• Lymph node metastasis
• Lymphocyte-to-monocyte ratio (LMR)
• Overall survival (OS)
• Platelet-to-lymphocyte ratio (PLR)
• Salivary adenoid cystic carcinoma (SACC)

• advanced
• antibody against programmed cell death 1
• hepatocellular carcinoma
• intensity-modulated radiotherapy
• nomogram

• the Self-Raised Scientific Research Fund of the Ministry of Health of Guangxi Province
• the Youth Program of Scientific Research Foundation of Guangxi Medical University Cancer Hospital

• Chronic liver disease
• Gut-liver axis
• Hepatic regeneration
• SSRIs
• Serotonin

• MASLD
• endothelial dysfunction
• neutrophil extracellular traps
• platelets

• PN-III-P4-ID-PCE2020-1091 Unitatea Executiva Pentru Finantarea Invatamantului Superior a Cercetarii Dezvoltarii si Inovarii

• atypical hepatocellular carcinoma
• conventional blood indicator
• derived index
• differential diagnosis
• sAGP

• This study did not receive any external funding

• Hepatocellular carcinoma
• Lymphocyte-to-monocyte ratio
• Neutrophil-to-lymphocyte ratio
• Platelet-to-lymphocyte ratio
• Prognosis
• SII
• SIRI
• Sorafenib

• hepatectomy
• hepatocellular carcinoma
• immune
• inflammatory
• recurrence

• Humans
• Carcinoma, Hepatocellular/pathology
• Hepatectomy/adverse effects
• Liver Neoplasms/pathology
• Neoplasm Recurrence, Local/surgery
• Inflammation/etiology
• Lymphocytes/pathology
• Biomarkers
• Retrospective Studies
• Prognosis
• Tumor Microenvironment

• 81972673 National Natural Science Foundation of China
• JCRCFZ-2022-028 Interdisciplinary Innovative Talents Foundation from Renmin Hospital of Wuhan University
• National Natural Science Foundation of China

• aspartate aminotransferase-to-platelet ratio index
• liver cancer
• nomogram
• pulmonary metastasis
• systemic inflammatory response index

• Humans
• Carcinoma, Hepatocellular/surgery
• Carcinoma, Hepatocellular/pathology
• Nomograms
• Liver Neoplasms/surgery
• Liver Neoplasms/pathology
• Retrospective Studies
• Prognosis
• Lung Neoplasms/surgery

• Key R & D Program Natural Science Foundation of Guangxi Province
• The Technology Development and Promotion Foundation of Guangxi Medical and Health Appropriate
• Natural Science Foundation of Guangxi Province

• Kupffer cell
• MASH
• MMP
• angiogenesis
• collagen
• endothelial cell
• monocyte
• myofibroblast

• Humans
• Carcinoma, Hepatocellular/pathology
• Esophageal and Gastric Varices/metabolism
• Esophageal and Gastric Varices/pathology
• Liver Neoplasms/pathology
• Gastrointestinal Hemorrhage
• Liver Cirrhosis
• Macrophages
• Fibrosis

• Deutsche Forschungsgemeinschaft

• aspartate aminotransferase to platelet ratio
• disease-free survival
• hepatocellular carcinoma
• overall survival

• BG20228542 Major Project of Scientific Research Foundation, Zhongshan city people's hospital
• 81871323 and 81801665 National Natural Science Foundation of China
• 2018B030311024 National Natural Science Foundation of Guangdong Province
• 21620447 the Scientific Research Cultivation and Innovation Foundation of Jinan University
• National Natural Science Foundation of China

• circulating tumor cells
• early recurrence
• hepatocellular carcinoma
• liver resection
• platelet count

• Derived indicator
• Diagnosis
• Hepatocellular carcinoma
• Prognosis
• Routine clinical indicator

Numerous studies showed that preoperative platelet-albumin-bilirubin (PALBI) grade was closely related to the prognostic outcome of patients with hepatocellular carcinoma (HCC). However, the conclusions were inconsistent. Therefore, we implemented the study to comprehensively evaluate the association between PALBI grade and prognosis in patients with HCC.

Relevant articles were collected from the specified databases until February 10, 2022. We included all studies exploring the relationship between PALBI grade and prognosis in HCC patients. We used the hazard ratio (HR) and 95% confidence interval (CI) to calculate the comprehensive analysis. All data analyses were performed using STATA 12.0.

Thirteen retrospective articles containing 15534 patients were included in the meta-analysis. The pooled results displayed that the high PALBI grade was obviously correlated with poor overall survival (OS) (HR: 1.71, 95% CI: 1.46-2.02) and disease-free survival/relapse-free survival (DFS/RFS) (HR:1.31; 95% CI: 1.11–1.54). Subgroup analyses further confirmed the reliability of the comprehensive results.

PALBI may be a valid prognostic indicator in HCC patients. More investigations were needed to test our findings.

Background: Increasing numbers of studies reported platelet (PLT)- related measures could play a creative role in many malignancies, while the prognostic impact of these measures in hepatocellular carcinoma (HCC) remains limited and controversial. It is worth exploring the predictive value of PLT-related measures in HCC. Methods: A total of 279 HCC patients with hepatectomy were analyzed in the retrospective cohort study. The optimal cut-off points of these PLT-related indices were obtained by the receiver operating characteristic (ROC) curve. The associations of these indices with clinical characteristics and overall survival (OS) were evaluated by Kaplan–Meier curves and Cox proportional hazards models. Results: High PLT count and low prognostic nutritional index (low-PNI) were significantly associated with larger tumor size. The low gamma-glutamyl transpeptidase-to-platelet ratio (low-GPR) group was inclined to more hepatitis infections. Survival curves indicated that preoperative high-PLT, low-GPR, and low-PNI had a worse prognosis after surgery in the cohort. In addition, PLT≥220 × 10⁹/L (HR, 2.274; 95% CI, 1.061-4.876; P = .035), PNI≥51.9 (HR, 0.503; 95% CI, 0.265-0.954; P = .035), and GPR≥0.2 (HR, 0.432; 95% CI, 0.204-0.912; P = .028) were identified as independent prognostic factors for survival outcomes in the multivariable analysis. Conclusion: High-PLT, low-GPR, and low-PNI as the preoperative predictors were associated with poor OS in HCC patients with hepatectomy. Our data reveal that they could be simple, easily obtained, and effective predictors for evaluation of survival outcomes in patients.

• blood platelets
• gamma-glutamyl transpeptidase-to-platelet ratio
• hepatocellular carcinoma
• prognosis
• prognostic nutritional index

Previous nomograms for hepatocellular carcinoma (HCC) did not include the neutrophil-to-lymphocyte ratio (NLR) or platelet-to-lymphocyte ratio (PLR). This study aimed to establish an effective nomogram capable of estimating the association between preoperative inflammatory factors and overall survival (OS) of HCC patients after hepatectomy.

To analyse the factors affecting the prognosis of HCC and establish a nomogram.

A total of 626 HCC patients (410 training set patients from the First Affiliated Hospital of Anhui Medical University and 216 validation set patients from the First Affiliated Hospital of University of Science and Technology of China) underwent hepatectomy from January 2014 to December 2017 and were followed up every 3–6 mo. The nomogram was based on OS-related independent risk factors identified by Cox regression analysis. The C-index, calibration curve, and area under the curve (AUC) were used to evaluate the nomogram’s accuracy.

The 1-, 2- and 3-year OS rates were 79.0%, 68.0% and 45.4% in the training cohort (median OS = 34 mo) and 92.1%, 73.9% and 51.2% in the validation cohort (median OS = 38 mo). Higher α-fetoprotein [hazard ratio (HR) = 1.812, 95% confidence interval (CI): 1.343–2.444], NLR (HR = 2.480, 95%CI: 1.856–3.312) and PLR (HR = 1.974, 95%CI: 1.490–2.616), tumour size ≥ 5 cm (HR = 1.323, 95%CI: 1.002–1.747), and poor differentiation (HR = 3.207, 95%CI: 1.944–5.290) were significantly associated with shortened OS. The developed nomogram integrating these variables showed good reliability in both the training (C-index = 0.71) and validation cohorts (C-index = 0.75). For predicting 1-, 2- and 3-year OS, the nomogram had AUCs of 0.781, 0.743 and 0.706 in the training cohort and 0.789, 0.815 and 0.813 in the validation cohort. The nomogram was more accurate in predicting prognosis than the AJCC TNM staging system.

The prognostic nomogram combining pathological characteristics and inflammation indicators could provide a more accurate individualized risk estimate for the OS of HCC patients with hepatectomy.

• Liver malignancy
• Nomogram
• Overall survival
• Neutrophil-to-lymphocyte ratio
• Platelet-to-lymphocyte ratio

The prognostic values of the neutrophil-to-lymphocyte ratio (NLR) and the platelet-to-lymphocyte ratio (PLR) in predicting the in-hospital mortality of Black African patients with advanced hepatocellular carcinoma (HCC) in palliative treatment is unknown.

To determine the prognostic value of NLR and PLR compared with that of Child–Turcotte–Pugh (CTP), model for end-stage liver disease (MELD) scores and the Barcelona clinic liver cancer staging system (BCLC).

The cutoffs, accuracies and association with the mortality of these prognostic scores were determined using a time-dependent area under receiver operating characteristic curves (AUC), the log rank test and Cox proportional hazards ratio.

A total of 104 patients with advanced HCC (median age=49.5 years, males=58.7%) were enrolled. All were hospitalized for an enlarged liver mass of at least 15.4 cm in size in the right thoracic quadrant. Overall, 46 (44.2%) patients died in hospital during follow-up. Patients with NLR >2.5 (log rank test=7.11, p=0.01) or PLR >92 (log rank test=5.63, p=0.02) had poor survival. Factors associated with the in-hospital mortality were the MELD score (p=0.01), NLR (p=0.03) and hemoglobin level (p=0.02). NLR exhibits better and stable accuracy in predicting the in hospital mortality at time points of 30 (AUC=0.618), 60 (AUC=0.680) and 90 (AUC=0.613) days of follow-up, compared with CTP, MELD scores, BCLC and PLR. However, PLR displayed an enhanced accuracy over 90 days of follow up (AUC=0.688).

NLR is useful in predicting the in-hospital mortality in Black African patients with advanced stage HCC in clinical practice. NLR and PLR may be used concomitantly for long-term follow-up.

• hepatocellular carcinoma
• neutrophil-to-lymphocyte ratio
• prognosis
• sub-Saharan Africa

• cancer microenvironment
• tumour biomarkers
• liver cancer
• predictive markers
• drug development
• acetylation
• phosphorylation
• cell invasion
• cell growth
• mechanisms of disease

Platelets are tightly connected with the liver, as both their production and their clearance are mediated by the liver. Platelets, in return, participate in a variety of liver diseases, ranging from non-alcoholic fatty liver diseases, (viral) hepatitis, liver fibrosis and hepatocellular carcinoma to liver regeneration. Due to their versatile functions, which include (1) regulation of hemostasis, (2) fine-tuning of immune responses and (3) release of growth factors and cellular mediators, platelets quickly adapt to environmental changes and modulate disease development, leading to different layers of complexity. Depending on the (patho)physiological context, platelets exert both beneficial and detrimental functions. Understanding the precise mechanisms through which platelet function is regulated at different stages of liver diseases and how platelets interact with various resident and non-resident liver cells helps to draw a clear picture of platelet-related therapeutic interventions. Therefore, this review summarizes the current knowledge on platelets in acute and chronic liver diseases and aims to shed light on how the smallest cells in the circulatory system account for changes in the (patho)physiology of the second largest organ in the human body.

• HCC
• NASH
• liver
• liver regeneration
• non-alcoholic fatty liver disease
• platelets

The prognosis for patients diagnosed of hepatocellular carcinoma (HCC) who have extrahepatic metastasis after liver resection is unsatisfactory. This study aimed to find out the relationship between the inflammation-related indexes and metastasis.

One thousand three hundred and sixty-six patients diagnosed of HCC who underwent curative resection were included in this study and divided into metastasis group (n=180) and non-metastasis group (n=1186). A receiver operating characteristic (ROC) curve was constructed to estimate the optimal cut-off value for inflammation-related indexes. Independent risk factors were identified by Cox regression analysis. The metastasis rate was analyzed by the Kaplan-Meier method, then the subgroup analyses were taken.

The cut-off values of NLR, PLR, LMR, NγLR, PNLR, and PNI were 2.65, 107.67, 5.47, 134.52, 335.03, and 51.23, respectively. Multivariate Cox analysis revealed that elevated serum AFP level (P=0.004), tumor size more than 5cm (P<0.001), multiple tumors (P=0.040), and higher PLR (P=0.042) were independent risk factors associated with extrahepatic metastasis. The Kaplan-Meier method showed that the high PLR group has a higher extrahepatic metastasis rate than the low PLR group. Meanwhile, the results of subgroup analyses were consistent with the conclusion.

The PLR is an independent risk factor of extrahepatic metastasis after radical hepatectomy for HCC patients. The high PLR indicates a higher rate of extrahepatic metastasis.

• extrahepatic metastasis
• hepatocellular carcinoma
• inflammation-related indexes
• liver resection

Thrombocytopenia was reported both detrimental and advantageous to hepatocellular carcinoma (HCC). However, there is little evidence showing clearly the clinical value of preoperative thrombocytopenia on the surgical outcome of patients with small HCC. This retrospective study aimed at elucidating the correlation between preoperative thrombocytopenia and surgical outcome of small HCC patients within Milan criteria treated with liver resection.

Data of hepatitis B virus (HBV)-related small HCC patients were retrospectively analyzed, and we performed the propensity score matching (PSM) analysis to overcome the imbalance of clinicopathological features. Patients enrolled were subsequently categorized into two groups according to preoperative platelet counts: thrombocytopenia group and non-thrombocytopenia group. Survival outcomes of the patients in both groups were described with the Kaplan-Meier method, and the difference was compared with a log-rank test. Cox regression analysis was applied to identify the risk factors of surgical outcome.

After PSM, the estimated 1-, 3-, and 5-year overall survival (OS) rates for small HCC patients in the thrombocytopenia group were 94.5%, 77.0%, and 57.6%, and 95.0%, 79.6%, and 68.0%, respectively, for small HCC patients in the non-thrombocytopenia group (P = 0.042). And the 1-, 3-, and 5-year estimated recurrence-free survival (RFS) rates for small HCC patients in the thrombocytopenia group were 70.4%, 51.0%, and 42.1%, and 83.8%, 63.7%, and 46.7%, respectively, for small HCC patients in the non-thrombocytopenia group (P = 0.035). Multivariate analysis indicated preoperative thrombocytopenia was a significant prognosticator of poor RFS (hazard ratio (HR) = 1.388, 95% confidence interval (CI) 1.028~1.874, P = 0.033).

Preoperative thrombocytopenia had an undesirable impact on the recurrence of small HCC patients treated with liver resection.

The online version contains supplementary material available at 10.1186/s12957-021-02160-2.

• Hepatocellular carcinoma
• Liver resection
• Platelet
• Thrombocytopenia

• Anti-metastasis
• Caulis Spatholobi
• Colon cancer
• TCIPA

Integrin-mediated platelet-tumor cell contacting plays an important role in promoting epithelial-mesenchymal transition (EMT) transformation of tumor cells and cancer metastasis, but whether it occurs in breast cancer cells is not completely clear.

The purpose of this study was to investigate the role of integrin α2β1 in platelet contacting to human breast cancer cell line MCF-7 and its effect on the EMT and the invasion of MCF-7 cells.

Human platelets were activated by thrombin, and separated into pellets and releasates before the co-incubation with MCF-7 cells. Cell invasion was evaluated by transwell assay. The surface integrins on pellets and MCF-7 cells were inhibited by antibodies. The effect of integrin α2β1 on Wnt-β-catenin pathway was assessed by integrin α2β1-silencing and Wnt-β-catenin inhibitor XAV. The therapeutic effect of integrin α2β1-silencing was confirmed in the xenograft mouse model.

Pellets promote the invasion and EMT of MCF-7 cells via direct contacting of surface integrin α2β1. The integrin α2β1 contacting activates Wnt-β-catenin pathway and promotes the expression of EMT proteins in MCF-7 cells. The activated Wnt-β-catenin pathway also promotes the autocrine of TGF-β1 in MCF-7 cells. Both Wnt-β-catenin and TGF-β1/pSmad3 pathways promote the expression of EMT proteins. Integrin α2β1-silencing inhibits breast cancer metastasis in vivo.

The direct interaction between platelets and tumor cells exerts its pro-metastatic function via surface integrin α2β1 contacting and Wnt-β-catenin activation. Integrin α2β1-silencing has the potential effect of inhibiting breast cancer metastasis.

• Direct interaction
• Epithelial-mesenchymal transition
• MCF-7 cell
• Platelet
• TGF-β1
• Wnt-β-catenin

• HCC
• hepatocellular carcinoma
• inflammation
• prognosis
• survival

• Cytokines
• Hepatitis C virus
• IL-1
• IL-6
• Serum amyloid A
• TNF-α

• albumin-bilirubin
• child–pugh
• hepatocellular carcinoma
• platelet-albumin-bilirubin
• survival

• Adult
• Bilirubin/blood
• Biomarkers, Tumor/blood
• Blood Platelets/metabolism
• Carcinoma, Hepatocellular/blood
• Carcinoma, Hepatocellular/mortality
• Carcinoma, Hepatocellular/virology
• Female
• Hepatectomy/mortality
• Hepatitis B/complications
• Humans
• Kaplan-Meier Estimate
• Liver Neoplasms/blood
• Liver Neoplasms/mortality
• Liver Neoplasms/virology
• Male
• Middle Aged
• Platelet Count
• Prognosis
• Proportional Hazards Models
• Retrospective Studies
• Serum Albumin/analysis
• Severity of Illness Index
• Treatment Outcome

• Curative resection
• Platelet-based nomogram
• hepatocellular carcinoma

In hepatocarcinogenesis induced by diethylnitrosamine (DEN) in B6C3F1 mice, the BrafV637E mutation, corresponding to the human BRAFV600E mutation, plays a pivotal role. The livers of transgenic mice with a hepatocyte‐specific human BRAFV600E mutation weighed 4.5 times more than that of normal mice and consisted entirely of hepatocytes, resembling DEN‐induced preneoplastic hepatocytes. However, these transgenic mice spontaneously died 7 wk after birth, therefore this study aimed to clarify the causes of death. In the transgenic mice, the liver showed thrombopoietin (TPO) overexpression, which is associated with eventual megakaryocytosis and thrombocytosis, and activated platelets were deposited in hepatic sinusoids. TPO was also overexpressed in the DEN‐induced hepatic tumors, and sinusoidal platelet deposition was observed in the hepatic tumors of humans and mice. Podoplanin was expressed in some of the Kupffer cells in the liver of the transgenic mice, indicating that platelet activation occurred via the interaction of podoplanin with C‐type lectin receptor 2 (CLEC‐2) on the platelet membrane. Additionally, erythrocyte dyscrasia and glomerulonephropathy/interstitial pneumonia associated with platelet deposition were observed. In the transgenic mice, aspirin (Asp) administration prevented platelet activation, reduced the liver/body weight ratio, decreased the platelet deposition in the liver, kidney, and lung, and prevented erythrocyte dyscrasia and ameliorated the renal/pulmonary changes. Thrombopoietin overproduction by BRAFV600E‐mutated hepatocytes may contribute to hepatocyte proliferation via thrombocytosis, platelet activation, and the interaction of platelets with hepatic sinusoidal cells, while hematologic, renal, and pulmonary disorders due to aberrant platelet activation may lead to spontaneous death in the transgenic mice.

• hepatic sinusoidal cells
• hepatocarcinogenesis
• platelets
• preneoplastic hepatocytes
• thrombopoietin

A definitive diagnosis of focal liver lesions (FLLs) requires invasive procedures for histopathologic examination. Thus, a simpler noninvasive diagnostic method, such as conventional ultrasonography combined with clinical data, is needed for the prediction of liver malignancy. The objective of this study was to examine the diagnostic accuracy of clinical data and ultrasonographic (US) features to differentiate benign and malignant liver lesions. Medical records and US images from dogs with FLLs that underwent abdominal US and histopathologic examinations following surgery or liver biopsy were retrospectively reviewed. Clinical data, including signalment, clinical signs and laboratory findings, and the US features of liver lesions that could act as predictive factors were assessed using univariate and multivariate analyses to evaluate the associations between predictive factors and liver malignancy. Based on the histopathologic results, 55 dogs with malignant lesions and 28 dogs with benign lesions were included in the study. The results of univariate analysis showed that several US features and platelet count were significantly associated with liver malignancy. Multivariate analysis revealed that the platelet count (thrombocytosis; odds ratio [OR]: 4.13, 95% confidence intervals [CI]: 1.81−9.41), lesion size (4.1 cm or greater; OR: 23.83, 95% CI: 3.74−151.95) and echotexture of FLLs (heterogenous; OR: 8.44; 95% CI: 1.37−51.91) were independent predictors for differentiating benign and malignant liver lesions, suggesting that a combination of clinical data and US findings of FLLs could predict liver malignancy in dogs.

• canine
• classification
• liver nodule
• malignancy
• ultrasonography

• Alpha-fetoprotein
• Biomarker
• Hepatocellular carcinoma
• Liver transplantation
• Prognostic score
• Recurrence
• Selection criteria
• Systemic inflammatory marker

• extrahepatic metastasis
• hepatoma
• nomogram
• platelet

• Aggressiveness
• C-reactive protein
• Hepatocellular carcinoma
• Neutrophil-lymphocyte ratio
• Platelet-lymphocyte ratio

• Hepatocellular cancer
• Inflammation
• Liver transplantation
• Platelet-to-lymphocyte ratio
• Recurrence

• Blood Platelets
• Carcinoma, Hepatocellular/blood
• Carcinoma, Hepatocellular/pathology
• Carcinoma, Hepatocellular/surgery
• Humans
• Liver Neoplasms/blood
• Liver Neoplasms/pathology
• Liver Neoplasms/surgery
• Liver Transplantation
• Lymphocyte Count
• Lymphocytes
• Neoplasm Recurrence, Local/epidemiology
• Platelet Count
• Postoperative Period
• Preoperative Period
• Risk Factors

• HCV
• MICA
• genetic association study
• hepatocellular carcinoma
• liver cirrhosis

• platelet
• liver
• cirrhosis
• regeneration
• inflammation

• Blood Platelets/metabolism
• Humans
• Inflammation/blood
• Inflammation/pathology
• Liver Cirrhosis/blood
• Liver Cirrhosis/pathology
• Liver Diseases/blood
• Liver Diseases/pathology
• Liver Regeneration/physiology

• R01 ES017537 NIEHS NIH HHS

The multikinase inhibitor sorafenib is the only currently approved drug for the indication of advanced hepatocellular carcinoma (HCC). It provides a limited gain in survival time but is frequently associated with adverse events. We currently lack simple prognostic factors in sorafenib-treated HCC patients. Various inflammation-based scores (IBSs) have been evaluated as predictors of tumor recurrence and survival in various malignancies (including HCC). The objective of the present study was to determine the prognostic value of IBSs for overall survival (OS) in advanced HCC patients prior to the initiation of sorafenib therapy.

Patients with Barcelona Clinic Liver Cancer stage C HCC were enrolled retrospectively between October 2007 and September 2015. To identify prognostic factors for OS, bivariate and multivariate analysis were performed using a Cox proportional hazards regression model.

161 patients (87.0% males; median age: 67; median OS: 9.1 months) were enrolled. A multivariate analysis identified a body mass index <25kg/m² (hazard ratio (HR)=1.55, p<0.017), macroscopic vascular invasion (HR=1.63, p< 0.001), an AST level >38 U/L (HR=2.65, p<0.001), Child Pugh B stage (HR=2.59, p<0.001) and a systemic immune-inflammation index (SII) ≥600 × 10⁹ (HR 1.72, p=0.002) as independent risk factors for OS in advanced HCC.

IBSs (such as the SII) are novel, simple, low-cost prognostic indices in patients with advanced HCC. They may be of value in determining whether these patients may benefit from sorafenib therapy.

• HCC
• inflammation-based scores
• prognostic factor
• sorafenib

• Inflammation
• Neoplasia
• Platelets
• Pseudohyperkalemia