Prognostic implications of alpha-fetoprotein and C-reactive protein elevation in hepatocellular carcinoma following resection (PACE): a large cohort study of 2770 patients.

BACKGROUND: Routine clinical staging for hepatocellular carcinoma (HCC) incorporates liver function, general health, and tumor morphology. Further refinement of prognostic assessments and treatment decisions may benefit from the inclusion of tumor biological marker alpha-fetoprotein (AFP) and systemic inflammation indicator C-reactive protein (CRP). METHODS: Data from a multicenter cohort of 2770 HCC patients undergoing hepatectomy were analyzed. We developed the PACE risk score (Prognostic implications of AFP and CRP Elevation) after initially assessing preoperative AFP and CRP's prognostic value. Subgroup analyzes were performed in BCLC cohorts A and B using multivariable Cox analysis to evaluate the prognostic stratification ability of the PACE risk score and its complementary utility for BCLC staging. RESULTS: Preoperative AFP ≥ 400ng/mL and CRP ≥ 10 mg/L emerged as independent predictors of poorer prognosis in HCC patients who underwent hepatectomy, leading to the creation of the PACE risk score. PACE risk score stratified patients into low, intermediate, and high-risk groups with cumulative 5-year overall (OS) and recurrence-free survival (RFS) rates of 59.6%/44.9%, 43.9%/38.4%, and 20.6%/18.0% respectively (all P < 0.001). Increased PACE risk scores correlated significantly with early recurrence and extrahepatic metastases frequency (all P < 0.001). The multivariable analysis identified intermediate and high-risk PACE scores as independently correlating with poor postoperative OS and RFS. Furthermore, the PACE risk score proficiently stratified the prognosis of BCLC stages A and B patients, with multivariable analyses demonstrating it as an independent prognostic determinant for both stages. CONCLUSION: The PACE risk score serves as an effective tool for postoperative risk stratification, potentially supplementing the BCLC staging system.

Somatostatin Octapeptide Inhibits Cell Invasion and Metastasis in Hepatocellular Carcinoma Through PEBP1.

BACKGROUND/AIMS: Hepatocellular carcinoma (HCC) is a major threat to human health. The condition carries a high risk of death; 45% of new cases occur in China. Surgical resection is the first choice for treatment of HCC, but 30.9% of patients experience recurrence within 6 months after the operation. To improve patient survival, we must determine how to reduce the probability of recurrence and metastasis and elucidate the underlying mechanism of disease. We therefore studied the effect of somatostatin octapeptide (octreotide) on the invasion and metastasis of HCC. METHODS: The migration and invasion cytological tests were used to detect the effect of octreotide on liver cancer cells (SK-Hep-1 and HepG2). PEBP1 RNAi was used to knockdown expression. Invasion and metastasis were measured with transwell migration and wound-healing assays. Western blotting was used to detect changes in levels of PEBP1 and invasion pathway proteins after octreotide treatment. The effect of octreotide was studied in vivo by establishing a pulmonary metastasis model using SK-Hep-1 cells in nude mice. In-vivo bioluminescence imaging and hematoxylin and eosin staining of lung tissue were used to verify the results. RESULTS: Increasing concentrations of octreotide were progressively more effective in halting the invasion and metastasis of liver cancer cells. Octreotide may upregulate PEBP1, TIMP-2, and E-cadherin while downregulating MMP-2 and Twist to inhibit cell invasion and metastasis. And downregulation of PEBP1 would also change the expression of MMP-2, TIMP-2 and Twist. The in-vivo experiments showed no cancer cell metastasis in 4 of the 6 mice in the octreotide-treatment group, while all of the mice in the control group displayed pulmonary metastasis of human HCC cells. And the survival period of the mice in the octreotide-treatment group was significantly prolonged. CONCLUSIONS: Octreotide may weaken invasion and metastasis through the upregulation of PEBP1. Octreotide may reduce the risk of recurrence and metastasis after surgery for liver cancer.

Prognostic implications of preoperative, postoperative, and dynamic changes of alpha-fetoprotein and des-gamma (γ)-carboxy prothrombin expression pattern for hepatocellular carcinoma after hepatic resection: a multicenter observational study.

Background: The utility of pre- and post-operative alpha-fetoprotein (AFP) and des-gamma (γ)-carboxy prothrombin (DCP) expression patterns and their dynamic changes as predictors of the outcome of hepatic resection for hepatocellular carcinoma (HCC) has yet to be well elucidated. Methods: From a multicenter database, AFP and DCP data during the week prior to surgery and the first post-discharge outpatient visit (within 1-2 months after surgery) were collected from patients with HCC who underwent hepatectomy. AFP-DCP expression patterns were categorized according to the number of positive tumor markers (AFP ≥ 20ng/mL, DCP ≥ 40mAU/mL), including double-negative, single-positive, and double-positive. Changes in the AFP-DCP expression patterns were delineated based on variations in the number of positive tumor markers when comparing pre- and post-operative patterns. Results: Preoperatively, 53 patients (8.3%), 337 patients (52.8%), and 248 patients (38.9%) exhibited double-negative, single-positive, and double-positive AFP-DCP expression patterns, respectively. Postoperatively, 463 patients (72.6%), 130 patients (20.4%), and 45 patients (7.0%) showed double-negative, single-positive, and double-positive AFP-DCP expression patterns, respectively. Survival analysis showed a progressive decrease in recurrence-free (RFS) and overall survival (OS) as the number of postoperative positive tumor markers increased (both P < 0.001). Multivariate analysis showed that postoperative AFP-DCP expression pattern, but not preoperative AFP-DCP expression pattern, was an independent risk factor for RFS and OS. Further analysis showed that for patients with positive preoperative markers, prognosis gradually improves as positive markers decrease postoperatively. In particular, when all postoperative markers turned negative, the prognosis was consistent with that of preoperative double-negative patients, regardless of the initial number of positive markers. Conclusions: AFP-DCP expression patterns, particularly postoperative patterns, serve as vital sources of information for prognostic evaluation following hepatectomy for HCC. Moreover, changes in AFP-DCP expression patterns from pre- to post-operation enable dynamic prognostic risk stratification postoperatively, aiding the development of individualized follow-up strategies.

Serum alpha-fetoprotein response as a preoperative prognostic indicator in unresectable hepatocellular carcinoma with salvage hepatectomy following conversion therapy: a multicenter retrospective study.

Background: This study evaluates the efficacy of alpha-fetoprotein (AFP) response as a surrogate marker for determining recurrence-free survival (RFS) in patients with unresectable hepatocellular carcinoma (uHCC) who undergo salvage hepatectomy following conversion therapy with tyrosine kinase inhibitor (TKI) and anti-PD-1 antibody-based regimen. Methods: This multicenter retrospective study included 74 patients with uHCC and positive AFP (>20 ng/mL) at diagnosis, who underwent salvage hepatectomy after treatment with TKIs and anti-PD-1 antibody-based regimens. The association between AFP response-defined as a ≥ 80% decrease in final AFP levels before salvage hepatectomy from diagnosis-and RFS post-hepatectomy was investigated. Results: AFP responders demonstrated significantly better postoperative RFS compared to non-responders (P<0.001). The median RFS was not reached for AFP responders, with 1-year and 2-year RFS rates of 81.3% and 70.8%, respectively. In contrast, AFP non-responders had a median RFS of 7.43 months, with 1-year and 2-year RFS rates at 37.1% and 37.1%, respectively. Multivariate Cox regression analysis identified AFP response as an independent predictor of RFS. Integrating AFP response with radiologic tumor response facilitated further stratification of patients into distinct risk categories: those with radiologic remission experienced the most favorable RFS, followed by patients with partial response/stable disease and AFP response, and the least favorable RFS among patients with partial response/stable disease but without AFP response. Sensitivity analyses further confirmed the association between AFP response and improved RFS across various cutoff values and in patients with AFP ≥ 200 ng/mL at diagnosis (all P<0.05). Conclusion: The "20-80" rule based on AFP response could be helpful for clinicians to preoperatively stratify the risk of patients undergoing salvage hepatectomy, enabling identification and management of those unlikely to benefit from this procedure.

Perioperative safety, oncologic outcome, and risk factors of salvage liver resection for initially unresectable hepatocellular carcinoma converted by transarterial chemoembolization plus tyrosine kinase inhibitor and anti-PD-1 antibody: a retrospective multicenter study of 83 patients.

BACKGROUND: To assess the perioperative safety, oncological outcomes, and determinants influencing the oncological outcomes of salvage liver resection for initially unresectable hepatocellular carcinoma (HCC) rendered resectable through transarterial chemoembolization (TACE) combined with tyrosine kinase inhibitors (TKIs) and anti-PD-1 antibodies (α-PD-1). METHODS: We retrospectively reviewed data from 83 consecutive patients across six tertiary hospitals who underwent salvage liver resection for initially unresectable HCC following conversion by TACE combined with TKIs and α-PD-1, emphasizing perioperative and oncological outcomes. Multivariate Cox regression analysis was employed to discern independent risk factors for postoperative recurrence-free survival (RFS). RESULTS: The median operative duration was 200 min, with a median blood loss of 400 ml. Intraoperative blood transfusions were necessitated for 27 patients. The overall perioperative complication rate was 48.2%, with a major complication rate of 16.9%. One patient died during the perioperative period due to postoperative liver failure. During the median follow-up period of 15.1 months, 24 patients experienced recurrence, with early and intrahepatic recurrence being the most common. Seven patients died during follow-up. Median RFS was 25.4 months, with 1- and 2-year RFS rates of 68.2% and 61.8%, respectively. Median overall survival was not reached, with 1- and 2-year overall survival rates of 92.2% and 87.3%, respectively. Multivariate Cox regression analysis revealed that pathological complete response (pCR) and intraoperative blood transfusion served as independent prognostic determinants for postoperative RFS. CONCLUSIONS: Our study provides preliminary evidence suggesting that salvage liver resection may be an effective and feasible treatment option for patients with unresectable HCC who achieve resectability after conversion therapy with TACE, TKIs, and α-PD-1. The perioperative safety of salvage liver resection for these patients was manageable and acceptable. However, further research, particularly prospective comparative studies, is needed to better evaluate the potential benefits of salvage liver resection in this patient population.

Association of hepatitis B virus DNA levels with efficacy and safety outcomes in patients with hepatitis B virus-associated advanced hepatocellular carcinoma receiving tyrosine kinase inhibitor plus anti-PD-1 antibody: a multicenter propensity-matched study.

BACKGROUND: The efficacy and safety of tyrosine kinase inhibitors (TKIs) combined with anti-PD-1 antibodies (α-PD-1) in advanced hepatocellular carcinoma (HCC) with high hepatitis B virus (HBV) DNA levels (>500 IU/mL) remain unclear. METHODS: We retrospectively assessed patients from seven medical institutions diagnosed with HBV-related HCC, undergoing treatment with TKIs and α-PD-1 in conjunction with antiviral therapies. Based on HBV-DNA levels, patients were categorized into either high (HHBV-DNA, >500 IU/mL) or low HBV-DNA (LHBV-DNA, ≤500 IU/mL) cohorts Propensity score matching (PSM) was used to minimize baseline imbalance between groups. RESULTS: 149 patients were included, with 66 patients exhibiting HBV-DNA > 500 IU/mL and 83 patients presenting HBV-DNA ≤ 500 IU/mL. Compared with the LHBV-DNA cohort, the HHBV-DNA cohort had a greater incidence of serum HBeAg positivity, tumor diameter ≥ 10 cm, and vascular invasion. Following PSM, 57 individuals were enrolled in each group. Oncological outcomes were comparable between HHBV-DNA and LHBV-DNA cohorts before and after PSM. Before PSM, the median PFS and OS were 6.1 months and 17.5 months in the HHBV-DNA cohort and 6.7 months and 19.3 months in the LHBV-DNA cohort (all P > 0.05). After PSM, the median PFS and OS were 6.0 months and 19.5 months in the HHBV-DNA cohort and 6.0 months and 17.1 months in the LHBV-DNA cohort, respectively (all P > 0.05). Safety profiles were equivalent across cohorts with no fatal incidents reported. Seven patients (4.7 %) had HBV reactivation. 1 (0.7 %) from HHBV-DNA and 6 (4.0 %) from LHBV-DNA (P = 0.134). Only one patient developed HBV-related hepatitis. CONCLUSIONS: The effectiveness and safety of TKIs plus α-PD-1 in advanced HCC with HBV-DNA > 500 IU/mL were not compromised in the context of concomitant antiviral therapy.

[The effect of different hepatic vascular exclusion for massive hemorrhage in hepatectomy].

OBJECTIVE: To analyze the effect of different hepatic vascular exclusions for massive hemorrhage in hepatectomy. METHODS: The clinical data of 2238 cases with hepatectomy treated from January 1995 to August 2009 was analyzed retrospectively in the cause of massive hemorrhage (blood loss ≥ 1000 ml), blood loss during liver resection and massive hemorrhage incidence with different methods of hepatic vascular exclusion. RESULTS: Among 2238 cases received hepatectomy, 215 cases (9.6%) had massive hemorrhage because of portal vein tumor thrombus extraction (26.0%), extensive adhesions around the tumor (24.7%), section of liver hemorrhage (23.7%), hepatic vascular injury (15.8%), and tumor rupture (9.8%). Among 2182 cases received hepatectomy without portal vein tumor thrombus extraction, 159 cases (7.3%) had massive hemorrhage, 1257 cases (57.6%) which blood loss were less than 400 ml. Hepatectomy with different hepatic vascular exclusion methods had different blood loss and massive hemorrhage incidence. CONCLUSION: Pringle combined with clamping infrahepatic vena cava method and the liver double-hanging maneuver through the retrohepatic avascular tunnel on the right of the inferior vena cava method can reduce blood loss and massive hemorrhage incidence in hepatectomy more effectively, especially for huge liver tumor resection.

[Study on virtual liver surgery planning applied to hepatic resection].

OBJECTIVE: To evaluate the impact of preoperative three-dimensional visualization and virtual liver surgery planning on hepatic resection. METHODS: All relevant structures (livers, portal vein, hepatic veins, and tumors) were extracted from multislice CT scans of 142 cases treated from May 2007 to May 2009. By the liver surgery planning system software Liv 1.0, reconstruction and image analysis of the relevant structures was performed and virtual resections of liver were carried out. Data were correlated to intraoperative findings. RESULTS: (1) Three-dimensional visualization revealed the spatial relationship of tumors to the intrahepatic vascular system, thus giving impressions how the neoplasms were situated. Virtual tumor resections corresponded to the intraoperative findings. (2) With the planning, an intended resection could be performed virtually and optimal identification of resection margins could be achieved. The ischemia and congestion territory within the remaining liver parenchyma could be calculated. Simulation resections could avoid liver parenchyma over resection and maintain a sufficient amount of liver tissue to sustain hepatic function. Virtual simulations of tumor resection were used successfully to plan of surgical procedures in the hepatic tumors. Hepatectomy was performed in 29 cases after virtual tumor resections but seemed impossible with conventional CT scan. Resection plans of 92 cases were optimized after virtual resections. (3) The mean liver volume of patients with primary hepatocellular carcinoma measured by the software and the real resected was (477 +/- 223) ml and (451 +/- 209) ml respectively. Comparison by means of linear regression analysis between volume measurement on the software and the real resected showed a nearly ideal correlation coefficient (R = 0.922, P < 0.01). The mean error was 6.1%. CONCLUSIONS: The three-dimensional tumor visualization and virtual simulation of tumor resections of the software Liv 1.0 provide an important reference for a valuable planning of complex hepatic resections. It is not only benefit to improve the predictability and security of hepatectomy but also helpful to improve the success rate of complex hepatic resections.

Down-regulation of the gax gene in smooth muscle cells of the splenic vein of portal hypertension patients.

BACKGROUND: The expression of gax, an anti-proliferative homeobox gene, is rapidly down-regulated in vascular smooth muscle cells (VSMCs) following arterial injury. Whether the down-regulation of gax is involved in modulating the proliferation of smooth muscle cells of the splenic vein in patients with portal hypertension has not yet been elucidated. The aim of this study was to investigate the expression of the mRNA of the gax gene in smooth muscle cells of the splenic vein in patients with portal hypertension. METHODS: Reverse transcriptase polymerase chain reaction (RT-PCR) was used to detect the expression of gax mRNA and immunohistochemistry staining was performed to demonstrate the expression of PCNA protein in the splenic veins of 28 patients with portal hypertension and those of 12 normal controls. This study was approved by the Institutional Ethics Committee and informed consent was obtained from all participants. RESULTS: RT-PCR showed that the expression of gax mRNA was PCNA-positive and negative in the splenic vein of patients with portal hypertension (1.08+/-0.04 and 1.39+/-0.27, respectively). There was a significant difference in the 28 patients compared with the 12 normal controls (P<0.01). The relative expression of PCNA protein in the vascular tissues was significantly higher in the experimental group than in the control group. CONCLUSIONS: Down-regulation of gax mRNA and the overexpression of PCNA protein were seen in smooth muscle cells of the splenic vein in patients with portal hypertension, regulating the proliferation, migration and phenotypic change and resulting in remodelling of the splenic vein, which may play an important role in the pathogenesis and maintenance of portal hypertension.