SCARB2 drives hepatocellular carcinoma tumor initiating cells via enhanced MYC transcriptional activity.

CSCs (Cancer stem cells) with distinct metabolic features are considered to cause HCC (hepatocellular carcinoma) initiation, metastasis and therapeutic resistance. Here, we perform a metabolic gene CRISPR/Cas9 knockout library screen in tumorspheres derived from HCC cells and find that deletion of SCARB2 suppresses the cancer stem cell-like properties of HCC cells. Knockout of Scarb2 in hepatocytes attenuates HCC initiation and progression in both MYC-driven and DEN (diethylnitrosamine)-induced HCC mouse models. Mechanistically, binding of SCARB2 with MYC promotes MYC acetylation by interfering with HDCA3-mediated MYC deacetylation on lysine 148 and subsequently enhances MYC transcriptional activity. Screening of a database of FDA (Food and Drug Administration)-approved drugs shows Polymyxin B displays high binding affinity for SCARB2 protein, disrupts the SCARB2-MYC interaction, decreases MYC activity, and reduces the tumor burden. Our study identifies SCARB2 as a functional driver of HCC and suggests Polymyxin B-based treatment as a targeted therapeutic option for HCC.

The role of intraoperative electron radiotherapy in centrally located hepatocellular carcinomas treated with narrow-margin (<1 cm) hepatectomy: a prospective, phase 2 study.

Background: Postoperative radiotherapy (RT) is known to play an important role in the treatment of hepatocellular carcinomas (HCCs), but the specific role of intraoperative electron radiotherapy (IOERT) in HCCs remains unclear. The aim of this study was to investigate the safety and efficacy of IOERT in centrally located HCCs treated with narrow-margin (<1 cm) hepatectomy. Methods: This was a single-center, phase 2, prospective non-randomized controlled study, including 268 patients with centrally located HCCs who underwent narrow-margin hepatectomy. The patients were subsequently allocated to the IOERT group (n=59) or to the control group (n=65). The primary outcome of the study was to compare recurrence-free survival (RFS) between the IOERT group and the control group, and the secondary outcome was to compare overall survival (OS) rate between the two groups. Results: Of 268 patients enrolled, a total of 124 were included in the study: 59 in IOERT group, 65 in control group. The 1-, 2-, 3-year RFS rates were 79.3%, 62.1% and 45.8% for patients in the IOERT group, and 47.6%, 28.6%, and 22.9% for patients in the control group, respectively (P=0.025). The 1-, 2-, and 3-year OS rates were 100.0%, 94.9%, and 83.7% for patients in the IOERT group, and 92.3%, 87.5%, and 79.4% for patients in the control group, respectively (P=0.314). Subgroup analysis of MVI (+) patients revealed that RFS and OS are significantly prolonged in the IOERT subgroup as compared to the control, whereas there was no significant difference of RFS and OS between the two groups in MVI (-) patients. Conclusions: IOERT for centrally located HCCs with concurrent narrow-margin hepatectomy was feasible and safe. Statistically better RFS rate was observed in the IOERT group compared to the control group. Subgroup analysis revealed that IOERT was more beneficial for postoperative survival of HCC patients with MVI. Trial Registration: ChiCTR-TRC-12002802; www.who.int/ictrp.

Establishment, validation and evaluation of predictive model for early relapse after R0 resection in hepatocellular carcinoma patients with microvascular invasion.

BACKGROUNDS: This is the first study to build and evaluate a predictive model for early relapse after R0 resection in hepatocellular carcinoma (HCC) patients with microvascular invasion (MVI). METHODS: The consecutive HCC patients with MVI who underwent hepatectomy in Cancer Hospital of Chinese Academy of Medical Science from Jan 2014 to June 2019 were retrospectively enrolled and randomly allocated into a derivation (N = 286) and validation cohort (N = 120) in a ratio of 7:3. Cox regression and Logistic regression analyses were performed and a predictive model for postoperative early-relapse were developed. RESULTS: A total of 406 HCC patients with MVI were included in our work. Preoperative blood alpha-fetoprotein (AFP) level, hepatitis B e antigen (HBeAg) status, MVI classification, largest tumor diameter, the status of serosal invasion, number of tumors, and the status of satellite nodules were incorporated to construct a model. The concordance index (C-index) was 0.737 and 0.736 in the derivation and validation cohort, respectively. The calibration curves showed a good agreement between actual observation and nomogram prediction. The C-index of the nomogram was obviously higher than those of the two traditional HCC staging systems. CONCLUSION: We have developed and validated a prediction model for postoperative early-relapse in HCC patient with MVI after R0 resection.

Establishment and Evaluation of a Predictive Model for Early Postoperative Recurrence of Hepatocellular Carcinoma in Patients with Microvascular Invasion.

OBJECTIVE: The present study aimed to identify the risk factors for early postoperative recurrence of hepatocellular carcinoma (HCC) in patients with microvascular invasion (MVI) and develop a predictive model. INCLUSION POPULATION AND METHODS: Patients who underwent surgery for HCC with pathological identification of MVI at the Cancer Hospital of the Chinese Academy of Medical Sciences from January 2014 to June 2019 were consecutively enrolled in this study. A total of 416 patients were included, divided into an early recurrence group (N = 169) and a non-early recurrence group (N = 247), taking 12 months as the cut-off point for early recurrence. Univariate and multivariate Cox analysis was adopted to screen for risk factors for recurrence, and independence of risk factors was determined by logistic regression analysis. All variables were included in the logistic regression analysis. As previous studies have shown that tumor diameter is a risk factor for recurrence, this was also included in the analyses. A predictive model for early recurrence was established and evaluated. RESULTS: The results indicate that MVI grouping, preoperative serum AFP, number of tumors, satellite nodules, hepatic capsule invasion, tumor diameter, and lymph node metastasis are independent risk factors for early postoperative recurrence. The above factors were adopted to develop a predictive model. The model had good discrimination and calibration in predicting early postoperative recurrence. Decision curve analysis demonstrated good clinical utility. CONCLUSION: MVI grouping, preoperative serum AFP, number of tumors, satellite nodules, hepatic capsule invasion, tumor diameter, and lymph node metastasis were shown to be independent risk factors for early postoperative recurrence. The predictive model developed by applying the above risk factors had good predictive value in patients with early postoperative recurrence.

Seeking survivals under COVID-19: The WhatsApp platform's shopping service operations.

Under COVID-19 outbreak, retail operations are seriously threatened. There are lots of cases in which physical stores basically have to stop operating. This creates problems to the firm, its employees, and consumers. Recently, Timberland in Hong Kong and various other brands such as Joyce Boutiques and The North Face have established the "WhatsApp Shopping Service Operation" (WSO) in which consumers can shop by using the well-established communication tool "WhatsApp." Salespeople in stores provide services via WhatsApp to assist the consumers without them having to visit the stores. We collect primary data from real-world cases and theoretically explore WSO. We build a standard consumer utility based model to derive the firm's optimal pricing and employment decisions under different cases. We evaluate the impacts of COVID-19 and values of WSO implementation from the "Worker-Consumer-Company" (WCC) welfare perspective. Our results interestingly imply that WSO is superior to the traditional online channel in terms of keeping business under the pandemic; meanwhile, implementing WSO can help stimulate demand in the physical store under COVID-19. However, whether WSO is effective to help increase the firm's profit and WCC welfare depends on both consumer type' distribution and consumers' fear of infection. When consumers' fear of infection is very polarized (i.e., extremely low or high), WSO is not recommended. We further propose that the government's subsidy for WSO implementation could be an effective way to help the firm improve its profit and WCC welfare. We also check the robustness of our study by extending the model to consider endogenous consumer type, endogenous service level, and WCC-welfare-oriented firm.

Prognostic value of the controlling nutritional status (CONUT) score in intrahepatic cholangiocarcinoma patients especially who had long-time alcohol consumption.

Our study is to investigate the preoperative prognostic value of the Controlling Nutritional Status score in intrahepatic cholangiocarcinoma patients after curative resection. One hundred and sixty-seven patients admitted to our hospital between January 2012 and December 2018 were included retrospectively. Time-dependent receiver operating characteristic (ROC) curve analysis was conducted to evaluate the ability of the Controlling Nutritional Status score to predict recurrence and survival. Patients with high Controlling Nutritional Status score (≥3) had significantly poorer RFS compared to those with low Controlling Nutritional Status score (low: <3) (p = 0.000) in Kaplan-Meier survival curve. Multivariate analyses identified Controlling Nutritional Status score, lymph node metastasis, tumor numbers and preoperative CEA as independent prognostic factors for RFS. Lymph node metastasis was the independent risk factor of OS. The Cox regression model with Controlling Nutritional Status score had better prognostic value for recurrence than the Cox regression model without Controlling Nutritional Status score in long-time alcohol consumption intrahepatic cholangiocarcinoma patients (AUC: 0.760 vs 0.706, p = 0.036). CONUT score may be a more powerful prognostic biomarker, which is tightly associated with other tumor characteristics, to predict recurrence but not survival, especially in long-time alcohol consumption intrahepatic cholangiocarcinoma patients after curative-intent surgery.

Postoperative adjuvant treatment strategy for hepatocellular carcinoma with microvascular invasion: a non-randomized interventional clinical study.

BACKGROUND: Microvascular invasion (MVI) is considered to be one of the important prognostic factors that affect postoperative recurrence in patients with hepatocellular carcinoma (HCC) with variable results across their treatment options. This study was carried out to investigate efficacy of postoperative adjuvant RT in HCC patients with MVI. METHODS: This was single center, prospective study carried out in HCC patients with MVI, aged 35-72 years. All patients were non-randomly allocated to receive standard postoperative treatment of HBV/HCV and nutritional therapy or RT in addition to standard postoperative treatment (1:1). The primary endpoints assessed were relapse-free survival and overall survival. The prognostic factors associated with survival outcomes were also analyzed. The safety events were graded according to NCI-CTCAE v4.03 criteria. RESULTS: Of the 115 patients eligible for study, 59 patients were included in analysis. Univariate analysis revealed that MVI classification (P = 0.009), post-operative treatment strategies (P = 0.009) were prognostic factors for worst RFS; tumor size (P = 0.011), MVI classification (P = 0.005) and post-operative treatment (P = 0.015) were associated for OS. The 1-, 2-, 3-year RFS rates were 86.2, 70.5 and 63.4% for patients in RT group, and 46.4, 36.1, and 36.1% in control group. For OS, corresponding rates were 96.6, 80.7, and 80.7% for patients in RT group and 79.7, 58.3, and 50.0% in control group. Subgroup classification of HCC patients according to low risk MVI showed significantly longer RFS (P = 0.035) and OS (P = 0.004) in RT group than control group, while for high risk MVI, RT depicted longer OS than control group with no significance (P = 0.106). Toxicities were usually observed in acute stage with no grade 4 toxicities. CONCLUSION: Postoperative adjuvant RT following hepatectomy offers better RFS for HCC patients with MVI than with standard postoperative therapy. Also, it will be useful to control microscopic lesions in both M1 (low risk) and M2 (high risk) subgroups of HCC patients with MVI. TRIAL REGISTRATION: Trial Registration number: ChiCTR1800017371 . Date of Registration: 2018-07-26. Registration Status: Retrospectively registered.

Surgical outcomes of hand-assisted laparoscopic liver resection vs. open liver resection: A retrospective propensity score-matched cohort study.

OBJECTIVE: Hand-assisted laparoscopic liver resection has the advantages of open and laparoscopic surgeries. There is still lack of comparison of surgical outcomes between hand-assistied laparoscopic liver resection (HALLR) and open liver resection (OLR). This study compared the surgical outcomes of the two approaches between well-matched patient cohorts. METHODS: Patients who received liver resection during January 2014 and October 2017 in Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College were included in this retrospective study. Propensity score matching (PSM) was performed to reduce selection bias between the two groups. Operation and short-term surgical outcomes were compared between the well matched groups. RESULTS: During this period, 232 patients with a median age of 55.1 years old received OLR, while 49 patients with a median age of 54.7 years old received HALLR. Compared with HALLR group, OLR group has a higher proportion in male patients (190/232, 81.9% vs. 34/49, 69.4%, P=0.048) and lower albumin (43.2±4.5 vs. 44.8±3.7, P=0.020). After PSM, 49 patients from each group were included in the following analysis. Two groups were well balanced in their baseline characteristics, liver functions, preoperative treatments, abdominal surgery history, and surgical difficulty. None perioperative mortality was observed in both groups. Operation time and postoperative complications were similar in two groups (P=0.935, P=0.056). The HALLR group showed less bleeding amount (177.8±217.1 mL vs. 283.1±225.0 mL, P=0.003) and shorter postoperative stay period (6.9±2.2 d vs. 9.0±3.5 d, P=0.001). CONCLUSIONS: We demonstrated that hand-assisted laparoscopic surgery is feasible and safe for liver resection, including some difficult cases. HALLR can provide better bleeding control and faster recovery after surgery.

Nomogram to Assist in Surgical Plan for Hepatocellular Carcinoma: a Prediction Model for Microvascular Invasion.

BACKGROUND: Microvascular invasion (MVI) relates to poor survival in hepatocellular carcinoma (HCC) patients. In this study, we aim at developing a nomogram for MVI prediction and potential assistance in surgical planning. METHODS: A total of 357 patients were assigned to training (n = 257) and validation (n = 100) cohort. Univariate and multivariate analyses were used to reveal preoperative predictors for MVI. A nomogram incorporating independent predictors was constructed and validated. Disease-free survival was compared between patients, and the potential of the predicted MVI in making surgical procedure was also explored. RESULTS: Pathological examination confirmed MVI in 140 (39.2%) patients. Imaging features including larger tumor, intra-tumoral artery, tumor type, and higher serum AFP independently correlated with MVI. The nomogram showed desirable performance with an AUROC of 0.803 (95% CI, 0.746-0.860) and 0.814 (95% CI, 0.720-0.908) in the training and validation cohorts, respectively. Good calibration were also revealed by calibration curve in both cohorts. The decision curve analysis indicated that the prediction nomogram was of promising usefulness in clinical work. In addition, survival analysis revealed that patients with positive-predicted MVI suffered a higher risk of early recurrence (P < 0.01). There was no difference in disease-free survival between anatomic or non-anatomic resection in large HCC or small HCC without nomogram-predicted MVI. However, anatomic resection improved disease-free survival in small HCC with nomogram-predicted MVI. CONCLUSIONS: The nomogram obtained desirable results in predicting MVI. Patients with predicted MVI were associated with early recurrence and anatomic resection was recommended for small HCC patients with predicted MVI.