Impact of metabolic dysfunction-associated steatotic liver disease on the efficacy of immunotherapy in patients with chronic hepatitis B-related hepatocellular carcinoma

Objective:To investigate the impact of metabolic dysfunction-associated steatotic liver disease(MASLD)on the efficacy of immune checkpoint inhibitor(ICI)-based therapy in patients with chronic hepatitis B(CHB)-related hepatocellular carcinoma(HCC).Methods:A total of 155 patients with CHB-related HCC who received ICI–based therapy(in the Department of Hepatology,Tianjin Second People’s Hospital and Department of Hepatobiliary Oncology,Tianjin Medical University Cancer Institute&Hospital)between April 2021 and December 2023 were evaluated.Patients were divided into two groups:MASLD concurrent with CHB[MASLD-CHB](n=38),and CHB(n=117).Results:The median progression-free survival(PFS,6.9 months vs.9.3 months;P=0.001),progressive disease(57.89%vs.37.61%;P=0.028),and disease control rate(42.11%vs.62.39%;P=0.028)in the MASLD-CHB group were significantly worse than the CHB group.The median overall survival was not attained.The percentage of CD4+PD1+(17.56%vs.8.89%;P<0.001)and CD8+PD1+T cells(10.50%vs.7.42%;P=0.005)in patient samples from the MASLD-CHB group were significantly higher than the CHB group.Concurrent MASLD[hazard ratio(HR)=1.921;95%CI,1.138–3.245;P=0.015]and alpha-fetoprotein levels after 3 months of treatment(HR=2.412;95%CI,1.360–4.279;P=0.003)were independent risk factors for PFS in all patients.Conclusions:ICI-based therapy in patients with CHB-related HCC and concurrent MASLD resulted in poorer efficacy and shorter PFS compared to patients with CHB-related HCC alone.

Association of HBV DNA replication.with antiviral treatment outcomes in the patients with early-stage HBV-related hepatocellular carcinoma undergoing curative resection

Background:It remains unclear what the antiviral therapy affects disease-free survival(DFS) and overall survival(OS)of patients with hepatitis B virus(HBV)-related hepatocellular carcinoma(HCC) at different tumor stages and baseline HBV DNA levels.In this study,we analyzed the association of antiviral treatment with DFS and OS based on the stratification of baseline HBV DNA load in early-stage(stages Ⅰ and Ⅱ) HCC patients.Methods:We included 445 patients with early-stage HBV-related HCC who underwent curative resection,and then classified them into four subgroups based on baseline HBV DNA load and antiviral therapy stratification.The KaplanMeier and Cox regression analyses were performed to determine the association of clinical characteristics with survival.Results:The median follow-up period was 74 months.For all patients,cumulative OS rates in the antiviral group were significantly higher than those in the non-antiviral group(log-rank test,P = 0.023),whereas no significant differences in DFS rates were observed.High baseline HBV DNA level was a risk factor associated with short DFS and OS in all patients.In patients with baseline HBV DNA levels ≥2000 lU/mL,antiviral treatment was significantly associated with prolonged DFS and OS(log-rank test,P = 0.041 and 0.001,respectively).In patients with HBV DNA levels <2000 lU/mL or undetectable,antiviral treatment did not show a significant benefit in prolonging DFS and OS.Conclusions:High baseline HBV DNA levels are associated with poor prognosis in the patients with early-stage HCC,and the antiviral treatment could generate survival benefits for the patients.Therefore,antiviral treatment should be given for these patients.However,the effect of antiviral treatment on the patients with low viral load remains unclear,and further investigation is warranted.

Prospective,single-center cohort studyanalyzing the efficacy of complete laparoscopic resection on recurrent hepatocellular carcinoma

Background:Laparoscopic hepatectomy is increasingly being used to treat hepatocellular carcinoma(HCC).However,few studies have examined the treatment of recurrent HCC in patients who received a prior hepatectomy.The present prospective study compared the clinical efficacy of laparoscopic surgery with conventional open surgery in HCC patients with postoperative tumor recurrence.Methods:We conducted a prospective study of 64 patients,all of whom had undergone open surgery once before,who were diagnosed with recurrent HCC between June 2014 and November 2014.The laparoscopic group(n = 31)underwent laparoscopic hepatectomy,and the control group(n = 33) underwent conventional open surgery.Operation time,intraoperative blood loss,surgical margins,postoperative pain scores,postoperative time until the patient could walk,anal exsufflation time,length of hospital stay,and inpatient costs were compared between the two groups.The patients were followed up for 1 year after surgery,and relapse-free survival was compared between the two groups.Results:All surgeries were successfully completed.No conversion to open surgery occurred in the laparoscopic group,and no serious postoperative complications occurred in either group.No significant difference in inpatient costs was found between the laparoscopic group and the control group(P = 0.079),but significant differences between the two groups were observed for operation time(116.7 ± 37.5 vs.148.2 ± 46.7 min,P = 0.031),intraoperative blood loss(117.5 ± 35.5 vs.265.9 ± 70.3 mL,P = 0.012),postoperative time until the patient could walk(1.6 ± 0.6vs.2.2 ± 0.8 days,P < 0.05),anal exsufflation time(2.1 ± 0.3 vs.2.8 ± 0.7 days,P = 0.041),visual analogue scale pain score(P < 0.05),postoperative hepatic function(P < 0.05),and length of hospital stay(4.5 ± 1.3 vs.6.0 ± 1.2 days,P = 0.014).During the 1-year postoperative follow-up period,6 patients in each group had recurrent HCC on the side of the initial operation,but no significant difference between groups was observed in the recurrence rate or relapse-free survival.In the laparoscopic group,operation time,postoperative time until the patient could walk,anal exsufflation time,and inpatient costs were not different(P > 0.05) between the patients with contralateral HCC recurrence(n=18) and those with ipsilateral HCC recurrence(n = 13).However,intraoperative blood loss was significantly less(97.7 ± 14.0 vs.186.3 ± 125.6 mL,P = 0.012) and the hospital stay was significantly shorter(4.2 ± 0.7 vs.6.1 ± 1.7 days,P = 0.021) for the patients with contralateral recurrence than for those with ipsilateral recurrence.Conclusions:For the patients who previously underwent conventional open surgical resection of HCC,complete laparoscopic resection was safe and effective for recurrent HCC and resulted in a shorter operation time,less intraoperative blood loss,and a faster postoperative recovery than conventional open surgery.Laparoscopic resection was especially advantageous for the patients with contralateral HCC recurrence.

Transarterial chemoembolization combined with recombinant human adenovirus type 5 H101 prolongs overall survival of patients with intermediate to advanced hepatocellular carcinoma: a prognostic nomogram study

Background: Patients with intermediate to advanced hepatocellular carcinoma(HCC) are most commonly treated with transarterial chemoembolization(TACE). Previous studies showed that TACE combined with recombinant human adenovirus type 5(H101) may provide a clinical survival benefit. In the present study, we aimed to determine the survival benefit of TACE with or without H101 for patients with intermediate to advanced HCC and to develop an e ective nomogram for predicting individual survival outcomes of these patients.Methods: We retrospectively collected data from 590 patients with intermediate to advanced HCC who were treated at Sun Yat?sen University Cancer Center between January 2007 and July 2015. After propensity score matching, 238 patients who received TACE with H101(TACE with H101 group) and 238 patients who received TACE without H101(TACE group) were analyzed. Overall survival(OS) was evaluated using the Kaplan–Meier method; the nomogram was developed based on Cox regression analysis. Discrimination and calibration were measured using the concordance index(c?index) and calibration plots.Results: Clinical and radiologic features were similar between the two groups. OS rates were significantly lower in the TACE group than in the TACE with H101 group(1?year OS rate, 53.8% vs. 61.3%; 2?year OS rate, 33.4% vs. 44.2%; 3?year OS rate, 22.4% vs. 40.5%; all P < 0.05). Multivariate Cox regression analysis for the entire cohort showed that alpha?fetoprotein level, alkaline phosphatase level, tumor size, metastasis, vascular invasion, and TACE with or without H101 were independent factors for OS, all of which were included in the nomogram. Calibration curves showed good agreement between nomogram?predicted survival and observed survival. The c?index of the nomogram for predict?ing OS was 0.716(95% confidence interval 0.686–0.746).Conclusions: TACE plus H101 extends the survival of patients with intermediate to advanced HCC. Our proposed nomogram provides individual survival prediction and stratification for patients with intermediate to advanced HCC who receive TACE with or without H101.

Impact of oral anti-hepatitis B therapy on the survival of patients with hepatocellular carcinoma initially treated with chemoembolization

Introduction:Most hepatocellular carcinomas(HCC) develop in a background of underlying liver disease including chronic hepatitis B.However,the effect of antiviral therapy on the long-term outcome of patients with hepatitis B virus(HBV)-related HCC treated with chemoembolization is unclear.This study aimed to evaluate the survival benefits of anti-HBV therapy after chemoembolization for patients with HBV-related HCC.Methods:A total of 224 HCC patients who successfully underwent chemoembolization were identified,and their survival and other relevant clinical data were reviewed.Kaplan-Meier and Cox regression analyses were performed to validate possible effects of antiviral treatment on overall survival(OS).Results:The median survival time(MST) was 15.9(95%confidence interval[CI],9.5-27.7) months in the antiviral group and 9.6(95%CI,7.8-13.7) months in the non-antiviral group(log-rank test,P = 0.044).Cox multivariate analysis revealed that antiviral treatment was a prognostic factor for OS(P = 0.008).Additionally,a further analysis was based on the stratification of the TNM tumor stages.In the subgroup of early stages,MST was significantly longer in the antiviral-treatment group than in the non-antiviral group(61.8 months[95%CI,34.8 months to beyond the follow-up period]versus 26.2[95%CI,14.5-37.7]months,P= 0.012).Multivariate analysis identified antiviral treatment as a prognostic factor for OS in the early-stage subgroup(P = 0.006).However,in the subgroup of advanced stages,MST of the antiviral-treated group was comparable to that of the non-antiviral group(8.4[95%CI,5.2-13.5]months versus 7.4[95%CI,5.9-9.3]months,P = 0.219).Multivariate analysis did not indicate that antiviral treatment was a significant prognostic factor in this subgroup.Conclusion:Antiviral treatment is associated with prolonged OS time after chemoembolization for HCC,especially in patients with early-stage tumors.

Littoral-cell angioma of the spleen:a case report

Littoral-cell angioma(LCA), a primary angioma which clinically belongs to splenic hemangioma, can be mostly found in normal spleen red sinus shore cells of reticuloendothelial cell system. The cells of LCA strongly express endothelial and tissue cell associated antigens that indicate a dual differentiation characteristic; whereas only endothelial cell markers are positive in normal spleen red sinus shore cells. Diagnosis of LCA relies on histopathology. Regular follow-up is needed to monitor recurrence and metastasis.

Surgical management of non-parasitic hepatic cyst with biliary communication: a case report

Non-parasitic hepatic cysts with biliary communication are rare. qhe clinical symptoms involved are not specific to this condition, thereby making diagnosis difficult and treatment controversial. Here, we report a case of 70-year-old woman complaining of abdominal satiety, combined with non-specific pain in the right upper quadrant, qhe abdominal contrast-enhanced MR.I-scan revealed a large and thick-walled septus cystic lesion in the liver. During operation, the biliary fistula was confirmed in the cyst cavity. A silica gel tube was inserted via the cystic duct for cholangiography, which demonstrated communication between the cyst and biliary tract. We performed wide-scale cyst wall resection; the biliary fistula was completely repaired by the closure of communicated bile ducts. The postoperative course was uneventful, and the patient was discharged with no sign ofcholangitis or any other symptoms. The novel surgical management via wide resection of the cyst wall and closure of biliary communication proved to be an adequate and effective procedure for treating nonparasitic hepatic cysts with biliary communication.

A modified radiofrequency ablation approach for treating distant lymph node metastasis in two patients with late-stage cancer

Patients with late-stage cancer commonly have distant lymph node metastasis;however,poor health often contraindicates surgical treatment.Although the quality of life and overall survival for these patients are low,there is neither a consensus nor a guide for treatment.Ablation technique and surrounding tissue damage are two possible reasons for limited study of radiofrequency ablation in patients with superficial distant lymph node metastasis.Here,we report two patients treated successfully with ultrasound-guided radiofrequency ablation for superficial distant lymph node metastasis.In these patients,deionized water was injected to the surrounding tissues of the lymph node to decrease heat injury.Results from these patients suggest that radiofrequency ablation may play an important role in the treatment of patients with distant lymph node metastasis.

Precision medicine in the treatment of pancreatic ductal adenocarcinoma

Pancreatic cancer has a poor prognosis. Current therapies for pancreatic cancer have limited effects. In the past decade, precision medicine has shown great potential for clinical applications. In this review, different strategies for applying precision medicine to the treatment of pancreatic cancer are described.

Hepatic artery infusion chemotherapy using mFOLFOX versus transarterial chemoembolization for massive unresectable hepatocellular carcinoma:a prospective non.randomized study

Background: Transarterial chemoembolization(TACE) is recommended as the standard care for unresectable hepatocellular carcinoma(HCC) at Barcelona Clinic Liver Cancer(BCLC) stage A-B. However, the efficacy of TACE on large(> 10 cm) stage A-B HCC is far from satisfactory, and it is proposed that hepatic artery infusion chemotherapy(HAIC)might be a better first-line treatment of this disease. Hence, we compared the safety and efficacy of HAIC with the modified FOLFOX(mFOLFOX) regimen and those ofTACE in patients with massive unresectable HCC.Methods: A prospective, non-randomized, phase II study was conducted on patients with massive unresectable HCC. The protocol involved HAIC with the mFOLFOX regimen(oxaliplatin, 85 mg/m^2 intra-arterial infusion; leucovorin,400 mg/m^2 intra-arterial infusion; and fluorouracil, 400 mg/m2 bolus infusion and 2400 mg/m^2 continuous infusion)every 3 weeks and TACE with 50 mg of epirubicin, 50 mg of lobaplatin, 6 mg of mitomycin, and lipiodol and polyvinyl alcohol particles. The tumor responses, time-to-progression(TTP), and safety were assessed.Results: A total of 79 patients were recruited for this study: 38 in the HAIC group and 41 in the TACE group. The HAIC group exhibited higher partial response and disease control rates than did the TACE group(52.6% vs. 9.8%, P < 0.001;83.8% vs. 52.5%, P = 0.004). The median TTPs for the HAIC and TACE groups were 5.87 and 3.6 months(hazard radio[HR] = 2.35,95% confidence interval [CI] = 1.16-4.76, P = 0.015). More patients in the HAIC group than in the TACE group underwent resection(10 vs. 3,P = 0.033). The proportions of grade 3-4 adverse events(AE) and serious adverse events(SAE) were lower in the HAIC group than in the TACE group(grade 3-4 AEs: 13 vs. 27, P = 0.007;SAEs: 6 vs. 15,p = 0.044). More patients in the TACE group than in the HAIC group had the study treatment terminated early due to intolerable treatment-related adverse events or the withdrawal of consent(10 vs. 2,P = 0.026).Conclusions: HAIC with mFOLFOX yielded significantly better treatment responses and less serious toxicity than did TACE. HAIC might represent a feasible and promising first-line treatment for patients with massive unresectable HCC.

Left jackknife position:a novel position for laparoscopic hepatectomy

Background: Laparoscopic hepatectomy for hepatocellular carcinoma(HCC) located in segment Ⅵ, Ⅶ, or Ⅷ of the liver is usually difficult because of poor operative exposure, due to the unique anatomical structure. In this study, we evaluated the practice of laparoscopic hepatectomy with the left jackknife position for patients with HCC located in segment Ⅵ, Ⅶ, or Ⅷ.Methods: A total of 10 patients were enrolled to undergo laparoscopic hepatectomy with the left jackknife position.Tumors located in segment Ⅵ, Ⅶ, or Ⅷ were assessed by preoperative dynamic computed tomography or magnetic resonance imaging. Operation time, intraoperative blood loss, postoperative fasting time, postoperative drainage time, major postoperative complications, and duration of postoperative hospital stay were recorded.Results: All surgeries were successfully completed. None of the patients required conversion to open surgery during the procedure, and no serious postoperative complications were observed.The median tumor size was 31 mm(range 23-41 mm) in diameter, the mean operation time was 166 ± 38 min, the mean intraoperative blood loss was220 ± 135 mL, and the median postoperative hospital stay was 4 days(range 2-7 days).Conclusions: For HCC located in segment Ⅵ, Ⅶ, or Ⅷ, laparoscopic hepatectomy with this novel position—the left jackknife position—is safe and effective during tumor resection by exposing a sufficient operating field.Trial registration ClinicalTrials.gov ID:

LIN28 expression and prognostic value in hepatocellular carcinoma patients who meet the Milan criteria and undergo hepatectomy

Stem cell marker LIN28,related closely with SOX2 and OCT4,has been studied as a biomarker for the maintainance of pluripotent cells in several malignancies.Our previous study showed that SOX2 and OCT4 were negative predictors for hepatocellular carcinoma(HCC).However,the predictive value of LIN28 in HCC outcome is still undetermined.We hypothesized that LIN28 may also play a role as a biomarker for HCC.To test this hypothesis,we examined the expression of LIN28 in 129 radically resected HCC tissues using reverse transcription-polymerase chain reaction and analyzed the association of LIN28 expression with clinicopathologic features and prognosis.Our study showed that LIN28 was expressed at a higher frequency in tumor tissues than in non-HCC tissues(45.0% vs.21.7%,P = 0.020).Moreover,LIN28 expression was significantly increased in cases with large tumor size(P = 0.010).Univariate analysis did not reveal a significant correlation between LIN28 expression and overall survival or recurrence-free survival.For HCC patients who met the Milan criteria,stratified analysis revealed shorter overall survival(P = 0.007) and recurrence-free survival(P < 0.001) in those with detectable LIN28 expression compared to those with no detectable LIN28 expression.Furthermore,multivariate analysis revealed that LIN28 was a negative independent predictor for both overall survival(hazard ratio= 7.093,P = 0.017) and recurrence-free survival(hazard ratio=5.518,P = 0.004) in patients who met the Milan criteria.Taken together,our results suggest that LIN28 identifies low-risk and high-risk subsets of HCC patients meeting the Milan criteria who undergo hepatectomy.

Sorafenib plus hepatic arterial infusion chemotherapy with oxaliplatin versus sorafenib alone for advanced hepatocellular carcinoma

Objective:To compare the efficacy of sorafenib plus hepatic arterial infusion chemotherapy(HAIC)with oxaliplatin to that of sorafenib alone in patients with advanced hepatocellular carcinoma(HCC).Methods:This was a retrospective,single-center trial.Between April 3,2017 and July 2,2018,104 patients with Child-Pugh A and advanced HCC received either 400 mg of sorafenib orally twice daily plus HAIC with oxaliplatin(oxaliplatin 85 mg/m^2,every 3 weeks via repetitive catheterization)(n=46,soraOXA group)or 400 mg of only sorafenib orally twice daily(n=58,sorafenib group).Overall survival,progression-free survival,objective response rate,and treatment-related adverse events were compared.Results:The median overall survival was 9.37 months(95%CI,7.05-11.68)in the soraOXA group versus 4.8 months(95%CI,2.98-6.62)in the sorafenib group(HR 0.46[95%CI,0.29-0.72];P<0.001).The soraOXA group also showed a higher objective response rate(16[34.8%]vs 1[1.7%];P<0.001)and a longer progressionfree survival rate(5.5 months[95%CI,2.32-8.68]vs 2.4 months[95%CI,1.65-3.15],HR 0.54[95%CI,0.36-0.81],P=0.003)than the sorafenib group.There was no significant difference in the overall incidence of any grade adverse events,grade 3/4 adverse events,serious adverse events,or incidence of treatment termination due to adverse events between the two groups.Conclusion:Compared with sorafenib alone,sorafenib plus HAIC with oxaliplatin showed favorable treatment outcomes in patients with advanced HCC.The merits of this approach need to be established with a prospective trial.

Modified Blumgart anastomosis without pancreatic duct-to-jejunum mucosa anastomosis for pancreatoduodenectomy：a feasible and safe novel technique

Objective：This study proposed a modified Blumgart anastomosis（m-BA）that uses a firm ligation of the main pancreatic duct with a supporting tube to replace the pancreatic duct-to-jejunum mucosa anastomosis,with the aim of simplifying the complicated steps of the conventional BA（c-BA）.Thus,we observe if a difference in the risk of postoperative pancreatic fistula（POPF）exists between the two methods.Methods：The m-BA anastomosis method has been used since 2010.From October 2011 to October 2015,147 patients who underwent pancreatoduodenectomy（PD）using BA in Tianjin Medical University Cancer Institute and Hospital were enrolled in this study.According to the type of pancreatojejunostomy（PJ）,50 patients underwent m-BA and 97 received c-BA.The two patient cohorts were compared prospectively to some extent but not randomized,and the evaluated variables were operation time,the incidence rate of POPF,and other perioperative complications.Results：The operation time showed no significant difference（P〉0.05）between the two groups,but the time of duct-to-mucosa anastomosis in the m-BA group was much shorter than that in the c-BA group（P〈0.001）.The incidence rate of clinically relevant POPF was 12.0%（6/50）in the modified group and 10.3%（10/97）in the conventional group（P〉0.05）,which means that the modified anastomosis method did not cause additional pancreatic leakage.The mean length of postoperative hospital stay of the m-BA group was 23 days,and that of the c-BA group was 22 days（P〉0.05）.Conclusions：Compared with the conventional BA,we suggest that the modified BA is a feasible,safe,and effective operation method for P J of PD with no sacrifice of surgical quality.In the multivariate analysis,we also found that body mass index（≥25

Proteasome Inhibitors Sensitize Hepatocellular Carcinoma Cells to TRAIL

OBJECTIVE To investigate the effect of proteasome inhibition on the sensitivity of carcinoma cells to TRAIL-inducing apoptosis, and to study the mechanism of the response. METHODS Human hepatocellular carcinoma cells, pretreated with the proteasome inhibitor, MG132, were cotreated with TRAIL. Western blot assays, immunoprecipitation and RT-PCR were performed to test the expression of the Bcl-2 family proteins and Bax mRNA. RESULTS We found that (i) proteasome inhibition sensitized the human hepatocellular carcinoma cells to TRAIL; and (ii) resulted in Bax accumulation before release of cytochrome C and induction of apoptosis. These results were associated with the ability of proteasome inhibitors to overcome Bcl-2-mediated antiapoptotic function; (iii) Bax is regulated by an ubiquitin/proteasome-dependent degradation pathway. CONCLUSION Proteasome inhibition sensitized hepatocellular carcinoma cells to TRAIL by the inhibition of the ubiquitin/proteasome-mediated Bax degradation pathway.

Long- versus short-interval follow-up after resection of hepatocellular carcinoma: a retrospective cohort study

Background:Average postoperative follow-up intervals vary in patients undergoing hepatocellular carcinoma(HCC)resection because of limited evidence regarding the optimal interval.We aimed to compare the associations of long-versus short-interval follow-up with survival and recurrence in risk-stratified HCC patients.Methods:We performed a retrospective cohort study between 2007 and 2014.In total,1227 patients treated by curative resection of Barcelona Clinic Liver Cancer stage A or B HCC were stratified as having a low(n=865)or high(n=362)risk of early recurrence(within the first 2 years after resection)based on prognostic factors identified by the least absolute shrinkage and selection operation algorithm.Patients were further classified into long-interval(every 4-6 months)and short-interval(every 2-4 months)follow-up subgroups based on follow-up within 2 years after resection(low risk,long vs.short:n=390 vs.n=475;high-risk,long vs.short:n=149 vs.n=213).Results:The short-interval follow-up did not prolong overall survival in either the low-risk(hazard ratio[HR]=1.152;95%confidence interval[CI]0.720-1.843)or high-risk(HR=1.213;95%CI 0.702-2.094)patients.Early recurrence occurred in 401 patients.For high-risk patients,the short-interval follow-up subgroup exhibited smaller intrahepatic recurrence than did the long-interval group(2.6 vs.3.5 cm,respectively,P=0.045).However,no significant difference in the rate of Barcelona Clinic Liver Cancer stage 0/A recurrence was found between the long-and short-interval follow-up groups in either low-or high-risk patients(63.1%vs.68.2%,respectively,P=0.580;31.3%vs.41.5%,respec-tively,P=0.280).The rate of curative intent treatment for recurrence(34.5%vs.39.7%,respectively,P=0.430;14.6%vs.20.3%,respectively,P=0.388)was also similar between the follow-up groups for low-and high-risk patients.Conclusions:Shortening the postoperative follow-up interval from every 4-6 months to every 2-4 months within the first 2 years after resection did not increase the rate of curative intent treatment or prolong the overall survival of patients with Barcelona Clinic Liver Cancer stage A or B HCC.

Choline suppresses hepatocellular carcinoma progression by attenuating AMPK/mTOR-mediated autophagy via choline transporter SLC5A7 activation

Background:Hepatocellular carcinoma(HCC)is one of the leading causes of cancer-associated death.Emerging evidence suggests that autophagy plays a critical role in HCC tumorigenesis,metastasis,and prognosis.Choline is an essential nutrient related to prolonged survival and reduced risk of HCC.However,it remains unclear whether this phenomenon is mediated by autophagy.Methods:Two HCC cell lines(HUH-7 and Hep3B)were used in the present study.Cell growth was evaluated by cell counting kit 8(CCK-8),colony formation,and in vivo mouse xenografts assays.Cell motility was calculated by wound healing and transwell assays.Autophagosomes were measured by transmission electron microscope(TEM),and autophagy flux was detected by mRFP-GFP-labeled LC3 protein.The mRNA level of genes was measured by quantitative real-time polymerase chain reaction(qRT-PCR).The protein levels were detected by Western blotting(WB).Results:We found that choline inhibited the proliferation,migration,and invasion of HCC cells by downregulating autophagy in vitro and in vivo.Upregulated expression of the solute carrier family 5 member 7(SLC5A7),a specific choline transporter,correlated with better HCC prognosis.We further discovered that choline could promote SLC5A7 expression,upregulate cytoplasm p53 expression to impair the AMPK/mTOR pathway,and attenuate autophagy.Finally,we found that choline acted synergistically with sorafenib to attenuate HCC development in vitro and in vivo.Conclusions:Our findings provide novel insights into choline-mediated autophagy in HCC,providing the foothold for its future application in HCC treatment.

Tumor growth and metastasis can be inhibited by maintaining genomic stability in cancer cells

The existence of cancer stem cells, stem-like cancer cells （SLCCs）, or tumor-initiating cells is considered as the cause of tumor formation and recurrence, indicating the importance of studying novel therapy that targets SLCCs. The origin of SLCCs is controversial because of two competing hypotheses： SLCCs are either transformed from tissue adult stem cells or dedifferentiated from transformed progenitor cells. Our previous research demonstrates that SLCCs are inducible by increasing genomic instability in cancer cells. In this study, to block the emergence of SLCCs, aminoethyl isothiourea （AET）, a compound that clears free radicals and is used to protect patients from radioactive exposure, was used as an agent that maintains genomic stability in combination with mitomycin C （MMC）, a commonly used chemotherapeutic drug that damages DNA. Using a rabbit tumor model with VX2 hepatic carcinoma, we found that MMC alone increased lung metastases and disadvantaged survival outcome, but the combination of MMC and AET reversed this effect and even prolonged overall survival. Moreover, in a VX2 xenograft model by immunocompromised mice, MMC alone enriched tumor-initiating cells, but the administration of MMC in combination with AET eliminated tumor cells effectively. Furthermore, MMC alone enhanced genomic instability, but MMC combined with AET attenuated the extent of genomic instability in primary VX2 tumor tissue. Taken together, our data suggest that the genomic protector AET can inhibit the induction of SLCCs, and this combination treatment by AET and cytotoxic agents should be considered as a promising strategy for future clinical evaluation.

Chinese expert consensus on conversion therapy for hepatocellular carcinoma(2021 edition)

Recent advances in systemic and locoregional treatments for patients with unresectable or advanced hepatocellular carcinoma(HCC)have resulted in improved response rates.This has provided an opportunity for selected patients with initially unresectable HCC to achieve adequate tumor downstaging to undergo surgical resection,a‘conversion therapy’strategy.However,conversion therapy is a new approach to the treatment of HCC and its practice and treatment protocols are still being developed.Review the evidence for conversion therapy in HCC and develop consensus statements to guide clinical practice.Evidence review:Many research centers in China have accumulated significant experience implementing HCC conversion therapy.Preliminary findings and data have shown that conversion therapy represents an important strategy to maximize the survival of selected patients with intermediate stage to advanced HCC;however,there are still many urgent clinical and scientific challenges for this therapeutic strategy and its related fields.In order to summarize and learn from past experience and review current challenges,the Chinese Expert Consensus on Conversion Therapy for Hepatocellular Carcinoma(2021 Edition)was developed based on a review of preliminary experience and clinical data from Chinese and non-Chinese studies in this field and combined with recommendations for clinical practice.Sixteen consensus statements on the implementation of conversion therapy for HCC were developed.The statements generated in this review are based on a review of clinical evidence and real clinical experience and will help guide future progress in conversion therapy for patients with HCC.