DGPRI, a new liver fibrosis assessment index, predicts recurrence of AFP-negative hepatocellular carcinoma after hepatic resection: a single-center retrospective study.

Although patients with alpha-fetoprotein-negative hepatocellular carcinoma (AFPNHCC) have a favorable prognosis, a high risk of postoperative recurrence remains. We developed and validated a novel liver fibrosis assessment index, the direct bilirubin-gamma-glutamyl transpeptidase-to-platelet ratio (DGPRI). DGPRI was calculated for each of the 378 patients with AFPNHCC who underwent hepatic resection. The patients were divided into high- and low-score groups using the optimal cutoff value. The Lasso-Cox method was used to identify the characteristics of postoperative recurrence, followed by multivariate Cox regression analysis to determine the independent risk factors associated with recurrence. A nomogram model incorporating the DGPRI was developed and validated. High DGPRI was identified as an independent risk factor (hazard ratio = 2.086) for postoperative recurrence in patients with AFPNHCC. DGPRI exhibited better predictive ability for recurrence 1-5 years after surgery than direct bilirubin and the gamma-glutamyl transpeptidase-to-platelet ratio. The DGPRI-nomogram model demonstrated good predictive ability, with a C-index of 0.674 (95% CI 0.621-0.727). The calibration curves and clinical decision analysis demonstrated its clinical utility. The DGPRI nomogram model performed better than the TNM and BCLC staging systems for predicting recurrence-free survival. DGPRI is a novel and effective predictor of postoperative recurrence in patients with AFPNHCC and provides a superior assessment of preoperative liver fibrosis.

Construction and Validation of a Novel Nomogram Predicting Recurrence in Alpha-Fetoprotein-Negative Hepatocellular Carcinoma Post-Surgery Using an Innovative Liver Function-Nutrition-Inflammation-Immune (LFNII) Score: A Bicentric Investigation.

Purpose: We developed a nomogram based on the liver function, nutrition, inflammation, and immunity (LFNII) score to predict recurrence-free survival (RFS) post-resection in patients with hepatocellular carcinoma (HCC) exhibiting alpha-fetoprotein (AFP) negativity (AFP ≤20 ng/mL). Patients and Methods: Clinical data of 661 patients diagnosed with alpha-fetoprotein-negative hepatocellular carcinoma (AFP-NHCC) who underwent surgical resection at two medical centers between 2012 and 2021 were collected. A total of 462 and 199 patients served as the training and validation sets, respectively. Pre-operative blood markers were collected and analyzed for LFNII. The LFNII score was formulated using the least absolute shrinkage and selection operator Cox regression model. A nomogram model was developed using the training set to incorporate other relevant clinicopathological indicators and predict postoperative recurrence. Model discrimination was assessed using the receiver operating characteristic curve, calibration was evaluated using a calibration curve, and clinical applicability was assessed using clinical decision curve analysis. A comparison with liver cancer staging was performed using the nomogram model. Finally, a cohort study was conducted to validate our findings. Results: We derived the LFNII scores from nine indicators. Elevated LFNII scores correlated with unfavorable clinicopathological features. The LFNII score area under the curve revealed superior predictive efficacy at 1-, 2-, and 5-year RFS intervals, with values of 0.675, 0.658, and 0.633, respectively. Multivariate Cox analysis revealed that a high LFNII score independently increased RFS risk in patients with AFP-NHCC. The C-index of the LFNII-nomogram model was 0.686 (95% confidence interval [CI], 0.651-0.721). The nomogram model's clinical application value surpassed that of standard HCC staging systems. Conclusion: The LFNII score-derived nomogram effectively predicted the RFS of patients with AFP-NHCC after curative resection.

Prediction of electrical properties of GAAFET based on integrated learning model.

As device feature sizes continue to decrease and fin field effect transistors reach their physical limits, gate all around field effect transistors (GAAFETs) have emerged with larger gate control areas and stackable characteristics for better suppression of second-order effects such as short-channel effects due to their gate encircling characteristics. Traditional methods for studying the electrical characteristics of devices are mostly based on the technology computer-aided design. Still, it is not conducive to developing new devices due to its time-consuming and inefficient drawbacks. Deep learning (DL) and machine learning (ML) have been well-used in recent years in many fields. In this paper, we propose an integrated learning model that integrates the advantages of DL and ML to solve many problems in traditional methods. This integrated learning model predicts the direct current characteristics, capacitance characteristics, and electrical parameters of GAAFET better than those predicted by DL or ML methods alone, with a linear regression factor (R2) greater than 0.99 and very small root mean square error. The proposed integrated learning model achieves fast and accurate prediction of GAAFET electrical characteristics, which provides a new idea for device and circuit simulation and characteristics prediction in microelectronics.

Effect of liver metastasis on the efficacy of immune checkpoint inhibitors in cancer patients: a systemic review and meta-analysis.

Liver metastasis is a frequent phenomenon in advanced tumor disease. Immune checkpoint inhibitors (ICIs) are a new class of therapeutics that can improve the prognosis of cancer patients. The purpose of this study is to elucidate the relationship between liver metastasis and survival outcomes of patients receiving ICIs treatment. We searched four main databases, including PubMed, EMBASE, Cochrane Library, and Web of Science. Overall survival (OS) and progression-free survival (PFS) were the survival outcomes of our concern. Hazard ratio (HR) with 95% confidence interval (CI) were used to evaluate the relationship between liver metastasis and OS/ PFS. Finally, 163 articles were included in the study. The pooled results showed that patients with liver metastasis receiving ICIs treatment had worse OS (HR=1.82, 95%CI:1.59-2.08) and PFS (HR=1.68, 95%CI:1.49-1.89) than patients without liver metastasis. The effect of liver metastasis on ICIs efficacy differed in different tumor types, and patients with urinary system tumors (renal cell carcinoma OS: HR=2.47, 95%CI:1.76-3.45; urothelial carcinoma OS: HR=2.37, 95%CI:2.03-2.76) had the worst prognosis, followed by patients with melanoma (OS: HR=2.04, 95%CI:1.68-2.49) or non-small cell lung cancer (OS: HR=1.81, 95%CI:1.72-1.91). ICIs efficacy in digestive system tumors (colorectal cancer OS: HR=1.35, 95%CI:1.07-1.71; gastric cancer/ esophagogastric cancer OS: HR=1.17, 95%CI:0.90-1.52) was less affected, and peritoneal metastasis and the number of metastases have a greater clinical significance than liver metastasis based on univariate data. For cancer patients receiving ICIs treatment, the occurrence of liver metastasis is associated with poor prognosis. Different cancer types and metastatic sites may hold a different prognostic effect on the efficacy of ICIs treatment in cancer patients.

Tenofovir versus entecavir on the prognosis of hepatitis B virus-related hepatocellular carcinoma: a systematic review and meta-analysis.

BACKGROUND: Tenofovir (TDF) and entecavir (ETV) are first-line treatments for patients with chronic hepatitis B virus (HBV) infection. However, the effect of TDF versus ETV on the prognosis of HBV-related hepatocellular carcinoma (HCC) has not been fully clarified yet. RESEARCH DESIGN AND METHODS: PubMed, Embase and Web of science were searched up to March, 2021. Meta-analyses were performed for overall survival (OS), disease-free survival (DFS) and recurrence-free survival (RFS) to assess the effect of TDF versus ETV on the prognosis of HBV-related HCC. RESULTS: A total of 10 studies comprising 4706 Asian patients were included. The pooled results revealed that TDF was associated with better OS (adjusted HR = 0.50, 95% CI: 0.40-0.62; I2 = 36.0%, p = 0.167) and better RFS/DFS (adjusted HR = 0.70, 95% CI: 0.55-0.89, I2 = 71.9%, p = 0.002) than ETV in treatment of HBV-related HCC. Subgroup analysis revealed that OS benefit from TDF was generally consistent, except for patients who underwent non-surgical treatment for HCC. Subgroup analysis also indicated that TDF reduces the risk of late recurrence (HR = 0.41, 95% CI: 0.18-0.0.93; I2 = 63.0%, p = 0.067) rather than early recurrence (HR = 0.99, 95% CI: 0.64-1.52; I2 = 61.3%, p = 0.076). CONCLUSIONS: Compared with ETV, TDF has the advantage of improving OS and reducing late recurrence of patients with HBV-related HCC patients who underwent resection.

Identification of the most effective subgroup of advanced hepatocellular carcinoma from immune checkpoint blocker treatment: a meta-analysis.

Aims: This work was designed to identify the subgroup of advanced hepatocellular carcinoma (HCC) patients for whom treatments containing immune checkpoint blockers (ICBs) were most effective. Materials & methods: A meta-analysis was performed to explore the subgroup population with the greatest benefit of treatments containing ICBs. Results: A total of 2228 patients from four randomized control trials were included. Treatments containing ICBs had better overall survival, progression-free survival and higher objective response rate over treatment without ICBs. Subgroup analysis revealed that treatments containing ICBs were highly effective in improving the overall survival of males, patients with macrovascular invasion and/or extrahepatic spread and viral-related HCC patients. Conclusion: Treatments containing ICBs are more effective for males, patients with macrovascular invasion and/or extrahepatic spread and viral-related HCC patients.

Immune checkpoint blockers (ICBs) have significantly improved the prognosis of advanced cancers. However, some patients still cannot benefit from ICBs. The use of ICBs in the treatment of advanced hepatocellular carcinoma (HCC) started late. The subgroup of advanced HCC patients that will benefit most from treatments containing ICBs is still largely unknown. Therefore, a meta-analysis (meta-analysis is a statistical method used to compare or synthesize research results on the same scientific problem) was performed to explore the subgroup population with the greatest benefit of treatments containing ICBs (ICBs alone or in combination with anti-VEGF agents). The results show that treatments containing ICBs are more effective for males, patients with macrovascular invasion and/or extrahepatic spread and viral-related HCC patients.

Application of machine learning algorithms in electronic medical records to predict amputation-free survival after first revascularization in patients with peripheral artery disease.

BACKGROUND: This study aimed to apply eight machine learning algorithms to develop the optimal model to predict amputation-free survival (AFS) after first revascularization in patients with peripheral artery disease (PAD). METHODS: Among 2130 patients from 2011 to 2020, 1260 patients who underwent revascularization were randomly assigned to training set and validation set in an 8:2 ratio. 67 clinical parameters were analyzed by lasso regression analysis. Logistic regression, gradient boosting machine, random forest, decision tree, eXtreme gradient boosting, neural network, Cox regression, and random survival forest (RSF) were applied to develop prediction models. The optimal model was compared with GermanVasc score in testing set comprising patients from 2010. RESULTS: The postoperative 1/3/5-year AFS were 90%, 79.4%, and 74.1%. Age (HR:1.035, 95%CI: 1.015-1.056), atrial fibrillation (HR:2.257, 95%CI: 1.193-4.271), cardiac ejection fraction (HR:0.064, 95%CI: 0.009-0.413), Rutherford grade ≥ 5 (HR:1.899, 95%CI: 1.296-2.782), creatinine (HR:1.03, 95%CI: 1.02-1.04), surgery duration (HR:1.03, 95%CI: 1.01-1.05), and fibrinogen (HR:1.292, 95%CI: 1.098-1.521) were independent risk factors. The optimal model was developed by RSF algorithm, with 1/3/5-year AUCs in training set of 0.866 (95% CI:0.819-0.912), 0.854 (95% CI:0.811-0.896), 0.844 (95% CI:0.793-0.894), in validation set of 0.741 (95% CI:0.580-0.902), 0.768 (95% CI:0.654-0.882), 0.836 (95% CI:0.719-0.953), and in testing set of 0.821 (95%CI: 0.711-0.931), 0.802 (95%CI: 0.684-0.919), 0.798 (95%CI: 0.657-0.939). The c-index of the model outperformed GermanVasc Score (0.788 vs 0.730). A dynamic nomogram was published on shinyapp (https://wyy2023.shinyapps.io/amputation/). CONCLUSION: The optimal prediction model for AFS after first revascularization in patients with PAD was developed by RSF algorithm, which exhibited outstanding prediction performance.

A novel prognostic scoring model based on copper homeostasis and cuproptosis which indicates changes in tumor microenvironment and affects treatment response.

Background: Intracellular copper homeostasis requires a complex system. It has shown considerable prospects for intervening in the tumor microenvironment (TME) by regulating copper homeostasis and provoking cuproptosis. Their relationship with hepatocellular carcinoma (HCC) remains elusive. Methods: In TCGA and ICGC datasets, LASSO and multivariate Cox regression were applied to obtain the signature on the basis of genes associated with copper homeostasis and cuproptosis. Bioinformatic tools were utilized to reveal if the signature was correlated with HCC characteristics. Single-cell RNA sequencing data analysis identified differences in tumor and T cells' pathway activity and intercellular communication of immune-related cells. Real-time qPCR analysis was conducted to measure the genes' expression in HCC and adjacent normal tissue from 21 patients. CCK8 assay, scratch assay, transwell, and colony formation were conducted to reveal the effect of genes on in vitro cell proliferation, invasion, migration, and colony formation. Results: We constructed a five-gene scoring system in relation to copper homeostasis and cuproptosis. The high-risk score indicated poor clinical prognosis, enhanced tumor malignancy, and immune-suppressive tumor microenvironment. The T cell activity was markedly reduced in high-risk single-cell samples. The high-risk HCC patients had a better expectation of ICB response and reactivity to anti-PD-1 therapy. A total of 156 drugs were identified as potential signature-related drugs for HCC treatment, and most were sensitive to high-risk patients. Novel ligand-receptor pairs such as FASLG, CCL, CD40, IL2, and IFN-Ⅱ signaling pathways were revealed as cellular communication bridges, which may cause differences in TME and immune function. All crucial genes were differentially expressed between HCC and paired adjacent normal tissue. Model-constructed genes affected the phosphorylation of mTOR and AKT in both Huh7 and Hep3B cells. Knockdown of ZCRB1 impaired the proliferation, invasion, migration, and colony formation in HCC cell lines. Conclusion: We obtained a prognostic scoring system to forecast the TME changes and assist in choosing therapy strategies for HCC patients. In this study, we combined copper homeostasis and cuproptosis to show the overall potential risk of copper-related biological processes in HCC for the first time.

Efficacy and safety of immune checkpoint inhibitors for hepatocellular carcinoma patients with macrovascular invasion or extrahepatic spread: a systematic review and meta-analysis of 54 studies with 6187 hepatocellular carcinoma patients.

BACKGROUND AND AIMS: The impacts of macrovascular invasion (MVI) or extrahepatic spread (EHS) on the efficacy and safety of immune checkpoint inhibitors (ICIs) among hepatocellular carcinoma (HCC) patients remain unclear. Thus, we conducted a systematic review and meta-analysis to clarify whether ICI therapy is a feasible treatment option for HCC with MVI or EHS. METHODS: Eligible studies published before September 14, 2022, were retrieved. In this meta-analysis, the objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and occurrence of adverse events (AEs) were outcomes of interest. RESULTS: Fifty-four studies involving 6187 individuals were included. The findings indicated that the presence of EHS in ICI-treated HCC patients may indicate an inferior ORR (OR 0.77, 95% CI 0.63-0.96), but may not significantly affect the PFS (multivariate analyses: HR 1.27, 95% CI 0.70-2.31) and OS (multivariate analyses: HR 1.23, 95% CI 0.70-2.16). Additionally, the presence of MVI in ICI-treated HCC patients may not have significant prognostic impact on ORR (OR 0.84, 95% CI 0.64-1.10), but may indicate inferior PFS (multivariate analyses: HR 1.75, 95% CI 1.07-2.84) and OS (multivariate analyses: HR 2.03, 95% CI 1.31-3.14). The presence of EHS or MVI in ICI-treated HCC patients may not significantly impact the occurrence of any serious immune-related adverse events (irAEs) (grades ≥ 3) (EHS: OR 0.44, 95% CI 0.12-1.56; MVI: OR 0.68, 95% CI 0.24-1.88). CONCLUSION: The presence of MVI or EHS in ICI-treated HCC patients may not significantly impact the occurrence of serious irAEs. However, the presence of MVI (but not EHS) in ICI-treated HCC patients may be a significant negative prognostic factor. Therefore, ICI-treated HCC patients with MVI warrant more attention.

Systemic therapy with or without locoregional therapy for advanced hepatocellular carcinoma: A systematic review and network meta-analysis.

We aim to identify the optimal treatment option of systemic therapy with or without locoregional therapy for advanced hepatocellular carcinoma (HCC). Outcomes of interest include overall survival (OS), progression-free survival (PFS), objective response rate (ORR), grade 3-4 treatment-related adverse events (TRAEs), and incidence of treatment discontinuation due to AEs. The surface under the cumulative ranking curve (SUCRA) probability values were applied to rank the interventions. 23 randomized-controlled trials including 14,303 patients with advanced HCC were included. Lenvatinib plus transcatheter arterial chemoembolization (TACE) ranked best regarding OS benefit (SUCRA: 0.99). Immuno-oncology (IO)-multikinase inhibitor (MKI)/vascular endothelial growth factor (VEGF) inhibitor combinations had a higher probability of providing better OS than IO-IO combinations. IO monotherapies demonstrated superior safety profile while combination therapies caused more toxicity in general. We conclude that combination therapies achieve remarkable efficacy in patients with advanced HCC and clinical decision making requires a careful balance of efficacy versus risk.

Mesenchymal Stromal/Stem Cell (MSC)-Based Vector Biomaterials for Clinical Tissue Engineering and Inflammation Research: A Narrative Mini Review.

Mesenchymal stromal/stem cells (MSCs) have the ability of self-renewal, the potential of multipotent differentiation, and a strong paracrine capacity, which are mainly used in the field of clinical medicine including dentistry and orthopedics. Therefore, tissue engineering research using MSCs as seed cells is a current trending directions. However, the healing effect of direct cell transplantation is unstable, and the paracrine/autocrine effects of MSCs cannot be effectively elicited. Tumorigenicity and heterogeneity are also concerns. The combination of MSCs as seed cells and appropriate vector materials can form a stable cell growth environment, maximize the secretory features of stem cells, and improve the biocompatibility and mechanical properties of vector materials that facilitate the delivery of drugs and various secretory factors. There are numerous studies on tissue engineering and inflammation of various biomaterials, mainly involving bioceramics, alginate, chitosan, hydrogels, cell sheets, nanoparticles, and three-dimensional printing. The combination of bioceramics, hydrogels and cell sheets with stem cells has demonstrated good therapeutic effects in clinical applications. The application of alginate, chitosan, and nanoparticles in animal models has also shown good prospects for clinical applications. Three-dimensional printing technology can circumvent the shortage of biomaterials, greatly improve the properties of vector materials, and facilitate the transplantation of MSCs. The purpose of this narrative review is to briefly discuss the current use of MSC-based carrier biomaterials to provide a useful resource for future tissue engineering and inflammation research using stem cells as seed cells.

Hepatitis B virus reactivation in patients undergoing immune checkpoint inhibition: systematic review with meta-analysis.

PURPOSE: Immune checkpoint inhibitors (ICIs) have been explored as first-line treatment in various types of previously untreatable malignancies, while limited evidence is available on the management of hepatitis B virus (HBV) in patients undergoing immunotherapy. We systematically reviewed data concerning challenges of hepatic adverse events including HBV reactivation and hepatitis in patients with chronic HBV infection undergoing immunotherapy. METHODS: A systematic search was conducted in Medline, web of science, Embase and Cochrane library up to May 31, 2022. Studies reporting the safety profile of ICIs in patients with HBV infection were eligible. Meta-analyses were conducted to generate odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: A total of 13 studies including 2561 patients were included for meta-analysis. The overall incidence rates of HBV reactivation in patients with chronic HBV infection and past HBV infection were 1.0% (95% CI 0-3%) and 0% (95% CI 0-0%), respectively. Among patients with chronic HBV infection, the incidence rates of HBV reactivation were 1.0% (95% CI 0-2%) and 10.0% (95% CI 4-18%) for patients with and without antiviral prophylaxis, respectively. Patients with chronic HBV infection were at a higher risk of HBV reactivation compared with those with past HBV infection [OR = 8.69, 95% CI (2.16-34.99)]. Antiviral prophylaxis significantly reduced the risk of HBV reactivation [OR = 0.12, 95% CI (0.02-0.67)] and HBV-associated hepatitis [OR = 0.05, 95% CI (0.01-0.28)] in patients with chronic HBV infection. CONCLUSIONS: Prophylactic antiviral therapy should be administered to patients with chronic HBV infection undergoing anticancer immunotherapy. Patients with past HBV infection are at lower risk of HBV reactivation compared with those with chronic HBV infection, they could be initiated with antiviral prophylaxis or monitored with the intent of on-demand antiviral therapy.

Evaluating liver function and the impact of immune checkpoint inhibitors in the prognosis of hepatocellular carcinoma patients: A systemic review and meta-analysis.

BACKGROUND: Most patients with hepatocellular carcinoma (HCC) have underlying cirrhosis and a compromised liver function. Immune checkpoint inhibitors (ICIs) have emerged as an important approach for HCC treatment. The purpose of our study was to explore the prognostic significance of liver function in HCC patients receiving ICIs. METHODS: Hazard ratios (HR) with 95% confidence intervals (CI) were used to evaluate the relationship between liver function and overall survival (OS)/progression-free survival (PFS). RESULTS: 41 articles with 4483 patients with HCC were included. The pooled results revealed that either Child-Pugh score (OS:HR = 2.01,95 %CI:1.69-2.38; PFS:HR = 1.39,95 %CI:1.15-1.68) or albumin-bilirubin (ALBI) score (OS:HR = 2.04,95 %CI:1.55-2.69; PFS:HR = 1.42,95 %CI:1.21-1.67) can predict the patient prognosis. The Child-Pugh score has some degree of subjectivity, and the ALBI score can better stratify patients. Therefore, the ALBI score was used to evaluate patients' liver function and determine treatment options. Further subgroup analysis found that the results of prospective studies were statistically significant only for the ALBI score with regards to OS (HR = 1.69,95 %CI:1.26-2.26). Meanwhile, the effect of liver function on the efficacy of ICIs in the large-sample studies was not as obvious as that in small-sample studies. Moreover, the incidence of adverse events did not significantly increase in patients with impaired liver function. CONCLUSION: Poor liver function is associated with a poor prognosis in patients with HCC receiving ICIs. The ALBI score is simpler and reliable for patient stratification than the Child-Pugh score. Although the survival time of patients with impaired liver function may be relatively short, ICIs still have great potential for therapeutic applications.

Early alpha-fetoprotein response predicts prognosis of immune checkpoint inhibitor and targeted therapy for hepatocellular carcinoma: a systematic review with meta-analysis.

BACKGROUND: The prognostic value of alpha-fetoprotein (AFP) response for efficacy of targeted therapy or immune checkpoint inhibitors (ICIs) has not been established. The purpose of this meta-analysis is to elucidate the relationship between AFP response and survival outcomes in hepatocellular carcinoma (HCC) patients who received targeted therapy or ICIs. METHODS: The hazard ratio (HR) with 95% confidence interval (CI) was used to evaluate the relationship between AFP response and overall survival (OS)/progression-free survival (PFS). RESULTS: Twenty-six articles containing 3056 HCC patients were finally included in the study. The pooled results showed that after targeted therapy or ICIs, patients with decrease in AFP had better prognosis (OS:HR = 0.48, 95%CI:0.40-0.56; PFS:HR = 0.39, 95%CI:0.33-0.46), while patients with increase in AFP had worse prognosis (OS:HR = 2.30, 95%CI:1.82-2.89; PFS:HR = 2.34, 95%CI = 1.69-3.24). Subgroup analysis revealed that compared to AFP decrease >50%, AFP decrease >20% can better predict the prognosis of patients who received targeted therapy (OS:HR = 0.51, 95%CI:0.41-0.62; PFS:HR = 0.39, 95%CI:0.30-0.51) or ICIs treatment (OS:HR = 0.34, 95%CI:0.16-0.71; PFS:HR = 0.22, 95%CI:0.10-0.47), and 8 weeks after targeted therapy may be the appropriate time point for AFP assessment. CONCLUSION: AFP decrease >20% within 8 weeks may be the appropriate definition for early AFP response which probably works best in predicting the efficacy of therapy. REGISTRATION: The review was not registered.

Adverse events of immune checkpoint inhibitors in hepatocellular carcinoma: a systemic review and meta-analysis.

The introduction of immune checkpoint inhibitors (ICIs) has reshaped the therapy of hepatocellular carcinoma (HCC). ICIs are a novel therapy with frequent adverse events (AEs), including treatment-related adverse events (trAEs) and immune-related adverse events (irAEs). However, no comprehensive overview of the toxicity spectrum of ICIs in HCC patients has been provided. Electronic databases were searched to identify eligible studies. A meta-analysis of the incidence rate of AEs in HCC patients treated with ICIs was performed. Lastly, the prognostic value of irAEs in HCC patients treated with ICIs was verified. Forty-seven studies with 6472 participations met the inclusion criteria. The pooled all-grade trAEs incidence rate was 83.4% (95% confidence interval [95% CI] 77.0-89.1%), ≥ grade 3 trAEs incidence rate was 33.0% (95% CI 26.9-39.5%), all-grade irAEs incidence rate was 34% (95% CI 22-47%), and ≥ grade 3 irAEs incidence rate was 9% (95% CI 5-14%). Aspartate aminotransferase (AST) increase (38%, 95% CI 35-40%) is the most common trAEs. Fatigue (14%, 95% CI 7-23%) is the most common irAEs. The pooled results also showed that 18.8% (95% CI 13.2-25.2%) of patients required systemic steroid therapy due to AEs, while 6.6% (95% CI 4.6-9.0%) of patients withdrew from treatment due to AEs. Additionally, patients experiencing irAEs may have a better progression-free survival (PFS) (multivariate analysis: hazard ratio [HR] = 0.41, 95% CI 0.27-0.61, I2 = 36.3%) but not overall survival (OS) (multivariate analysis: HR = 0.54, 95% CI 0.22-1.36, I2 = 83.2%) than those with no irAEs. Our study presents a systemic assessment of the AEs profile in HCC patients receiving ICIs, providing important reference for clinicians on toxicity profile. Besides, patients with irAEs may have a better PFS. More large-scale and prospective studies are needed to confirm our conclusions.

Systemic immune-inflammation index predicts prognosis of cancer immunotherapy: systemic review and meta-analysis.

Objective: This meta-analysis was designed to explore the association between the systemic immune-inflammation index (SII) and the therapeutic effect of immune checkpoint inhibitors. Materials & methods: The authors retrieved relevant studies published before May 25, 2022. Hazard ratio (HR) with 95% CI was used to evaluate the relationship between SII and overall survival (OS) and progression-free survival (PFS). Results: 14 articles comprising 2721 patients were included in this study. The pooled results proved that high SII levels were closely related to poor prognosis in cancer patients receiving immune checkpoint inhibitors (OS HR = 2.40; 95% CI: 2.04-2.82; PFS HR = 1.57; 95% CI: 1.33-1.86) and that an SII value of 750 was appropriate as a cut-off value (OS HR = 2.20; 95% CI: 1.83-2.63; PFS HR = 1.54; 95% CI: 1.33-1.80). Conclusion: High SII levels (>750) may be an indicator of worse OS and PFS in cancer patients treated with immune checkpoint inhibitors.

Immune checkpoint inhibitors (ICIs) have substantially improved the prognosis of many patients with advanced cancer. However, some patients still do not benefit from ICIs. Therefore, determining indicators that can identify patients who may benefit from ICIs is essential. As a noninvasive, convenient and inexpensive clinical indicator, the systemic immune­inflammation index is expected to solve the aforementioned issue. Through this meta-analysis, the authors demonstrated that patients with cancers with high systemic immune­inflammation index levels had shorter survival and a smaller degree of clinical benefit after ICI treatment. Moreover, a systemic immune­inflammation index value of 750 is recommended to be the cut-off value for stratifying patients.

A Prediction Model Based on Blood Biomarker for Mortality Risk in Patients with Acute Venous Thromboembolism.

Background: Most studies to date have focused on predicting the risk of venous thromboembolism (VTE), but prediction models about mortality risk in VTE are rarely reported. We sought to develop and validate a multivariable model to predict the all-cause mortality risk in patients with acute VTE in emergency settings. Methods: A total of 700 patients were included from Qilu Hospital of Shandong University and were randomly assigned into training set (n=490) and validation set (n=210) in an 7:3 ratio. Multivariate logistics regression analysis was performed to identify independent variables and develop a prediction model, which was validated internally using bootstrap method. The discrimination, calibration and clinical utility were evaluated by receiver operating characteristic curve (ROC) analysis, Hosmer-Lemeshow (HL) test, Kaplan-meier (KM) analysis and decision curve analysis (DCA). Results: There were 52 patients (10.6%) dying and 437 (89.4%) surviving in training set. Age (odds ratio [OR]: 4.158, 95% confidence interval [CI]: 2.426-7.127), pulmonary embolism (OR: 1.779, 95% CI: 1.124-2.814), platelet count (OR: 0.507, 95% CI: 0.310-0.830), D-dimer (OR: 1.826, 95% CI: 1.133-2.942) and platelet/lymphocyte ratio (OR: 2.166, 95% CI: 1.259-3.727) were independent risk variables associated with all-cause mortality. The model had good predictive capability with an AUC of 0.746 (95% CI: 0.668,0.825), a sensitivity of 0.769 (95% CI: 0.607,0.889), a specificity of 0.672 (95% CI: 0.634,0.707). The validation model had an AUC of 0.739 (95% CI: 0.685,0.793), a sensitivity of 0.690 (95% CI: 0.580,0.787), a specificity of 0.693 (95% CI: 0.655,0.729). The model is well calibrated and the HL test showed a good fit (χ2=5.291, p=0.726, Nagelkerke R2=0.137). KM analysis and DCA showed a good clinical utility of the nomogram. Conclusion: This study identified independent variables affecting all-cause mortality in patients with acute VTE, and developed a prediction model and provided a nomogram with good prediction capability and clinical utility.

Self-Assembled Nano-Peptide Hydrogels with Human Umbilical Cord Mesenchymal Stem Cell Spheroids Accelerate Diabetic Skin Wound Healing by Inhibiting Inflammation and Promoting Angiogenesis.

Background: Non-healing skin wounds are a common complication in diabetic patients. Vector biomaterials embedded with mesenchymal stem cells (MSCs) are considered a promising treatment approach. In this study, we presented a novel and effective approach to accelerate diabetic skin wound healing. Methods and Materials: Human umbilical cord mesenchymal stem cells (hUC-MSCs) were shaped into spheres. RADA16-I, KLT, and RGD nanopeptides were selected for self-assembly into hydrogels. hUC-MSCs spheroids (hUC-MSCsp) were combined in vitro with self-assembled nanopeptide hydrogels and subsequently transplanted into a mouse model of diabetic skin trauma. Results: Compared with the PBS, hUC-MSCs, hUC-MSCsp, and hUC-MSCs with hydrogel groups, hUC-MSCsp with hydrogel significantly accelerated wound healing (p<0.01) and shortened the healing time (10 vs 14 vs 21 days). The expressions of IL-6, IL-10, IL-1ß, and TNF-α were significantly decreased (p<0.001). The expression of VEGF was significantly higher in the hUC-MSCsp with hydrogel group (p<0.05), and the density of neovascularization in the fresh skin tissue at the wound was also remarkably increased (p<0.01). Conclusion: Nanopeptide hydrogels loaded with hUC-MSCsp accelerated diabetic skin wound healing by inhibiting inflammation and promoting angiogenesis compared with conventional stem cell transplantation, which deserves further investigation.

Advantages of Self-assembled Nano Peptide Hydrogels in Biological Tissue Engineering.

With the development of tissue engineering research, biological scaffolds have been widely studied and applied in the field of regenerative medicine. Self-assembling nanopeptide hydrogels have good biocompatibility, and their seed cells can be used for their biological activities and have no toxic side effects. The products can be absorbed and degraded by the organism and have great advantages in tissue engineering and regenerative medicine. Studies have shown that the self-assembled nano peptide hydrogel and adipose-derived mesenchymal stem cells (ADMSCs) mixed solution are "biological ink". 3D related biological printing technology can be used to print related tissue models and induce ADMSCs to differentiate into blood vessels. It is further illustrated that the use of self-assembled nano peptide hydrogel scaffolds to load stem cells has a good application prospect in stem cell transplantation and 3D biological printing.

The Prognostic Value of Natural Killer Cells and Their Receptors/Ligands in Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis.

Background: Natural killer (NK) cells play major roles in eliminating tumor cells. Preliminary studies have shown that NK cells and their receptors/ligands have prognostic value in malignant tumors. However, the relevance of NK cells and their receptors/ligands level to the prognosis of hepatocellular carcinoma (HCC) remains unclear. Methods: Several electronic databases were searched from database inception to November 8, 2021. Random effects were introduced to this meta-analysis. The relevance of NK cells and their receptors/ligands level to the prognosis of HCC was evaluated using hazard ratios (HRs) with 95% confidence interval (95%CI). Results: 26 studies were included in the analysis. The pooled results showed that high NK cells levels were associated with better overall survival (HR=0.70, 95%CI 0.57-0.86, P=0.001) and disease-free survival (HR=0.61, 95%CI 0.40-0.93, P=0.022) of HCC patients. In subgroup analysis for overall survival, CD57+ NK cells (HR=0.70, 95%CI 0.55-0.89, P=0.004) had better prognostic value over CD56+ NK cells (HR=0.69, 95%CI 0.38-1.25, P=0.224), and intratumor NK cells had better prognostic value (HR=0.71, 95%CI 0.55-0.90, P=0.005) over peripheral NK cells (HR=0.66, 95%CI 0.41-1.06, P=0.088). In addition, high level of NK cell inhibitory receptors predicted increased recurrence of HCC, while the prognostic role of NK cell activating receptors remained unclear. Conclusion: NK cells and their inhibitory receptors have prognostic value for HCC. The prognostic role of NK cell activating receptors is unclear and more high-quality prospective studies are essential to evaluate the prognostic value of NK cells and their receptors/ligands for HCC.