Endoscopic-catheter-directed infusion of diluted(-)-noradrenaline for atypical hemobilia caused by liver abscess:A case report

BACKGROUND Hemobilia occurs when there is a fistula between hepatic blood vessels and biliary radicles,and represents only a minority of upper gastrointestinal hemorrhages.Causes of hemobilia are varied,but liver abscess rarely causes hemobilia and only a few cases have been reported.Here,we present a case of atypical hemobilia caused by liver abscess that was successfully managed by endoscopic hepatobiliary intervention through endoscopic retrograde cholangiopancreatography(ERCP).CASE SUMMARY A 54-year-old man presented to our emergency department with a history of right upper quadrant abdominal colic and repeated fever for 6 d.Abdominal sonography and enhanced computed tomography revealed that there was an abscess in the right anterior lobe of the liver.During hospitalization,the patient developed upper gastrointestinal bleeding.Upper gastrointestinal endoscopy revealed a duodenal ulcer bleeding that was treated with three metal clamps.However,the hemodynamics was still unstable.Hence,upper gastrointestinal endoscopy was performed again and fresh blood was seen flowing from the ampulla of Vater.Selective angiography did not show any abnormality.An endoscopic nasobiliary drainage(ENBD)tube was inserted into the right anterior bile duct through ERCP,and subsequently cold saline containing(-)-noradrenaline was infused into the bile duct lumen through the ENBD tube with no episode of further bleeding.CONCLUSION Hemobilia should be considered in the development of liver abscess,and endoscopy is essential for diagnosis and management of some cases.

Four-year experience with more than 1000 cases of total laparoscopic liver resection in a single center

BACKGROUND Laparoscopic liver resection(LLR)has become a safe surgical procedure that needs additional summarization.AIM To review 4 years of total LLR surgeries,exceeding 1000 cases,which were performed at a single center.METHODS Patients who underwent LLR at West China Hospital of Sichuan University between January 2015 and December 2018 were identified.Surgical details,including the interventional year,category of liver disease,and malignant liver tumors prognosis,were evaluated.The learning curve for LLR was evaluated using the cumulative sum method.The Kaplan-Meier method was used to perform survival analysis.RESULTS Ultimately,1098 patients were identified.Hepatocellular carcinoma(HCC)was the most common disease that led to the need for LLR at the center(n=462,42.08%).The average operation time was 216.94±98.51 min.The conversion rate was 1.82%(20/1098).The complication rate was 9.20%(from grade II to V).The 1-year and 3-year overall survival rates of HCC patients were 89.7%and 81.9%,respectively.The learning curve was grouped into two phases for local resection(cases 1-106 and 107-373),three phases for anatomical segmentectomy(cases 1-44,45-74 and 75-120),and three phases for hemihepatectomy(cases 1-17,18-48 and CONCLUSION LLR may be considered a first-line surgical intervention for liver resection that can be performed safely for a variety of primary,secondary,and recurrent liver tumors and for benign diseases once technical competence is proficiently attained.

Gallbladder carcinosarcoma with a poor prognosis: A case report

BACKGROUND Carcinosarcoma of the gallbladder is a rare malignant tumor with a very poor prognosis.To date,only approximately 100 patients have been reported in the English literature.The prognosis of this tumor type is poor,the preoperative diagnosis is difficult,and there is a possibility of a misdiagnosis.We present an unsuccessful case of carcinosarcoma of the gallbladder with a preoperative misdiagnosis and rapid early postoperative recurrence.Therefore,we have a deeper understanding of the poor prognosis of gallbladder carcinosarcoma(GBC)patients.CASE SUMMARY The patient is a 65-year-old male.He was admitted to the hospital because of right upper abdomen distending pain and discomfort for half a month.Abdominal magnetic resonance imaging revealed a polycystic mass in the right lobe of the liver and the fossa of the gallbladder.After admission,the patient was diagnosed with a liver abscess,which was treated by abscess puncture drainage.Obviously,this treatment was unsuccessful.Hepatectomy and cholecystectomy were performed one month after the puncture.Postoperative pathologic examination revealed carcinosarcoma of the gallbladder,and the resected specimen contained two tumor components.One month after surgery,the patient's tumor recurred in situ and started to compress the duodenum,resulting in duodenal obstruction and bleeding.The treatment was not effective.The patient died of gastrointestinal hemorrhage and hypovolemic shock.CONCLUSION Carcinosarcoma of the gallbladder is a rare malignant tumor that is easily misdiagnosed preoperatively and has a poor prognosis.

Effects of tetrahedral framework nucleic acid/wogonin complexes on osteoarthritis

Osteoarthritis, a disorder characterized by articular cartilage deterioration, varying degrees of inflammation, and chondrocyte apoptosis, is the most common chronic joint disease. To slow or reverse its progression, inflammation should be inhibited, and chondrocyte proliferation should be promoted. Tetrahedral framework nucleic acids can be internalized by chondrocytes(even inflammatory chondrocytes) and can enhance their proliferation and migration. Wogonin, a naturally occurring flavonoid,suppresses oxidative stress and inhibits inflammation. In this study, tetrahedral framework nucleic acids were successfully selfassembled and used to load wogonin. We confirmed the effective formation of tetrahedral framework nucleic acid/wogonin complexes by dynamic light scattering, zeta potential analysis, transmission electron microscopy, and fluorescence spectrophotometry. Tetrahedral framework nucleic acids, wogonin, and especially tetrahedral framework nucleic acid/wogonin complexes effectively alleviated inflammation in vitro and in vivo and prevented cartilage destruction. In addition, these materials remarkably downregulated the expression of inflammatory mediators and matrix metalloproteinases, upregulated chondrogenic markers, and promoted tissue inhibitor of metalloproteinase 1 and B-cell lymphoma 2 expression. In vivo, after treatment with tetrahedral framework nucleic acid/wogonin complexes, the bone mineral density in regenerated tissues was much higher than that found in the untreated groups. Histologically, the complexes enhanced new tissue regeneration, significantly suppressed chondrocyte apoptosis, and promoted chondrogenic marker expression. They also inhibited cell apoptosis, increased chondrogenic marker expression, and suppressed the expression of inflammatory mediators in osteoarthritis. Therefore, we believe that tetrahedral framework nucleic acid/wogonin complexes can be used as an injectable form of therapy for osteoarthritis.

Fas-670 A/G polymorphism predicts prognosis of hepatocellular carcinoma after curative resection in Chinese Han population

Background:Apoptosis,also called programmed cell death,is a genetically controlled process against hyperproliferation and malignancy.The Fas-Fas ligand(FasL)system is considered a major pathway for apoptosis in cells and tissues.Thus,this study aimed to investigate whether single nucleotide polymor-phisms(SNPs)in Fas and FasL gene may have effects on the recurrence and survival of patients with hepatocellular carcinoma(HCC)after curative hepatectomy.Methods:We investigated the relationship between Fas rs1800682,rs2234767 and FasL rs763110 poly-morphisms and recurrence-free survival(RFS)as well as overall survival(OS)in 117 Chinese Han patients with HCC who underwent hepatectomy.Results:In Kaplan-Meier survival analysis,only Fas rs1800682(-670 A/G)was associated with RFS and OS.Compared with AA genotype,the AG/GG genotype was significantly associated with better RFS(P=0.008)and OS(P=0.020).Moreover,multivariate Cox regression analysis showed that Fas rs1800682 remained as a significant independent predictor of RFS for HCC patients with hepatectomy[AG/GG vs.AA:adjusted hazard ratio=0.464,95%confidence interval:0.275-0.782,P=0.004],but was not an independent predictor of OS(P=0.395).Conclusions:This study demonstrated that Fas-670 G allele may play a protective role in the recurrence and survival of HCC patients with hepatectomy.Furthermore,Fas rs1800682 polymorphism might be a promising biomarker for HCC patients after hepatectomy.

Low-temperature 3D-printed collagen/chitosan scaffolds loaded with exosomes derived from neural stem cells pretreated with insulin growth factor-1 enhance neural regeneration after traumatic brain injury

There are various clinical treatments for traumatic brain injury,including surgery,drug therapy,and rehabilitation therapy;howeve r,the therapeutic effects are limited.Scaffolds combined with exosomes represent a promising but challenging method for improving the repair of traumatic brain injury.In this study,we determined the ability of a novel 3D-printed collagen/chitosan scaffold loaded with exosomes derived from neural stem cells pretreated with insulin-like growth factor-1(3D-CC-INEXOS) to improve traumatic brain injury repair and functional recove ry after traumatic brain injury in rats.Composite scaffolds comprising collagen,chitosan,and exosomes derived from neural stem cells pretreated with insulin-like growth fa ctor-1(INEXOS) continuously released exosomes for 2weeks.Transplantation of 3D-CC-INExos scaffolds significantly improved motor and cognitive functions in a rat traumatic brain injury model,as assessed by the Morris water maze test and modified neurological seve rity scores.In addition,immunofluorescence staining and transmission electron microscopy showed that3D-CC-INExos implantation significantly improved the recove ry of damaged nerve tissue in the injured area.In conclusion,this study suggests that transplanted3D-CC-INExos scaffolds might provide a potential strategy for the treatment of traumatic brain injury and lay a solid foundation for clinical translation.

Colorectal cancer-derived extracellular vesicles induce liver premetastatic immunosuppressive niche formation to promote tumor early liver metastasis

Dear Editor,To date,the effect of colorectal cancer(CRC)-derived extracellular vesicles(EVs)on liver pre-metastatic niche(PMN)remain incompletely understood.1 To investigate the role of CRC-derived EVs in the remodeling of the liver PMN,we isolated EVs from CT26 cell culture supernatant.The characteristics of EVs(the morphology,size,and markers)were identified by transmission electron microscopy(TEM),Nanoparticle Tracking Analysis(NTA),and western blotting(Supplementary Fig.S1a–e).Then,BALB/c mice with an intact liver immune status were pretreated with CRCderived EVs and phosphate-buffered saline(PBS)for one month,and a liver metastasis model was established via spleen injection of tumor cells to determine whether EVs influence liver metastasis(Fig.1a).Two hours after the operation,in vivo imaging indicated that the animal model was successfully established,and the tumor fluorescence intensity in the liver was consistent between the two groups(Supplementary Fig.S2a,b).Amazingly,the liver tumor fluorescence intensity in the EVs group was significantly stronger than that in the PBS group after 24 h(Fig.1b;Supplementary Fig.S2c,d).The number of liver tumor nodules in the EVs group was also significantly higher than that in the PBS group on day 4(Fig.1c;Supplementary Fig.S2e,f).

Is liver transplantation superior to liver resection for hepatocellular carcinoma within Milan criteria?

We read with great interest the recent meta-analysis written by Koh and colleagues entitled“Liver resection versus liver transplantation for hepatocellular carcinoma within Milan criteria:a meta-analysis of 18,421 patients”(1),which was published in the latest issue of Hepatobiliary Surgery Nutrition.

The efficiency of postoperative liver failure and mortality risk scores after liver resection for perihilar cholangiocarcinoma

With great interest,we read the literature by Noji et al.entitled“Validation study of postoperative liver failure and mortality risk scores after liver resection for perihilar cholangiocarcinoma”(1),which was published in the latest issue of Hepatobiliary Surgery Nutrition.The authors have reached an important conclusion that postoperative mortality risk score(POMRS)and post-hepatectomy liver failure score(PHLFS)proposed by the Academic Medical Center(AMC)and Memorial Sloan Kettering Cancer Center(MSKCC)require optimization before use in clinical practice.However,after a careful reading of this study,we would like to address several fundamental flaws related to this article.

Chest, pericardium, abdomen, and thigh penetrating injury by a steel rebar: A case report

BACKGROUND Combined penetrating trauma involving the chest, pericardium, abdomen, and thigh is rare and lethal. It is difficult to quickly rescue patients with penetrating injuries from long steel bars.CASE SUMMARY A previously healthy 56-year-old male worker presented with a length of rebar that penetrated the chest-abdomen-pelvic cavity and was palpable on the anterior side of the neck and thigh. On radiological imaging, the left chest wall-left chest cavity-mediastinum-abdominal cavity-right groin area-right thigh demonstrated a strip-like density shadow, about 1.5 cm thick, with the heart, stomach wall, and part of the intestine involved. There was a left-sided pleural effusion, left lung compression of about 50%-60%, and a small amount of left pleural effusion/blood accumulation;possible perforation of hollow organs;and double multiple ribs fractures on the side. An emergency green channel was opened to provide a rescue process for smooth and timely diagnostic and treatment to save the patient's life. The patient was followed at 4 mo after discharge and showed good recovery.CONCLUSION For pre-hospital emergency treatment in locations that are not fully prepared for surgery, we do not recommend cutting the steel bars outside the body. We advocate pulling out foreign bodies intact to reduce secondary injuries.

Role of Noncoding RNAs in the Tumor Immune Microenvironment of Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is one of the most preva-lent malignancies. It has high mortality and poor clinical out-comes, but the molecular mechanisms in the pathogenesis of HCC are not understood. The tumor immune microenviron-ment (TIME) is a highly intricate system with distinct popula-tions of innate and adaptive immune cells, as well as other stromal cells. They interact and evolve with tumor cells to influence tumor growth, migration, invasion, immune eva-sion, and response to therapy. Emerging evidence has shown noncoding RNAs (ncRNAs) are prominent regulators of TIME in HCC. In this review, we elaborate on the functions and molecular mechanisms of ncRNAs in remodeling TIME of HCC and discuss their diagnostic and therapeutic potential for HCC treatment.

Epigenome-wide development and validation of a prognostic methylation score in intrahepatic cholangiocarcinoma based on machine learning strategies

Background:Clinical parameter-based nomograms and staging systems provide limited information for the prediction of survival in intrahepatic cholangiocarcinoma(ICC)patients.In this study,we developed a methylation signature that precisely predicts overall survival(OS)after surgery.Methods:An epigenome-wide study of DNA methylation based on whole-genome bisulfite sequencing(WGBS)was conducted for two independent cohorts(discovery cohort,n=164;validation cohort,n=170)from three hepatobiliary centers in China.By referring to differentially methylated regions(DMRs),we proposed the concept of prognostically methylated regions(PMRs),which were composed of consecutive prognostically methylated CpGs(PMCs).Using machine learning strategies(Random Forest and the least absolute shrinkage and selector regression),a prognostic methylation score(PMS)was constructed based on 14 PMRs in the discovery cohort and confirmed in the validation cohort.Results:The C-indices of the PMS for predicting OS in the discovery and validation cohorts were 0.79 and 0.74,respectively.In the whole cohort,the PMS was an independent predictor of OS[hazard ratio(HR)=8.12;95% confidence interval(CI):5.48-12.04;P<0.001],and the C-index(0.78)of the PMS was significantly higher than that of the Johns Hopkins University School of Medicine(JHUSM)nomogram(0.69,P<0.001),the Eastern Hepatobiliary Surgery Hospital(EHBSH)nomogram(0.67,P<0.001),American Joint Committee on Cancer(AJCC)tumor-node-metastasis(TNM)staging system(0.61,P<0.001),and MEGNA prognostic score(0.60,P<0.001).The patients in quartile 4 of PMS could benefit from adjuvant therapy(AT)(HR=0.54;95%CI:0.32-0.91;log-rank P=0.043),whereas those in the quartiles 1-3 could not.However,other nomograms and staging system failed to do so.Further analyses of potential mechanisms showed that the PMS was associated with tumor biological behaviors,pathway activation,and immune microenvironment.Conclusions:The PMS could improve the prognostic accuracy and identify patients who would benefit from AT for ICC patients,and might facilitate decisions in treatment of ICC patients.

Efficacy and Safety of Second-line Treatments in Patients with Advanced Hepatocellular Carcinoma after Sorafenib Failure:A Meta-analysis

Background and Aims:In the last decade,several second-line therapies followed by sorafenib in patients with advanced hepatocellular carcinoma(HCC)have been reported.But the outcomes were different from each other.This meta-analysis aimed to evaluate the efficacy and safety of the second-line therapies followed by sorafenib in patients with advanced HCC.Methods:Embase(1974 to October 2019)and Ovid MEDLINE(1946 to October 2019)were searched for randomized clinical trials on second-line therapies followed by sorafenib in patients with advanced HCC.The quality of each study was assessed by the modified Jadad scale.Statistical analysis was carried out by RevMan5.3 software.Efficacy and safety were analyzed.Efficacy included overall survival(OS),disease control rate,time to progression,and progression-free survival.Results:Eight studies involving 3,173 patients were eligible.No difference in OS was found between the second-line treatment group and the control group(HR=0.87,95%CI:0.74-1.01,p=0.06).Disease control rate(relative risk(RR)=1.36,95%CI:1.16-1.60,p=0.0002),time to progression(HR=0.64,95%CI:0.51-0.81,p=0.0002)and progression-free survival(HR=0.60,95%CI:0.46-0.77,p<0.0001)were significantly improved by the second-line therapies.There was a slight difference in adverse events of any grade(RR=1.07,95%CI:1.00-1.14,p=0.03)between the two groups.Conclusions:These second-line therapies followed by sorafenib may potentially improve the prognosis in patients with advanced HCC.Compared with other second-line therapies,regorafenib seemed to be more effective.

Spontaneous rupture of hepatocellular carcinoma trans-arterial embolization or hepatectomy?

Spontaneous rupture and hemorrhage of hepatocellular carcinoma(HCC)is one of the serious complications leading to death in patients with primary liver cancer.Approximately 9-10%of those patients with liver cancer die of from spontaneous rupture and hemorrhage,which is often accompanied by abdominal metastasis and seriously affects their prognosis(1).

Body mass index and survival after cancer diagnosis:A pan-cancer cohort study of 114430 patients with cancer

The recommendation encouraging patients with cancer to keep a normal body mass index(BMI)is largely extrapolated from data on risk of developing cancer.We tested the prospective association between peri-diagnostic(within 1 year post-diagnosis)BMI and all-cause mortality in patients with incident cancers.During 7.2 years of follow-up,42%(48,340)of the 114430 patients with cancer died.Spline analysis revealed that compared with a BMI of 22.5,a BMI lower than 22.5 was associated with increased risk of all-cause mortality across 24 cancer types.A BMI higher than 22.5 was associated with reduced all-cause mortality,while a non-linear association was observed;the lowest risk was found at a BMI of 29.6–34.2,and the risk started to return to and above unity at very high BMI values.The reduced mortality risk of high BMI was observed in 23 of 24 cancer types and maintained after attempts to remove potential selection bias,confounding by smoking and comorbidities,and reserve causality.

Is FOLFOX-HAIC superior to transarterial chemoembolization in treating large hepatocellular carcinoma?

We read with interest the recent article by Li et al.(1)reported a randomized phase III trial that compared the efficacy of hepatic artery infusion(HAIC)with oxaliplatin,fluorouracil,and leucovorin with transarterial chemoembolization(TACE)for large hepatocellular carcinoma(HCC)(diameter≥7 cm).The authors found a lower incidence of serious adverse events in the FOLFOX-HAIC group;furthermore,the overall and progression-free survival was better in the FOLFOX-HAIC group than in the TACE group.Likewise,HAIC provided survival benefits in various subgroups.However,although the authors discussed some limitations,several fundamental flaws have yet to be fixed.

Smoking, smoking cessation, and survival after cancer diagnosis in 128,423 patients across cancer types

Dear Editor,Given the systemic and substantial health consequences of smoking and the significant cancer risk from smoking[1,2],it is expected that cancer patients would quit smoking after cancer diagnosis.However,the smoking rate among cancer survivors is only slightly lower than that among the general population[3,4],and 64%of smokers diagnosed with cancer continued to smoke even after they learned they had cancer[5].In addition,some former smokers may resume smoking after surviving cancer[6].A number of previous studies have investigated the association between smoking and clinical outcomes in cancer patients[1,7–10].Nevertheless,most studies were conducted in smoking-related cancers,and evidence for non-smoking-related cancers is limited.There is an urgent need for more convincing evidence showing the harms of smoking and the benefits of smoking cessation to promote smoking cessation in cancer patients and survivors.We systematically studied the associations of smoking status,smoking intensity,age at initiation,and smoking cessation at cancer diagnosis with all-cause mortality in a prospective cohort of 128,423 cancer patients across 23 cancer types from the MD Anderson Cancer Patients and Survivors Cohort.

Interleukin-37 promotes colitis-associated carcinogenesis via SIGIRR-mediated cytotoxic T cells dysfunction

Interleukin-37b(hereafter called IL-37)was identified as fundamental inhibitor of natural and acquired immunity.The molecular mechanism and function of IL-37 in colorectal cancer(CRC)has been elusive.Here,we found that IL-37 transgenic(IL-37tg)mice were highly susceptible to colitis-associated colorectal cancer(CAC)and suffered from dramatically increased tumor burdens in colon.Nevertheless,IL-37 is dispensable for intestinal mutagenesis,and CRC cell proliferation,apoptosis,and migration.Notably,IL-37 dampened protective cytotoxic T cell-mediated immunity in CAC and B16-OVA models.CD8^(+)T cell dysfunction is defined by reduced retention and activation as well as failure to proliferate and produce cytotoxic cytokines in IL-37tg mice,enabling tumor evasion of immune surveillance.The dysfunction led by IL-37 antagonizes IL-18–induced proliferation and effector function of CD8+T cells,which was dependent on SIGIRR(single immunoglobulin interleukin-1 receptor-related protein).Finally,we observed that IL-37 levels were significantly increased in CRC patients,and positively correlated with serum CRC biomarker CEA levels,but negatively correlated with the CD8+T cell infiltration in CRC patients.Our findings highlight the role of IL-37 in harnessing antitumor immunity by inactivation of cytotoxic T cells and establish a new defined inhibitory factor IL-37/SIGIRR in cancerimmunity cycle as therapeutic targets in CRC.

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.