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Abstract Background Additional resection for invasive cancer at perihilar cholangiocarcinoma (pCCA) resection margins has become a consensus. However, controversy still exists regarding whether additional resection is necessary for residual biliary intraepithelial neoplasia (BilIN). Method Consecutive patients with pCCA from two hospitals were enrolled. The incidence and pattern of resection margin BilIN were summarized. Prognosis between patients with negative margins (R0) and BilIN margins were analyzed. Cox regression with a forest plot was used to identify independent risk factors associated with overall survival (OS) and recurrence-free survival (RFS). Subgroup analysis was performed based on BilIN features and tumor characteristics. Results 306 pCCA patients receiving curative resection were included. 255 had R0 margins and 51 had BilIN margins. There was no significant difference in OS (P = 0.264) or RFS (P = 0.149) between the two group. Specifically, 19 patients with BilIN at distal bile ducts and 32 at proximal bile ducts. 42 patients showed low-grade BilIN, and 9 showed high-grade. Further analysis revealed no significant difference in long-term survival between different locations (P = 0.354), or between different grades (P = 0.772). Portal vein invasion, poor differentiation and lymph node metastasis were considered independent risk factors for OS and RFS, while BilIN was not. Subgroup analysis showed no significant difference in long-term survival between the lymph node metastasis subgroup, or between the portal vein invasion subgroup. Conclusion For pCCA patients underwent curative resection, residual BilIN at resection margin is acceptable. Additional resection is not necessary for such patients to achieve absolute R0 margin.

Abstract Early and accurate diagnosis of focal liver lesions is crucial for effective treatment and prognosis. We developed and validated a fully automated diagnostic system named Liver Artificial Intelligence Diagnosis System (LiAIDS) based on a diverse sample of 12,610 patients from 18 hospitals, both retrospectively and prospectively. In this study, LiAIDS achieved an F1-score of 0.940 for benign and 0.692 for malignant lesions, outperforming junior radiologists (benign: 0.830-0.890, malignant: 0.230-0.360) and being on par with senior radiologists (benign: 0.920-0.950, malignant: 0.550-0.650). Furthermore, with the assistance of LiAIDS, the diagnostic accuracy of all radiologists improved. For benign and malignant lesions, junior radiologists’ F1-scores improved to 0.936-0.946 and 0.667-0.680 respectively, while seniors improved to 0.950-0.961 and 0.679-0.753. Additionally, in a triage study of 13,192 consecutive patients, LiAIDS automatically classified 76.46% of patients as low risk with a high NPV of 99.0%. The evidence suggests that LiAIDS can serve as a routine diagnostic tool and enhance the diagnostic capabilities of radiologists for liver lesions.

Introduction: For patients with large unresectable hepatocellular carcinoma (HCC), the effectiveness of conventional transarterial chemoembolization (cTACE) remains suboptimal. This study investigated the efficacy and safety of modified TACE using low-dose chemotherapy with blank microspheres (BMS-TACE) plus low-dose lenvatinib (LD-LEN) and microwave ablation (MWA) in patients with large unresectable HCC. Methods: In this prospective, single-arm, phase 2 study, patients with unresectable HCC exceeding the up-to-seven criteria, with maximum tumor diameter ≥7 cm, and without macrovascular invasion or extrahepatic metastases, received initial BMS-TACE (lipiodol, low-dose doxorubicin, and lobaplatin up to 30 mg each, and blank microspheres; subsequently modified and repeated in most patients) plus LD-LEN (4–8 mg/day) and MWA. The primary endpoint was downstaging rate (DSR); secondary endpoints were objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and adverse events. Results: From November 2019 to March 2022, 43 patients were enrolled. Median follow-up was 21.2 months. Median largest tumor diameter was 11.2 cm (interquartile range [IQR], 7–25). Following BMS-TACE and LD-LEN, downstaging occurred in 37 (86.0%) patients, 32 of whom received MWA, and 8 of whom had a complete response (CR) without MWA. ORR was 93.0% (CR in 32 [74.4%] and partial response in 8 [18.6%] patients). The 1-, 2-, and 3-year PFS rates were 57.5%, 25.9%, and 18.1%, respectively (median PFS, 14.7 months [95% CI: 8.1–19.5]). The 1-, 2-, and 3-year OS rates were 85.8%, 67.7%, and 61.6%, respectively (median OS, 36.4 months [95% CI: 26.8-not reached]). After BMS-TACE, a significant decline in CD11b+/CD33+/HLA-DR- myeloid-derived suppressor cells and early elevation in CXCR5+/CD8+ and CXCR5+/CD4+ T cells were observed (both p < 0.05). Conclusion: BMS-TACE plus LD-LEN and MWA resulted in promising efficacy and tolerable toxicity in patients with large unresectable HCC exceeding the up-to-seven criteria with a maximum tumor diameter ≥7 cm and without macrovascular invasion or extrahepatic metastases.

Abstract The majority of hepatocellular carcinoma (HCC) cases are diagnosed at an advanced stage. Currently, there are only a few therapeutic methods available for patients with advanced HCC and extrahepatic metastasis (EHM). Systemic chemotherapy, such as FOLFOX4 (infusions of fluorouracil, leucovorin, and oxaliplatin), has been reported for treating advanced HCC with EHM, but its effectiveness is very poor. In this randomized, double-blind, placebo-controlled study, we aimed to assess the efficacy and safety of FOLFOX4 with all-trans-retinoic acid (ATRA) as a palliative treatment for HCC patients with EHM, compared to FOLFOX4 with a placebo. The primary endpoint was overall survival (OS), and subsequently, an exploratory model was developed based on bioinformatics to predict the efficacy of FOLFOX4-ATRA treatment. A total of 108 patients were randomly assigned in a 1:1 ratio to receive either FOLFOX4-ATRA or FOLFOX4-placebo. The intention-to-treat (ITT) population showed a median OS of 16.2 months for the FOLFOX4-ATRA group, compared with 10.7 months for the FOLFOX4-placebo group (HR 0.56, 95% CI 0.33–0.93; p = 0.025). The median progression-free survival (PFS) was 7.1 months for the FOLFOX4-ATRA group and 4.2 months for the FOLFOX4-placebo group (HR 0.62, 95% CI 0.41–0.94; p = 0.024). A panel of proteins with unique upregulation during complete response (CR) (SOD3, TTR, SSC5D, GP5, IGKV1D-33) and partial response (PR) (TGFB1, GSS, IGHV5-10-1) effectively predicted CR and PR in patients treated with FOLFOX4-ATRA, as compared to FOLFOX4-placebo. The results suggest that FOLFOX4-ATRA is a safe and effective treatment for patients with advanced HCC and EHM in eastern China.

Background & aimsThe effectiveness of adjuvant immunotherapy to diminish recurrence and improve long-term prognosis following curative-intent surgical resection for hepatocellular carcinoma (HCC) is of increased interest, especially among individuals at high risk of recurrence. The objective of the current study was to investigate the impact of adjuvant immunotherapy on long-term recurrence and survival after curative resection among patients with intermediate/advanced HCC.MethodsUsing a prospectively-collected multicenter database, patients who underwent curative-intent resection for Barcelona Clinic Liver Cancer (BCLC) stage B/C HCC were identified. Propensity score matching (PSM) analysis was used to compare recurrence-free survival (RFS) and overall survival (OS) between patients treated with and without adjuvant immune checkpoint inhibitors (ICIs). Multivariate Cox-regression analysis further identified independent factors of RFS and OS.ResultsAmong the 627 enrolled patients, 109 patients (23.3%) received adjuvant immunotherapy. Most ICI-related adverse reactions were grading I-II. PSM analysis created 99 matched pairs of patients with comparable baseline characteristics between patients treated with and without adjuvant immunotherapy. In the PSM cohort, the median RFS (29.6 vs. 19.3 months, P=0.031) and OS (35.1 vs. 27.8 months, P=0.036) were better among patients who received adjuvant immunotherapy versus patients who did not. After adjustment for other confounding factors on multivariable analyzes, adjuvant immunotherapy remained independently associated with favorable RFS (HR: 0.630; 95% CI: 0.435-0.914; P=0.015) and OS (HR: 0.601; 95% CI: 0.401-0.898; P=0.013). Subgroup analyzes identified potentially prognostic benefits of adjuvant immunotherapy among patients with intermediate-stage and advanced-stage HCC.ConclusionThis real-world observational study demonstrated that adjuvant immunotherapy was associated with improved RFS and OS following curative-intent resection of intermediate/advanced HCC. Future randomized controlled trials are warranted to establish definitive evidence for this specific population at high risks of recurrence.

AbstractIntroduction This study aimed to investigate the association between cardiorespiratory fitness (CRF) and perioperative morbidity and long-term mortality in operable patients with early-stage non-small cell lung cancer (NSCLC).Patients and Methods This prospective study included consecutive patients with early-stage NSCLC who underwent presurgical cardiopulmonary exercise testing between November 2014 and December 2019 (registration number: ChiCTR2100048120). Logistic and Cox proportional hazards regression were applied to evaluate the correlation between CRF and perioperative complications and long-term mortality, respectively. Propensity score overlap weighting was used to adjust for the covariates. We performed sensitivity analyses to determine the stability of our results.Results A total of 895 patients were followed for a median of 40 months [interquartile range 25]. The median age of the patients was 59 years [range 26–83], and 62.5% were male. During the study period, 156 perioperative complications and 146 deaths were observed. Low CRF was associated with a higher risk of death (62.9 versus 33.6 per 1000 person-years; weighted incidence rate difference, 29.34 [95% CI, 0.32 to 58.36] per 1000 person-years) and perioperative morbidity (241.6 versus 141.9 per 1000 surgeries; weighted incidence rate difference, 99.72 [95% CI, 34.75 to 164.70] per 1000 surgeries). A CRF of ≤ 20 ml/kg/min was significantly associated with a high risk of long-term mortality (weighted hazard ratio, 1.98 [95% CI, 1.31 to 2.98], p

Summary: Objective: Positive resection margin indicates worse prognosis. The present study identified the independent risk factors of R1 resection in pancreaticoduodenectomy (PD) and distal pancreatosplenectomy (DP) for patients with pancreatic ductal adenocarcinoma (PDAC). Method: Consecutive patients who were operated from 1st December 2017 to 30th December 2018 were analyzed retrospectively. A standardized pathological examination with digital whole-mount slide images (DWMSIs) was utilized for evaluation of resection margin status. R1 was defined as microscopic tumor infiltration within 1 mm to the resection margin. The potential risk factors of R1 resection for PD and DP were analyzed separately by univariate and multivariate logistic regression analyses. Results: For the 192 patients who underwent PD, and the 87 patients who underwent DP, the R1 resection rates were 31.8% and 35.6%, respectively. Univariate analysis on risk factors of R1 resection for PD were tumor location, lymphovascular invasion, N staging, and TNM staging; while those for DP were T staging and TNM staging. Multivariate logistic regression analysis showed the location of tumor in the neck and uncinate process, and N1/2 staging were independent risk factors of R1 resection for PD; while those for DP were T3 staging. Conclusions: The clarification of the risk factors of R1 resection might clearly make surgeons take reasonable decisions on surgical strategies for different surgical procedures in patients with PDAC, so as to obtain the first attempt of R0 resection.

Purpose: To compare the survival outcomes of postoperative adjuvant aspirin with surgery alone in patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) and portal vein tumor thrombus (PVTT). Methods: From June 2013 to July 2015, an open-label, randomized controlled study was conducted in patients with resectable HBV-related HCC and PVTT. Patients were randomly assigned to undergo surgical resection and postoperative adjuvant aspirin (n = 40) or hepatectomy alone (n = 40). The primary end point was overall survival (OS). The secondary end points were time to recurrence of primary tumor (t-TTR) and time to recurrence of PVTT (p-TTR). The expression levels of COX1 and COX2 in surgical specimens of the aspirin group were correlated with patients’ survival. Results: The median OS were 16.2 and 13.4 months for the adjuvant aspirin and surgery alone groups, respectively. The median t-TTR were 5.3 and 3.2 months for the adjuvant aspirin and surgery alone groups, respectively. There was no significant difference in the OS and t-TTR between the two groups of patients (P = 0.078 and 0.336, respectively). The median p-TTR were 12.0 months and 5.4 months for the adjuvant aspirin group and the surgery alone group, respectively. Patients in the adjuvant aspirin group had markedly longer p-TTR (P = 0.001). Increased expressions of COX1 or COX2 in tumor tissues denoted better prognosis for patients receiving adjuvant aspirin. Conclusion: For patients with resectable HBV-related HCC and PVTT, postoperative adjuvant aspirin significantly prolonged time to recurrence of PVTT than surgery alone. Expression of COX1 or COX2 may predict survival in these patients.

Aim To compare the short- and long-term treatment outcomes of open radiofrequency ablation combined with splenectomy and pericardial devascularization versus liver transplantation for hepatocellular carcinoma patients with portal hypertension and hypersplenism. Methods During the study period, the treatment outcomes of consecutive HCC patients with portal hypertension and hypersplenism who underwent open radiofrequency ablation, splenectomy and pericardial devascularization (the study group) were compared with the treatment outcomes of a case-matched control group of HCC patients who underwent liver transplantation. Results The study group consisted of 32 patients, and the control group comprised 32 patients selected from 155 patients who were case-matched by tumor size, age, gender, MELD sore, tumor location, TNM classification, degree of splenomegaly and Child–Pugh staging. Baseline data on preoperative laboratory tests and tumor characteristics were comparable between the two groups. The mean follow-up was 43.2 ± 5.3 months and 44.9 ± 5.8 months for the study and control groups, respectively. Although the disease-free survival rates of the control group were better than those of the study group (P

Abstract. Background:. Chemotherapy is a common treatment for advanced hepatocellular carcinoma, but the effect is not satisfactory. The study aimed to retrospectively evaluate the effects of adding all-trans-retinoic acid (ATRA) to infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) for advanced hepatocellular carcinoma (HCC). Methods:. We extracted the data of patients with advanced HCC who underwent systemic chemotherapy using FOLFOX4 or ATRA plus FOLFOX4 at the Eastern Hepatobiliary Surgery Hospital, First Hospital of Jilin University, and Zhejiang Sian International Hospital and retrospectively compared for overall survival. The Cox proportional hazards model was used to calculate the hazard ratios for overall survival and disease progression after controlling for age, sex, and disease stage. Results:. From July 2013 to July 2018, 111 patients with HCC were included in this study. The median survival duration was 14.8 months in the ATRA plus FOLFOX4 group and 8.2 months in the FOLFOX4 only group (P

Abstract Aims Patients with cirrhosis and clinically significant portal hypertension (CSPH) usually have concomitant secondary hypersplenism, and splenectomy (Spx) is an option for treating these patients in the Asia‐Pacific region. CSPH is the most important risk factor for postoperative liver dysfunction (PLD) in patients with hepatocellular carcinoma (HCC) and cirrhosis undergoing liver resection. However, the impact of simultaneous Spx and hepatectomy in patients with HCC and CSPH remains unclear. In this study, we aimed to determine the impact of simultaneous Spx on the posthepatectomy outcomes in these patients. Methods This study included 691 consecutive patients with hepatitis B virus‐related HCC, cirrhosis, and CSPH. These included 565 patients who underwent hepatectomy only (non‐Spx group) and 126 who underwent simultaneous hepatectomy and splenectomy (Spx group). We analyzed the effect of 25 preoperative and 5 intraoperative factors on postoperative outcomes using logistic regression. To overcome any possible selection bias, confounders were balanced by propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) analyses, and subgroup analyses were performed within the PSM‐matched groups. Results Logistic regression analyses revealed that Spx was an independent protective factor for severe postoperative liver dysfunction (SPLD; odds ratio [OR] = 0.22, 95% confidence interval [CI]: 0.11–0.43, p

Background The role of adjuvant transarterial chemoembolisation (TACE) to reduce postoperative recurrence varies widely among patients undergoing hepatectomy with curative intent for hepatocellular carcinoma (HCC). Personalised predictive tool to select which patients may benefit from adjuvant TACE is lacking. This study aimed to develop and validate an online calculator for estimating the reduced risk of early recurrence from adjuvant TACE for patients with HCC.Methods From a multi-institutional database, 2590 eligible patients undergoing curative-intent hepatectomy for HCC were enrolled, and randomly assigned to the training and validation cohorts. Independent predictors of early recurrence within 1 year of surgery were identified in the training cohort, and subsequently used to construct a model and corresponding prediction calculator. The predictive performance of the model was validated using concordance indexes (C-indexes) and calibration curves, and compared with conventional HCC staging systems. The reduced risk of early recurrence when receiving adjuvant TACE was used to estimate the expected benefit from adjuvant TACE.Results The prediction model was developed by integrating eight factors that were independently associated with risk of early recurrence: alpha-fetoprotein level, maximum tumour size, tumour number, macrovascular and microvascular invasion, satellite nodules, resection margin and adjuvant TACE. The model demonstrated good calibration and discrimination in the training and validation cohorts (C-indexes: 0.799 and 0.778, respectively), and performed better among the whole cohort than four conventional HCC staging systems (C-indexes: 0.797 vs 0.562–0.673, all p

BackgroundReports on Lenvatinib-based therapies show promising treatment outcomes for patients with unresectable hepatocellular carcinoma (uHCC). However, the effect and safety of Lenvatinib-based therapies still need to be further studies.MethodsThis was a retrospective, single-center study on the safety and treatment efficacy of Lenvatinib-based combination therapies for uHCC Patients. The primary endpoints were progression-free survival (PFS) and overall survival (OS). The secondary endpoints were progressive disease (PD), stable disease (SD), partial response (PR), and complete response (CR).ResultsOf 91 patients, there were 16 females and 75 males with uHCC who received systemic therapies based on Lenvatinib in our center. Forty-six patients (50.5%) received Lenvatinib combined with PD-1 antibody treatment. All these patients also received local therapy with the exception of 2 patients. The remaining 36 patinets received Lenvatinib combined with transcatheter arterial chemoembolization (TACE), 1 patient treated Lenvatinib combined with radiotherapy, 8 patients received Lenvatinib alone. At a median treatment time of 8 months, the objective response rate (ORR) of the entire cohort was 58.2% (53 patients), including 7 patients with CR and 46 patients with PR. 21 patients (23.1%) had SD. The disease control rate (DCR) of all patients was 81.3% (74 patients). However, 17 patients (18.7%) developed PD. The 1- and 2-year cumulative OS rates for the entire cohort were 66.8% and 39.3%, while the corresponding PFS rates were 38.0% and 17.1%, respectively. Univariate and multivariate Cox regression analysis revealed multiple tumor sites to be an independent OS risk factor for uHCC patients (HR=2.204, 95% CI=1.104-4.399, P=0.025). The most frequently reported adverse events in all patients were AST elevation (51.6%), followed by hypertension (33.0%), ALT elevation (26.4%), and decreased appetite (25.3%). After a combination treatment of Lenvatinib-based therapies, 15 patients met the criteria for salvage liver resection and underwent down-staging hepatectomy with a curative intent. The combination of PD-1 treatment was not very effective in improving the prognosis of uHCC patients treated with Lenvatinib combined with TACE.ConclusionOur study demonstrated that a proportive of patients benefited from Lenvatinib-based combination therapies with manageable safety profiles, allowing these patients to undergo downstaging surgery with curative intent.

BackgroundGallbladder cancer (GBC) is highly lethal and resistant to most chemotherapeutic drugs. GBC was reported to carry multiple genetic mutations such as TP53, K-RAS, and ERBB2/3. Here, we unexpectedly identified a patient with GBC harboring germline BRCA1 p.Arg1325Lys heterozygous mutation. We sought to determine if olaparib, the poly ADP-ribose polymerase inhibitor (PARPi) commonly treated for BRCA mutation, can inhibit cancer development via a therapeutic trial on this patient.Case presentationThe patient received GBC R0 resection after an 8-week olaparib treatment. After surgery and 6-month follow-up treatment with olaparib, the patient’s blood carbohydrate antigen 19-9 (CA19-9) level declined from 328 to 23.6 U/ml. No recurrence in CT scanning was observed, indicating a disease-free survival of 6 months with conventional therapy. Two months later, CT examination and CA19-9 level showed cancer relapse. A blood biopsy revealed a new ERBB3 p.Gly337Arg mutation. GBC cell lines ectopically expressing BRCA1 p.Arg1325Lys together with ERBB3 p.Gly337Arg mutations were challenged with olaparib and/or afatinib, an ERBB2/3 inhibitor. The dual mutation cells were more responsive to the combined olaparib with afatinib than a single drug in the cell proliferation assay.ConclusionOlaparib is effective in a GBC patient with a BRAC1 mutation. The efficacy of olaparib and afatinib in both cultured BRAC1 and ERBB3 mutation cell lines suggests that a combined regimen targeting BRCA1/2 and ERBB2/3 mutations may be an optimal strategy to treat GBC patients who carry both gene mutations.

Portal vein tumor thrombus (PVTT) is very common and it plays a major role in the prognosis and clinical staging of hepatocellular carcinoma (HCC). We have published the first version of the guideline in 2016 and revised in 2018. Over the past several years, many new evidences for the treatment of PVTT become available, especially for the advent of new targeted drugs and immune checkpoint inhibitors which have further improved the prognosis of PVTT. So, the Chinese Association of Liver Cancer and Chinese Medical Doctor Association revised the 2018 version of the guideline to adapt to the development of PVTT treatment. Future treatment strategies for HCC with PVTT in China would depend on new evidences from more future clinical trials.

Background and aimsThe efficacy and safety of systemic atezolizumab and bevacizumab (atezo/bev) in treatment of patients with unresectable hepatocellular carcinoma (HCC) have been demonstrated. However, the efficacy of this treatment in patients with HCC and extrahepatic portal vein tumor thrombus (ePVTT) is not satisfactory. This study aimed to study the efficacy and safety of combining intensity-modulated radiotherapy (IMRT) with systemic atezo/bev in treatment of these patients.MethodsThis multicenter prospective study included patients with ePVTT treated with IMRT combined with atezo/bev from March to September 2021 in three centers in China. The outcomes of this study included objective response rate (ORR), overall survival (OS), progression-free survival (PFS), time to progression (TTP), and association between response and tumor mutational burden (TMB). Treatment-related adverse events (TRAEs) were analyzed to assess safety.ResultsOf 30 patients in this study, the median follow-up was 7.4 months. Based on the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, the ORR was 76.6%, the median OS for the entire cohort was 9.8 months, the median PFS was 8.0 months, and the median TTP was not reached. This study failed to establish a significant correlation between TMB with any of the following outcomes, including ORR, OS, PFS or TTP. The most common TRAEs at all levels were neutropenia (46.7%), and the most common grade 3/4 TRAE was hypertension (16.7%). There was no treatment-related deaths.ConclusionsIMRT combined with atezo/bev showed encouraging treatment efficacy with an acceptable safety profile, making this treatment to be a promising option for HCC patients with ePVTT. Further studies are required to support the findings of this preliminary study.Clinical trial registrationhttp://www.chictr.org.cn, Identifier ChiCTR2200061793.

BackgroundThe effect of type 2 diabetes mellitus (T2DM) on survival of patients with hepatocellular carcinoma (HCC) after laparoscopic liver resection (LLR) has not been reported. This study aimed to explore the relationship between preoperative T2DM and long-term prognosis in HCC patients undergoing LLR.MethodsHCC patients receiving LLR as initial treatment at four cancer centers were retrospectively included in this study. Clinicopathological factors associated with the prognosis of HCC patients were identified using univariate and multivariate Cox regression analysis. Recurrence-free survival (RFS) and overall survival (OS) curves between different cohorts of patients were generated using the Kaplan-Meier method and compared using the log-rank test.ResultsOf 402 HCC patients included, 62 patients had T2DM and 340 patients did not have T2DM. The OS and RFS of patients with T2DM were significantly worse compared to those without T2DM (P = 0.001 and 0.032, respectively). In Cox multivariate analysis, T2DM was identified as an independent risk factors for OS (HR = 2.31, 95% CI = 1.38–3.85, P = 0.001) and RFS (HR = 1.66, 95% CI = 1.08–2.55, P = 0.020).ConclusionsFollowing laparoscopic surgical approach, HCC patients with T2DM had poorer prognoses than those without T2DM. Preoperative T2DM was an independent risk factor for HCC patients. Thus, patients with concurrent HCC and T2DM should be closely monitored after LLR.

Abstract Background and aims Although adjuvant transcatheter arterial chemoembolization (TACE) for resected hepatocellular carcinoma (HCC) may improve survival for some patients, identifying which patients can benefit remains challenging. The present study aimed to construct a survival prediction calculator for individualized estimating the net survival benefit of adjuvant TACE for patients with resected HCC. Methods From a multicenter database, consecutive patients undergoing curative resection for HCC were enrolled and divided into the developing and validation cohorts. Using the independent survival predictors in the developing cohort, two nomogram models were constructed for patients with and without adjuvant TACE, respectively, which predictive performance was validated internally and externally by measuring concordance index (C-index) and calibration. The difference between two estimates of the prediction models was the expected survival benefit of adjuvant TACE. Results A total of 2514 patients met the inclusion criteria for the study. The nomogram prediction models for patients with and without adjuvant TACE were, respectively, built by incorporating the same eight independent survival predictors, including portal hypertension, Child–Pugh score, alpha-fetoprotein level, tumor size and number, macrovascular and microvascular invasion, and resection margin. These two prediction models demonstrated good calibration and discrimination, with all the C-indexes of greater than 0.75 in the developing and validation cohorts. A browser-based calculator was generated for individualized estimating the net survival benefit of adjuvant TACE. Conclusions Based on large-scale real-world data, an easy-to-use online calculator can be adopted as a decision aid to predict which patients with resected HCC can benefit from adjuvant TACE.

Abstract To study the impact of total splenectomy (TS) on peripheral lymphocytes and their subsets in patients with hypersplenism associated with cirrhotic portal hypertension (CPH). We studied 102 consecutive patients who received TS from January 2008 to January 2020 due to CPH-related hypersplenism. A similar number of healthy individuals are used as healthy controls (HC). The total lymphocyte counts and their percentages of B lymphocytes, total T lymphocytes (cluster of differentiation (CD)3+) and their subsets (CD4+, CD8+), and natural killer (NK) cells in preoperative peripheral blood samples in hypersplenism patients were significantly lower than that of the HCs (both P 0.05). However, the percentages of CD3+ cells was significantly higher 1 month after than before surgery (P 0.05). Patients with hypersplenism associated with CPH were significantly immunosuppressed preoperatively. After TS, the total lymphocyte count and percentages of B lymphocytes, and total T lymphocytes and their subsets increased significantly, resulting in improved immune functions.

Background & aimThe association of perioperative blood transfusion (PBT) with long-term survival in perihilar cholangiocarcinoma (pCCA) patients after surgical resection with curative intent is controversial and may differ among different stages of the disease. This study aimed to investigate the impact of PBT on long-term survival of patients with different stages of pCCA.MethodsConsecutive pCCA patients from three hospitals treated with curative resection from 2012 to 2019 were enrolled and divided into the PBT and non-PBT groups. Propensity score matching (PSM) was used to balance differences in baseline characteristics between the PBT and non-PBT groups. Kaplan–Meier curves and log-rank test were used to compare overall survival (OS) and recurrence-free survival (RFS) between patients with all tumor stages, early stage (8th AJCC stage I), and non-early stage (8th AJCC stage II-IV) pCCA in the PBT and non-PBT groups. Cox regression analysis was used to determine the impact of PBT on OS and RFS of these patients.Results302 pCCA patients treated with curative resection were enrolled into this study. Before PSM, 68 patients (22 patients in the PBT group) were in the early stage and 234 patients (108 patients in the PBT group) were in the non-early stage. Patients with early stage pCCA in the PBT group had significantly lower OS and RFS rates than those in the non-PBT group. However, there were with no significant differences between the 2 groups with all tumor stages and non-early stage pCCA. After PSM, there were 18 matched pairs of patients with early stage and 72 matched pairs of patients with non-early stage. Similar results were obtained in the pre- and post-PSM cohorts: patients with early stage pCCA in the PBT group showed significantly lower OS and RFS rates than those in the non-PBT group, but there were no significant differences between the 2 groups for patients with all tumor stages and non-early stage pCCA. Cox regression analysis demonstrated that PBT was independently associated with worse OS and RFS for patients with early stage pCCA.ConclusionsPBT had a negative impact on long-term survival in patients with early stage pCCA after curative resection, but not in patients with non-early stage pCCA.

BackgroundThe GALAD and ASAP scores are two well-recognized algorithms to estimate the risk of hepatocellular carcinoma (HCC) based on gender, age, alpha-fetoprotein (AFP), protein induced by vitamin K absence or Antagonist-II (PIVKA-II) and AFP-L3 (included in the GALAD score but not in the ASAP score). The current study sought to compare the diagnostic performance of each score to detect HCC among patients infected with hepatitis C virus (HCV).MethodsA multicenter case-control study was undertaken in which blood samples were collected from HCVinfected patients with and without HCC. Using the area under the receiver operating characteristic curve (AUROC), ASAP and GALAD scores were compared relative to diagnostic performance to detect any stage HCV-HCC and early-stage HCV-HCC.ResultsThe analytic cohort included 168 HCV-HCC patients and a control group of 193 HCV-infected patients. The ASAP score had a higher AUROC to detect any stage HCV-HCC versus the GALAD score, both in the overall group (0.917 vs. 0.894, P=0.057) and in the cirrhosis subgroup (0.909 vs. 0.889, P=0.132). Similar results were noted relative to the detection of early-stage HCV-HCC, whether defined by BCLC staging (stage 0-A: 0.898 vs. 0.860, P=0.026) or 8th TNM staging (stage I: 0.899 vs. 0.870, P=0.070). In subgroup analysis to detect AFP-negative HCV-HCC, the ASAP score also demonstrated a higher AUROC than the GALAD score to detect any stage HCV-HCC in the AFP-negative subgroup (0.815 vs. 0.764, P=0.063).ConclusionsThe ASAP score had better diagnostic performance for early detection of HCV-HCC compared with the GALAD score. The ASAP score may be preferrable to the GALAD score for HCC screening and surveillance among HCV-infected patients.

Objective: To establish a new classification of biliary tumor thrombus (BTT). Methods: Overall survival of patients with BTT was first used to determine whether it correlated with current hepatocellular carcinoma staging systems. Univariate and multivariate analyses were used to determine factors affecting the overall survival (OS) to form the basis of our new classification for BTT. Results: All 6 international staging systems showed overlapping survival curves. Univariate followed by multivariate analyses showed that total bilirubin and intrahepatic/extrahepatic BTT were significant risk factors of OS. Based on these data, a new BTT classification was defined as: Type I: intrahepatic BTT; and Type II: extrahepatic BTT involving a common bile duct or common hepatic duct. Type I was further subdivided into type Ia: BTT involving a second-order intrahepatic duct or above, and type Ib: BTT involving a first-order intrahepatic duct. Type II was further subdivided into type IIa and type IIb using a cut-off total bilirubin (TB) > 300 μmol/L. The numbers (percentages) of patients with types I and II BTT were 69 (34.2%) and 133 (65.8%), respectively. The median OS of type I patients was significantly higher than that of type II patients (37.5 months vs. 23.2 months; P = 0.002). Using subgroup analyses, OS outcomes were significantly different between the subgroups of type IIb and type IIa, although there was no significant difference between the type Ia and type Ib subgroups (P = 0.07). Conclusions: A new BTT classification was established to predict prognoses of HCC patients with BTT who underwent liver resection.

Abstract Background Gemcitabine plus platinum as the first-line chemotherapy for cholangiocarcinoma (CCA) has limited efficacy. The aim of this study was to evaluate the effectiveness of modified FOLFIRINOX (mFOLFIRINOX) compared to that of gemcitabine plus oxaliplatin (Gemox) for patients with locally advanced or metastatic CCA. Methods From January 2016 to December 2019, consecutive patients who were diagnosed with locally advanced or metastatic CCA were treated with either mFOLFIRINOX or Gemox as a first-line chemotherapy. The main endpoint was Progression free survival (PFS). The second endpoints were Overall survival (OS), Disease control rate (DCR) and incidence of severe toxicity (grade 3–4). Tumors were evaluated at baseline and thence every 4–6 weeks. The study was designed and carried out in accordance with the principles of the declaration of Helsinki, approved by the Ethics Committee of Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine (XHEC-D-2020-154) and registered with ClinicalTrials.gov , number NCT04305288 (registration date: 12/03/2020). Results Of 49 patients in this study, 27 were in the FOLFIRINOX regimen group and 22 in the Gemox regimen group. There were no significant differences between groups in baseline characteristics. The DCR was 77.8% in the mFOLFIRINOX group and 63.5% in the Gemox group. The corresponding median PFS was 9.9 months (95% confidence interval [CI], 7.3–12.4) in the mFOLFIRINOX group versus 6.4 months (95% CI,3.6–9.2, p = 0.040) in the Gemox group. The corresponding median OS was 15.7 months (95% CI, 12.5–19.0) versus 12.0 months (95% CI, 9.3–14.8, p = 0.099). Significantly more grade 3–4 vomiting occurred in the mFOLFIRINOX than the Gemox groups (7 (25.9%) vs 1 (4.5%), p = 0.044). Conclusions First-line mFOLFIRINOX offered more promising results in patients with advanced or metastatic CCA.

Background: Hepatocellular carcinoma (HCC) is one of the most common malignancies in China. Most HCC patients are firstly diagnosed at an advanced stage, and systemic treatments are the mainstay of treatment. Summary: In recent years, immune checkpoint inhibitors have made a breakthrough in the systemic treatment of middle-advanced HCC, breaking the single therapeutic pattern of molecular targeted agents. To better guide the clinical treatment for effective and safe use of immunotherapeutic drugs, the Chinese Association of Liver Cancer and Chinese Medical Doctor Association has gathered multidisciplinary experts and scholars in relevant fields to formulate the “Chinese Clinical Expert Consensus on Immunotherapy for Hepatocellular Carcinoma (2021)” based on current clinical studies and clinical medication experience for reference in China. Key messages: The consensus contained 17 recommendations, including the preferred regimen for first- and second-line immunotherapy, evaluation and monitoring before/during/after treatment, management of complications, precautions for special patients and potential population for immunotherapy.

Abstract Background To study the influence of preoperative transcatheter arterial chemoembolization (TACE) on the incidence of microvascular invasion (MVI) and long‐term survival outcomes in hepatocellular carcinoma (HCC) patients. Methods Between January 1, 2010 and December 1, 2014, consecutive HCC patients who underwent curative liver resection were enrolled in this study. Univariable and multivariable regression analyses were used to identify independent predictive factors of MVI. Propensity score matching (PSM) was used to compare the incidences of MVI and prognosis between patients who did and did not receive preoperative TACE. Factors associated with Disease‐Free Survival (DFS) and Overall survival (OS) were identified using Cox regression analyses. Results Of 1624 patients, 590 received preoperative TACE. The incidence of MVI was significantly lower in patients with preoperative TACE than those without preoperative TACE (39.15% vs. 45.36%, p = 0.015). After PSM, the incidences of MVI were similar in the two groups (38.85% vs. 41.10%, p = 0.473). Multivariable regression analysis revealed preoperative TACE to have no impact on the incidence of MVI. Before PSM, survival of patients with preoperative TACE was significantly worse than those without preoperative TACE (p = 0.032 for DFS and p = 0.027 for OS). After PSM, the difference became insignificant (p = 0.465 for DFS and p = 0.307 for OS). After adjustment for other prognostic variables in the propensity‐matched cohort, preoperative TACE was still found not to be associated with DFS and OS after HCC resection. Both before and after PSM, the prognosis of patients was not significantly different between the two groups for BCLC stages 0, A, and B. Conclusions Preoperative TACE did not influence the incidence of MVI and prognosis of patients with HCC who underwent ‘curative’ liver resection.

Background: Hepatocellular carcinoma (HCC) is the most common type of liver cancer and causes many cancer-related deaths worldwide; in China it is the second most prevalent cause of cancer deaths. Most patients are diagnosed clinically with advanced stage disease. Summary: For more than a decade, sorafenib, a small molecular weight tyrosine kinase-inhibitor (SMW TKI) was the only molecular targeted drug available with a survival benefit for the treatment of advanced HCC. With the development of novel TKIs and immune checkpoint inhibitors (ICIs) for advanced HCC, the management of patients has been greatly improved. However, though angiogenic-based targeted therapy remains the backbone for the systemic treatment of HCC, to date no Chinese guidelines for novel molecular targeted therapies to treat advanced HCC have been established. Our interdisciplinary panel on the treatment of advanced HCC comprising hepatologists, hepatobiliary surgeons, oncologists，radiologists，pathologists, orthopedic surgeons, traditional Chinese medicine physicians and interventional radiologists have reviewed the literature in order to develop updated treatment regimens. Key Messages: Panel consensus statements for the appropriate use of new molecular targeted drugs including doses, combination therapies, adverse reaction management as well as efficacy evaluation and predictions for treatment of advanced HCC with evidence levels based on published data are presented, thereby providing an overview of molecular targeted therapies for healthcare professionals.

Introduction: The aim of this study was to select qualified patients with hepatocellular carcinoma (HCC) who underwent right hepatectomy (RH) via intraoperative indocyanine green retention test at 15 min (ICG-R15) of the left hemiliver, which prevents severe posthepatectomy liver failure (PHLF).Methods: Twenty HCC patients who were preoperatively planned to undergo RH were enrolled. Intraoperative ICG-R15 of left hemiliver was measured after the right Glissonean pedicle was completely blocked. Patients then underwent RH if intraoperative ICG-R15 was ≤ 10%. Otherwise, patients underwent staged RH (SRH), either associating liver partitioning and portal vein ligation for staged hepatectomy (ALPPS) or portal vein ligation (PVL), followed by stage-2 RH. The comparison group consisted of patients with a ratio of standard left liver volume (SLLV) of > 40% and preoperative ICG-R15 ≤ 10% who underwent RH. The clinical outcomes of these two groups were compared.Results: Of the 20 patients, six underwent stage-1 RH, six underwent ALPPS, five underwent PVL followed by stage-2 RH, and three failed to proceed to stage-2 RH after PVL. No significant differences were found among the 17 patients who underwent stage-1 or stage-2 RH in the study group, the 19 patients in the comparison group, the 11 patients in the stage-2 RH group, and the six patients in the stage-1 RH group in incidences of PHLF, postoperative complications, hospital stay, and HCC recurrence within 1 year after RH. Compared with the stage-1 ALPPS group, the mean operative time and blood loss of the stage-1 PVL group were significantly less (p

Aim: To compare the short- and long-term treatment outcomes of bisegmentectomy 7–8 vs. right hepatectomy for patients with hepatocellular carcinoma and cirrhosis.Methods: Thirty six cirrhotic HCC patients with infiltration of right hepatic vein in segments 7–8 underwent bisegmentectomy 7–8 for small-for-size remanant liver under right hemi-hepatectomy. Its outcome was compared with a case-matched control group of cirrhotic HCC patients who underwent right hemi-hepatectomy during the study period.Results: The study group consisted of 36 patients and the control group 36 patients selected from 1,526 patients matched with age, tumor size, tumor location, and Pugh-Child staging. There were no significant differences between the two groups in operative parameters and in perioperative main complications which included hemorrhage, bile leakage, ascites, pleural effusion, and liver failure. The overall morbidity rate and morbidity rate classified according to Clavien's classification were similar. There was no in-hospital mortality or 90 day post-operative mortality. The mean follow-up was 30 and 32 months for the study group and control group, respectively. The disease free survival rate (DFS) for the study group was just significantly better than the control group. The median DFS was 24 months for the study group and 8 months for the control group (P = 0.049). Meanwhile, the median cumulative overall survival was 35 months for the study group and 27 months for the control group (P = 0.494).Conclusion: Bisegmentectomy 7–8 was safe and feasible for selected cirrhosis patients, and did not increase the perioperative risk and inferior long-term overall survival outcomes. It extended the indications for liver resection in patients with borderline volumes of future liver remnant for HCC cirrhotic liver.

BackgroundOccurrence of portal vein tumor thrombus (PVTT) worsens the outcomes of hepatocellular carcinoma (HCC) and imparts high economic burden on society. Patients with high risks of having hypercoagulation are more likely to experience thrombosis. Herein, we examined how preoperative international normalized ratio (INR) was related to the incidence and extent of PVTT, and associated with survival outcomes in HCC patients following R0 liver resection (LR).MethodsPatients with HCC and PVTT were enrolled from six major hospitals in China. The overall survival (OS) and recurrence-free survival (RFS) rates of individuals with different INR levels were assessed with Cox regression analysis as well as Kaplan-Meier method.ResultsThis study included 2207 HCC patients, among whom 1005 patients had concurrent PVTT. HCC patients in the Low INR group had a significantly higher incidence of PVTT and more extensive PVTT than the Normal and High INR groups (P

BackgroundHepatocellular carcinoma (HCC) is one of the most serious consequences of chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. This study sought to investigate long-term outcomes after liver resection for HCC among patients with HBV/HCV co-infection (HBV/HCV-HCC) compared with patients with HBV infection (HBV-HCC).MethodsPatients who underwent curative-intent liver resection for HCC were identified from a multicenter Chinese database. Using propensity score matching (PSM), patients with HBV/HCV-HCC were matched one-to-one to patients with HBV-HCC. Overall survival (OS) and recurrence-free survival (RFS) were compared between the two groups before and after PSM.ResultsAmong 2,467 patients identified, 93 (3.8%) and 2,374 (96.2%) patients had HBV/HCV-HCC and HBV-HCC, respectively. Compared with patients with HBV-HCC, patients with HBV/HCV-HCC were older, have poorer liver-related characteristics but better tumor-related characteristics. PSM created 88 pairs of patients with comparable liver- and tumor-related characteristics (all P > 0.2). In the PSM cohort, the 3- and 5-year RFS rates in patients with HBV/HCV-HCC were 48.3% and 38.9%, which were significantly poorer than patients with HBV-HCC (61.8% and 49.2%, P = 0.037). Meanwhile, the 3- and 5-year OS rates in patients with HBV/HCV-HCC were also poorer than patients with HBV-HCC (65.4% and 51.1% vs. 73.7% and 63.0%), with a difference close to be significant between them (P = 0.081).ConclusionComparing to patients with HBV-HCC, liver resection resulted in relatively poorer long-term surgical outcomes in patients with HBV/HCV-HCC.

ObjectivesTo investigate the prognostic significance of the systemic immune-inflammation index (SII) in patients after radical cholecystectomy for gallbladder cancer (GBC) using overall survival (OS) as the primary outcome measure.MethodsBased on data from a multi-institutional registry of patients with GBC, significant prognostic factors after radical cholecystectomy were identified by multivariate Cox proportional hazards model. A novel staging system was established, visualized as a nomogram. The response to adjuvant chemotherapy was compared between patients in different subgroups according to the novel staging system.ResultsOf the 1072 GBC patients enrolled, 691 was randomly selected in the discovery cohort and 381 in the validation cohort. SII>510 was found to be an independent predictor of OS (hazard ratio [HR] 1.90, 95% confidence interval [CI] 1.42-2.54). Carbohydrate antigen 199(CA19-9), tumor differentiation, T stage, N stage, margin status and SII were involved in the nomogram. The nomogram showed a superior prediction compared with models without SII (1-, 3-, 5-year integrated discrimination improvement (IDI):2.4%, 4.1%, 5.4%, P

Abstract Background Intratumoral immune infiltrates have manifested a robust prognostic signature in patients with hepatocellular carcinoma (HCC). We hypothesized that a novel tissue-related immune signature (TRIS) could improve the prediction of postoperative survival for patients diagnosed with early/intermediate HCC. Methods Twenty-eight immune features were immunohistochemically examined on 352 HCC specimens. The LASSO Cox regression model was used to construct a five-feature-based TRIS. The univariate and multivariate Cox analyses were performed. Based on independent predictors, the immune-clinical prognostic index (ICPI) was established. Performance assessment was measured with C-index and compared with seven traditional staging systems. The independent validation cohort (n = 393) was included to validate the model. Results By using the LASSO method, the TRIS were constructed on the basis of five immune features, CD3intratumoral (T), CD27T, CD68peritumoral (P), CD103T, and PD1T. Multivariate Cox analysis showed that the TRIS was an independent prognostic predictor. In the training cohort, γ-glutamyl transferase, tumor diameter, tumor differentiation, and TRIS were incorporated into the ICPI. The ICPI presented satisfactory discrimination ability, with C-index values of 0.691 and 0.686 in the training and validation cohorts, respectively. Compared with seven conventional staging systems (C-index, training cohort, 0.548–0.597; validation cohort, 0.519–0.610), the ICPI exhibited better performance for early/intermediate-stage HCCs. Further, the patients were categorized into three subgroups with X-tile software, and the stratified ICPI presented a superior corrected Akaike information criterion and homogeneity in both cohorts. Conclusions Our ICPI was a useful and reliable prognostic tool which may offer good individualized prediction capability for HCC patients with early/intermediate stage.

Anatomic location/size and number of lesions, inadequate volume of future liver remnant, or poor coexisting premorbid conditions preclude surgery in the majority of patients with hepatocellular carcinoma (HCC). Liver transplantation can cure some patients with poor liver function, but few patients are eligible because of scarcity of donors. Without specific anti-cancer treatment, the prognosis of HCC is poor. Various locoregional therapies are used to treat patients who are not candidates for surgery, and have emerged as tools for palliation, tumor down-staging, and bridging therapy prior to liver transplantation. Currently, local ablative therapy even competes with partial hepatectomy and liver transplantation as a primary treatment for small HCC. HCC is well suited to treatment with loco-regional therapy because it has a tendency to stay within the liver, with distant metastasis generally occurring late in the course of disease. This suggests that an effective local-regional therapy can have a great impact on HCC patients who are not candidates for surgical treatment. Loco-regional therapy can further be justified because patients with HCC usually die of liver failure consequent to intrahepatic growth resulting in liver tissue destruction, rather than extrahepatic metastases. Keywords: Hepatocellular carcinoma, Hepatectomy, Loco-regional therapy, TACE, Local ablation

Abstract Background Suturing the proximal pancreatic stump and performing pancreaticoenterostomy for the distal pancreatic stump following central pancreatectomy is a conventional procedure. This reconstruction after resection of the pathological pancreatic lesion brings changes in anatomy and physiology. In this study, an innovative one-stage robotic end-to-end pancreatic anastomosis was reported to replace the conventional pancreaticoenterostomy following central pancreatectomy. Materials and methods The clinical data of 11 consecutive patients who underwent robotic central pancreatectomy with end-to-end pancreatic anastomosis between August 2017 and December 2017 were analyzed retrospectively. Results All operations were completed successfully without any conversion to open surgery. Nine patients had benign tumors, one had a mass-forming chronic pancreatitis, and one had an isolated pancreatic metastasis from a renal cancer. The mean gap left after central pancreatectomy was 4.3 ± 1.0 cm. The median operative time was 121 (range, 105 to 199) min. The median blood loss was 50 (range, 20 to 100) ml. Seven (63.6%) patients developed complications which included Clavien–Dindo Grade I complications in five patients, a Grade II complication in one patient, and a Grade IIIa complication in one patient. Seven patients developed a Grade B postoperative pancreatic fistula, and two patients a biochemical leak. There was no Grade C or worse pancreatic fistula. Magnetic resonance cholangiopancreatography at postoperative 6 months showed no stricture in any of the main pancreatic ducts. Three patients had an asymptomatic and small pancreatic pseudocyst. Conclusion Robotic central pancreatectomy with end-to-end pancreatic anastomosis was safe and feasible. It restores the normal anatomy of the pancreas. With its good short-and long-term outcomes, it could be an alternative reconstructive method to pancreaticoenterostomy following central pancreatectomy.

Portal vein tumor thrombus (PVTT) is one of the most serious forms of hepatocellular carcinoma (HCC) vessel metastasis and has a poor survival rate. However, the molecular mechanism of PVTT has not yet been elucidated. In this study, the molecular mechanism of AXL expressed in tumor-derived endothelial cells (TECs) in vessel metastasis was investigated. High AXL expression was observed in TECs, but not in the tumor cells of HCC patients with PVTT and this was associated with poor overall survival (OS) and disease-free survival (DFS). AXL overexpression was positively associated with CD 31 expression both in vitro and in vivo. AXL promoted the cell proliferation, tube formation, and migration of both TECs and normal endothelial cells (NECs). High expression of AXL in TECs promoted the cell migration, but not the proliferation of HCC cells. Further studies demonstrated that AXL promoted cell migration and tube formation through activation of the PI3K/AKT/SOX2/DKK-1 axis. AXL overexpression in HUVECs promoted tumor growth and liver or vessel metastasis of HCC in xenograft nude mice, which could be counteracted by treatment with R428, an AXL inhibitor. R428 reduced tumor growth and CD 31 expression in HCC in PDX xenograft nude mice. Therefore, AXL over-expression in TECs promotes vessel metastasis of HCC, which indicates that AXL in TECs could be a potential therapeutic target in HCC patients with PVTT.

Data on prognostic factors associated with outcome following resection of perihilar cholangiocarcinoma vary. We sought to define and characterize current available evidence on prognostic factors associated with perihilar cholangiocarcinoma after resection. The PubMed, Embase, and Cochrane library were systematically searched for relevant studies published before December 2019. Prognostic factors were identified from multivariate regression analyses in studies. Only high-quality studies were included (Newcastle–Ottawa Scale > 6 stars). A total of 45 studies involving 7338 patients were analyzed. The meta-analysis demonstrated that serum bilirubin levels (hazard ratio: 1.76, 95% confidence interval: 1.27–2.44), serum CA19-9 levels (hazard ratio: 1.32, 95% confidence interval: 1.05–1.65), tumor size (hazard ratio: 1.27, 95% confidence interval: 1.04–1.55), major vascular involvement (hazard ratio: 1.61, 95% confidence interval: 1.09–2.38), distance metastasis (hazard ratio: 17.60, 95% confidence interval: 2.01–154.09), perioperative blood transfusion (hazard ratio: 1.36, 95% confidence interval: 1.15–1.62), T-stage (hazard ratio: 1.96, 95% confidence interval: 1.47–2.61), lymph node metastasis (hazard ratio: 2.06, 1.83–2.31), resection margin status (hazard ratio: 2.34, 95% confidence interval: 1.89–2.89), not-well histology differentiation (hazard ratio: 2.03, 95% confidence interval: 1.69–2.44), perineural invasion (hazard ratio: 2.37, 95% confidence interval: 1.59–3.55), and lymphovascular invasion (hazard ratio: 1.41, 95% confidence interval: 1.15–1.73) were prognostic factors for poorer overall survival. Adjuvant chemotherapy (hazard ratio: 0.37, 95% confidence interval: 0.25–0.55) had a positive effect on prolonged overall survival. In addition, positive resection margin status (hazard ratio: 1.96, 95% confidence interval: 1.47–2.61) and lymph node metastasis (hazard ratio: 2.06, 95% confidence interval: 1.83–2.31) were associated with poorer disease-free survival. The prognostic factors identified in the present meta-analysis can be used to characterize patients in clinical practice and enrich prognostic tools, which could be included in future trial designs and generate hypotheses to be tested in future research to promote personalized treatment.

Background: Although adjuvant transcatheter arterial chemoembolization (TACE) has been used to prevent recurrence after surgery in patients with hepatocellular carcinoma (HCC), the survival benefits from adjuvant TACE remain controversial. We sought to systematically evaluate the data on the effectiveness of adjuvant TACE for HCC, as well as identify patient populations that might benefit from adjuvant TACE. Methods: The PubMed, Embase, Medline and Cochrane library were systematically searched for studies published before July 2019 that compared adjuvant TACE versus surgery alone for HCC. The study endpoints were overall survival (OS) and disease-free survival (DFS). Patients with large HCC (⩾5 cm), multinodular HCC, microvascular invasion (MVI), or portal vein tumor thrombosis (PVTT) were analyzed in subgroup analyses. Results: Twenty-four studies with 6977 patients were included in the analytic cohort. The pooled analysis demonstrated that adjuvant TACE was associated with a better OS and DFS [hazard ratio (HR): 0.67 and 0.67, both p

Background Previous trials showed that antiangiogenesis or anti-programmed death protein 1/programmed death ligand 1 (PD-1/PD-L1) monotherapy only showed marginal effect in triple-negative breast cancer (TNBC). Preclinical studies demonstrated that antiangiogenic therapy could sensitize breast cancer to PD-1/PD-L1 blockade via reprogramming tumor microenvironment. Combinational treatment of checkpoint blockade and antiangiogenesis for TNBC has not been reported.Methods Patients with advanced TNBC with less than three lines of systemic therapy were enrolled in an open-label, non-comparative, two-arm, phase II trial at Sun Yat-sen Memorial Hospital. Camrelizumab (intravenously every 2 weeks) with apatinib orally at either continuous dosing (d1–d14) or intermittent dosing (d1–d7) was given until disease progression or unacceptable toxicities. Primary endpoint was objective response rate (ORR).Results From January 2018 to April 2019, 40 patients were enrolled, including 10 in the apatinib intermittent dosing cohort and 30 in the apatinib continuous dosing cohort. The ORR was 43.3% (13 of 30) in the continuous dosing cohort, while no objective response was observed in the intermittent dosing cohort. The disease control rate was 63.3% (19 of 30) in the apatinib continuous dosing cohort, and 40.0% (4 of 10) in the apatinib intermittent dosing cohort, respectively. The median progression-free survival (PFS) was 3.7 (95% CI 2.0 to 6.4) months and 1.9 (95% CI 1.8 to 3.7) months in the continuous dosing and intermittent dosing cohort, respectively. In the continuous dosing cohort, the median PFS of patients with partial response (8.3 months, 95% CI 5.9 to not reached) was significantly longer than that of patients with stable disease/progressive disease/not evaluable (2.0 months, 95% CI 1.7 to 3.0). The most common adverse events (AEs) included elevated aspartate aminotransferase/alanine aminotransferase and hand-foot syndrome. Overall, 26.7% and 20.0% of patients experienced grade ≥3 AEs in the continuous dosing and intermittent dosing cohort, respectively. In the continuous dosing cohort, a high percentage of baseline tumor-infiltrating lymphocytes (>10%) was associated with higher ORR and favorable PFS (p=0.029, 0.054, respectively).Conclusions The ORR by this chemo-free regimen was dramatically higher than previously reported ORR by anti-PD-1/PD-L1 antibody or apatinib monotherapy. Camrelizumab combined with apatinib demonstrated favorable therapeutic effects and a manageable safety profile in patients with advanced TNBC.Trial registration number NCT03394287.

Background: To improve the early diagnosis of hepatocellular carcinoma (HCC), more effective diagnostic biomarkers are needed. A combination of biomarkers is reported to distinguish individuals with early-stage HCC from at-risk individuals. Methods: Participants in this study were recruited from six hospitals in China. Literature review was used to choose 19 candidate proteins, a case-control study in the discovery stage was used to identify five proteins (P5) that constituted a diagnostic model. In the training and validation stages, the effectiveness of P5 for detecting early-stage HCC was tested (cross-sectional study). Finally, a nested case-control study independent of the other stages was set up to evaluate the P5 in the preclinical diagnosis of HCC. Findings: Between February 2013 and June 2017, a total of 1396 participants were recruited. A panel of 5 proteins (P5: OPN, GDF15, NSE, TRAP5 and OPG) showed high diagnostic accuracy when differentiating the early-stage HCC from the at-risk group, with AUCs of 0·892, 0·907 and 0·852 for the training stage, validation cohort 1 and cohort 2 data sets, respectively. In the prediction set, the sensitivity of P5 for diagnosing preclinical HCC increased with time, starting from 12 months before to the time of definitive clinical diagnosis (range, 46·15% to 86·67%). Interpretation: The P5 panel has the potential to screen populations at high risk of developing HCC and can enable the early diagnosis of HCC. Funding: Research supported by grants from eight funds. All sources of funding were declared at the end of the text. Keywords: Peripheral blood, Multi-tumor markers, Earlier detection, Liver cancer, Multi-center study

Abstract Background The majority of hepatocellular carcinoma patients (HCCs) with extrahepatic metastases die of progressive intrahepatic tumor. There have been little data on the role of primary tumor resection (PTR) for HCCs with extrahepatic metastases but with resectable primary tumors. Methods A retrospective study was conducted on HCCs with extrahepatic metastases with resectable primary tumors who either underwent or did not undergo PTR in the SEER registry between 2004 and 2013. The overall and cancer‐specific survivals (OS and CSS) were assessed by the log‐rank test and the Cox proportional hazard regression model. A propensity score matching was conducted to minimize biases. Validation was performed in another cohort from the Sun Yat‐sen Memorial Hospital (SYSMH). Results Of the 529 HCCs with extrahepatic metastases with resectable primary tumors included into this study, 230 patients underwent PTR and 299 did not. The percentages of patients who underwent PTR increased from 38.6% in 2004 to 70.3% in 2013. In the propensity score‐matched patients, PTR was associated with improved OS (HR 0.310, P

Over-expression of aspartyl (asparagynal)-β-hydroxylase (ASPH) contributes to hepatocellular carcinoma (HCC) invasiveness, but the role of ASPH hydroxylase activity in this process remains to be defined. As such, the current study investigated the role of ASPH hydroxylase activity in downstream signalling of HCC tumorgenesis and, specifically, metastasis development. Over-expression of wild-type ASPH, but not a hydroxylase mutant, promoted HCC cell migration in vitro, as well as intrahepatic and distant metastases in vivo. The enhanced migration and epithelial to mesenchymal transition (EMT) activation was notably absent in response to hydroxylase activity blockade. Vimentin, a regulator of EMT, interacted with ASPH and likely mediated the effect of ASPH hydroxylase activity with cell migration. The enhanced hydroxylase activity in tumor tissues predicted worse prognoses of HCC patients. Collectively, the hydroxylase activity of ASPH affected HCC metastasis through interacting with vimentin and regulating EMT. As such, ASPH might be a promising therapeutic target of HCC. Keywords: ASPH, Hydroxylase, Hepatocellular carcinoma, Metastasis, Epithelial-mesenchymal transition, Vimentin

Objective: Based on a large series of histopathologically confirmed hepatic angiomyolipomas, we retrospectively studied the typical diagnostic features of hepatic angiomyolipoma and proposed a treatment strategy for this disease. Materials and methods: From December 1997 to December 2007, 74 consecutive patients who received definitive treatment for hepatic angiomyolipoma, at a single tertiary center, were studied. Results: There was a marked female predominance (54 females vs. 20 males) and the mean age was 42 years. Forty patients had no symptoms and the tumors were detected incidentally during a medical check-up. From this study, we proposed the typical diagnostic features of hepatic angiomyolipoma to be the absence of risk factors for malignancy, normal tumor marker levels, and typical imaging features on ultrasound (USG), abdominal contrast computed tomography (CT), or magnetic resonance imaging (MRI). Only 23% of patients could have been diagnosed before surgery using these features. One patient (1.4%) had a malignant angiomyolipoma, and died with distant metastases 14 months after surgery. After a median follow-up of 64 months, there was no recurrence in the other 73 patients. Conclusion: Patients with typical diagnostic features suggestive of hepatic angiomyolipoma could be observed with regular surveillance. Definitive treatment should be performed when the tumor has symptoms/complications, when the tumor is enlarging, or when a malignant lesion cannot be ruled out.

While hepatic resection or local ablative therapy may provide a potentially curative treatment for hepatocellular carcinoma (HCC), more than half of these patients develop recurrent HCC within 5 years after treatment. Thus identification of any therapy which can decrease or delay the incidence of recurrence will improve the results of treatment. However, no chemopreventive agent has been approved for HCC. Methods: A MEDLINE database, Embase, Cancerlit (National Cancer Institute), and CBM (Chinese Biomedical Database) search from 1990 to 2009 was performed to identify relevant articles using the keywords “hepatocellular carcinoma,” “vitamin analogue,” and “chemoprevention.” Additional papers were identified by a manual search of the references from the key articles. The fixed effect model was used for a meta-analysis. Results: Oral administration of acyclic retinoids (vitamin A analogue), and menatetrenone (vitamin K2 analogue) have been tested as chemopreventive agents after hepatic resection or local ablative therapy for HCC. There were one and four randomised, controlled trials (RCTs) which evaluated the efficacy of polyprenoic acid and menatetrenone, respectively. All studies were conducted in Japan. One RCT showed the preventive effect of polyprenoic acid in lowering the incidence of HCC recurrence after hepatic resection or percutaneous ethanol injection, and this effect lasted up to 199 weeks after randomization (or 151 weeks after completion of retinoid administration). Four RCTs evaluated the preventive efficacy of menatetrenone on HCC recurrence after hepatic resection or local ablative therapy. The results of three studies, as well as the meta-analysis of all four studies, showed significantly better tumour recurrencefree survival. The beneficial effect on the overall survival was less definite. Conclusion: There is evidence to suggest that chemopreventive therapy after partial hepatectomy or local ablative therapy is beneficial in prolonging disease-free survival, but the evidence is less for an effect on the overall survival. To confirm the beneficial role of vitamin A or K analogues in the chemoprevention of HCC further and larger randomised trials are now required.

CXC ligand 17 (CXCL17) is a novel CXC chemokine whose clinical significance remains largely unknown. In the present study, we characterized the prognostic value of CXCL17 in patients with hepatocellular carcinoma (HCC) and evaluated the association of CXCL17 with immune infiltration. We examined CXCL17 expression in 227 HCC tissue specimens by immunohistochemical staining, and correlated CXCL17 expression patterns with clinicopathological features, prognosis, and immune infiltrate density (CD4 T cells, CD8 T cells, B cells, natural killer cells, neutrophils, macrophages). Kaplan-Meier survival analysis showed that both increased intratumoral CXCL17 (P = 0.015 for overall survival [OS], P = 0.003 for recurrence-free survival [RFS]) and peritumoral CXCL17 (P = 0.002 for OS, P

Introduction. Both hepatocellular carcinoma (HCC) presenting during pregnancy and HCC presenting with obstructive jaundice due to a tumor cast in the biliary tract are very rare. The management of these patients remains challenging. Presentation of Case. A 23-year-old lady presented with obstructive jaundice at 38 weeks of gestation. Investigations showed HCC with a biliary tumor thrombus. She received percutaneous transhepatic biliary drainage (PTBD) and caesarean section. Right hepatectomy, extrahepatic bile duct resection, and left hepaticojejunostomy were carried out when the jaundice improved. The postoperative course was uneventful. She was discharged home on postoperative day 10. Histopathology showed HCC with a tumor thrombus in the bile duct. The surgical margins were clear. One year after surgery, the mother was disease-free and the baby was well. Conclusion. With proper management, curative treatment is possible in a pregnant patient who presented with obstructive jaundice due to a biliary tumor thrombus from HCC.

Background: The high incidence of early recurrence after liver resection (LR) for hepatocellular carcinoma (HCC) is the main obstacle in achieving good long-term survival outcomes. The aim of the present study is to develop a prognostic model in predicting the risk of very early (1-year) recurrence. Material and methods: Consecutive patients who underwent LR for HCC with curative intent at multicenters in China were enrolled in this study. The VERM-pre (the Preoperative Very Early Recurrence Model of HCC) with good performance was derived and validated by internal and external cohorts retrospectively and by another two-center cohort prospectively. Results: Seven thousand four hundred one patients were enrolled and divided randomly into three cohorts. Eight variables (tumor diameter, tumor number, macrovascular invasion, satellite nodule, alpha-fetoprotein, level of HBV-DNA, γ-GT, and prothrombin time) were identified as independent risk factors for recurrence-free survival on univariate and multivariate analyses. The VERM-pre model was developed which showed a high capacity of discrimination (C-index: 0.722; AUROC at 1-year: 0.722)) and was validated comprehensively by the internal, external, and prospective cohorts, retrospectively. Calibration plots showed satisfactory fitting of probability of early HCC recurrence in the cohorts. Three risk strata were derived to have significantly different recurrence-free survival rates (low-risk: 80.4-85.4%; intermediate-risk: 59.7-64.8%; high-risk: 32.6-42.6%). In the prospective validation cohort, the swimming plot illustrated consistent outcomes with the beginning predictive score. Conclusion: The VERM-pre model accurately predicted the 1-year recurrence rates of HCC after LR with curative intent. The model was retrospectively and prospectively validated and then developed as the online tool. [ABSTRACT FROM AUTHOR]