A multicenter clinical AI system study for detection and diagnosis of focal liver lesions.

Early and accurate diagnosis of focal liver lesions is crucial for effective treatment and prognosis. We developed and validated a fully automated diagnostic system named Liver Artificial Intelligence Diagnosis System (LiAIDS) based on a diverse sample of 12,610 patients from 18 hospitals, both retrospectively and prospectively. In this study, LiAIDS achieved an F1-score of 0.940 for benign and 0.692 for malignant lesions, outperforming junior radiologists (benign: 0.830-0.890, malignant: 0.230-0.360) and being on par with senior radiologists (benign: 0.920-0.950, malignant: 0.550-0.650). Furthermore, with the assistance of LiAIDS, the diagnostic accuracy of all radiologists improved. For benign and malignant lesions, junior radiologists' F1-scores improved to 0.936-0.946 and 0.667-0.680 respectively, while seniors improved to 0.950-0.961 and 0.679-0.753. Additionally, in a triage study of 13,192 consecutive patients, LiAIDS automatically classified 76.46% of patients as low risk with a high NPV of 99.0%. The evidence suggests that LiAIDS can serve as a routine diagnostic tool and enhance the diagnostic capabilities of radiologists for liver lesions.

Comparing Long-Term survival benefits of hepatocellular carcinoma between thermal ablation monotherapy and combined therapy with transarterial Chemoembolization: A propensity score matched study.

PURPOSE: To compare the long-term survival benefits of hepatocellular carcinoma (HCC) in thermal ablation (TA) monotherapy and TA combined with transarterial chemoembolization (TACE) using propensity score matching (PSM). MATERIALS AND METHODS: Between 1 January 2015 and 28 February 2021, 432 consecutive patients (357 men, 75 women; age range, 20-87 years) with HCC (Barcelona Clinic Liver Cancer stage 0-B) underwent ultrasonography-guided percutaneous TA, which included radiofrequency ablation (n = 340) and microwave ablation (n = 92). The association between combined treatment of TACE prior to TA versus TA monotherapy and survival prognosis was evaluated, including (a) local tumor progression (LTP) by using a logistic regression model, and (b) disease-free survival (DFS) and (c) overall survival (OS) by using a Cox proportional hazards model according to propensity score matched data. RESULTS: After PSM, the final matched cohort consisted of 146 patients, with 73 receiving TA monotherapy and 73 receiving TA combined with TACE. The cumulative LTP rates did not show a significant difference between the two groups (P = 0.960). Neither the DFS nor OS rate was significantly different between the two groups (P = 0.070 and P = 0.680, respectively). The multivariate analysis identified two significant findings. Firstly, ultrasound echo, minimal ablative margin, and high risk of tumor burden score were found to be associated with LTP. Secondly, the type of TA, Child-Turcotte-Pugh grade, ablation time, and lymphocyte-monocyte ratio were identified as independent prognostic factors for OS. CONCLUSION: The differences in LTP, DFS, and OS rates of HCC patients were found to be statistically non-significant between TA monotherapy and TACE + TA groups. For HCC patients with BCLC stage 0-B, the combination treatment of TACE prior to TA may be not associated with long-term survival benefits relative to TA monotherapy.

ALKBH5 promotes hypopharyngeal squamous cell carcinoma apoptosis by targeting TLR2 in a YTHDF1/IGF2BP2-mediated manner.

Hypopharyngeal squamous cell carcinoma (HPSCC) is one of the most aggressive cancers and is notorious for its extremely poor prognosis. However, very few molecular biological studies have been performed. As a novel method of epigenetic gene modulation, N6-methyladenosine (m6A) RNA modification occurs in HPSCC. The expression of the m6A demethylase AlkB homolog 5 (ALKBH5) is frequently downregulated in human HPSCC. Furthermore, we found that ALKBH5 impaired cell proliferation by regulating human Toll-like receptor 2 (TLR2) in an m6A-dependent manner in HPSCC cells. ALKBH5 decreased TLR2 m6A modification, which could be recognized by the m6A readers IGF2BP2 and YTHDF1. IGF2BP2 facilitates TLR2 mRNA stability, whereas YTHDF1 promotes TLR2 mRNA translation. The current work uncovered a critical function of ALKBH5 in TLR2 regulation and provides a novel role for m6A demethylation of mRNA in HPSCC. The inhibition of m6A modification of ALKBH5 in HPSCC deserves further clinical investigation.

A deep learning model for prediction of post hepatectomy liver failure after hemihepatectomy using preoperative contrast-enhanced computed tomography: a retrospective study.

Objective: Post-hepatectomy liver failure (PHLF) remains clinical challenges after major hepatectomy. The aim of this study was to establish and validate a deep learning model to predict PHLF after hemihepatectomy using preoperative contrast-enhancedcomputed tomography with three phases (Non-contrast, arterial phase and venous phase). Methods: 265 patients undergoing hemihepatectomy in Sir Run Run Shaw Hospital were enrolled in this study. The primary endpoint was PHLF, according to the International Study Group of Liver Surgery's definition. In this study, to evaluate the proposed method, 5-fold cross-validation technique was used. The dataset was split into 5 folds of equal size, and each fold was used as a test set once, while the other folds were temporarily combined to form a training set. Performance metrics on the test set were then calculated and stored. At the end of the 5-fold cross-validation run, the accuracy, precision, sensitivity and specificity for predicting PHLF with the deep learning model and the area under receiver operating characteristic curve (AUC) were calculated. Results: Of the 265 patients, 170 patients with left liver resection and 95 patients with right liver resection. The diagnosis had 6 types: hepatocellular carcinoma, intrahepatic cholangiocarcinoma, liver metastases, benign tumor, hepatolithiasis, and other liver diseases. Laparoscopic liver resection was performed in 187 patients. The accuracy of prediction was 84.15%. The AUC was 0.7927. In 170 left hemihepatectomy cases, the accuracy was 89.41% (152/170), and the AUC was 82.72%. The accuracy was 77.47% (141/182) with liver mass, 78.33% (47/60) with liver cirrhosis and 80.46% (70/87) with viral hepatitis. Conclusion: The deep learning model showed excellent performance in prediction of PHLF and could be useful for identifying high-risk patients to modify the treatment planning.

USP15 Represses Hepatocellular Carcinoma Progression by Regulation of Pathways of Cell Proliferation and Cell Migration: A System Biology Analysis.

BACKGROUND: Hepatocellular carcinoma (HCC) leads to 600,000 people's deaths every year. The protein ubiquitin carboxyl-terminal hydrolase 15 (USP15) is a ubiquitin-specific protease. The role of USP15 in HCC is still unclear. METHOD: We studied the function of USP15 in HCC from the viewpoint of systems biology and investigated possible implications using experimental methods, such as real-time polymerase chain reaction (qPCR), Western blotting, clustered regularly interspaced short palindromic repeats (CRISPR), and next-generation sequencing (NGS). We investigated tissues samples of 102 patients who underwent liver resection between January 2006 and December 2010 at the Sir Run Run Shaw Hospital (SRRSH). Tissue samples were immunochemically stained; a trained pathologist then scored the tissue by visual inspection, and we compared the survival data of two groups of patients by means of Kaplan-Meier curves. We applied assays for cell migration, cell growth, and wound healing. We studied tumor formation in a mouse model. RESULTS: HCC patients (n = 26) with high expression of USP15 had a higher survival rate than patients (n = 76) with low expression. We confirmed a suppressive role of USP15 in HCC using in vitro and in vivo tests. Based on publicly available data, we constructed a PPI network in which 143 genes were related to USP15 (HCC genes). We combined the 143 HCC genes with results of an experimental investigation to identify 225 pathways that may be related simultaneously to USP15 and HCC (tumor pathways). We found the 225 pathways enriched in the functional groups of cell proliferation and cell migration. The 225 pathways determined six clusters of pathways in which terms such as signal transduction, cell cycle, gene expression, and DNA repair related the expression of USP15 to tumorigenesis. CONCLUSION: USP15 may suppress tumorigenesis of HCC by regulating pathway clusters of signal transduction for gene expression, cell cycle, and DNA repair. For the first time, the tumorigenesis of HCC is studied from the viewpoint of the pathway cluster.

Development and validation of a clinical-radiomics model to predict recurrence for patients with hepatocellular carcinoma after curative resection.

PURPOSE: Recurrence is the leading cause of death in hepatocellular carcinoma (HCC) patients with curative resection. In this study, we aimed to develop a preoperative predictive model based on high-throughput radiomics features and clinical factors for prediction of long- and short-term recurrence for these patients. METHODS: A total of 270 patients with HCC who were followed up for at least 5 years after curative hepatectomy between June 2014 and December 2017 were enrolled in this retrospective study. Regions of interest were manually delineated in preoperative T2-weighted images using ITK-SNAP software on each HCC tumor slice. A total of 1197 radiomics features were extracted, and the recursive feature elimination method based on logistic regression was used for radiomics signature building. Tenfold cross-validation was applied for model development. Nomograms were constructed and assessed by calibration plot, which compares nomogram-predicated probability with observed outcome. Receiver-operating characteristic was then generated to evaluate the predictive performance of the model in the development and test cohorts. RESULTS: The 10 most recurrence-free survival-related radiomics features were selected for the radiomics signatures. A multiparametric clinical-radiomics model combining albumin and radiomics score for recurrence prediction was further established. The integrated model demonstrated good calibration and satisfactory discrimination, with the area under the curve (AUC) of 0.864, 95% CI 0.842-0.903, sensitivity of 0.889, and specificity of 0.644 in the test set. Calibration curve showed good agreement concerning 5-year recurrence risk predicted by the nomogram. In addition, the AUC of 1-, 2-, 3-, and 4-year recurrence was 0.935 (95% CI 0.836-1.000), 0.861 (95% CI 0.723-0.999), 0.878 (95% CI 0.762-0.994), and 0.878 (95% CI 0.762-0.994) in the test set, respectively. CONCLUSIONS: The clinical-radiomics model integrating radiomics features and clinical factors can improve recurrence predictions beyond predictions made using clinical factors or radiomics features alone. Our clinical-radiomics model is a valid method to predict recurrence that should improve preoperative prognostic performance and allow more individualized treatment decisions.

Gasdermin D-mediated pyroptosis suppresses liver regeneration after 70% partial hepatectomy.

Pyroptosis is a kind of programmed cell death primarily mediated by gasdermin D (GSDMD) and shown to regulate multiple diseases. However, its contribution to liver regeneration, a fine-tuned tissue repair process mediated primarily by hepatocytes after mass loss, remains unclear. Herein, we found that caspase-11/GSDMD-mediated pyroptosis was activated in regenerating liver after 70% partial hepatectomy. Impeding pyroptosis by deleting GSDMD significantly reduced liver injury and accelerated liver regeneration. Mechanistically, GSDMD deficiency up-regulates the activation of hepatocyte growth factor/c-Met and epidermal growth factor receptor mitogenic pathways at the initiation phase. Moreover, activin A and glypican 3 (GPC3), two terminators of liver regeneration, were inhibited when GSDMD was absent. In vitro study suggested the expressions of activin A and GPC3 were induced by interleukin (IL)-1ß and IL-18, whose maturations were regulated by GSDMD-mediated pyroptosis. Similarly, pharmacologically inhibiting GSDMD recapitulates these phenomena. Conclusion: This study characterizes the role of GSDMD-mediated pyroptosis in liver regeneration and lays the foundation for enhancing liver restoration by targeting GSDMD in liver patients with impaired regenerative capacity.

MicroRNA-146b-5p suppresses cholangiocarcinoma cells by targeting TRAF6 and modulating p53 translocation.

BACKGROUND: In view of the poor prognosis and high mortality of cholangiocarcinoma, there is a need for new therapeutic strategies. This study aims to reveal the biological function of miR-146b-5p in cholangiocarcinoma cell and its possible mechanism. METHODS: The expression level and prognostic information on miR-146b-5p in cholangiocarcinoma were obtained in TCGA database. The biological function of miR-146b-5p on proliferation and vitality of cholangiocarcinoma cell HUCCT-1 was examined by EdU and MTT assay, and the apoptosis of HUCCT-1 cells transfected with miR-146b-5p mimic, mimic control, inhibitor, inhibitor control was detected by flow cytometry analysis. The western blot was done to evaluate the effect of miR-146b-5p targeting substrate and the expression of p53 in whole-cell protein and mitochondria fractions. RESULTS: Our finding revealed that miR-146b-5p expression in patients with CHOL was lower than the normal group(p＜0.001). MiR-146b-5p expression was down-regulated in human cholangiocarcinoma HUCCT-1 and RBE cells compared to normal control HIBEC and other cancer cells. The miR-146b-5p mimic could inhibit HUCCT-1 cell proliferation (p＜0.05) and promote HUCCT-1 cell apoptosis significantly (p＜0.05). The results of western blot showed that miR-146b-5p mimic could directly target TRAF6 3'UTR region and up-regulate the expression of p53 in mitochondria and miR-146b-5p inhibitor could down-regulated the level of p53 in mitochondria. CONCLUSION: MiR-146b-5p is a cholangiocarcinoma suppressor by inhibiting cell proliferation and promoting cell apoptosis with targeting TRAF6, possibly via modulating p53 translocation to mitochondria.

A clinical-radiomics model incorporating T2-weighted and diffusion-weighted magnetic resonance images predicts the existence of lymphovascular invasion / perineural invasion in patients with colorectal cancer.

PURPOSE: Lymphovascular invasion (LVI) and perineural invasion (PNI) are independent prognostic factors in patients with colorectal cancer (CRC). In this study, we aimed to develop and validate a preoperative predictive model based on high-throughput radiomic features and clinical factors for accurate prediction of LVI/PNI in these patients. METHODS: Two hundred and sixty-three patients who underwent colorectal resection for histologically confirmed CRC between 1 February 2011 and 30 June 2020 were retrospectively enrolled. Between 1 February 2011 and 30 September 2018, 213 patients were randomly divided into a training cohort (n = 149) and a validation cohort (n = 64) by a ratio of 7:3. We used a 10000-iteration bootstrap analysis to estimate the prediction error and confidence interval for two cohorts. The independent test cohort consisted of 50 patients between 1 October 2018 and 30 June 2020. Regions of interest (ROIs) were manually delineated in high-resolution T2-weighted and diffusion-weighted images using ITK-SNAP software on each CRC tumor slice. In total, 3356 radiomic features were extracted from each ROI. Next, we used the maximum relevance minimum redundancy and least absolute shrinkage and selection operator algorithms to select the strongest of these features to establish a clinical-radiomics model for predicting LVI/PNI. Receiver-operating characteristic and calibration curves were then plotted to evaluate the predictive performance of the model in the training, validation, and independent test cohorts. RESULTS: A multiparametric clinical-radiomics model combining MRI-reported extramural vascular invasion (EMVI) status and a Radiomics score for the LVI/PNI estimation was established. This model had significant predictive power in the training cohort (area under the curve [AUC] 0.91; 95% confidence interval [CI]: 0.85-0.97), validation cohort (AUC: 0.88; 95% CI: 0.79-89), and independent test cohorts (AUC 0.83, 95% CI 0.72-0.95). The model performed well in the independent test cohort with sensitivity of 0.818, specificity of 0.714, and accuracy of 0.760. Calibration curve and decision curve analysis demonstrated clinical benefits. CONCLUSION: Multiparametric clinical-radiomics models can accurately predict LVI/PNI in patients with CRC. Our model has predictive ability that should improve preoperative diagnostic performance and allow more individualized treatment decisions.

Pinin promotes tumor progression via activating CREB through PI3K/AKT and ERK/MAPK pathway in prostate cancer.

Pinin (PNN), a desmosome associated protein, was demonstrated to be over-expressed and act as a tumor-promoting factor in ovarian cancer, hepatocellular carcinoma and colorectal cancer. However, the precise role of PNN in prostate cancer is still unknown. In the study, we reported that PNN was upregulated in prostate cancer tissues and PNN expression was positively associated with Gleason score, tumor stage and tumor metastasis. PNN promoted cell growth and tumorigenicity in vitro and in vivo, and modulated cell growth through driving G1/S transition via CDK6, CDK2, and Cyclin D1 in prostate cancer cells. Furthermore, PNN accelerated cell invasion, migration and EMT processes of prostate cancer cells, accompanied with the up-regulation of MMP-2, MMP-9, N-cadherin, Vimentin and down-regulation of E-cadherin. Mechanism study demonstrated that the proliferation- and motility-promoting effects of PNN on prostate cancer cells dependent on the activation of CREB, which was reversed by CREB inhibition. More important, PNN activated CREB via PI3K/AKT and ERK/MAPK pathway. Collectively, these findings indicated that PNN plays important roles in prostate cancer tumorigenesis and progression and it is a potential therapeutic target for prostate cancer treatment.

Preoperative C-reactive protein/albumin ratio to predict mortality and recurrence of patients with hepatocellular carcinoma after curative resection / Relación proteína C reactiva/albúmina preoperatoria para predecir la mortalidad y la recurrencia de los pacientes después de la resección curativa de carcinoma hepatocelular

Background & objectives: Recent studies have shown that the C-reactive protein-to-albumin ratio (CAR) can predict the mortality in patients with hepatocellular carcinoma (HCC). The aim of the present study was to investigate the utility of preoperative CAR for predicting postoperative overall and tumor free survival among HCC patients after radical surgery. Methods: Preoperative neutrophil-to-lymphocyte ratio (NLR), clinicopathological parameters, laboratory data and patient demographics of 187 patients with HCC receiving initial radical liver resection from Sir Run Run Shaw hospital were evaluated. Multivariate analyses were performed to identify clinical characteristics associated with overall survival (OS) and tumor free survival (TFS). Subsequently, the prognostic value of CAR was evaluated using the area under the curve (AUC) compared with other systemic inflammation-based prognostic scores. Results: Multivariate analysis revealed that the tumor number [hazard ratio (HR)=2.668; p=0.018] was independently associated with OS. While, the CRP/Alb ratio [HR=0.477; p=0.006] and the tumor number [HR=2.458; p=0.006] were significantly associated with TFS. The AUC values of the CRP/Alb ratio (6 months: 0.868; 12 months: 0.787; 36 months: 0.680) were higher than those of the GPS, mGPS and NLR at all time points in OS. Conclusion: Preoperative CRP/Alb ratio is an independent prognostic marker with tumor free survival in patients with HCC after curative resection and the prognostic ability was comparable to other applied inflammation-based prognostic scores in both overall and tumor-free survival, especially at the early stage

Antecedentes y objetivos: Estudios recientes han demostrado que la relación proteína C reactiva/albúmina (CAR) puede predecir la mortalidad en pacientes con carcinoma hepatocelular (HCC). El objetivo del presente estudio fue investigar la utilidad de la CAR preoperatoria para predecir la supervivencia postoperatoria general y libre de tumores entre los pacientes con HCC después de la cirugía radical. Métodos: Se evaluaron la relación preoperatoria de neutrófilos a linfocitos (NLR), los parámetros clínico-patológicos, los datos de laboratorio y los datos demográficos de 187 pacientes con HCC que recibieron resección hepática radical inicial en el Hospital Sir Run Run Shaw. Se realizaron análisis multivariables para identificar las características clínicas asociadas con la supervivencia general (SG) y la supervivencia libre de tumor (SST). Posteriormente, se evaluó el valor pronóstico de la CAR utilizando el área bajo la curva (AUC) en comparación con otras puntuaciones de pronóstico basadas en la inflamación sistémica. Resultados: El análisis multivariado reveló que el número de tumores (cociente de riesgos instantáneos [CRI]: 2,668; p=0,018) se asoció de manera independiente con la SG. Mientras, la relación CRP/Alb (hazard ratio [HR]: 0,477; p=0,006) y el número de tumores (HR: 2,458; p=0,006) se asociaron significativamente con SST. Los valores de AUC de la relación CRP/Alb (6 meses: 0,868; 12 meses: 0,787 y 36 meses: 0,680) fueron superiores a los del GPS, mGPS y NLR en todos los puntos temporales en SG. Conclusión: La proporción preoperatoria de CRP/Alb no solo puede predecir la supervivencia general en pacientes con HCC después de la resección curativa, sino que también tiene un rendimiento favorable en la predicción de recidiva tumoral, especialmente en las primeras etapas

Preoperative C-reactive protein/albumin ratio to predict mortality and recurrence of patients with hepatocellular carcinoma after curative resection.

BACKGROUND & OBJECTIVES: Recent studies have shown that the C-reactive protein-to-albumin ratio (CAR) can predict the mortality in patients with hepatocellular carcinoma (HCC). The aim of the present study was to investigate the utility of preoperative CAR for predicting postoperative overall and tumor free survival among HCC patients after radical surgery. METHODS: Preoperative neutrophil-to-lymphocyte ratio (NLR), clinicopathological parameters, laboratory data and patient demographics of 187 patients with HCC receiving initial radical liver resection from Sir Run Run Shaw hospital were evaluated. Multivariate analyses were performed to identify clinical characteristics associated with overall survival (OS) and tumor free survival (TFS). Subsequently, the prognostic value of CAR was evaluated using the area under the curve (AUC) compared with other systemic inflammation-based prognostic scores. RESULTS: Multivariate analysis revealed that the tumor number [hazard ratio (HR)=2.668; p=0.018] was independently associated with OS. While, the CRP/Alb ratio [HR=0.477; p=0.006] and the tumor number [HR=2.458; p=0.006] were significantly associated with TFS. The AUC values of the CRP/Alb ratio (6 months: 0.868; 12 months: 0.787; 36 months: 0.680) were higher than those of the GPS, mGPS and NLR at all time points in OS. CONCLUSION: Preoperative CRP/Alb ratio is an independent prognostic marker with tumor free survival in patients with HCC after curative resection and the prognostic ability was comparable to other applied inflammation-based prognostic scores in both overall and tumor-free survival, especially at the early stage.