Multifaceted roles of lymphatic and blood endothelial cells in the tumor microenvironment of hepatocellular carcinoma:A comprehensive review

The tumor microenvironment is a complex network of cells,extracellular matrix,and signaling molecules that plays a critical role in tumor progression and metastasis.Lymphatic and blood vessels are major routes for solid tumor metastasis and essential parts of tumor drainage conduits.However,recent studies have shown that lymphatic endothelial cells(LECs)and blood endothelial cells(BECs)also play multifaceted roles in the tumor microenvironment beyond their structural functions,particularly in hepatocellular carcinoma(HCC).This comprehensive review summarizes the diverse roles played by LECs and BECs in HCC,including their involvement in angiogenesis,immune modulation,lymphangiogenesis,and metastasis.By providing a detailed account of the complex interplay between LECs,BECs,and tumor cells,this review aims to shed light on future research directions regarding the immune regulatory function of LECs and potential therapeutic targets for HCC.

Clinical practice guidelines on liver transplantation for hepatocellular carcinoma in China(2018 edition)

Introduction Over 300000 people in China die each year of hepatocellular carcinoma(HCC),which accounts for approximately half of HCCrelated deaths worldwide.Liver transplantation(LT)is generally recognized as one of the most effective therapeutic approaches for end-stage liver diseases.Since the beginning of the second LT boom in the 1990s,LT in China has been developed rapidly with professional and large-scale trends,and it is approaching or has reached the level of developed countries in terms of quantity and quality.According to the China Liver Transplant Registry,the number of transplants for HCC accounted for 36.8%of the total number of LT cases during the past 5 years in the mainland of China.In order to develop an effective,safe and standardized protocol to guide the national LT practice,the clinical guidelines of LT for HCC was launched in 2014 by multidisciplinary experts from Chinese Society of Organ Transplantation,Chinese Medical Association and Chinese Association of Organ Transplantation,Chinese Medical Doctor Association.Recently,there have been new clinical and scientific advances in the field of LT and to keep abreast of these achievements,the original clinical practice guidelines need to be updated.

Two case reports and literature review for hepatic epithelioid angiomyolipoma: Pitfall of misdiagnosis

BACKGROUND Hepatic epithelioid angiomyolipoma(HEAML) is a rare liver disease and is easily misdiagnosed. Enhanced recognition of HEAML is beneficial to the differential diagnosis of rare liver diseases.CASE SUMMARY We presented two cases of HEAML in Changzheng Hospital, Naval Medical University, and then collected and analyzed all reports about HEAML recorded in PubMed, MEDLINE, China Science Periodical Database, and VIP database from January 2000 to March 2018. A total of 409 cases of HEAML in 97 reports were collected, with a ratio of men to women of 1:4.84 and an age range from 12 years to 80 years(median 44 years). Among the patients with clinical symptoms mentioned, 61.93%(205/331) were asymptomatic, 34.74%(115/331) showed upper or right upper quadrant abdomen discomfort, while a few of them showed abdominal mass, gastrointestinal symptoms, low fever, or weight loss. The misdiagnosis rate of HEAML was as high as 40.34%(165/409) due to its nonspecific imaging findings. Most of the tumors were solitary and round in morphology, with clear boundaries. Ultrasound scan indicated low echo with internal nonuniformity and rich blood supply in most cases. Computer tomography/magnetic resonance imaging enhanced scan showed varied characteristics. The ratio of fast wash-in and fast wash-out, fast wash-in and slow wash-out, and delayed enhancement was roughly 4:5:1. A definite diagnosis of HEAML depended on the pathological findings of the epithelioid cells in lesions and the expression of human melanoma black 45, smooth muscle actin,melanoma antigen, and actin by immunohistochemical staining. HEAML had a relatively low malignant rate of 3.91%. However, surgical resection was the main treatment for HEAML, due to the difficulty diagnosing before operation.CONCLUSION HEAML is a rare and easily misdiagnosed disease, and it should be diagnosed carefully, taking into account clinical course, imaging, pathological,and immunohistochemical findings.

Two-in-one:A pooled analysis of primary hepatic neuroendocrine carcinoma combine d/collide d with hepatocellular carcinoma

To the Editor:Primary hepatic neuroendocrine carcinoma(PHNEC)combined/collided with hepatocellular carcinoma(HCC)is a rare and intriguing disease with characteristics of two histologically different cancers.Usually,a combined type refers to the cases in which hepatic neuroendocrine carcinoma(HNEC)and HCC components intermingle with each other and cannot be clearly separated in the transitional areas,while a collision type refers to those in which the two distinct cancers occurred simultaneously and independently.Sometimes it is difficult to readily distinguish these two types.We searched PubMed,Medline,China Science Periodical Database,and VIP Database with the publication from January 1980 to January 2019,using the keywords(“hepatic neuroendocrine carcinoma”or“HNEC”)and(“hepatocellular carcinoma”or“HCC”).After manually excluding records on secondary HNEC and other types of liver cancer,a total of 28 cases in 24 reports[1–24]were identified and summarized in Table 1.

Primary hepatic squamous cell carcinoma with abdominal incision metastasis after hepatectomy

To the Editor:Primary hepatic squamous cell carcinoma(PHSCC)is a rare and easily misdiagnosed disease.We reported a PHSCC case with abdominal incision metastasis after hepatectomy,and reviewed the clinical course,imaging,pathology and immunohistochemical findings.Our case may provide a better understanding of PHSCC.

Machine learning approach to predict acute kidney injury after liver surgery

BACKGROUND Acute kidney injury(AKI)after surgery appears to increase the risk of death in patients with liver cancer.In recent years,machine learning algorithms have been shown to offer higher discriminative efficiency than classical statistical analysis.AIM To develop prediction models for AKI after liver cancer resection using machine learning techniques.METHODS We screened a total of 2450 patients who had undergone primary hepatocellular carcinoma resection at Changzheng Hospital,Shanghai City,China,from January 1,2015 to August 31,2020.The AKI definition used was consistent with the Kidney Disease:Improving Global Outcomes.We included in our analysis preoperative data such as demographic characteristics,laboratory findings,comorbidities,and medication,as well as perioperative data such as duration of surgery.Computerized algorithms used for model development included logistic regression(LR),support vector machine(SVM),random forest(RF),extreme gradient boosting(XGboost),and decision tree(DT).Feature importance was also ranked according to its contribution to model development.RESULTS AKI events occurred in 296 patients(12.1%)within 7 d after surgery.Among the original models based on machine learning techniques,the RF algorithm had optimal discrimination with an area under the curve value of 0.92,compared to 0.87 for XGBoost,0.90 for DT,0.90 for SVM,and 0.85 for LR.The RF algorithm also had the highest concordance-index(0.86)and the lowest Brier score(0.076).The variable that contributed the most in the RF algorithm was age,followed by cholesterol,and surgery time.CONCLUSION Machine learning algorithms are highly effective in discriminating patients at high risk of developing AKI.The successful application of machine learning models may help guide clinical decisions and help improve the long-term prognosis of patients.

Immunometabolic inflammation and hepatocellular carcinoma

To the Editor: Inflammation-cancer transformation and metabolomics are hot topics in hepatocellular carcinoma (HCC). Cancer-related inflammation and anti-cancer immunity co-exist in cancer progression and the microenvironmental conditions dictate the direction [1].

Criteria-specific long-term survival prediction model for hepatocellular carcinoma patients after liver transplantation

AIM: To establish a model to predict long-term survival of hepatocellular carcinoma(HCC) patients after liver transplantation(MHCAT).METHODS: Two hundred and twenty-three patients with HCC were followed for at least six years to identify independent risk factors for long-term survival after liver transplantation(LT). The criteria for HCC liver transplantation included the Milan, University of California San Francisco, Hangzhou and Shanghai Fudan criteria. The Cox regression model was used to build MHCAT specifying these criteria. A survival analysis was carried out for patients with high or low risk.RESULTS: The one-, three- and five-year cumulativesurvival of HCC patients after LT was 78.9%, 53.2% and 46.4%, respectively. Of the HCC patients, the proportion meeting the Hangzhou and Fudan criteria was significantly higher than the proportion meeting the Milan criteria(64.6% vs 39.5%, 52.0% vs 39.5%, P < 0.05). Moreover, the proportion meeting the Hangzhou criteria was also significantly higher than the proportion meeting other criteria(P < 0.01). Pre-operative alfa-fetoprotein level, intraoperative blood loss and retransplantation were common significant predictors of long-term survival in HCC patients with reference to the Milan, University of California San Francisco and Fudan criteria, whereas in MHCAT based on the Hangzhou criteria, total bilirubin, intraoperative blood loss and retransplantation were independent predictors. The c-statistic for MHCAT was 0.773-0.824, with no statistical difference among these four criteria. According to the MHCAT scoring system, patients with low risk showed a higher five-year survival than those with high risk(P < 0.001).CONCLUSION: MHCAT can effectively predict longterm survival for HCC patients, but needs to be verified by multi-center retrospective or randomized controlled trials.

Dopaminergic neurons show increased low-molecular-mass protein 7 activity induced by 6-hydroxydopamine in vitro and in vivo

Background:Abnormal expression of major histocompatibility complex class I(MHC-I)is increased in dopaminergic(DA)neurons in the substantia nigra(SN)in Parkinson’s disease(PD).Low-molecular-mass protein 7(β5i)is a proteolytic subunit of the immunoproteasome that regulates protein degradation and the MHC pathway in immune cells.Methods:In this study,we investigated the role of β5i in DA neurons using a 6-hydroxydopamine(6-OHDA)model in vitro and vivo.Results:We showed that 6-OHDA upregulatedβ5i expression in DA neurons in a concentration-and time-dependent manner.Inhibition and downregulation ofβ5i induced the expression of glucose-regulated protein(Bip)and exacerbated 6-OHDA neurotoxicity in DA neurons.The inhibition of β5i further promoted the activation of Caspase 3-related pathways induced by 6-OHDA.β5i also activated transporter associated with antigen processing 1(TAP1)and promoted MHC-I expression on DA neurons.Conclusion:Taken together,our data suggest that β5i is activated in DA neurons under 6-OHDA treatment and may play a neuroprotective role in PD.