Risk of cardiovascular death in patients with hepatocellular carcinoma based on the Fine-Gray model

BACKGROUND Hepatocellular carcinoma(HCC)is one of the most common types of cancers worldwide,ranking fifth among men and seventh among women,resulting in more than 7 million deaths annually.With the development of medical tech-nology,the 5-year survival rate of HCC patients can be increased to 70%.How-ever,HCC patients are often at increased risk of cardiovascular disease(CVD)death due to exposure to potentially cardiotoxic treatments compared with non-HCC patients.Moreover,CVD and cancer have become major disease burdens worldwide.Thus,further research is needed to lessen the risk of CVD death in HCC patient survivors.METHODS This study was conducted on the basis of the Surveillance,Epidemiology,and End Results database and included HCC patients with a diagnosis period from 2010 to 2015.The independent risk factors were identified using the Fine-Gray model.A nomograph was constructed to predict the CVM in HCC patients.The nomograph performance was measured using Harrell’s concordance index(C-index),calibration curve,receiver operating characteristic(ROC)curve,and area under the ROC curve(AUC)value.Moreover,the net benefit was estimated via decision curve analysis(DCA).RESULTS The study included 21545 HCC patients,of whom 619 died of CVD.Age(<60)[1.981(1.573-2.496),P<0.001],marital status(married)[unmarried:1.370(1.076-1.745),P=0.011],alpha fetoprotein(normal)[0.778(0.640-0.946),P=0.012],tumor size(≤2 cm)[(2,5]cm:1.420(1.060-1.903),P=0.019;>5 cm:2.090(1.543-2.830),P<0.001],surgery(no)[0.376(0.297-0.476),P<0.001],and chemotherapy(none/unknown)[0.578(0.472-0.709),P<0.001]were independent risk factors for CVD death in HCC patients.The discrimination and calibration of the nomograph were better.The C-index values for the training and validation sets were 0.736 and 0.665,respectively.The AUC values of the ROC curves at 2,4,and 6 years were 0.702,0.725,0.740 in the training set and 0.697,0.710,0.744 in the validation set,respectively.The calibration curves showed that the predicted probab-ilities of the CVM prediction model in the training set vs the validation set were largely consistent with the actual probabilities.DCA demonstrated that the prediction model has a high net benefit.CONCLUSION Risk factors for CVD death in HCC patients were investigated for the first time.The nomograph served as an important reference tool for relevant clinical management decisions.

Intratumoural microorganism can affect the progression of hepatocellular carcinoma

BACKGROUND Several recent studies have confirmed that intratumoural microorganisms can affect the occurrence and development of hepatocellular carcinoma(HCC);however,their role in tumor progression remains unclear.Hence,there is a need for further research on the role of intratumoural microorganisms in HCC.AIM To investigate the changes in intratumoural microorganisms in HCC and the effect of Propionibacterium on HCC progression.METHODS HCC and normal liver tissue specimens were subjected to fluorescence in situ hybridization(FISH).After performing 16S rRNA sequencing on HCC and peritumoral tissues to analyze the differences between the two groups.Propionibacterium was cocultured with HCC cells in vitro.Changes in cell proliferation and migration capacity were evaluated.The expression of NF-κB pathway related proteins in tumor cells was compared.The orthotopic liver implantation model and the subcutaneous xenograft model were constructed.liver tissues and subcutaneous tumors were collected 2 weeks later.RESULTS FISH demonstrated the presence of microorganisms in HCC and normal liver tissues.16S rRNA sequencing revealed an abundance of Lysobacter,Lachnospiraceae,Pseudomonas,and Lactobacillus in HCC tissues.The distribution and abundance of Propionibacterium showed differences between HCC and peritumoral tissues(P<0.05).In vitro studies demonstrated that Propionibacterium and its metabolite propionic acid(PA)inhibited the proliferation and migration of HCC cells(P<0.05).The expression of the proteins in NF-κB signaling pathway also decreased in HCC cells(P<0.05).CONCLUSION Microorganisms in HCC and normal liver tissues displayed significant disparities.The PA-producing bacterium Propionibacterium in HCC exerts an effect on the NF-κB pathway,thereby affecting the biological behavior of HCC.

ASARA,a prediction model based on Child-Pugh class in hepatocellular carcinoma patients undergoing transarterial chemoembolization

Background:Due to the high heterogeneity among hepatocellular carcinoma(HCC)patients receiving transarterial chemoembolization(TACE),the prognosis of patients varies significantly.The decisionmaking on the initiation and/or repetition of TACE under different liver functions is a matter of concern in clinical practice.Thus,we aimed to develop a prediction model for TACE candidates using risk stratification based on varied liver function.Methods:A total of 222 unresectable HCC patients who underwent TACE as their only treatment were included in this study.Cox proportional hazards regression was performed to select the independent risk factors and establish a predictive model for the overall survival(OS).The model was validated in patients with different Child-Pugh class and compared to previous TACE scoring systems.Results:The five independent risk factors,including alpha-fetoprotein(AFP)level,maximal tumor size,the increase of albumin-bilirubin(ALBI)grade score,tumor response,and the increase of aspartate aminotransferase(AST),were used to build a prognostic model(ASARA).In the training and validation cohorts,the OS of patients with ASARA score≤2 was significantly higher than that of patients with ASARA score>2(P<0.001,P=0.006,respectively).The ASARA model and its modified version“AS(ARA)”can effectively distinguish the OS(P<0.001,P=0.004)between patients with Child-Pugh class A and B,and the C-index was 0.687 and 0.706,respectively.For repeated TACE,the ASARA model was superior to Assessment for Retreatment with TACE(ART)and ALBI grade,maximal tumor size,AFP,and tumor response(ASAR)among Child-Pugh class A patients.For the first TACE,the performance of AS(ARA)was better than that of modified hepatoma arterial-embolization prognostic(mHAP),mHAP3,and ASA(R)models among Child-Pugh class B patients.Conclusions:The ASARA scoring system is valuable in the decision-making of TACE repetition for HCC patients,especially Child-Pugh class A patients.The modified AS(ARA)can be used to screen the ideal candidate for TACE initiation in Child-Pugh class B patients with poor liver function.

miR-30b inhibits autophagy to alleviate hepatic ischemiareperfusion injury via decreasing the Atg12-Atg5 conjugate

AIM: To explore the role and potential mechanism of miR-30 b regulation of autophagy in hepatic ischemiareperfusion injury(IRI).METHODS: An animal model of hepatic IRI was generated in C57BL/6 mice. For in vitro studies, AML12 cells were immersed in mineral oil for 1 h and then cultured in complete Dulbecco's Modified Eagle's Medium(DMEM)/F12 to simulate IRI. Mice and cells were transfected with miR-30 b agomir/mimics or antagomir/inhibitor to examine the effect of miR-30 b on autophagy to promote hepatic IRI. The expression of miR-30 b was measured by real-time polymerase chain reaction. Apoptotic cells were detected by terminal uridine nickend labeling(TUNEL) staining, and cell viability was detected by methylthiazole tetrazolium assay. The expression of light chain 3, autophagy-related gene(Atg)12, Atg5, P62, and caspase-3 were detected by western blotting analysis.RESULTS: miR-30 b levels were significantly downregulated after hepatic IRI, and the numbers of autophagosomes were increased in response to IRI both in vivo and in vitro. These findings demonstrate that low levels of miR-30 b could promote hepatic IRI. Furthermore, we found that miR-30 b interacted with Atg12-Atg5 conjugate by binding to Atg12. Overexpression of miR-30 b diminished Atg12 and Atg12-Atg5 conjugate levels, which promoted autophagy in response to IR. In contrast, downregulation of miR-30 b was associated with increased Atg12-Atg5 conjugate levels and increased autophagy.CONCLUSION: miR-30 b inhibited autophagy to alleviate hepatic ischemia-reperfusion injury via decreasing the Atg12-Atg5 conjugate.

Impact of non-oncological factors on tumor recurrence after liver transplantation in hepatocellular carcinoma patients

Hepatocellular carcinoma (HCC) is the most common primary neoplasm of the liver and is one of the leading causes of cancer-related death worldwide. Liver transplantation (LT) has become one of the best curative therapeutic options for patients with HCC, although tumor recurrence after LT is a major and unaddressed cause of mortality. Furthermore, the factors that are associated with recurrence are not fully understood, and most previous studies have focused on the biological properties of HCC, such as the number and size of the HCC nodules, the degree of differentiation, the presence of hepatic vascular invasion, elevated serum levels of alpha-fetoprotein, and the tumor stage outside of the Milan criteria. Thus, little attention has been given to factors that are not directly related to HCC (i.e., &#x0201c;non-oncological factors&#x0201d;), which have emerged as predictors of tumor recurrence. This review was performed to assess the effects of non-oncological factors on tumor recurrence after LT. The identification of these factors may provide new research directions and clinical strategies for the prophylaxis and surveillance of tumor recurrence after LT, which can help reduce recurrence and improve patient survival.

Effects of heme oxygenase-1-modified bone marrow mesenchymal stem cells on microcirculation and energy metabolism following liver transplantation

AIM To investigate the effects of heme oxygenase-1(HO-1)-modified bone marrow mesenchymal stem cells(BMMSCs)on the microcirculation and energy metabolism of hepatic sinusoids following reduced-size liver transplantation(RLT)in a rat model.METHODS BMMSCs were isolated and cultured in vitro using an adherent method,and then transduced with HO-1-bearing recombinant adenovirus to construct HO-1/BMMSCs.A rat acute rejection model following 50%RLT was established using a two-cuff technique.Recipients were divided into three groups based on the treatment received:normal saline(NS),BMMSCs and HO-1/BMMSCs.Liver function was examined at six time points.The levels of endothelin-1(ET-1),endothelial nitric-oxide synthase(e NOS),inducible nitric-oxide synthase(i NOS),nitric oxide(NO),and hyaluronic acid(HA)were detected using an enzyme-linked immunosorbent assay.The portal vein pressure(PVP)was detected by Power Lab ML880.The expressions of ET-1,i NOS,e NOS,and von Willebrand factor(v WF)protein in the transplanted liver were detected using immunohistochemistry and Western blotting.ATPase in the transplanted liver was detected by chemical colorimetry,and the ultrastructural changes were observed under a transmission electron microscope.RESULTS HO-1/BMMSCs could alleviate the pathological changes and rejection activity index of the transplanted liver,and improve the liver function of rats following 50%RLT,with statistically significant differences compared with those of the NS group and BMMSCs group(P<0.05).In term of the microcirculation of hepatic sinusoids:The PVP on POD7 decreased significantly in the HO-1/BMMSCs and BMMSCs groups compared with that of the NS group(P<0.01);HO-1/BMMSCs could inhibit the expressions of ET-1 and i NOS,increase the expressions of e NOS and inhibit amounts of NO production,and maintain the equilibrium of ET-1/NO(P<0.05);and HO-1/BMMSCs increased the expression of v WF in hepatic sinusoidal endothelial cells(SECs),and promoted the degradation of HA,compared with those of the NS group and BMMSCs group(P<0.05).In term of the energy metabolism of the transplanted liver,HO-1/BMMSCs repaired the damaged mitochondria,and improved the activity of mitochondrial aspartate aminotransferase(ASTm)and ATPase,compared with the other two groups(P<0.05).CONCLUSION HO-1/BMMSCs can improve the microcirculation of hepatic sinusoids significantly,and recover the energy metabolism of damaged hepatocytes in rats following RLT,thus protecting the transplanted liver.

Application value of mixed reality in hepatectomy for hepatocellular carcinoma

BACKGROUND As a new digital holographic imaging technology,mixed reality(MR)technology has unique advantages in determining the liver anatomy and location of tumor lesions.With the popularization of 5 G communication technology,MR shows great potential in preoperative planning and intraoperative navigation,making hepatectomy more accurate and safer.AIM To evaluate the application value of MR technology in hepatectomy for hepatocellular carcinoma(HCC).METHODS The clinical data of 95 patients who underwent open hepatectomy surgery for HCC between June 2018 and October 2020 at our hospital were analyzed retrospectively.We selected 95 patients with HCC according to the inclusion criteria and exclusion criteria.In 38 patients,hepatectomy was assisted by MR(Group A),and an additional 57 patients underwent traditional hepatectomy without MR(Group B).The perioperative outcomes of the two groups were collected and compared to evaluate the application value of MR in hepatectomy for patients with HCC.RESULTS We summarized the technical process of MR-assisted hepatectomy in the treatment of HCC.Compared to traditional hepatectomy in Group B,MR-assisted hepatectomy in Group A yielded a shorter operation time(202.86±46.02 min vs 229.52±57.13 min,P=0.003),less volume of bleeding(329.29±97.31 mL vs 398.23±159.61 mL,P=0.028),and shorter obstructive time of the portal vein(17.71±4.16 min vs 21.58±5.24 min,P=0.019).Group A had lower alanine aminotransferas and higher albumin values on the third day after the operation(119.74±29.08 U/L vs 135.53±36.68 U/L,P=0.029 and 33.60±3.21 g/L vs 31.80±3.51 g/L,P=0.014,respectively).The total postoperative complications and hospitalization days in Group A were significantly less than those in Group B[14(37.84%)vs 35(60.34%),P=0.032 and 12.05±4.04 d vs 13.78±4.13 d,P=0.049,respectively].CONCLUSION MR has some application value in three-dimensional visualization of the liver,surgical planning,and intraoperative navigation during hepatectomy,and it significantly improves the perioperative outcomes of hepatectomy for HCC.

Mesenchymal stem cells improve the outcomes of liver recipients via regulating CD4*T helper cytokines in rats

BACKGROUND： Bone marrow mesenchymal stem cells （BMMSCs） exert immunosuppressive activities in transplantation. This study aimed to determine whether BMMSCs reduce acute re- jection and improve outcomes of liver transDlantation in rats.

Reorganization characteristics of speech cortex during speech restoration following total laryngectomy A functional magnetic resonance imaging follow-up

During speech restoration following laryngectomy, language-related cortical areas develop connections with new primary motor neurons. The present study followed up 18 patients after total resection of laryngeal carcinoma. According to an evaluation of pronunciation, patients were assigned to three groups： poor, moderate and good pronunciation. Functional magnetic resonance imaging revealed significant increases in the number of activated voxels and the intensity of activation changes in the left middle frontal gyrus, left precentral gyrus, left postcentral gyrus, left supplementary motor area, left anterior cingulate gyrus and right fusiform gyrus between the moderate pronunciation group compared with the poor and good pronunciation groups. We propose that these brain regions play an important role in the progress of speech restoration, and improvements in pronunciation learning for patients following laryngectomy. However, during the later period of speech restoration, the number of activated voxels and intensity changes in these regions decreased to the level of healthy controls, indicating that the learning and instruction effects weakened once patients had mastered pronunciation techniques

Nano-Bacillus Calmette-Guérin immunotherapies for improved bladder cancer treatment

Cancer immunotherapy has rapidly become the fourth mainstream treatment alternative after surgery,radiotherapy,and chemotherapy,with some promising results.It aims to kill tumor cells by mobilizing or stimulating cytotoxic immune cells.However,the clinical applications of tumor immunotherapies are limited owing to a lack of adequate delivery pathways and high toxicity.Recently,nanomaterials and genetic engineering have shown great potential in overcoming these limitations by protecting the delivery of antigens,activating targeted T cells,modulating the immunosuppressive tumor microenvironment,and improving the treatment efficacy.bacillus Calmette-Gué;rin(BCG)is a live attenuated Mycobacterium bovis vaccine used to prevent tuberculosis,which was first reported to have antitumor activity in 1927.BCG therapy can activate the immune system by inducing various cytokines and chemokines,and its specific immune and inflammatory responses exert antitumor effects.BCG was first used during the 1970s as an intravesical treatment agent for bladder cancer,which effectively improved immune antitumor activity and prevented tumor recurrence.More recently,nano-BCG and genetically engineered BCG have been proposed as treatment alternatives for bladder cancer due to their ability to induce stronger and more stable immune responses.In this study,we outline the development of nano-BCG and genetically engineered BCG for bladder cancer immunotherapy and review their potential and associated challenges.

Clinical and immunological features of convalescent pediatric patients infected with the SARS-CoV-2 Omicron variant in Tianjin, China

COVID-19 has spread surprisingly fast worldwide, and new variants continue to emerge. Recently, the World Health Organization acknowledged a new mutant strain “Omicron”, with children were accounting for a growing share of COVID-19 cases compared with other mutant strains. However, the clinical and immunological characteristics of convalescent pediatric patients after Omicron infection were lacking. In this study, we comparatively analyzed the clinical data from pediatric patients with adult patients or healthy children and the effects of SARSCoV-2 vaccine on the clinical and immune characteristics in convalescent pediatric patients. Our results indicated that convalescent pediatric patients had unique clinical and immune characteristics different from those of adult patients or healthy children, and SARS-CoV-2 vaccination significantly affected on the clinical and immune characteristics and the prevention of nucleic acid re-detectable positive(RP) in convalescent patients. Our study further deepens the understanding of the impact of Omicron on the long-term health of pediatric patients and provides a valuable reference for the prevention and treatment of children infected with Omicron.

Clinical Features and Clonal Origin of Diffuse Hepatocellular Carcinoma

To the Editor：Diffuse hepatocellular carcinoma （D-HCC）,also known as cirrhosis-like HCC,is a rare and peculiar type of HCC.[1] The World Health Organization （WHO） defines D-HCC as follows：small tumor nodules distributed diffusely all over the liver presents like cirrhotic-associated regenerative nodules.[2] Surgical resection,radiotherapy,and medication cannot bring good results for D-HCC,and the prognosis of D-HCC is poor.

Whole-body magnetic resonance imaging vs.clinical evaluation of enthesitis in patients with spondyloarthritis

To the Editor:Enthesitis is an inflammation of the iliac attachment of ligaments or tendons.In spondyloarthropathies,peripheral enthesitis precedes joint symptoms and is associated with a higher degree of erosive disease.Four methods are available for evaluation of enthesitis,including tenderness,conventional radiography,ultrasonography,and magnetic resonance imaging(MRI).However,over 100 entheses are found in the human body.