Resected Primary Hepatocellular Carcinoma Research Articles

Hepatitis C treatment and long-term outcome of patients with hepatocellular carcinoma after resection.

This study aimed to investigate the survival outcomes of antiviral agents (direct-acting antivirals [DAAs] or interferon [IFN]) in patients with hepatitis C virus who underwent liver resection for primary hepatocellular carcinoma. This retrospective single-center study included 247 patients, between 2013 and 2020, being treated with DAAs (n=93), IFN (n=73), or no treatment (n=81). Overall survival (OS), recurrence-free survival (RFS), and risk factors were analyzed. After a median follow-up time of 50.4months, the rates of 5-year OS and RFS in the IFN, DAA, and no treatment groups were 91.5% and 55.4%, 87.2% and 39.8%, and 60.9% and 26.7%, respectively. One hundred and twenty-eight (51.6%) patients developed recurrence; recurrence was mostly (86.7%) intrahepatic, and 58 (23.4%) developed early recurrence, most of which received no antiviral treatment. The OS and RFS were similar between patients who received antiviral treatment before (50.0%) and after surgery, but longer survival was observed in patients achieving sustained virologic response. In multivariate analysis, antiviral treatment was protective for OS (hazard ratio [HR] 0.475, 95% confidence interval [CI]: 0.242-0.933) with significance but not RFS, in contrast to microvascular invasion (OS HR 3.389, 95% CI: 1.637-7.017; RFS HR 2.594, 95% CI: 1.520-4.008). In competing risk analysis, DAAs (subdistribution HR 0.086, 95% CI: 0.007-0.991) were protective against hepatic decompensation events but not recurrence events. In patients with hepatitis C virus, antiviral treatment suggested OS benefit for primary hepatocellular carcinoma after resection, and DAAs might be protective against hepatic decompensation. Following adjustment for oncological factors, IFN and DAA treatment was not significantly advantageous relative to the other.

Detailed analysis of recurrent sites after wedge resection for primary hepatocellular carcinoma considering the potential usefulness of anatomic resection: a retrospective cohort study.

We investigated the detailed recurrent sites after wedge liver resection for primary hepatocellular carcinoma (HCC). We retrospectively reviewed 278 patients with primary HCC who underwent curative liver resection between 2000 and 2016. Recurrent sites were divided into four groups: around the initial HCC (segmental recurrence), within the same section as the primary HCC (sectional recurrence), within the same lobe as the primary HCC (lobar recurrence), and contralateral or extrahepatic recurrence (extra recurrence). Recurrence was observed in 101 of 147 patients who underwent wedge resection. At first recurrence, segmental recurrence was observed in 18 patients (17.8%), while 28 patients (27.7%) were with sectional recurrence and 48 patients (47.5%) were with lobar recurrence. However, the cumulative recurrent sites of each patient showed extra recurrence in 53 patients (52.5%) at initial recurrence, 79 patients (78.2%) until the second recurrence, 89 patients (88.1%) until the third recurrence, 94 patients (93.0%) until the fourth, and 96 patients (95.0%) until the fifth recurrence. Some intrahepatic recurrence after wedge resection might have been avoided if anatomic resection had been performed instead. However, the number of contralateral or extrahepatic recurrences increased with the number of recurrences.

SAT273 - Sarcopenia predict complications after hepatic resection for primary hepatocellular carcinoma (HCC) in patients with advanced chronic liver disease (ACLD) and clinically significant portal hypertension (CSPH)

SAT273 - Sarcopenia predict complications after hepatic resection for primary hepatocellular carcinoma (HCC) in patients with advanced chronic liver disease (ACLD) and clinically significant portal hypertension (CSPH)

Long-Term Survival Impact of High-Grade Complications after Liver Resection for Hepatocellular Carcinoma: A Retrospective Single-Centre Cohort Study.

Background and Objectives: Although complications after liver resection for hepatic cancer are common, the long-term impact of these complications on oncological outcomes remains unclear. This study aimed to investigate the potential effect of high-grade postoperative complications on long-term mortality and cancer recurrence after surgical resection of hepatocellular carcinoma. Materials and Methods: In a retrospective cohort study, patients undergoing curative liver resection for primary hepatocellular carcinoma between 2005 and 2016 were evaluated. The Clavien–Dindo (CD) grading system was used to classify patients into two groups of either high-grade complications (grade III or IV) or none or low-grade complications (grade 0 to II) within 30 days after surgery. The primary endpoint was all-cause mortality. Secondary endpoints were cancer-specific mortality and cancer recurrence. Weighted Cox proportional hazards regression models were used to calculate the adjusted hazard ratio (aHR) with a 95% confidence interval (CI) for the outcomes of interest. Results: A total of 1419 patients with a median follow-up time of 46.6 months were analysed. Among them, 93 (6.6%) developed high-grade complications after surgery. The most common complications were bile leakage (n = 30) in CD grade III and respiratory failure (n = 13) in CD grade IV. High-grade complications were significantly associated with all-cause mortality (aHR: 1.78, 95% CI: 1.55–2.06) and cancer-specific mortality (aHR: 1.34, 95% CI: 1.13–1.60), but not cancer recurrence (aHR: 0.92, 95% CI: 0.84–1.02). Independent influential factors for complications were sex, diabetes mellitus, clinically significant portal hypertension, oesophageal varices, multifocal cancer, intraoperative blood loss, and anaesthesia duration. Conclusions: Patients who had high-grade postoperative complications had a greater risk of long-term mortality after liver resection for hepatocellular carcinoma. Prevention of postoperative complications may serve as an effective strategy for improving long-term survival.

Sarcopenia Predicts Major Complications after Resection for Primary Hepatocellular Carcinoma in Compensated Cirrhosis.

Simple SummarySarcopenia, which is defined as a loss of skeletal muscle mass, function and strength, is the result of major metabolic changes often observed in advanced liver disease. Its evaluation mirrors the nutritional and functional status of the patients, and thus has been recently implicated as an outcome predictor of patients with liver diseases and hepatocellular carcinoma. This study provides evidence that sarcopenia, as assessed by the skeletal muscle index, is associated with age and body mass index in liver surgery candidates. More importantly, it is associated with higher rates of major complications (Clavien-Dindo grade III or IV) in patients with compensated advanced chronic liver disease and/or portal hypertension undergoing liver resection for primary hepatocellular carcinoma.The burden of post-operative complications of patients undergoing liver resection for hepatocellular carcinoma (HCC) is a cause of morbidity and mortality. Recently, sarcopenia has been reported to influence the outcome of patients with cirrhosis. We aimed to assess factors associated with sarcopenia and its prognostic role in liver surgery candidates. We included all patients with compensated advanced chronic liver disease (cACLD) undergoing liver resection for primary HCC consecutively referred to the University of Bologna from 2014 to 2019 with an available preoperative abdominal CT-scan performed within the previous three months. A total of 159 patients were included. The median age was 68 years, and 80.5% of the patients were male. Sarcopenia was present in 82 patients (51.6%). Age and body mass index (BMI) were associated with the presence of sarcopenia at multivariate analysis. Thirteen (8.2%) patients developed major complications and 14 (8.9%) presented PHLF grade B-C. The model for end-stage liver disease score was associated with the development of major complications, whereas cACLD presence, thrombocytopenia, portal hypertension (PH), Child-Pugh score and Albumin-Bilirubin score were found to be predictors of clinically significative PHLF. The rate of major complications was 11.8% in sarcopenic patients with cACLD compared with no complications (0%) in patients without sarcopenia and cACLD (p = 0.032). The rate of major complications was significantly higher in patients with (16.3%) vs. patients without (0%) sarcopenia (p = 0.012) in patients with PH. In conclusion, sarcopenia, which is associated with age and BMI, may improve the risk stratification of post-hepatectomy major complications in patients with cACLD and PH.

Myeloid-derived suppressor cell infiltration is associated with a poor prognosis in patients with hepatocellular carcinoma.

The clinicopathological features of myeloid-derived suppressor cell (MDSC) and CD8+ T-cell infiltration in hepatocellular carcinoma (HCC) are poorly understood. The present study examined MDSC and CD8+ T-cell infiltration in surgically resected primary HCC specimens and investigated the association of MDSC and CD8+ T-cell infiltration with clinicopathological features and patient outcomes. Using a database of 466 patients who underwent hepatic resection for HCC, immunohistochemical staining of CD33 (an MDSC marker) and CD8 was performed. High infiltration of MDSCs within the tumor was observed in patients with a poorer Barcelona Clinic Liver Cancer stage, larger tumor size, more poorly differentiated HCC, and greater presence of portal venous thrombosis, microscopic vascular thrombosis and macroscopic intrahepatic metastasis. MDSC infiltration and CD8+ T-cell infiltration were independent predictors of recurrence-free survival and overall survival, respectively. Stratification based on the MDSC and CD8+ T-cell status of the tumors was also associated with recurrence-free survival (10 year-recurrence-free survival; MDSChighCD8+ T-cellLow, 3.68%; others, 25.7%) and overall survival (10 year-overall survival; MDSChighCD8+ T-cellLow, 12.0%; others, 56.7%). In conclusion, the present large cohort study revealed that high MDSC infiltration was associated with a poor clinical outcome in patients with HCC. Furthermore, the combination of the MDSC and tumor-infiltrating CD8+ T-cell status enabled further classification of patients based on their outcomes.

Impact of Nuclear Factor Erythroid 2-Related Factor 2 in Hepatocellular Carcinoma: Cancer Metabolism and Immune Status.

We examined phosphorylated nuclear factor erythroid 2–related factor 2 (P‐NRF2) expression in surgically resected primary hepatocellular carcinoma (HCC) and investigated the association of P‐NRF2 expression with clinicopathological features and patient outcome. We also evaluated the relationship among NRF2, cancer metabolism, and programmed death ligand 1 (PD‐L1) expression. In this retrospective study, immunohistochemical staining of P‐NRF2 was performed on the samples of 335 patients who underwent hepatic resection for HCC. Tomography/computed tomography using fluorine‐18 fluorodeoxyglucose was performed, and HCC cell lines after NRF2 knockdown were analyzed by array. We also analyzed the expression of PD‐L1 after hypoxia inducible factor 1α (HIF1A) knockdown in NRF2‐overexpressing HCC cell lines. Samples from 121 patients (36.1%) were positive for P‐NRF2. Positive P‐NRF2 expression was significantly associated with high alpha‐fetoprotein (AFP) expression, a high rate of poor differentiation, and microscopic intrahepatic metastasis. In addition, positive P‐NRF2 expression was an independent predictor for recurrence‐free survival and overall survival. NRF2 regulated glucose transporter 1, hexokinase 2, pyruvate kinase isoenzymes L/R, and phosphoglycerate kinase 1 expression and was related to the maximum standardized uptake value. PD‐L1 protein expression levels were increased through hypoxia‐inducible factor 1α after NRF2 overexpression in HCC cells. Conclusions: Our large cohort study revealed that P‐NRF2 expression in cancer cells was associated with clinical outcome in HCC. Additionally, we found that NRF2 was located upstream of cancer metabolism and tumor immunity.

Postresection Period-Specific Hazard of Recurrence as a Framework for Surveillance Strategy in Patients with Hepatocellular Carcinoma: A Multicenter Outcome Study

Introduction: In spite of the high frequency of recurrence of hepatocellular carcinoma (HCC) after resection, little evidence exists to directly help to plan a reasonable schedule for the frequency and intensity of postoperative surveillance for recurrence. Methods: 1,918 consecutive patients with Child-Turcott-Pugh class A who had T1- or T2-staged HCCs detected by active surveillance and underwent curative resection for their tumors at 3 teaching hospitals in Korea, followed by recurrence screening at 6-monthly or shorter intervals. To set an evidence-based timetable for postoperative surveillance, we investigated the annual hazard rate of recurrence through postoperative year 10 in patients undergoing hepatectomy for HCC, and the clinical and morphological phenotypes associated with early versus late recurrence. Results: The estimated hazard rate for recurrence peaked during year 0–1 (21.7%), with a subsequent gradual decrease through 5 years, followed by stabilization at <7.0% until year 10, except in the case of cirrhotics, who had a rate of 10.5% during year 4–5. Multivariate time-to-recurrence analysis by recurrence period revealed that serum alpha-fetoprotein ≥200 ng/mL, larger size of tumor, tumor multiplicity, microvascular invasion, capsular invasion, and higher METAVIR fibrosis stage were significantly related to disease recurrence within 5 years after resection, while cirrhosis (METAVIR F4) alone was related to disease recurrence beyond 5 years (Ps < 0.05). Post-relapse overall survival was better in the latter group (p = 0.033). Conclusions: Our chronological and morphological insights into recurrence after resection of primary HCCs may help implement an optimal intensity of surveillance for recurrence.

Effect of timing of surgical resection of primary hepatocellular carcinoma on survival outcomes in elderly patients and prediction of clinical models

BackgroundThe effect of time delay from diagnosis to surgery on the prognosis of elderly patients with liver cancer is not well known. We investigated the effect of surgical timing on the prognosis of elderly hepatocellular carcinoma patients undergoing surgical resection and constructed a Nomogram model to predict the overall survival of patients.MethodsA retrospective analysis was performed on elderly patients with primary liver cancer after hepatectomy from 2012 to 2018. The effect of surgical timing on the prognosis of elderly patients with liver cancer was analyzed using the cut-off times of 18 days, 30 days, and 60 days. Cox was used to analyze the independent influencing factors of overall survival in patients, and a prognostic model was constructed.Results A total of 232 elderly hepatocellular carcinoma patients who underwent hepatectomy were enrolled in this study. The cut-off times of 18, 30, and 60 days were used. The duration of surgery had no significant effect on overall survival. Body Mass Index, Child-Pugh classification, Tumor size Max, and Length of stay were independent influencing factors for overall survival in the elderly Liver cancer patients after surgery. These factors combined with Liver cirrhosis and Venous tumor emboli were incorporated into a Nomogram. The nomogram was validated using the clinical data of the study patients, and exhibited better prediction for 1-year, 3-year, and 5-year overall survival.ConclusionsWe demonstrated that the operative time has no significant effect on delayed operation in the elderly patients with hepatocellular carcinoma, and a moderate delay may benefit some patients. The constructed Nomogram model is a good predictor of overall survival in elderly patients with hepatectomy.

A Powerful Nomogram Based on the Novel D-Index to Predict Prognosis After Surgical Resection of Hepatocellular Carcinoma.

PurposeConventional staging and scoring systems such as the Tumor, Node, and Metastasis; Cancer of the Liver Italian Program; Barcelona Clinic Liver Cancer; and Okuda have failed to predict overall survival (OS) in patients with resected primary hepatocellular carcinoma. Thus, we aimed to establish a novel D-index and nomogram to improve prognostic accuracy.Patients and MethodsWe selected 396 patients who underwent liver resection between January 2007 and February 2015 at the First Affiliated Hospital of Wenzhou Medical University. These patients were randomly divided into the training and validation groups in a ratio of 7:3.ResultsWe generated a nomogram using five independent risk factors, including the D-index (calculated by total bilirubin × tumor size/the ratio of fat-to-muscle area 0.5) in the training set. The predictive performance of the nomogram was similar in both the training and validation cohorts according to the concordance index. The nomogram demonstrated the strongest predictive power for 1-year, 3-year, and 5-year OS, with the area under the receiving operating characteristic curve being 0.8486, 0.7785, and 0.752, respectively. The calibration curves exhibited stable capabilities in both cohorts. The stratification of the Kaplan-Meier curve was significant (P < 0.001).ConclusionThe associated nomogram of the D-index demonstrated a powerful and accurate predictive ability for OS in patients with primary hepatocellular carcinoma.

ARID1A Deficiency Is Associated With High Programmed Death Ligand 1 Expression in Hepatocellular Carcinoma.

The clinicopathological features of carcinomas expressing AT‐rich interaction domain 1a (ARID1A) and programmed death ligand 1 (PD‐L1) in HCC are poorly understood. Here, we examined ARID1A and PD‐L1 expression in surgically resected primary hepatocellular carcinoma (HCC) and the association of ARID1A and PD‐L1 expression with clinicopathological features and patient outcomes. Their association with ARID1A expression and tumor‐associated CD68‐positive macrophage was further explored. Using a database of 255 patients who underwent hepatic resection for HCC, immunohistochemical staining of ARID1A, PD‐L1, and CD68 was performed. We also analyzed the expression PD‐L1 after ARID1A knockdown in HCC cell lines. Samples from 81 patients (31.7%) were negative for ARID1A. Negative ARID1A expression was significantly associated with male sex, high alpha‐fetoprotein, high des‐gamma‐carboxyprothrombin, large tumor size, high rate of poor differentiation, microscopic intrahepatic metastasis, and PD‐L1 expression. In addition, negative ARID1A expression was an independent predictor for recurrence‐free survival, overall survival, and positive PD‐L1 expression. Stratification based on ARID1A and PD‐L1 expression in cancer cells was also significantly associated with unfavorable outcomes. PD‐L1 protein expression levels were increased through phosphoinositide 3‐kinase/AKT signaling after ARID1A knockdown in HCC cells. HCC with ARID1A‐low expression was significantly correlated with high levels of tumor‐associated CD68‐positive macrophage. Conclusion: Our large cohort study showed that ARID1A expression in cancer cells was associated with a poor clinical outcome in patients with HCC, PD‐L1 expression in cancer cells, and tumor microenvironment. Therefore, ARID1A may be a potential molecular biomarker for the selection of patients with HCC for anti‐programmed death 1/PD‐L1 antibody therapy.

One Single Site Clinical Study: To Evaluate the Safety and Efficacy of Immunotherapy With Autologous Dendritic Cells, Cytokine-Induced Killer Cells in Primary Hepatocellular Carcinoma Patients.

Dendritic cells (DCs) and cytokine-induced killer (CIK) cells play an important role in the anti-tumor immune response. In this study, we evaluated the clinical effectiveness of DC/CIK-CD24 immunotherapies to primary hepatocellular carcinoma patients who received radical resection. 36 resected primary hepatocellular carcinoma (HCC) patients were enrolled from August 2014 to December 2015. All patients received two or four times of DC/CIK immunotherapy after radical resection. 1–4 years patients’ survival rates were evaluated during the follow-up. The 4-year survival rate of patients who received two times of immunotherapy was 47.1%, and the rate of those who received four times of immunotherapies was 52.6%. Compared to baseline, after receiving the DC/CIK-CD24 autotransfusion, the serum Treg concentration of the patients decreased, while CD3+, CD4+, CD56+ increased slightly. The adverse effect of immunotherapy was I–II° transient fever and could be tolerable. DC/CIK-CD24 immunotherapy can delay the relapse time.

Development and validation of a risk score for predicting mortality after resection of primary hepatocellular carcinoma.

Background: Primary hepatocellular carcinoma (PHCC) has a poor prognosis and high short-term mortality rate, even after resection. Thus, early diagnosis in PHCC cases can help improve quality of life via personalized management strategies.Results: The risk score system (RSS) were classified as low risk (<5 points), medium risk (5–10 points), or high risk (>10 points). The areas under the receiver operating characteristic curves were 0.80 in the training cohort and 0.69 in the validation cohort, which indicated satisfactory prognostic performance. The Hosmer-Lemeshow goodness of fit test (P>0.05) revealed consistent performance in both groups. The concordance index (C-index: 0.663, 95% CI: 0.618–0.708) revealed excellent discrimination and good calibration in the validation cohort.Conclusions: This simple RSS, which is based on clinical and laboratory data from patients undergoing resection of PHCC, might allow clinicians and medical staff to better manage PHCC.Materials and Methods: A total of 672 PHCC cases were retrospectively obtained from the First Affiliated Hospital of Wenzhou Medical University between January 2007 and February 2015. Cox proportional hazard models were used to identify independent predictors of mortality. Kaplan-Meier curves and the log-rank test were used to examine the relationships between the prognostic factors and overall mortality.

A comparative study of machine learning algorithms for predicting acute kidney injury after liver cancer resection.

ObjectiveMachine learning methods may have better or comparable predictive ability than traditional analysis. We explore machine learning methods to predict the likelihood of acute kidney injury after liver cancer resection.MethodsThis is a secondary analysis cohort study. We reviewed data from patients who had undergone resection of primary hepatocellular carcinoma between January 2008 and October 2015.ResultsThe analysis included 1,173 hepatectomy patients, 77 (6.6%) of whom had AKI and 1,096 (93.4%) who did not. The importance matrix for the Gbdt algorithm model shows that age, cholesterol, tumor size, surgery duration and PLT were the five most important parameters. Figure 1 shows that Age, tumor size and surgery duration had weak positive correlations with AKI. Cholesterol and PLT also had weak negative correlations with AKI. The models constructed by the four machine learning algorithms in the training group were compared. Among the four machine learning algorithms, random forest and gbm had the highest accuracy, 0.989 and 0.970 respectively. The precision of four of the five algorithms was 1, random forest being the exception. Among the test group, gbm had the highest accuracy (0.932). Random forest and gbm had the highest precision, both being 0.333. The AUC values for the four algorithms were: Gbdt (0.772), gbm (0.725), forest (0.662) and DecisionTree (0.628).ConclusionsMachine learning technology can predict acute kidney injury after hepatectomy. Age, cholesterol, tumor size, surgery duration and PLT influence the likelihood and development of postoperative acute kidney injury.

Effect of surgical delay on survival outcomes in patients undergoing curative resection for primary hepatocellular carcinoma

Background: There is currently conflicting evidence regarding the effect of delays from time of diagnosis to time of surgery on survival outcomes in patients with hepatocellular carcinoma (HCC). We sought to investigate the impact of time-to-surgery (TTS) on overall survival (OS) for patients who underwent curative resection for primary HCC. Conclusions: We performed a retrospective review of all patients who underwent liver resection for HCC between 2000 and 2015. We investigated the TTS on survival outcomes in the overall cohort by iteratively dichotomizing the TTS at each integer value, and computing hazard ratios at each cutoff value using a user-written STATA implementation of a previously-published R package. Optimal windows for surgery were proposed by inspecting and evaluating the time points whereby either upper or lower 95% confidence limit of hazard ratios crossed the line of no difference (ie. HR=1). Results: A total of 863 consecutive patients underwent curative liver resection for primary HCC in our institution during the study period. Median TTS was 27 days (IQR 14-42 days). In the overall patient cohort, TTS was not observed to have a significant bearing on OS. We subsequently proceeded to investigate the extent to which TTS modifies the relative hazard of death by modelling the interactions between TTS and other prognostic factors [Table 1]. For elderly patients (>70 years), patients with Child-Pugh B liver disease, ASA status 2/3, tumour size >5cm, tumour size >10cm, presence of microvascular invasion, extrahepatic invasion and satellite nodules, it was observed that the HR decreased and OS improved as TTS increased. However for patients with liver cirrhosis, multifocal tumours or portal hypertension, an increasing TTS was found to portend higher risks of death. Conclusion: Modest delays in time to surgery appear to be associated with improved survival in certain subsets of patients undergoing surgery for HCC.

Use of a Novel Index, the A-Index, and Its Associated Nomogram to Predict Overall Survival Rates after Radical Resection of Primary Hepatocellular Carcinoma

Background: Several international staging or scoring systems don't accurately predict overall survival (OS) after radical resection of primary hepatocellular carcinoma (PHCC). Therefore, we attempted to overcome this limitation by constructing a new index (the A-index) and its associated nomogram. Methods: We selected 672 patients who underwent curative resection of PHCC between January 2007 and February 2015 at the first affiliated hospital of the Wenzhou medical university. The subjects were randomly divided into the training and validation cohorts, in the ratio of 7:3. All relevant variables of the training cohort were screened using univariate and multivariate Cox analyses to obtain independent risk factors for drawing the nomogram. Receiver operating characteristics (ROC) curves were used to compare the prognostic effects of the nomogram, A-index, BCLC, Okuda, CLIP, TNM, and combined group of four systems plus A-index. Clinical utility was assessed by decision curve analysis (DCA). We prepared the nomogram using eight independent risk factors including the A-index. Findings: The nomogram showed the strongest predictive power for the 1-year, 3-year, and 5-year OS, with the area under the ROC curve being 0.8182, 0.7892, and 0.7669, respectively. Correction curves showed consistent performance for both groups, stratification of the Kaplan-Meier curve was significant, and DCA showed the superiority of nomograms considering clinical effects. Interpretation: The A-index and its nomogram can be used for predicting PHCC patient prognosis after hepatectomy, the predictive power of the nomogram integrating the A-index for OS was optimal. Funding Statement: The authors state: Not applicable. Declaration of Interests: All authors declare that they have no financial and personal relationships with other people or organizations that can inappropriately influence our work. Ethics Approval Statement: The research was approved by our hospital ethics committee. Patient consent was obtained by telephone.

A comparability study of immunohistochemical assays for PD-L1 expression in hepatocellular carcinoma

Programmed death ligand 1 (PD-L1) protein expression by immunohistochemistry is a promising biomarker for PD-1/PD-L1 blockade in hepatocellular carcinoma. There are a number of commercially available PD-L1 assays. Our study aimed to compare the analytical performance of different PD-L1 assays and evaluate the reliability of pathologists in PD-L1 scoring. Consecutive sections from tumor samples from 55 patients with surgically resected primary hepatocellular carcinoma were stained with four standardized PD-L1 assays (22C3, 28–8, SP142, and SP263). We also correlated the PD-L1 protein level by immunohistochemistry with the mRNA level of those genes associated with tumor immune microenvironment by the NanoString platform. Five pathologists independently assessed PD-L1 expression on tumor cells [tumor proportion score] together with tumor-infiltrating immune cells (combined positive score). The 22C3, 28–8, and SP263 assays had comparable sensitivity in detecting PD-L1 expression, whereas the SP142 assay was the least sensitive assay. The inter-assay agreement measured by intraclass correlation coefficients for the tumor proportion score and combined positive score were 0.646 and 0.780, respectively. The inter-rater agreement was good to excellent (the overall intraclass correlation coefficient for the tumor proportion score and combined positive score was 0.946 and 0.809, respectively). Pathologists were less reliable in scoring combined positive score than tumor proportion score, particularly when using the SP142 assay. Up to 18% of samples were misclassified by individual pathologists in comparison to the consensus score at the cutoff of combined positive score ≥ 1. The combined positive score by the 22C3 assay demonstrated the strongest correlation with immune-related gene mRNA signatures, closely followed by combined positive scores by the 28–8 and SP263 assays. In conclusion, the 22C3, 28–8, and SP263 assays are highly concordant in PD-L1 scoring and suggest the interchangeability of these three assays. Further improvement of the accuracy in assessing PD-L1 expression at a low cutoff is still necessary.

Effect of surgical delay on survival outcomes in patients undergoing curative resection for primary hepatocellular carcinoma: Inverse probability of treatment weighting using propensity scores and propensity score adjustment

BackgroundThe evidence is conflicting regarding the effect of delays from the time of diagnosis to surgery on the survival in patients with hepatocellular carcinoma. We sought to investigate the impact of time to surgery on overall survival for patients who underwent curative resection for primary hepatocellular carcinoma. MethodsWe performed a retrospective review of all patients who underwent liver resection for primary hepatocellular carcinoma between the years 2000 and 2015. Using 30-, 60-, and 90-day cutoffs, we investigated the effect of time to surgery on survival outcomes by dichotomizing the patients and using inverse probability of treatment weighting to ensure comparability. We also investigated time to surgery in prognostic subgroups by modeling the statistical interaction between time to surgery and the relevant prognostic variable in multivariable Cox models. ResultsA total of 863 patients underwent liver resection for primary hepatocellular carcinoma during the study period. Using 30-, 60-, and 90-day cutoffs, time to surgery did not have a significant bearing on overall survival. For elderly patients (>70 years), patients with Child-Pugh B liver disease, American Society of Anesthesiologists status 2/3, tumor size >5cm, tumor size ≥10cm and presence of extrahepatic invasion, hazard ratio decreased and overall survival improved as time to surgery increased. However, for patients with liver cirrhosis or portal hypertension, increasing time to surgery was found to portend higher risks of death. ConclusionTime to surgery does not have a significant bearing on overall survival, and modest delays even appear to be associated with improved survival in specific subsets of patients. The importance of these findings is that patients with hepatocellular carcinoma should be fully optimized before and not rushed to surgery because of concerns of tumor progression and a diminished survival.

Use of a novel index, the A-index, and its associated nomogram to predict overall survival rates after resection of primary hepatocellular carcinoma

BackgroundSeveral international staging or scoring systems don’t accurately predict overall survival (OS) after resection of primary hepatocellular carcinoma (PHCC). Therefore, we attempted to overcome this limitation by constructing the A-index and its associated nomogram. MethodsWe selected 672 patients who underwent curative resection of PHCC between January 2007 and February 2015 at the first affiliated hospital of the Wenzhou medical university. These subjects were randomly divided into the training (n = 470) and the validation group (n = 202) according to the ratio of 7:3. ResultsWe prepared the nomogram using eight independent risk factors including the A-index (calculated by 100 × aspartate transaminase /albumin /albumin) in the training cohort. The concordance index (C-index) of the nomogram for both training and validation set was similar in indicating the OS rate. The nomogram showed the strongest predictive power for the 1-year, 3-year, and 5-year OS, with the area under the ROC curve being 0.8182, 0.7892, and 0.7669, respectively. Correction curves showed consistent performance for both groups, stratification of the Kaplan-Meier curve was significant (P < 0.001), and decision curve analysis (DCA) showed the superiority of nomograms considering clinical effects. ConclusionsThe predictive power of the nomogram integrating the A-index for OS was optimal.

Expression and Significance of LncRNA-MINCR and CDK2 mRNA in Primary Hepatocellular Carcinoma.

To investigate the expression of long-chain non-coding RNA MINCR (LncRNAMINCR) and Cyclin-Dependent Kinase 2 (CDK2) mRNA in primary hepatocellular carcinoma, and to analyze the relationship between its expression and clinical pathological parameters and prognosis of hepatocellular carcinoma. Seventy-five surgically resected primary hepatocellular carcinoma tissues and paracancerous tissues were selected. Real-time PCR was used to detect the expression of LncRNA-MINCR and CDK2 mRNA in hepatocellular carcinoma tissues and adjacent tissues. The relationship of clinicopathological parameters and prognosis between hepatocellular carcinoma and LncRNA-MINCR and CDK2 mRNA were analyzed. Pearson correlation coefficient describes the correlation between LncRNA-MINCR and CDK2 mRNA. The expression of LncRNA-MINCR and CDK2 mRNA in primary hepatocellular carcinoma tissues was higher than that in the adjacent tissues [(5.51±0.62) vs (1.62±0.51), (4.52±0.73) vs (1.85±0.95), P<0.05]. The expression of LncRNA-MINCR in the primary hepatocellular carcinoma group was positively correlated with CDK2 mRNA (r=0.352, P<0.05), and the expression of LncRNA-MINCR in the paracancerous tissue group was not correlated with CDK2 mRNA (r=0.024, P>0.05). LncRNA-MINCR expression was associated with TNM staging, lymph node metastasis, and cirrhosis (P<0.05). CDK2 mRNA expression was associated with tumor diameter, TNM stage, lymph node metastasis, and serum alpha-fetoprotein levels (P<0.05). The 3-year survival rate of patients with high expression of LncRNAMINCR was lower than that of LncRNA-MINCR low expression group [53.49% vs 77.38%, 2=13.024, P<0.05). The 3-year survival rate of patients with high CDK2 mRNA expression was lower than that of CDK2 mRNA low expression group [51.29] % vs 80.38%, 2 = 10.15, P < 0.05]. The expression of LncRNA-MINCR and CDK2 mRNA in primary hepatocellular carcinoma tissues increased significantly. The two play a synergistic role in the invasion, invasion and metastasis of hepatocarcinoma cells. High expression of LncRNA-MINCR and CDK2 mRNA indicates poor prognosis in patients with hepatocellular carcinoma.