detection and subtyping of hepatic echinococcosis using plain CT images with the goal of providing interpretable assistance to radiologists and clinicians. METHODS: We developed EDAM, an echinococcosis diagnostic AI system, to provide accurate and generalisable CT analysis for distinguishing hepatic echinococcosis from hepatic cysts and normal controls (no liver lesions), as well as subtyping hepatic echinococcosis as alveolar or cystic echinococcosis. EDAM includes a slice-level prediction model for lesion classification and segmentation and a patient-level diagnostic model for patient classification. We collected a plain CT database (n=700: 395 cystic echinococcosis, 122 alveolar echinococcosis, 130 hepatic cysts, and 53 normal controls) for developing EDAM, and two additional independent cohorts (n=156) for external validation of its performance and generalisation ability. We compared the performance of EDAM with 52 experienced radiologists in diagnosing and subtyping hepatic echinococcosis. FINDINGS: EDAM showed reliable performance in patient-level diagnosis on both the internal testing data (overall area under the receiver operating characteristic curve [AUC]: 0·974 [95% CI 0·936-0·994]; accuracy: 0·952 [0·939-0·965] for cystic echinococcosis, 0·981 [0·973-0·989] for alveolar echinococcosis; sensitivity: 0·966 [0·951-0·979] for cystic echinococcosis, 0·944 [0·908-0·970] for alveolar echinococcosis) and the external testing set (overall AUC: 0·953 [95% CI 0·840-0·973]; accuracy: 0·929 [0·915-0·947] for cystic echinococcosis, 0·936 [0·919-0·950] for alveolar echinococcosis; sensitivity: 0·913 [0·879-0·944] for cystic echinococcosis, 0·868 [0·841-0·897] for alveolar echinococcosis). The sensitivity of EDAM was robust across images from different CT manufacturers. EDAM outperformed most of the enrolled radiologists in detecting both alveolar echinococcosis and cystic echinococcosis. INTERPRETATION: EDAM is a clinically applicable AI system that can provide patient-level diagnoses with interpretable results. The accuracy and generalisation ability of EDAM demonstrates its potential for clinical use, especially in underdeveloped areas. FUNDING: Project of Qinghai Provincial Department of Science and Technology of China, National Natural Science Foundation of China, and Tsinghua-Fuzhou Institute of Data Technology Project. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Spheroid on-demand printing and drug screening of endothelialized hepatocellular carcinoma model at different stages.

Hepatocellular carcinoma (HCC) poses a significant threat to human health and medical care. Its dynamic microenvironment and stages of development will influence the treatment strategies in clinics. Reconstructing tumor-microvascular interactions in different stages of the microenvironment is an urgent need forin vitrotumor pathology research and drug screening. However, the absence of tumor aggregates with paracancerous microvascular and staged tumor-endothelium interactions leads to bias in the antitumor drug responses. Herein, a spheroid-on-demand manipulation strategy was developed to construct staged endothelialized HCC models for drug screening. Pre-assembled HepG2 spheroids were directly printed by alternating viscous and inertial force jetting with high cell viability and integrity. A semi-open microfluidic chip was also designed to form a microvascular connections with high density, narrow diameter, and curved morphologies. According to the single or multiple lesions in stages Ⅰ or Ⅰ HCC, endothelialized HCC models from micrometer to millimeter scale with dense tumor cell aggregation and paracancerous endothelial distribution were successively constructed. A migrating stage Ⅰ HCC model was further constructed under TGF-ßtreatment, where the spheroids exhibited a more mesenchymal phenotype with a loose cell connection and spheroid dispersion. Finally, the stage ⅠHCC model showed stronger drug resistance compared to the stage Ⅰ model, while the stage III showed a more rapid response. The corresponding work provides a widely applicable method for the reproduction of tumor-microvascular interactions at different stages and holds great promise for the study of tumor migration, tumor-stromal cell interactions, and the development of anti-tumor therapeutic strategies.

Improved prognostic prediction model for liver cancer based on biomarker data screened by combined methods.

Liver cancer is a common cause of death from cancer in the population, with the 4th highest mortality rate from cancer worldwide. The high recurrence rate of hepatocellular carcinoma after surgery is an important cause of high mortality among patients. In this paper, based on eight scheduled core markers of liver cancer, an improved feature screening algorithm was proposed based on the analysis of the basic principles of the random forest algorithm, and the system was finally applied to liver cancer prognosis prediction to improve the prediction of biomarkers for liver cancer recurrence, and the impact of different algorithmic strategies on the prediction accuracy was compared and analyzed. The results showed that the improved feature screening algorithm was able to reduce the feature set by about 50% while ensuring that the prediction accuracy was reduced within 2%.

Advances in the pharmacological treatment of hepatic alveolar echinococcosis: From laboratory to clinic.

Hepatic alveolar echinococcosis (HAE) is a zoonotic parasitic disease caused by the larvae of Echinococcus multilocularis. Because of its characteristics of diffuse infiltration and growth similar to tumors, the disability rate and mortality rate are high among patients. Although surgery (including hepatectomy, liver transplantation, and autologous liver transplantation) is the first choice for the treatment of hepatic alveolar echinococcosis in clinic, drug treatment still plays an important and irreplaceable role in patients with end-stage echinococcosis, including patients with multiple organ metastasis, patients with inferior vena cava invasion, or patients with surgical contraindications, etc. However, Albendazole is the only recommended clinical drug which could exhibit a parasitostatic rather than a parasitocidal effect. Novel drugs are needed but few investment was made in the field because the rarity of the cases. Drug repurposing might be a solution. In this review, FDA-approved drugs that have a potential curative effect on hepatic alveolar echinococcosis in animal models are summarized. Further, nano drug delivery systems boosting the therapeutic effect on hepatic alveolar echinococcosis are also reviewed. Taken together, these might contribute to the development of novel strategy for advanced hepatic alveolar echinococcosis.

Scalable Formation of Highly Viable and Functional Hepatocellular Carcinoma Spheroids in an Oxygen-Permeable Microwell Device for Anti-Tumor Drug Evaluation.

For high-throughput anti-cancer drug screening, microwell arrays may serve as an effective tool to generate uniform and scalable tumor spheroids. However, microwell arrays are commonly anchored in non-oxygen-permeable culture plates, leading to limited oxygen supply for avascular spheroids. Herein, a polydimethylsiloxane (PDMS)-based oxygen-permeable microwell device is introduced for generating highly viable and functional hepatocellular carcinoma (HCC) spheroids. The PDMS sheets at the bottom of the microwell device provide a high flux of oxygen like in vivo neighboring hepatic sinusoids. Owing to the better oxygen supply, the generated HepG2 spheroids are larger in size and exhibit higher viability and proliferation with less cell apoptosis and necrosis. These spheroids also exhibit lower levels of anaerobic cellular respiration and express higher levels of liver-related functions. In anti-cancer drug testing, spheroids cultured in PDMS plates show a significantly stronger resistance against doxorubicin because of the stronger stem-cell and multidrug resistance phenotype. Moreover, higher expression of vascular endothelial growth factor-A produces a stronger angiogenesis capability of the spheroids. Overall, compared to the spheroids cultured in conventional non-oxygen-permeable plates, these spheroids can be used as a more favorable model for early-stage HCCs and be applied in high-throughput anti-cancer drug screening.

MVI-Mind: A Novel Deep-Learning Strategy Using Computed Tomography (CT)-Based Radiomics for End-to-End High Efficiency Prediction of Microvascular Invasion in Hepatocellular Carcinoma.

Microvascular invasion (MVI) in hepatocellular carcinoma (HCC) directly affects a patient's prognosis. The development of preoperative noninvasive diagnostic methods is significant for guiding optimal treatment plans. In this study, we investigated 138 patients with HCC and presented a novel end-to-end deep learning strategy based on computed tomography (CT) radiomics (MVI-Mind), which integrates data preprocessing, automatic segmentation of lesions and other regions, automatic feature extraction, and MVI prediction. A lightweight transformer and a convolutional neural network (CNN) were proposed for the segmentation and prediction modules, respectively. To demonstrate the superiority of MVI-Mind, we compared the framework's performance with that of current, mainstream segmentation, and classification models. The test results showed that MVI-Mind returned the best performance in both segmentation and prediction. The mean intersection over union (mIoU) of the segmentation module was 0.9006, and the area under the receiver operating characteristic curve (AUC) of the prediction module reached 0.9223. Additionally, it only took approximately 1 min to output a prediction for each patient, end-to-end using our computing device, which indicated that MVI-Mind could noninvasively, efficiently, and accurately predict the presence of MVI in HCC patients before surgery. This result will be helpful for doctors to make rational clinical decisions.

Treatment of Complicated Hepatic Alveolar Echinococcosis Disease With Suspicious Lymph Node Remote Metastasis Near the Inferior Vena Cava-Abdominal Aorta: A Case Report and Literature Review.

Echinococcosis is a human-animal parasitic disease caused by Echinococcosis tapeworm larvae in humans. From a global perspective, it is mainly prevalent in the mid-high latitudes of the Northern Hemisphere, and it is a widespread infectious disease. Its form, host and release areas are slightly different. In clinical practice, Echinococcus granulosus (hepatic cystic echinococcosis) is the most common. Its growth mode is swelling growth and its metastasis is more common in implanted metastasis; However, hepatic alveolar echinococcosis (HAE) is rare. It has been reported that HAE can metastasize through the blood or lymph nodes, and its invasive growth pattern is known as "carcinoma". At this time, it may be accompanied by invasion of the portal vein and inferior vena cava(IVC)or metastasis to distant organs outside the liver (such as lung, brain, lymph nodes). Most patients are in the middle or late stages, making treatment complicated. World Health Organization guidelines recommend radical resection of HAE; However, there is no consensus on lymph node dissection. To date, there have been no reports of cases of HAE accompanied by inferior vena cava-para-abdominal aortic suspected lymph node metastasis and infection. This article reports a clinical case of a complex HAE treated by the surgical method of "middle liver resection + abdominal enlarged lymph node resection + inferior vena cava repair", and histological examination was performed to illustrate the differences in microscopic pathology of alveolar echinococcosis invading the liver and lymph nodes at different magnifications. This article reviews the relevant literature on HAE and derives the latest treatment methods for HAE to provide a reference for future clinical cases of similar alveolar echinococcosis and maximize the benefits of patients.

Application of informatics in cancer research and clinical practice: Opportunities and challenges.

Cancer informatics has significantly progressed in the big data era. We summarize the application of informatics approaches to the cancer domain from both the informatics perspective (e.g., data management and data science) and the clinical perspective (e.g., cancer screening, risk assessment, diagnosis, treatment, and prognosis). We discuss various informatics methods and tools that are widely applied in cancer research and practices, such as cancer databases, data standards, terminologies, high-throughput omics data mining, machine-learning algorithms, artificial intelligence imaging, and intelligent radiation. We also address the informatics challenges within the cancer field that pursue better treatment decisions and patient outcomes, and focus on how informatics can provide opportunities for cancer research and practices. Finally, we conclude that the interdisciplinary nature of cancer informatics and collaborations are major drivers for future research and applications in clinical practices. It is hoped that this review is instrumental for cancer researchers and clinicians with its informatics-specific insights.

Combining Preoperative and Postoperative Inflammatory Indicators Can Better Predict the Recurrence of Hepatocellular Carcinoma After Partial Hepatectomy.

PURPOSE: Previous studies have shown that various preoperative inflammatory indicators can predict the prognosis of hepatocellular carcinoma (HCC), but the role of postoperative inflammatory indicators remains unclear. This study aimed to explore the prognostic value of postoperative inflammatory indicators and whether combining preoperative and postoperative inflammatory indicators can improve the predictive performance of the prognostic model. PATIENTS AND METHODS: Eighty-eight patients with primary HCC were included in this study. A preoperative model, postoperative model, and combined model that integrated preoperative and postoperative inflammatory indicators were established. The prognostic value of the models was evaluated by the area under the curve of time-dependent receiver operating characteristic curves (td-AUC). RESULTS: Multivariate analysis of preoperative and postoperative inflammatory indicators and clinicopathological indicators found that tumor number, alpha-fetoprotein (AFP) level, and the preoperative platelet-lymphocyte ratio (prePLR), preoperative prognostic nutritional index (prePNI), and postoperative neutrophil-lymphocyte ratio (postNLR) were independent prognostic factors for the disease-free survival. The prognostic efficacy of the postNLR at 2 years and 3 years was better than that of tumor number, AFP level, and the prePLR, and prePNI. The combined model had higher td-AUC values than the preoperative model, postoperative model, American Joint Committee on Cancer 8th edition stage, and Barcelona Clinic Liver Cancer stage at 2 years (0.814 vs 0.754, 0.765, 0.513 and 0.527, respectively), and 3 years (0.786 vs 0.749, 0.753, 0.509 and 0.529, respectively). The predictive performance of the combined model was better than that of the preoperative model, postoperative model, and traditional clinical stage. CONCLUSION: Postoperative inflammatory indicators were valuable prognostic indicators. The combination of preoperative and postoperative inflammatory indicators improved the predictive performance of the prognostic model. We should pay more attention to postoperative inflammatory indicators.

Prognostic value of the postoperative neutrophil-lymphocyte ratio in solid tumors: A meta-analysis.

PURPOSE: Numerous studies have demonstrated that a variety of systemic inflammatory markers were associated with the survival of different tumors. However, the association between elevated postoperative neutrophil-lymphocyte ratio (postNLR) and long-term outcomes, including overall survival (OS), disease-free survival (DFS), in patients with solid tumors remains controversial. A systematic review was conducted to explore the association between the postNLR and long-term outcomes in solid tumors. MATERIALS AND METHODS: Relevant literature was identified using PubMed, Embase, Web of Science, and the Cochrane Library from the initiation of the databases to October 2020. Data were extracted from included studies reporting hazard ratio (HR) and 95% confidence intervals (CI), and were pooled using generic inverse-variance and random-effects modeling. 25 studies reporting on7539 patients were included in the analysis. RESULTS: Elevated postNLR was associated with poor OS (HR 1.87, 95% CI = 1.53-2.28; P < 0.00001), and worse DFS (HR 1.69, 95% CI = 1.28-2.22; P = 0.0002). Subgroup analyses showed that the trend of the pooled HR for most of the subgroups was not changed, and the heterogeneity of the same tumor type was not obvious. However, there was no correlation between high postNLR obtained within 7days and poor DFS (n = 3, HR 1.25, 95CI% = 0.54-2.88; P = 0.60). CONCLUSIONS: Elevated postNLR might be a readily available and inexpensive biomarker for long-term outcomes in solid tumors. Multicenter and prospective studies are needed to explore the impact of the postNLR on the prognosis of solid tumors.

HBx acts as an oncogene and promotes the invasion and metastasis of hepatocellular carcinoma both in vivo and vitro.

BACKGROUND AND AIMS: Hepatitis B virus X (HBx) has been reported to be closely related to hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). This study aimed to detect the expression pattern of HBx and explore whether HBx protein can promote HCC invasion and metastasis both in vivo and vitro. METHODS: HBx expression was detected in HCC tissues via immunochemistry. A recombinant adenovirus vector containing the HBx gene was constructed and transfected into the HCC cell line SMMC-7721. Wound healing, transwell migration, and invasion assays were performed to evaluate migration and invasion potentials. A splenic implant tumor nude mice model was established to confirm its invasion and metastatic abilities in vivo. RESULTS: The positive rate of HBx in HCC tissues was 67.89%. HBx overexpression significantly promoted the migration and invasion abilities of SMMC-7721 cells in vitro. The tumor model showed that splenic implant tumor volume and number of liver metastatic tumor nodes were significantly larger and higher in the HBx overexpression group than in the control group. CONCLUSIONS: HBx is highly expressed in HCC tissues and promotes HCC invasion and metastasis both in vivo and vitro with oncogene activity, thereby suggesting that HBx can serve as a novel therapeutic target in HCC.

Preoperative plus postoperative neutrophil-lymphocyte ratio for predicting overall survival following partial hepatectomy for hepatocellular carcinoma.

The preoperative neutrophil-lymphocyte ratio (NLR) and the postoperative NLR have been reported to be prognostic factors for malignant tumors. However, the prognostic value of combining the preoperative NLR and postoperative NLR for hepatocellular carcinoma (HCC) remains unclear. In the present study, a cohort of 70 patients with primary HCC were retrospectively reviewed. The optimal cut-offs for continuous variables were determined by the maximally selected rank statistics. The prognostic factors included preoperative NLR, postoperative NLR, preoperative NLR plus postoperative NLR, change in postoperative NLR, and postoperative NLR minus preoperative NLR. The predictive powers of the aforementioned prognostic factors were analyzed by the area under the time-dependent receiver operating characteristic (td-AUC) curve. Prognostic values were assessed by univariate and multivariate analyses. An increased preoperative NLR was found to be associated with higher preoperative neutrophil levels, lower preoperative lymphocyte levels and larger tumor sizes (all P<0.05). An increased postoperative NLR was associated with higher postoperative neutrophil levels and lower postoperative lymphocyte levels (all P<0.05). Multivariate analysis identified the preoperative NLR plus postoperative NLR as an independent prognostic risk factor (HR, 2.985; 95% CI, 1.648-5.407; P<0.001). The preoperative NLR plus postoperative NLR had higher td-AUC values than the preoperative NLR, postoperative NLR, postoperative NLR change, and postoperative NLR minus the preoperative NLR in the first to fourth years after surgery. The preoperative NLR plus postoperative NLR, considering both the preoperative and postoperative treatment phases, is a novel and promising prognostic factor for patients with HCC and requires further investigation in the future.

Ultrasonic Pressure Ballistic System-Assisted Minimally Invasive Pancreatic Necrosectomy for Necrotizing Pancreatitis.

Background: Although minimally invasive pancreatic necrosectomy (MIPN) is a new invasive technique for necrotizing pancreatitis, it has some disadvantages. This study aimed to improve the debridement technique with an ultrasonic pressure ballistic system. We hypothesized that this system would facilitate debridement and improve the safety of the procedure. Materials and Methods: Between October 2016 and January 2019, 5 patients diagnosed with necrotizing pancreatitis were enrolled in the clinical cohort. All patients underwent debridement due to infective necrosis. Access for debridement was typically established with percutaneous puncture. Then MIPN was performed. During the procedure, ultrasonic pressure was applied to liquefy the necrotic material and make it absorbable. The effect of debridement was assessed by analyzing the average bleeding volume, operation time, and complications. Postoperative clinical parameters were evaluated. Results: Debridement was performed successfully for all patients. Semisolid necrotic tissue was dissolved with ultrasonic pressure. Viscous pus was rapidly aspirated with the suction applied with negative pressure, which greatly enhanced efficiency. This approach enhanced the visibility of blood vessels, which improved safety. No major complications were encountered. Two patients (40%) developed puncture site infections. The average blood loss during the operation was 13 ± 6 mL. The average operation time was 78 ± 31 minutes. Postoperative APACHE II scores were significantly lower than preoperative scores (P < .05). White blood cells, C-reactive protein, and procalcitonin levels declined postoperatively. Conclusions: The ultrasonic pressure ballistic system could potentially enhance MIPN and make it safer.

Interaction Effects of AFB1 and MC-LR Co-exposure with Polymorphism of Metabolic Genes on Liver Damage: focusing on SLCO1B1 and GSTP1.

AFB1 and MC-LR are two major environmental risk factors for liver damage worldwide, especially in warm and humid areas, but there are individual differences in health response of the toxin-exposed populations. Therefore, we intended to identify the susceptible genes in transport and metabolic process of AFB1 and MC-LR and find their effects on liver damage. We selected eight related SNPs that may affect liver damage outcomes in AFB1 and MC-LR exposed persons, and enrolled 475 cases with liver damage and 475 controls of healthy people in rural areas of China. The eight SNPs were genotyped by PCR and restriction fragment length polymorphism. We found that SLCO1B1 (T521C) is a risk factor for liver damage among people exposed to high AFB1 levels alone or combined with MC-LR, and that GSTP1 (A1578G) could indicate the risk of liver damage among those exposed to high MC-LR levels alone or combined with high AFB1 levels. However, GSTP1 (A1578G) could reduce the risk of liver damage in populations exposed to low MC-LR levels alone or combined with high AFB1 levels. In conclusion, SLCO1B1 (T521C) and GSTP1 (A1578G) are susceptible genes for liver damage in humans exposed to AFB1 and/or MC-LR in rural areas of China.

Surgical management for bile duct injury.

The management of bile duct injury (BDI) remains a considerable challenge in hepatobiliary surgery. BDI is mainly iatrogenic, and mostly occurs in cholecystectomy. Laparoscopic cholecystectomy (LC) has been performed widely, however, the incidence of BDI associated with LC increases 2-3 times compared to that in open cholecystectomy (OC). BDI also occurs in robotic cholecystectomy. In China, the evidence-based Practice Guideline for Diagnosis and Treatment of BDI was published by the Biliary Surgery Group of Surgery Branch of Chinese Medical Association, with the purpose of reducing the incidence of BDI as well as promoting its optimal diagnosis and treatment. Surgery remains the mainstay of treatment for BDI and traumatic bile duct stricture. The definitive repair involves a series of procedures including exposing the proximal and distal bile duct, anastomotic bile duct tissue preparation, minimally invasive tissue anastomoses, and so on. Successful management is a surgical challenge requiring great specialized experience and precise surgical skill. The application of precision biliary surgery is recommended for promoting standardized management of BDI.

Prevalence of metabolic syndrome among adults with liver function injury in rural area of Southwest China: A cross-sectional study.

Abnormal liver function (ALF) plays a key role in metabolic syndrome (MetS), but only few data on the relationship between MetS and the risk factors for ALF (e.g., biotoxins) are available. We aimed to provide the prevalence of MetS and its association with the risk factors for ALF in rural area of Southwest China. A cross-sectional study within the hepatocellular carcinoma cohort was conducted, and included 5493 people with age from 30 to 85 years old. MetS was defined according to the Joint Scientific Statement. We observed that the prevalence of MetS was 31.8% (39.0% in women and 19.8% in men). Logistic regression analysis showed that significantly increased risk of MetS was found in those showing ALF (OR = 3.00, 95% CI: 2.43-3.71). Significantly decreased risk of MetS was found in those with higher HBV DNA titers (OR = 0.49, 95% CI: 0.33-0.74), and in those with higher aflatoxin B1 exposure (estimated daily intake, EDI) (OR = 0.60, 95% CI: 0.53-0.67). No significant change was found in those with higher microcystin-LR exposure (EDI). Therefore, the different risk factors for ALF might exert different effects on MetS. However, there should be an interaction effect existing that might decide the severity of MetS.

Serum microcystin levels positively linked with risk of hepatocellular carcinoma: A case-control study in southwest China.

Microcystins have been reported to be carcinogenic by animal and cell experimentation, but there are no data on the linkage between serum microcystins and hepatocellular carcinoma (HCC) risk in humans. We conducted a clinical case-control study to investigate the association between serum microcystins and HCC risk after controlling several known risk factors, such as hepatitis B virus, alcohol, and aflatoxin. From December 2013 to May 2016, 214 patients newly diagnosed with HCC along with 214 controls (frequency-matched by age and sex) were recruited from three hospitals in Chongqing, southwest China. Basic information on lifestyle and history of disease was obtained by questionnaire. Blood samples were collected and analyzed for serum microcystin-LR (MC-LR) and aflatoxin-albumin adduct by enzyme-linked immunosorbent assay and for hepatitis B surface antigen status by chemiluminescence assay. Binary logistic regression analyses were performed to assess the independent effects of MC-LR and its joint effects with other factors on HCC risk. The adjusted odds ratio for HCC risk by serum MC-LR was 2.9 (95% confidence interval [CI], 1.5-5.5) in all patients. Notably, a clear relationship between increased MC-LR level (Q2, Q3, and Q4) and HCC risk was observed with elevated adjusted odds ratios (1.3, 2.6, and 4.0, respectively). Positive interactions with the additive model were investigated between MC-LR and hepatitis B virus infection (synergism index = 3.0; 95% CI, 2.0-4.5) and between MC-LR and alcohol (synergism index = 4.0; 95% CI, 1.7-9.5), while a negative interaction was found between MC-LR and aflatoxin (synergism index = 0.4; 95% CI, 0.3-0.7). Additionally, serum MC-LR was significantly associated with tumor differentiation (r = -0.228, P < 0.001). CONCLUSION: We provide evidence that serum MC-LR was an independent risk factor for HCC in humans, with an obvious positive interaction with hepatitis B virus and alcohol but a negative interaction with aflatoxin. (Hepatology 2017;66:1519-1528).