PIM2 Expression Induced by Proinflammatory Macrophages Suppresses Immunotherapy Efficacy in Hepatocellular Carcinoma.

Cancer immunotherapy restores or enhances the effector function of T cells in the tumor microenvironment, but the efficacy of immunotherapy has been hindered by therapeutic resistance. Here, we identify the proto-oncogene serine/threonine protein kinase PIM2 as a novel negative feedback regulator of IFNγ-elicited tumor inflammation, thus endowing cancer cells with aggressive features. Mechanistically, IL1ß derived from IFNγ-polarized tumor macrophages triggered PIM2 expression in cancer cells via the p38 MAPK/Erk and NF-κB signaling pathways. PIM2+ cancer cells generated by proinflammatory macrophages acquired the capability to survive, metastasize, and resist T-cell cytotoxicity and immunotherapy. A therapeutic strategy combining immune checkpoint blockade (ICB) with IL1ß blockade or PIM2 kinase inhibition in vivo effectively and successfully elicited tumor regression. These results provide insight into the regulatory and functional features of PIM2+ tumors and suggest that strategies to influence the functional activities of inflammatory cells or PIM2 kinase may improve the efficacy of immunotherapy. SIGNIFICANCE: Cross-talk between T cells and macrophages regulates cancer cell PIM2 expression to promote cancer aggressiveness, revealing translational approaches to improve response to ICB in hepatocellular carcinoma.

Prognostic Values of Alpha-Fetoprotein and Des-Gamma-Carboxyprothrombin in Hepatocellular Carcinoma in China: An Analysis of 4792 Patients.

BACKGROUND: The importance of alpha-fetoprotein (AFP) and des-gamma-carboxyprothrombin (DCP) in hepatocellular carcinoma (HCC) has been studied extensively in Japan, where hepatitis C virus is the predominant aetiology of HCC. The clinical profiles of HCC regarding the state of AFP and DCP in a hepatitis B virus epidemic area have not been comprehensively investigated, and the value of these tumour markers in evaluating the response to treatment and the detection of recurrence has yet to be determined. PATIENTS AND METHODS: A total of 4792 patients treated in our centre were continuously analysed regarding accessible AFP and DCP data pre- and posttreatment. Baseline characteristics were summarized, and comparisons of progression-free survival (PFS) and overall survival (OS) rates were made independently. The prognostic significance of each factor was tested with the Cox proportional hazards model. Patients who had AFP and DCP data pretreatment, pre- and posttreatment, and those who were continuously monitored more than twice were analysed separately. RESULTS: A total of 2600 patients (53.4%) were positive for AFP and DCP; 362 (7.6%) and 1211 (25.3%) patients were AFP- or DCP-positive, respectively, and 619 patients (12.9%) were negative for both AFP and DCP. Patients in the AFP single-positive or double-negative groups had the best OS (P<0.001). Patients with less than 50% responses in AFP and DCP after treatments suffered from worse prognostic survival (P<0.001). In the multivariate analysis, elevated AFP and DCP were identified as independent prognostic factors of PFS and OS. In addition, different tumour markers were related to different clinical and pathological traits. CONCLUSION: The present study comprehensively explored the clinical value of classical tumour markers for HCC using the "point-to-line" method. Positivity of pretreatment AFP and DCP or less than 50% treatment response rates exhibited more aggressive HCC, resulting in poor PFS and OS in HCC patients.

Tescalcin is an unfavorable prognosis factor that regulats cell proliferation and survival in hepatocellular carcinoma patients.

BACKGROUND: Hepatocellular carcinoma (HCC) is a major health problem and a primary cause of cancer-related death worldwide. Although great advances have achieved recently by large-scale high-throughput analysis, the precise molecular mechanism underlying HCC progression remains to be clearly elucidated. We investigated the relationship between Tescalcin (TESC), a candidate oncogene, and clinicopathological features of HCC patients and explored the role of TECS in HCC development. METHODS: To identify new genes involved in HCC development, we analyzed The Cancer Genome Atlas liver cancer database, and TESC was selected for further investigation. HCC tissue microarray analysis for TESC and its association with clinicopathological features were performed to investigate its clinical significance. TESC was knocked down by using short-hairpin RNAs. Cell proliferation was analyzed by WST-1 assay and cell counting. Cell apoptosis was tested by fluorescence-activated cell sorting. A subcutaneous xenograft tumor model in nude mice was established to determine the in vivo function of TESC. Affymetrix microarray was used to identify its molecular mechanism. RESULTS: TESC was significantly increased in HCC tissues compared with the adjacent normal liver tissues. High expression of TESC was detected in 61 of 172 HCC patients by tissue microarray. Large tumor (> 5 cm) and elevated total bilirubin were associated with high TESC expression (both P < 0.050). In multivariate analysis, TESC was identified as an independent prognostic factor for short overall survival of HCC patients. TESC knockdown impaired HCC cell growth in vitro and in vivo. TESC knockdown significantly increased cell apoptosis in HCC cell lines. Furthermore, Affymetrix microarray analysis revealed that TESC knockdown inhibited tumor proliferation-related pathways while activated cell death-related pathways. CONCLUSION: TESC was identified as an independent prognostic factor for short overall survival of HCC patients, and was critical for HCC cell proliferation and survival.

Preventive effect of celecoxib in sorafenib-related hand-foot syndrome in hepatocellular carcinoma patients, a single-center, open-label, randomized, controlled clinical phase III trial.

Skin toxicity, especially hand-foot syndrome (HFS), is one of the most common sorafenib-induced adverse events (AEs) in hepatocellular carcinoma (HCC) patients, leading to treatment interruption and failure. Mucocutaneous inflammation may cause HFS; therefore, we investigated whether celecoxib can alleviate HFS, improve patients' quality of life and increase survival when administered in conjunction with active therapy. Our randomized, open-label study prospectively enrolled 116 advanced HCC patients receiving sorafenib as targeted therapy from July 2015 to July 2016. All patients were randomly assigned (1:1) via a computer-generated sequence to receive sorafenib with or without celecoxib. Sorafenib-related AEs were recorded, Survival was compared between the two groups. Compared to the Sorafenib group, the SoraCele group had lower incidence rates of ≥ grade 2 and grade 3 HFS (63.8% vs 29.3%, P < 0.001; 19.0% vs 3.4%, P = 0.008, respectively), hair loss, rash and abdominal pain. Kaplan-Meier analysis revealed a lower risk of ≥ grade 2 HFS (HR, 0.384; P = 0.002) and a lower dose reduction/interruption rate (46.6% to 15.5%, P < 0.001) in the SoraCele group. Cox proportional hazards regression analysis demonstrated that celecoxib was the only independent predictive factor of developing ≥ grade 2 HFS (HR, 0.414; P = 0.004). Longer progression-free survival (PFS) was also observed in the SoraCele group (P = 0.039), although overall survival was not prolonged (P = 0.305). These results suggest that sorafenib + Celecoxib administration alleviated sorafenib-related skin toxicity. Longer PFS was achieved in clinical practice, although overall survival was not prolonged (ClinicalTrials.gov: NCT02961998).

Intention to control low central venous pressure reduced blood loss during laparoscopic hepatectomy: A double-blind randomized clinical trial.

BACKGROUND: Excessive intraoperative hemorrhage is a critical factor of poor prognoses after hepatectomy. Low central venous pressure during parenchymal transection is recognized to effectively reduce intraoperative hemorrhage in open procedures. However, the role of controlled low central venous pressure in laparoscopic hepatectomy is still controversial. METHODS: In the present randomized clinical trial, we set up a standard boundary of low central venous pressure according to our Pilot Study, then enrolled patients scheduled for elective laparoscopic hepatectomy and allocated them randomly to a group undergoing central venous pressure reduction by anesthesiologic interventions or a control group. The primary efficacy endpoint was total intraoperative blood loss and perioperative adverse events. Analyses were performed following the intention-to-treat principle, and patients and surgeons were blinded (ClinicalTrials.gov, Number: NCT03422913). RESULTS: Between January 2017 and October 2018, 146 out of 469 patients were randomized and eligible for inclusion in the final analyses. Based on the retrospective training cohort, we set a central venous pressure of 5 cm H2O as a cutoff value (standard low central venous pressure). Compared with patients in the control group, those in the controlled low central venous pressure group had a significantly lower central venous pressure during resection (4.83 ± 3.41 cm H2O vs 9.26 ± 3.38 cm H2O; P < .001) and significantly reduced total intraoperative blood loss (188.00 ± 162.00 mL vs 346.00 ± 336.00 mL; P < .001). The perioperative adverse events were comparable in both study groups (P = .313). CONCLUSION: The safety and efficacy of controlled low central venous pressure were demonstrated in complex laparoscopic hepatectomy for the first time by our study, and this technique is recommended to be applied routinely in laparoscopic hepatectomy.

Radiofrequency ablation versus laparoscopic hepatectomy for hepatocellular carcinoma: A real world single center study.

BACKGROUND: Both radiofrequency ablation (RFA) and laparoscopic hepatectomy (LH) are minimally invasive approach for hepatocellular carcinoma (HCC) at early stage. This study aimed to compare the efficacy of RFA and LH for treating HCC with a large cohort. METHODS: From March 2014 to July 2016, 477 patients who underwent RFA (n = 314) or LH (n = 163) for HCC tumors meeting the criteria were included. Overall survival (OS) and recurrence-free survival (RFS) were compared. Propensity score matching (PSM) was performed to balance for the factors that may affect the choice of treatment. RESULTS: Collectively, the 1-, 2- and 3-year OS rates were significantly greater after LH than RFA, as well the corresponding RFS rates, before and after PSM by 2:1. However, the RFA group had fewer major complications (P=0.004), shorter postoperative stays (P=0.023) and lower hospital charges (P<0.001) than the LH group. In the subgroup analysis, RFA demonstrated comparable RFS in treating less than 3 cm tumor (P=0.22) located in noncentral bisection (SII, SIII, SVI, SVII) and tumor between 3 cm and 5 cm (P=0.07) located in central bisections (SIV, SV, SVIII). The female, HBV infection, and RFA are factors of worse OS, and the latter two factors also indicated higher RFS. CONCLUSIONS: Though, LH possessed superior intrahepatic control rate than RFA in most condition of tumor smaller than 5 cm, the RFA could be an optimal approach achieved comparable outcomes in patients with centrally located HCC, with fewer major complications, shorter postoperative stays and lower hospital charges.

A nomogram predicting the recurrence of hepatocellular carcinoma in patients after laparoscopic hepatectomy.

BACKGROUND: Patients with hepatocellular carcinoma (HCC) undergoing surgical resection still have a high 5-year recurrence rate (~ 60%). With the development of laparoscopic hepatectomy (LH), few studies have compared the efficacy between LH and traditional surgical approach on HCC. The objective of this study was to establish a nomogram to evaluate the risk of recurrence in HCC patients who underwent LH. METHODS: The clinical data of 432 patients, pathologically diagnosed with HCC, underwent LH as initial treatment and had surgical margin > 1 cm were collected. The significance of their clinicopathological features to recurrence-free survival (RFS) was assessed, based on which a nomogram was constructed using a training cohort (n = 324) and was internally validated using a temporal validation cohort (n = 108). RESULTS: Hepatitis B surface antigen (hazard ratio [HR], 1.838; P = 0.044), tumor number (HR, 1.774; P = 0.003), tumor thrombus (HR, 2.356; P = 0.003), cancer cell differentiation (HR, 0.745; P = 0.080), and microvascular tumor invasion (HR, 1.673; P =0.007) were found to be independent risk factors for RFS in the training cohort, and were used for constructing the nomogram. The C-index for RFS prediction in the training cohort using the nomogram was 0.786, which was higher than that of the 8th edition of the American Joint Committee on Cancer TNM classification (C-index, 0.698) and the Barcelona Clinic Liver Cancer staging system (C-index, 0.632). A high consistency between the nomogram prediction and actual observation was also demonstrated by a calibration curve. An improved predictive benefit in RFS and higher threshold probability of the nomogram were determined by receiver operating characteristic curve analysis, which was also confirmed in the validation cohort compared to other systems. CONCLUSIONS: We constructed and validated a nomogram able to quantify the risk of recurrence after initial LH for HCC patients, which can be clinically implemented in assisting the planification of individual postoperative surveillance protocols.

Stereotactic Body Radiotherapy as a Salvage Therapy after Incomplete Radiofrequency Ablation for Hepatocellular Carcinoma: A Retrospective Propensity Score Matching Study.

(1) Background: To investigate the clinical outcomes between radiofrequency ablation (RFA) and stereotactic body radiotherapy (SBRT) for residual hepatocellular carcinoma (RHCC). (2) Methods: 139 patients were diagnosed with the RHCC after post-operative checkup, among whom 39 and 33 patients underwent RFA or SBRT as salvage treatments, respectively. We applied the propensity score matching (PSM) to adjust for imbalances in treatment assignment. Local disease progression, progression-free survival (PFS), overall survival (OS), and treatment-related side effects were the study endpoints. (3) Results: Before PSM, the SBRT group demonstrated significantly lower local disease progression rate (6/33 vs. 23/39; p = 0.002), better PFS (the 1- and 3-year PFS were 63.3% and 49.3% vs. 41.5% and 22.3%, respectively, p = 0.036), and comparable OS (the 1- and 3-year OS were 85.4% and 71.1% vs. 97.3% and 57.6%, respectively, p = 0.680). After PSM of 23 matched cases, the SBRT group demonstrated significantly lower local disease progression rate, better PFS and comparable OS. Centrally located tumor predicted the worse OS. No acute grade 3+ toxicity was observed in both groups. (4) Conclusion: SBRT might be the preferred treatment for RHCC, especially for patients with larger tumors or tumors abutting major vessels, rather than repeated RFA.

Assessing Hepatic Fibrosis Using 2-D Shear Wave Elastography in Patients with Liver Tumors: A Prospective Single-Center Study.

The purpose of this study was to investigate the diagnostic performance of 2-D shear wave elastography (2-D-SWE) in evaluations of liver stiffness in patients with liver tumors before resection. A total of 121 consecutive patients with hepatocellular carcinoma (HCC) (n = 93), intra-hepatic cholangiocarcinoma (n = 6), mixed hepatocellular carcinoma and intra-hepatic cholangiocarcinoma (n = 6), liver metastases (n = 10) and benign tumors (n = 6) were prospectively enrolled in this study from June 2015 to March 2016. Three valid 2-D-SWE measurements for each patient and median liver stiffness values were calculated. Fibrosis staging was evaluated according to the METAVIR scoring system. A receiver operating characteristic curve analysis was used to assess diagnostic performance. In this study, we found that median liver stiffness values were significantly higher in patients with primary liver tumors than in those with liver metastases and benign tumors (11.80 kPa vs. 5.85 kPa, p < 0.001). In addition, liver stiffness, assessed using 2-D-SWE, was highly correlated with pathologically confirmed liver fibrosis stage. Liver fibrosis stage and liver stiffness values were analyzed using Spearman's correlation (0.708, p < 0.001). The median liver stiffness values were as follows: F1, 6.7 kPa; F2, 6.33 kPa; F3, 9.2 kPa; F4, 13.7 kPa. The area under the receiver operating characteristic curves of the liver stiffness values that predicted significant fibrosis (≥F2), severe fibrosis (≥F3) and cirrhosis (=F4) were 83.5%, 91.6% and 88.1%, respectively. According to the Youden index, the optimal cutoff values for predicting significant fibrosis (≥F2), severe fibrosis (≥F3) and cirrhosis (=F4) were 7.05 kPa (sensitivity = 74.6%, specificity = 100.0%), 9.45 kPa (sensitivity = 78.8%, specificity = 100.0%) and 11.1 kPa (sensitivity = 83.1%, specificity = 89.3%), respectively. We conclude that 2-D-SWE is a useful, accurate and non-invasive method for evaluating hepatic fibrosis in patients with liver tumors adapted to hepatectomy (ClinicalTrials.gov ID: NCT02958592).

Left jackknife position: a novel position for laparoscopic hepatectomy.

BACKGROUND: Laparoscopic hepatectomy for hepatocellular carcinoma (HCC) located in segment VI, VII, or VIII of the liver is usually difficult because of poor operative exposure, due to the unique anatomical structure. In this study, we evaluated the practice of laparoscopic hepatectomy with the left jackknife position for patients with HCC located in segment VI, VII, or VIII. METHODS: A total of 10 patients were enrolled to undergo laparoscopic hepatectomy with the left jackknife position. Tumors located in segment VI, VII, or VIII were assessed by preoperative dynamic computed tomography or magnetic resonance imaging. Operation time, intraoperative blood loss, postoperative fasting time, postoperative drainage time, major postoperative complications, and duration of postoperative hospital stay were recorded. RESULTS: All surgeries were successfully completed. None of the patients required conversion to open surgery during the procedure, and no serious postoperative complications were observed. The median tumor size was 31 mm (range 23-41 mm) in diameter, the mean operation time was 166 ± 38 min, the mean intraoperative blood loss was 220 ± 135 mL, and the median postoperative hospital stay was 4 days (range 2-7 days). CONCLUSIONS: For HCC located in segment VI, VII, or VIII, laparoscopic hepatectomy with this novel position-the left jackknife position-is safe and effective during tumor resection by exposing a sufficient operating field. Trial registration ClinicalTrials.gov ID: NCT02809287.

Parecoxib prevents complications in hepatocellular carcinoma patients receiving hepatic transarterial chemoembolization: a prospective score-matched cohort study.

Transarterial chemoembolization(TACE) is the palliative treatment of choice for patients with unresectable hepatocellular carcinoma (HCC). The 242 patients prospectively enrolled in this study were diagnosed with HCC and received TACE at Sun Yat-Sen University Cancer Center between October 2014 and March 2015. Patients were divided into study and control groups based on whether parecoxib sodium was administered postoperatively. Postoperative pain, body temperature, vomiting, changes in liver function, physical activity level, length of hospital stay, and tumor control were evaluated. Compared to the control group after propensity score matching, the study group presented less severe postoperative fever. The daily maximum temperatures in the study and control groups were 37.39 vs. 37.82°C on postoperative day 1 (P < 0.001), 37.10 vs. 37.51°C on day 2 (P < 0.001), and 36.90 vs. 37.41°C on day 3 (P < 0.001). The study group also exhibited greater physical activity (P < 0.05) and had shorter hospital stays (7.21 days vs. 7.92 days, P = 0.041). There were no differences in pain scores. Thus administration of parecoxib sodium to HCC patients after TACE effectively relieved fever, promoted postoperative recovery, and shortened the hospital stay.

Prospective, single-center cohort study analyzing the efficacy of complete laparoscopic resection on recurrent hepatocellular carcinoma.

BACKGROUND: Laparoscopic hepatectomy is increasingly being used to treat hepatocellular carcinoma (HCC). However, few studies have examined the treatment of recurrent HCC in patients who received a prior hepatectomy. The present prospective study compared the clinical efficacy of laparoscopic surgery with conventional open surgery in HCC patients with postoperative tumor recurrence. METHODS: We conducted a prospective study of 64 patients, all of whom had undergone open surgery once before, who were diagnosed with recurrent HCC between June 2014 and November 2014. The laparoscopic group (n = 31) underwent laparoscopic hepatectomy, and the control group (n = 33) underwent conventional open surgery. Operation time, intraoperative blood loss, surgical margins, postoperative pain scores, postoperative time until the patient could walk, anal exsufflation time, length of hospital stay, and inpatient costs were compared between the two groups. The patients were followed up for 1 year after surgery, and relapse-free survival was compared between the two groups. RESULTS: All surgeries were successfully completed. No conversion to open surgery occurred in the laparoscopic group, and no serious postoperative complications occurred in either group. No significant difference in inpatient costs was found between the laparoscopic group and the control group (P = 0.079), but significant differences between the two groups were observed for operation time (116.7 ± 37.5 vs. 148.2 ± 46.7 min, P = 0.031), intraoperative blood loss (117.5 ± 35.5 vs. 265.9 ± 70.3 mL, P = 0.012), postoperative time until the patient could walk (1.6 ± 0.6 vs. 2.2 ± 0.8 days, P < 0.05), anal exsufflation time (2.1 ± 0.3 vs. 2.8 ± 0.7 days, P = 0.041), visual analogue scale pain score (P < 0.05), postoperative hepatic function (P < 0.05), and length of hospital stay (4.5 ± 1.3 vs. 6.0 ± 1.2 days, P = 0.014). During the 1-year postoperative follow-up period, 6 patients in each group had recurrent HCC on the side of the initial operation, but no significant difference between groups was observed in the recurrence rate or relapse-free survival. In the laparoscopic group, operation time, postoperative time until the patient could walk, anal exsufflation time, and inpatient costs were not different (P > 0.05) between the patients with contralateral HCC recurrence (n = 18) and those with ipsilateral HCC recurrence (n = 13). However, intraoperative blood loss was significantly less (97.7 ± 14.0 vs. 186.3 ± 125.6 mL, P = 0.012) and the hospital stay was significantly shorter (4.2 ± 0.7 vs. 6.1 ± 1.7 days, P = 0.021) for the patients with contralateral recurrence than for those with ipsilateral recurrence. CONCLUSIONS: For the patients who previously underwent conventional open surgical resection of HCC, complete laparoscopic resection was safe and effective for recurrent HCC and resulted in a shorter operation time, less intraoperative blood loss, and a faster postoperative recovery than conventional open surgery. Laparoscopic resection was especially advantageous for the patients with contralateral HCC recurrence.