Research progress of ferroptosis regulating lipid peroxidation and metabolism in occurrence and development of primary liver cancer

As a highly aggressive tumor,the pathophysiological mechanism of primary liver cancer has attracted much attention.In recent years,factors such as ferroptosis regulation,lipid peroxidation and metabolic abnormalities have emerged in the study of liver cancer,providing a new perspective for understanding the development of liver cancer.Ferroptosis regulation,lipid peroxidation and metabolic abnormalities play important roles in the occurrence and development of liver cancer.The regulation of ferroptosis is involved in apoptosis and necrosis,affecting cell survival and death.Lipid peroxidation promotes oxidative damage and promotes the invasion of liver cancer cells.Metabolic abnormalities,especially the disorders of glucose and lipid metabolism,directly affect the proliferation and growth of liver cancer cells.Studies of ferroptosis regulation and lipid peroxidation may help to discover new therapeutic targets and improve therapeutic outcomes.The understanding of metabolic abnormalities can provide new ideas for the prevention of liver cancer,and reduce the risk of disease by adjusting the metabolic process.This review focuses on the key roles of ferroptosis regulation,lipid peroxidation and metabolic abnormalities in this process.

Effect of CT-Guided Microwave Ablation Combined with TACE on Liver Function and Survival of Patients with Primary Liver Cancer

Objective:To explore the effect of transarterial chemoembolization(TACE)+CT-guided microwave ablation(MWA)on treating patients with primary liver cancer.Methods:78 primary liver cancer cases were enrolled and divided into groups according to their assigned surgical plans.The control group was treated with TACE alone,and the observation group was treated with TACE+CT-guided MWA.The efficacy of the treatment and the liver function indicators and follow-up results of the patients of the two groups were compared.Results:The efficacy of the treatment received by the observation group was higher than that of the control group.Besides,the patients in the observation group exhibited better improvement in liver function indicators after 3 months of treatment.Furthermore,the survival rates of 1 and 2 years after surgery of the observation group were all higher than those of the control group(P<0.05).Conclusion:TACE combined with CT-guided MWA is more effective in treating primary liver cancer compared to TACE alone.Besides,it resulted in better improvement of liver function and long-term survival rate.Therefore,this treatment regime should be popularized.

Current status of yttrium-90 microspheres radioembolization in primary and metastatic liver cancer

Liver malignancy,including primary liver cancer and metastatic liver cancer has become one of the most common causes of cancer-related death worldwide due to the high malignant degree and limited systematic treatment strategy.Radioembolization with yttrium-90(^(90)Y)-loaded microspheres is a relatively novel technology that has made significant progress in the local treatment of liver malignancy.The different steps in the extensive work-up of radioembolization for patients with an indication for treatment with^(90)Y microspheres,from patient selection to follow up,both technically and clinically,are discussed in this paper.It describes the application and development of^(90)Y microspheres in the treatment of liver cancer.

Multifunctional roles of inflammation and its causative factors in primary liver cancer:A literature review

Primary liver cancer is a severe and complex disease,leading to 800000 global deaths annually.Emerging evidence suggests that inflammation is one of the critical factors in the development of hepatocellular carcinoma(HCC).Patients with viral hepatitis,alcoholic hepatitis,and steatohepatitis symptoms are at higher risk of developing HCC.However,not all inflammatory factors have a pathogenic function in HCC development.The current study describes the process and mechanism of hepatitis development and its progression to HCC,particularly focusing on viral hepatitis,alcoholic hepatitis,and steatohepatitis.Furthermore,the roles of some essential inflammatory cytokines in HCC progression are described in addition to a summary of future research directions.

The Relationship between Golgi Protein 73, Alpha-Fetoprotein, Liver Function Indicators, and Traditional Chinese Medicine Syndrome Types of Primary Liver Cancer

Objective Our objective was to analyze the correlation between Golgi protein 73(GP73),alpha-fetoprotein(AFP),liver function indicators,and traditional Chinese medicine(TCM)syndrome types of primary liver cancer(hereinafter referred to as"liver cancer").Methods In total,156 liver cancer patients(liver cancer group)and 52 healthy individuals(health group)were selected as the research subjects to detect their GP73,AFP expression,and liver function-related indicators.The obtained data were statistically analyzed using SPSS 21.0 software.Results(1)The positive expression rate of GP73 in the liver cancer group was 50%;the positive expression rates of qi stagnation and blood stasis syndrome,heat tgxin in liver and galader yndroeand yndefceny flieran kidney yndg1i,%54.3,and 59.6%,respectively.There was no statistically significant difference betwgep the groups(p>0.05),The positive expreion rate of AFP was 50%.he positiy 32.8 expression rates of qi stagnation and blood stasis syndrome,heat-toxin in liyer ane gallbladder syndrome,and yin deficiency of liver and kidney syndrome were 41.7,54.3 an59.6%,respectively.There was a statistically significant difference between the groups(p<0.05).(2)The GP73 levels of patients with different syndrome types in the liver cancer group were ranked from high to low as yin deficiency of liver and ki41.3 syndrome,heat toxin in liver and gallbladder syndrome,and qi stagnation and brooa stasis syndrome.The differences between the groups were statistically significant(p<0.05).The AFP levels of patients with different syndrome types in the liver cancer group were ranked from high to low as heat toxin in liver and gallbladder syndrome,yin deficiency of liver and kidney syndrome,and qi stagnation and blood stasis syndrome.There was no statistically significant difference between the groups(p>0.05).(3)Analysis of liver function indicators in the liver cancer group:the alanine transaminase s(ALT)levels of patients with different syndrome types were in descending order from high to low,including yin deficiency of liver and kidney syndrome,heat toxin in liver and gallbladder syndrome,and qi stagnation and blood stasis syndrome.The differences between groups were statistically significant(p<0.05).The aspartate aminotransferase(AST)levels of patients with different syndrome types were ranked from high to low as follows:heat toxin in liver and gallbladder syndrome,yin deficiency of liver and kidney syndrome,and qi stagnation and blood stasis syndrome.The difference between groups was statistically significant(p<0.05).The levels of albumin(ALB)in patients with different syndrome types were ranked from high to low,including heat toxin in liver and gallbladder syndrome,qi stagnation and blood stasis syndrome,and yin deficiency of liver and kidney syndrome.The differences between groups were statistically significant(p<0.05).Conclusion GP73 and indicators such as ALT,AST,and ALB are of great significance in the diagnosis of TCM syndrome differentiation and classification of liver cancer patients.

Real-world 10-year retrospective study of the guidelines for diagnosis and treatment of primary liver cancer in China

BACKGROUND Hepatocellular carcinoma(HCC) is a common malignant tumor worldwide. Many regions across the world have issued various HCC diagnosis and treatment protocols to improve the diagnosis and targeted treatment of patients with HCC. However, real-world studies analysing the practice, application value, and existing problems of the China Liver Cancer(CNLC) staging system are scarce.AIM To analyze the current situation and problems associated with the Guidelines for Diagnosis and Treatment of Primary Liver Cancer in China.METHODS We collected the medical records of all patients with HCC admitted to the First Affiliated Hospital of Zhengzhou University from January 1, 2011 to December 31, 2019, and recorded the hospitalization information of those patients until December 31, 2020. All information on the diagnosis and treatment of the target patients was recorded, and their demographic and sociological characteristics, CNLC stages, screening situations, and treatment methods and effects were analyzed. The survival status of the patients was obtained from follow-up data.RESULTS This study included the medical records of 3022 patients with HCC. Among these cases, 304 patients were screened before HCC diagnosis;their early-stage diagnosis rate was 69.08%, which was significantly higher than that of patients with HCC who were diagnosed without screening and early detection(33.74%). Herein, patients with no clinical outcome at discharge were followed up, and the survival information of 1128 patients was obtained. A Cox model was used to analyse independent risk factors affecting overall survival, which were revealed as age > 50 years, no screening, alpha-fetoprotein > 400 ng/mL, Child–Pugh grade B, and middle and late CNLC stages. Based on the Cox model survival analysis, in our study, patients with HCC identified via screening had significant advantages in overall and tumorfree survival after hepatectomy.CONCLUSION Early diagnosis and treatment can be achieved by screening groups at high risk for HCC based on the guidelines;however, real-world compliance is poor.

Tumor budding as a potential prognostic marker in determining the behavior of primary liver cancers

Hepatocellular(HCC)and intrahepatic cholangiocarcinoma(ICC),the most common primary tumors of the liver,are among the most important causes of cancer deaths worldwide.Because patients with primary liver tumors are frequently diagnosed at an advanced stage and have high mortality,many efforts have been made to identify new markers to determine their behavior and treatment,similar to those in other solid organ tumors.Recently,morphological assessment of tumor budding(TB)has been revealed as a promising prognostic finding to predict tumor behavior and survival across several different tumor types.Currently,the TB score in colorectal cancer has been revealed as an important parameter in pathology report protocols to determine the course of the disease.Regarding the liver,despite enormous data showing that many mechanisms involved in TB are associated with tumor behavior in both HCC and ICC,studies focusing on the role of TB in predicting the behavior and prognosis of these tumors have started to be investigated very recently.The purpose of this review is to present data about TB in primary tumors of the liver,pointing out the potential role of this parameter in determining the course of the disease,and emphasize the need to increase the number of further studies focusing on the evaluation of this parameter with an overview of the mechanisms involved in TB.

Microwave ablation combined with transarterial chemoembolization containing doxorubicin hydrochloride liposome for treating primary and metastatic liver cancers

Aims:To determine the safety and efficacy of microwave ablation(MWA)and transarterial chemoembolization(TACE)with doxorubicin hydrochloride liposome(DHL)in patients with primary liver cancer(PLC)and metastatic liver cancer(MLC).Materials and methods:The medical records of patients with primary or metastatic liver cancer who underwent MWA combined with TACE containing DHL from March 2019 to March 2022 were collected and analyzed.Treatment-related adverse events(AEs)were recorded.Local tumor response was evaluated according to the modified RECIST criteria.Local tumor progression-free survival(LTPFS)and overall survival(OS)were calculated using the Kaplan-Meier method.Results:Altogether,96 patients with liver cancer were included(PLC,n=45;MLC,n=51).Forty(41.7%)patients experienced AEs during treatment,and eight(8.3%)patients developed grade 3 AEs.Compared to before treatment,the serum total bilirubin level and neutrophil to lymphocyte ratio significantly increased after treatment.The median LTPFS was 14.5 months in patients with PLC and 10.7 months in patients with MLC.The median OS was not reached in patients with PLC or MLC.The 1-month and 3-month disease control rates reached more than 80%in both groups.Conclusion:MWA combined with TACE with DHL may be a safe and effective method for the treatment of liver cancer.

Analysis of the intestinal flora in patientswith primary liver cancer

Objective To investigate the differences in intestinal flora of patients with primary liver cancer and ofhealthy individuals and to investigate the effect of the differential flora on the development of liver cancer.Methods Overall, 67 patients with primary liver cancer who received systematic and complete treatmentbetween January 2019 and December 2020 at the Sixth People’s Hospital of Qingdao and had completeclinical data were enrolled in this study, and 26 individuals who were healthy on physical examination inthe same period were used as healthy controls. Macro genome and 16s ribosome Deoxyribo Nucleic Acid(rDNA) high-throughput sequencing were performed on the stool flora of the enrolled patients and controls,and the differences in the intestinal flora were analyzed using the LEfSe bioinformatics software.Results Compared with the control samples, all the tested patient samples showed statistically significantdifferences in the number of colonies of 5 bacterial phyla, 5 orders, 8 families, 11 genera, and 14 species(P < 0.05).Conclusion Compared with healthy people, patients with primary liver cancer have significant differencesin the intestinal flora composition. The alteration of the intestinal flora may be correlated with the occurrenceof primary liver cancer, and the intestinal flora may become a novel target for the prevention and treatmentof primary liver cancer.

Outcomes of liver transplantation as an oncologic surgery for different primary liver cancers:A real-world,population-based study

To the Editor:Although liver transplantation is likely used to treat individuals with end-stage liver disease because of non-neoplastic reasons,the adoption of liver transplantation in the management of primary liver cancer has been expanding in the past decades[1-3].Prior population-based studies for liver transplantation,in the cancer sphere,focused on delineating the outcomes of patients with hepatocellular carcinoma(HCC)treated with transplantation versus other locoregional treatments[4-6].

Primarily screening and analyzing ESTs differentially expressed in rats' primary liver cancer

Objective： To screen and analyze key express sequence tags （ESTs） which were differentially displayed in every period of SD rats＇ primary hepatic carcinoma and reveal the molecular mechanism of carcinogenesis. Methods： Using diethylnitrosamine （DENA） as a cancerigenic agent, animal models with different phases of primary hepatic cancer were constructed in SD rats. Rats were respectively sacrificed at d 14, d 28, d 56, d 77, d 105 and d 112 after the rats received DENA by gavage, then the livers were harvested. One part of the livers was classified according to their pathological changes, while the other was reserved for molecular mechanism studies on hepatocarcinogenesis. The differentially expressed genes were isolated from both normal and morbid tissues by mRNA differential display technique （DDRT-PCR）. After the fragments were sequenced, bioinformatics were .used to analyze the results. Results： Twelve differentially expressed cDNA fragments were obtained. Nine fragments had the homology with known cDNA clones, especially EST-7 was similar to BN/SsNHsdMCW mitochondrion gene and the identity was 100% which suggested EST-7 may be the part of BN/SsNHsdMCW mitochondrion gene. In contrast, other three fragments （EST-1, EST-3 and EST-5） had extremely low identity to any genes registered in GENBANK databases. Conclusions： BN/SsNHsdMCW mitochondrion gene was expressed in different periods of hepatocarcinogenesis. Moreover, EST-I, EST-3 and EST-5 were suggested to contribute to the development of rat hepatocarcinogenesis, and thus may be candidates of new targets of oncogenes or cancer suppressor genes.

Comprehensive treatment for primary liver cancer

IntroductionPrimary liver cancer (PLC) is one of the mostcommon malignancies in China. Since the1990s, it has been the first leading cause of cancerdeath in the rural areas versus the 2nd in the urbanareas in this country. 45% of all the newly en-countered cases in the world each year are from themainland of China, and the situation is extremelyworsened in its high risk southeast coastal area.Liver resection is chosen as an optimal treatmentfor liver cancer, yet the low resectability and highpostoperative recurrence prevent the long-term sur-vival of patients. Therefore, proper comprehensivetreatment of PLC for the improvement of the overalltherapeutic efficacy has been the focus of clinicalpractice and research. In comparison with single treatment, compre-

A race to uncover a panoramic view of primary liver cancer

Introduction Primary liver cancer,the second most common cause of cancer related death worldwide1,presents ethnic,etiological,sex,and geographical diversity2(Figure 1A).At the histological level,liver cancer includes two major types:hepatocellular carcinoma(HCC,about 80%)and cholangiocarcinoma(CCA,about 15%).Many etiological factors contribute to HCC development,such as hepatitis

HIGH DOSE INTRA-ARTERIAL HEPATIC INFUSIONAL CHEMOTHERAPY WITH DRUG FILTRATION (HAI-F) FOR PRIMARY LIVER CANCER(A PRELIMINARY REPORT)

Fifteen patients with unresectable hepatocellular carcinoma were treated with unresectable hepatocellular carcinoma were treated with high dose MMC or ADR via hepatic artery with drug filtration in our hospital from April to December 1988. Among them, 11 cases (73%) had symptoms relief, 3 cases (20%) tumor minimal remission and AFP decreased in 4 cases (33%). One case dide of hep'atoma 8 months after HAI-F and another case was followed up only 2 months after treatment, the remaining 13 cases are alive for 5 to 10 months after HAI-F. The reasons of unsatisfactory results were analyzed and possible ways of improvement were suggested.

EXPERIMENTAL PRIMARY LIVER CANCER IN TREE SHREWS EXPOSED TO HUMAN HEPATITIS B VIRUS AND AFLATOXIN B_(1)

On the basis of the successful establishment of an animal model in tree shrews experimentally in fected with human hepatitis B virus (HHBV), a study on the hepatocarcinogenic effects of HHBV and aflatoxin B1 (AFB1) by using this animal model was conducted through a lifelong experiment. Among 41 tree shrews exposed to AFB1, 17 were experimentally infected by HHBV and 24 were uninfected. After 158 weeks, significant difference of primary liver cancer (PLC) incidence was present between the HHBV infected (52.94%) and uninfected (12.5%) groups (p<0.05). No difference was found between these two groups in the amount of AFB4 ingestion. Moreover, 1/9 of the tree shrews infected only by HHBV but not exposed to AFB4 developed PLC. No PLC was found in 6 tree shrews that had neither been infected with HHBV nor been exposed to AFB4. These results suggest the possible etiologic relationship between HHBV infection and PLC, as well as the synergetic effects of HHBV and AFB4 during PLC development.

Changed clinical aspects of primary liver cancer in China during the past 30 years

BACKGROUND: Primary liver cancer (PLC) is one of the most frequently seen tumors in China. Thirty years ago, patients with PLC were often detected at relatively late stage, with a palpable mass or marked clinical symptoms and poor prognosis. In the past 30 years, the diagnosis and treatment of PLC have been greatly improved with better prognosis. METHODS: In order to study the changes of PLC during the 30 years, the clinical data of 3250 patients with PLC from 10 medical institutions of China were collected, ana- lyzed , and compared with those of 3254 PLC patients be- fore the 30 years. RESULTS: In the 3250 patients aged 1-80 years, with an average age of 49.1 years, the male to female ratio (2.3:1) was lower than that before the 30 years. 73.5% of the 3250 patients sought medical advice within 3 months after the onset of the disease in contrast to 63.8% before the 30 years. Compared with those patients before the 30 years the symptoms and signs were alleviated generally. The HBsAg positive rate was 81.0%, but the HCV-Ab positive rate was 13.2%. The AFP level in 75% of patients was elevated, but in the remaining 25% was normal. 1912 patients (58.8%) were confirmed pathologically. Among them 1755 patients (91.8%) had hepatocellular carcinoma. The overall resec- tion rate was 46.3%. Those who had early, middle, late stage carcinoma accounted for 29.9%, 51.5%, and 18.6%respectively in contrast to 0.4%, 47.0%, and 52.6% repor- ted before the 30 years. The 1-, 3-, 5-year survival rates of the patients were 66.1%, 39.7%, and 32.5% respectively, whereas 93.5%, 70.1%, and 59.1% for the early stage pa- tients, and 65.3%, 30.5%, and 23.5% for the middle stage patients. The half and 1-year survival rates of the late stage patients were 52.5%, and 14.7%, respectively. CONCLUSION: Comparison with the clinical data before and after the 30 years show that PLC can be diagnosed ear- ly. More PLC patients tend to undergo resection while re- ceiving a better conservative treatment, which ensures a prognosis.

Impact of Operative and Peri-operative Factors on the Long-term Prognosis of Primary Liver Cancer Patients Undergoing Hepatectomy

This study examined the impact of the operative and peri-operative factors on the long-term prognosis of patients with primary liver cancer undergoing hepatectomy. A total of 222 patients with primary liver cancer who underwent hepatectomy were followed up from January 1986 to December 2010 at Chinese PLA General Hospital. The post-operative complication rate was 14.0% for all cases, 13.7% for hepatocellular carcinoma（HCC）, 10.0% for cholangiocarcinoma. The 1-, 3-, 5- and 10-year overall survival rates in patients with primary liver cancer after resection were 76.6%, 57.6%, 41.4%, and 21.0%. The survival rates were significantly higher in the HCC group than in the cholangiocarcinoma group（P=0.000）, in the non-anatomical resection group than in the anatomical resection group（P=0.005）, in the female group than in the male group（P=0.002）, in patients receiving no blood transfusion than in those who were given intra-operative blood transfusion（P=0.000）, in patients whose intra-operative blood loss was less than 400 m L than in those who intra-operatively lost more than 400 m L（P=0.000）. No significant difference was found in the survival rate between the HBs Ag-positive group and the HBs Ag-negative group（P=0.532）. Our study showed that anatomical resection, blood loss and blood transfusion were predictors of poor survival after hepatectomy for primary liver cancer patients, and concomitant hepatitis B virus infection bore no relation with the post-resection survival.

Factors related to pleural effusion following hepatectomy for primary liver cancer

BACKGROUND: Pleural effusion frequently complicates hepatectomy and multiple factors contribute to its development following hepatectomy for primary liver cancer. The purpose of this study was to evaluate these factors. METHODS: From March 2003 to May 2005, 228 consecutive patients with primary liver cancer underwent hepatectomy in our department were evaluated retrospectively to identify factors related to postoperative pleural effusion. RESULTS: Among the 228 patients, postoperative pleural effusions arose in 58 (25.4%). Univariate analysis showed significant differences in postoperative ascites, subphrenic collection, Pringle manoeuvre length, drainage amount on postoperative day 1, albumin level on postoperative day 7, alanine aminotransferase (ALT) level on postoperative days I and 3, prealbumin level on postoperative days 3 and 7, and tumor size (P<0.05). Ordinal regression analysis revealed that subphrenic collection, drainage on postoperative day I and ALT plus prealbumin on postoperative days I and 3 were statistically significantly related to postoperative pleural effusion (P<0.05). CONCLUSION: Subphrenic collection and operative injury to the liver appeared to be significantly related to pleural effusion after hepatectomy for primary liver cancer.

Therapeutic effect of transcatheter arterial chemoembolization and percutaneous injection of acetic acids on primary liver cancer

BACKGROUND: The resection rate of primary liver tumor in China is only about 20%. A lot of patients with moderate and advanced liver tumor may lose the chance of opera- tion. The objective of present research was to study the ef- ficacy of transcatheter arterial chemoembolization (TACE) combined with percutaneous injection of chemical agents and acetic acids in the treatment of patients with primary liver cancer (PLC). METHODS: Thirty-three patients with middle and ad- vanced stage of PLC were divided into two groups: percu- taneous injection of chemical agents and acetic acids (15 patients, group A) and TACE (18 patients, group B). RESULTS: Tumor diameter and serum AFP level reduced to 86.6% and 83.3% in group A, and 55.5% and 40% in group B, respectively. There was significant difference be- tween the two groups ( P < 0 . 0 1 ) . The 1-, 2-, 3-, 4-year survival rates of group A were 96.7%, 86.6%, 51.3%, 33.3%, respectively and in group B were 66.7%, 44.4%, 16.7%, 0%, respectively (P<0.01). CONCLUSION: TACE combined with percutaneous injec- tion of chemical agents and acetic acids is efficacious to in- crease the survival rate of patients with PLC.

Hepatectomy in the treatment of very big primary liver cancer: report of 86 cases

Objective: To study the indications for resection ofvery big primary liver cancer and the operative re-sults.Methods: From January 1985 to June 1996, 86 pa-tients with very big primary liver cancer (≥15cm indiameter) underwent hepatectomy in our hospital.The volume of bleeding and blood transfusion wasrecorded during the operation. After the operation,the draining quantity from their abdominal cavities,and the days of transfusion and hospitalization wererecorded. The occurrence of complications and sur-vival time of the patient were followed up.Results: The postoperative mortality was 3.48% andthe occurrence rate of complications was 31.40%, whichwas significantly correlated with preoperative lowerlevel of serum albumin or the elevated γ-globulin lev-el and the amount of resected liver tissue. But their liverfunction before operation was fairly good, the 1-, 3-and 5-year survival rates after hepatectomy were58.2%, 35.7% and 17.64%.Conclusions: Patients with very big primary liver can-cer, should be subjected to hepatectomy if their liverfunction before operation are normal and the marginsare distinct between the tumor and liver tissues. Afterthe operation, other treatments are suitable for goodeffects.