Morphology of immune-mediated hepatitis: A comparison between immune checkpoint inhibitor therapy and combined immune checkpoint inhibitor/anti-angiogenic therapy.

BACKGROUND: The combination of immune checkpoint inhibitors (ICIs) with anti-angiogenic drugs has shown promising anticancer effects. However, ICIs can trigger immune-mediated hepatitis (IMH). We aimed to clarify whether the combined use of anti-angiogenic drugs and ICIs would increase the severity of IMH. METHODS: One hundred IMH patients (ICI monotherapy vs. ICI plus anti-angiogenic therapy 30 vs. 70) were retrospectively enrolled. Clinicopathological parameters were compared between the two groups. RESULTS: IMH mainly showed variable degrees of panlobular hepatitis (84 %), while some cases presented mixed cholangio-hepatitic (14 %) or cholangitic (2 %) pattern. The incidence of moderate-severe injury was not significantly different between the two groups (combination vs. monotherapy 38.6 % vs. 20.0 %, p = 0.109). Specifically, the rates of marked lobular injury and portal inflammation were higher in the combination group than in the monotherapy cohort (p < 0.005), while the frequencies of interface hepatitis, bile duct injury, histiocytosis aggregates, and endothelialitis were comparable between the two groups (p > 0.05). Compared to mild IMH cases, severe IMH cases showed higher immunostaining expression levels of PD-L1 (60.7 % vs. 19.4 %, p < 0.0001). Treatments and outcomes of IMH were not significantly different between the two groups (p > 0.05). CONCLUSIONS: Compared to ICI monotherapy, the administration of anti-angiogenic drugs in combination with ICIs was not associated with increased hepatotoxicity.

Radiographic and α-fetoprotein response predict pathologic complete response to immunotherapy plus a TKI in hepatocellular carcinoma: a multicenter study.

BACKGROUND: Pathologic complete response (pCR) following preoperative systemic therapy is associated with improved outcomes after subsequent liver transplant/resection in hepatocellular carcinoma (HCC). However, the relationship between radiographic and histopathological response remains unclear. METHODS: We retrospectively examined patients with initially unresectable HCC who received tyrosine kinase inhibitor (TKI) plus anti-programmed death 1 (PD-1) therapy before undergoing liver resection between March 2019 and September 2021 across 7 hospitals in China. Radiographic response was evaluated using mRECIST. A pCR was defined as no viable tumor cells in resected samples. RESULTS: We included 35 eligible patients, of whom 15 (42.9%) achieved pCR after systemic therapy. After a median follow-up of 13.2 months, tumors recurred in 8 non-pCR and 1 pCR patient. Before resection, there were 6 complete responses, 24 partial responses, 4 stable disease cases, and 1 progressive disease case, per mRECIST. Predicting pCR by radiographic response yielded an area under the receiver operating characteristic curve (AUC) of 0.727 (95% CI: 0.558-0.902), with an optimal cutoff value of 80% reduction in the enhanced area in MRI (called major radiographic response), which had a 66.7% sensitivity, 85.0% specificity, and a 77.1% diagnostic accuracy. When radiographic response was combined with α-fetoprotein response, the AUC was 0.926 (95% CI: 0.785-0.999); the optimal cutoff value was 0.446, which had a 91.7% sensitivity, 84.6%, specificity, and an 88.0% diagnostic accuracy. CONCLUSIONS: In patients with unresectable HCC receiving combined TKI/anti-PD 1 therapy, major radiographic response alone or combined with α-fetoprotein response may predict pCR.

Toripalimab combined with lenvatinib and GEMOX is a promising regimen as first-line treatment for advanced intrahepatic cholangiocarcinoma: a single-center, single-arm, phase 2 study.

Advanced intrahepatic cholangiocarcinoma (ICC) has a dismal prognosis. Here, we report the efficacy and safety of combining toripalimab, lenvatinib, and gemcitabine plus oxaliplatin (GEMOX) as first-line therapy for advanced ICC. Thirty patients with pathologically confirmed advanced ICC received intravenous gemcitabine (1 g/m2) on Days 1 and 8 and oxaliplatin (85 mg/m2) Q3W for six cycles along with intravenous toripalimab (240 mg) Q3W and oral lenvatinib (8 mg) once daily for one year. The expression of programmed death-ligand 1 (PD-L1) and genetic status was investigated in paraffin-embedded tissues using immunohistochemistry and whole-exome sequencing (WES) analysis. The primary endpoint was the objective response rate (ORR). Secondary outcomes included safety, overall survival (OS), progression-free survival (PFS), disease control rate (DCR) and duration of response (DoR). As of July 1, 2022, the median follow-up time was 23.5 months, and the ORR was 80%. Twenty-three patients achieved partial response, and one achieved complete response. Patients (21/30) with DNA damage response (DDR)-related gene mutations showed a higher ORR, while patients (14/30) with tumor area positivity ≥1 (PD-L1 staining) showed a trend of high ORR, but without significant difference. The median OS, PFS, and DoR were 22.5, 10.2, and 11.0 months, respectively. The DCR was 93.3%. Further, 56.7% of patients experienced manageable grade ≥3 adverse events (AEs), commonly neutropenia (40.0%) and leukocytopenia (23.3%). In conclusion, toripalimab plus lenvatinib and GEMOX are promising first-line regimens for the treatment of advanced ICC. A phase-III, multicenter, double-blinded, randomized study to validate our findings was approved by the National Medical Products Administration (NMPA, No. 2021LP01825).Trial registration Clinical trials: NCT03951597.

Gene-based cancer-testis antigens as prognostic indicators in hepatocellular carcinoma.

Cancer/testis antigens (CTAs) are reproductive tissue-restricted genes, frequently ectopic expressed in tumors. CTA genes associate with a poor prognosis in some solid tumors, due to their potential roles in the tumorigenesis and progression. However, whether CTAs relate with hepatocellular carcinoma (HCC) remains unclear. In this study, the prognostic signatures based on CTA genes were investigated and validated in three cohorts including Chinese HCC patients with hepatitis B virus infection (CHCC-HBV), International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA) cohorts. Univariate, LASSO, and multivariate Cox regression analyses were used to screen prognostic genes and develop the prognostic gene signature. A prognosis model was established with six CTA genes (SSX1, CTCFL, OIP5, CEP55, NOL4, and TPPP2) in CHCC-HBV cohort, and further validated in the ICGC and TCGA cohorts. The CTA signature was an essential prognostic predictor independent of other clinical pathological factors. High-risk group exhibited up-regulated cell cycle-related and tumor-related pathways and more M0 macrophage, activated mast cell, activated memory CD4+ T cell, and memory B cell infiltration. Furthermore, CTA signature correlated with the sensitivity to multiple chemotherapy drugs. Our results highlighted that the CTA gene profiling was a prognostic assessment tool for HCC patients.

Hepatectomy After Conversion Therapy Using Tyrosine Kinase Inhibitors Plus Anti-PD-1 Antibody Therapy for Patients with Unresectable Hepatocellular Carcinoma.

BACKGROUND: Combined treatment with tyrosine kinase inhibitors (TKI) plus anti-PD-1 antibodies showed high anti-tumor efficacy and made conversion resection possible for patients with unresectable hepatocellular carcinoma (HCC). However, long-term survival has not been reported. METHODS: A cohort of consecutive patients who received combined TKI/anti-PD-1 antibodies as first-line treatment for initially unresectable HCC at the authors' hospital between August 2018 and September 2020 was eligible for this study. Patients who were responding to systemic therapy and met the criteria for hepatectomy underwent liver resection with curative intention. The study also investigated the association of clinical factors with successful conversion resection and postoperative recurrence. RESULTS: The study enrolled 101 patients including 24 patients (23.8 %) who underwent R0 resection a median of 3.9 months (interquartile range: 2.5-5.9 months) after initiation of systemic therapy. Patients with an Eastern cooperative oncology group performance status of 0, fewer intrahepatic tumors, or a radiographic response to systemic therapy were more likely to be able to receive curative resection. After a median follow-up period of 21.5 months, hepatectomy was independently associated with a favorable overall survival (hazard ratio [HR], 0.050; 95 % confidence interval [CI], 0.007-0.365; P = 0.003). For the 24 patients who underwent surgery, the 12-month recurrence-free survival and overall survival rates were respectively 75% and 95.8%. Achieving a pathologic complete response (n = 10) to systemic therapy was associated with a favorable recurrence-free survival after resection, with a trend toward significance (HR, 0.345; 95% CI, 0.067-1.785; P = 0.187). CONCLUSIONS: Selected patients with initially unresectable HCC can undergo hepatectomy after systemic therapy with combined TKI/anti-PD-1 antibodies. In this study, conversion resection was associated with a favorable prognosis.

Anti-PD-1 antibodies plus lenvatinib in patients with unresectable hepatocellular carcinoma who progressed on lenvatinib: a retrospective cohort study of real-world patients.

Background: Lenvatinib, a multi-targeted tyrosine kinase inhibitor (TKI), has proven efficacy as the first-line treatment for patients with advanced hepatocellular carcinoma (HCC). However, there is no standard effective second-line treatment option following progression on lenvatinib therapy. Because of the comprehensive coverage of therapeutic targets of lenvatinib, the remission rate of other TKI treatments in HCC patients resistant to lenvatinib is quite low. Methods: In this study, the effectiveness and safety of anti-programmed cell death protein-1 (PD-1) antibodies plus lenvatinib were assessed in 46 patients between April 2018 and April 2020 at the Zhongshan Hospital, Fudan University, by retrospectively reviewing their clinical data. Patients with unresectable HCC who progressed on lenvatinib were given standard doses of lenvatinib and anti-PD-1 antibodies. They were followed-up every 6-8 weeks with medical imaging and laboratory tests and treatment-related adverse reactions were investigated. Results: The objective response and the disease control rates were 23.9% (11/46) and 71.7% (33/46), respectively by Response Evaluation Criteria in Solid Tumours 1.1 (RECIST). After a median follow-up period of 15.6 [interquartile range (IQR), 11.2-22.0] months, the median progression-free survival (PFS) and overall survival (OS) were 6.9 months [95% confidence interval (CI): 2.1-11.8] and 14.5 months (95% CI: 6.8-22.3), respectively. The most common treatment-related adverse events were anorexia (43.5%), hypothyroidism (43.5%), hypertension (36.9%), fatigue (34.8%), and diarrhea (26.1%). Grade 3/4 events occurred in 16 patients (34.8%). Emotional functioning and overall quality of life were improved significantly following the initiation of anti-PD-1 antibodies plus lenvatinib therapy (fatigue, 4.9±7.5 vs. 11.1±12.7, P=0.03; diarrhea, 12.3±20.9 vs. 18.5±16.8, P=0.01; pain, 5.5±10.3 vs. 11.1±13.9, P=0.01). Conclusions: The combination of anti-PD-1 antibodies and lenvatinib may benefit patients with unresectable HCC who progressed on lenvatinib. This study provides a real-world data and treatment choice for patients progressed with lenvatinib.

Expression and Clinical Significance of MPS-1 in Hepatocellular Carcinoma.

PURPOSE: Ribosomal protein metallopanstimulin-1 (MPS-1) is implicated in tumorigenesis. However, to date, the underlying role of MPS-1 in the generation, progression and prognosis of hepatocellular carcinoma (HCC) remains unknown. This study aims to investigate the expression of MPS-1 in HCC and its significance for the prognosis of HCC. METHODS: The Oncomine and GEPIA databases were used to analyze the expression pattern of MPS-1 in HCC. Immunohistochemical staining was performed on tissue microarrays containing 169 HCC tissue samples to examine the expression of MPS-1. In addition, univariate and multivariate Cox regression analyses and Kaplan-Meier analysis were used to verify the correlation between clinicopathological factors in HCC patients and its clinical prognostic significance. RESULTS: MPS-1 was more highly expressed in HCC than in normal tissues, and MPS-1 expression was correlated with serum AFP levels (P = 0.003), liver cirrhosis (P = 0.024), tumor embolus (P = 0.009) and tumor recurrence (P < 0.003). MPS-1 was an independent prognostic factor for the overall survival of HCC (HR, 1.92; 95% CI, 1.01-3.68), and a higher expression of MPS-1 predicted poorer survival. Furthermore, high expression of MPS-1 indicated a poor prognosis in patients with AFP positivity, cirrhosis or HBsAg positivity. CONCLUSION: These findings demonstrate that MPS-1 is highly expressed in HCC and serves as an independent prognostic marker, highlighting the potential role of MPS-1 as a novel biomarker and therapeutic target for HCC.

Development of a Prognostic Scoring System for Hepatocellular Carcinoma Patients With Main Portal Vein Tumor Thrombus Undergoing Conventional Transarterial Chemoembolization: An Analysis of 173 Patients.

BACKGROUND: Patients with hepatocellular carcinoma (HCC) with main portal vein tumor thrombus (mPVTT) have poor prognosis. Promising systemic therapies, such as target therapies, have limited benefits. The purpose of this study is to retrospectively evaluate the benefits of conventional TACE (c-TACE) and to establish a prognostic stratification of HCC patients with mPVTT. METHODS: This is a single center retrospective study conducted over 5 years (duration of performing c-TACE), on consecutive HCC patients with mPVTT receiving c-TACE. Univariable and multivariable analysis were used to explore factors independently associated with overall survival (OS). Based on Cox-regression analysis, prognostic models were developed and internally validated by bootstrap methods. Discrimination and performance were measured by Akaike information criterion, concordance index, and likelihood ratio test. RESULTS: A total of 173 patients were included. Median OS was 6.0 months (95%CI: 3.92~8.08). The independent variables correlated with survival were largest tumor diameter, tumor number, mPVTT extension, and AFP. In the final model, patients were assigned 2 points if largest tumor diameter ≥8 cm, or tumor number ≥2, 1point if main trunk was complete obstructed, or AFP ≥400 ng/ml. By summing up these points, patients were divided into three risk groups according to the score at the 15rd and 85th percentiles, in which median OS were 18, 7, and 3.5months, respectively (p<0.001). The model shown optimal discrimination, performance, and calibration. CONCLUSIONS: c-TACE could provide survival benefits in HCC patients with mPVTT and the proposed prognostic stratification may help to identify good candidates for the treatment, and those for whom c-TACE may be futile.

Downstaging and Resection of Initially Unresectable Hepatocellular Carcinoma with Tyrosine Kinase Inhibitor and Anti-PD-1 Antibody Combinations.

BACKGROUND: Combined therapy with tyrosine kinase inhibitors (TKIs) and anti-PD-1 antibodies has shown high tumor response rates for patients with unresectable hepatocellular carcinoma (HCC). However, using this treatment strategy to convert initially unresectable HCC to resectable HCC was not reported. METHODS: Consecutive patients with unresectable HCC who received first-line therapy with combined TKI/anti-PD-1 antibodies were analyzed. Tumor response and resectability were evaluated via imaging every 2 months (±2 weeks) using RECIST v1.1. Resectability criteria were (1) R0 resection could be achieved with sufficient remnant liver volume and function; (2) intrahepatic lesions were evaluated as partial responses or stable disease for at least 2 months; (3) no severe or persistent adverse effects occurred; and (4) hepatectomy was not contraindicated. RESULTS: Sixty-three consecutive patients were enrolled. Of them, 10 (15.9%) underwent R0 resection in 3.2 months (range: 2.4-8.3 months) after the initiation of combination therapy. At baseline, these 10 patients had a median largest tumor diameter of 9.3 cm, 7 had Barcelona Clinic Liver Cancer stage C (vascular invasion) disease, 2 had stage B, and 1 had stage A. Before surgery, 6 patients were evaluated as a partial response, 3 stable disease, and 1 partial response in the intrahepatic lesion but a new metastatic lesion in the right adrenal gland. Six patients (60%) achieved a pathological complete response. One patient died from immune-related adverse effects 2.4 months after hepatectomy. After a median follow-up of 11.2 months (range: 7.8-15.9 months) for other 9 patients, 8 survived without disease recurrence, and 1 experienced tumor recurrence. CONCLUSIONS: Combination of TKI/anti-PD-1 antibodies is a feasible conversion therapy for patients with unresectable HCC to become resectable. This study represents the largest patient cohort on downstaging role of combinational systemic therapy on TKI and PD-1 antibody for HCC.

Organ specific responses to first-line lenvatinib plus anti-PD-1 antibodies in patients with unresectable hepatocellular carcinoma: a retrospective analysis.

BACKGROUND: We evaluated organ-specific response rates (OSRRs) to first-line lenvatinib plus anti-PD-1 antibodies in patients with advanced hepatocellular carcinoma (HCC). METHODS: This retrospective analysis included Chinese patients with unresectable/advanced HCC who received first-line lenvatinib (8 mg/day) plus ≥3 infusions of anti-PD-1 antibodies between October 2018 and May 2020. Tumor and macrovascular tumor thrombi (MVTT) treatment responses were evaluated every 2 months using RECIST v1.1. The overall response rate (ORR)/OSRR was defined as the percentage of patients with a best overall response of complete or partial response (CR or PR). RESULTS: In total, 60 patients were included in the analysis; 96.7% had measurable intrahepatic lesions, 55% had MVTT and 26.7% had extrahepatic disease. In all 60 patients, the ORR was 33.3%, median progression-free survival was 7.0 months (95% CI, 1.7-12.3) and median overall survival was not reached. The OSRR for MVTT (54.5%) was higher versus intrahepatic tumors (32.8%), extrahepatic lung metastases (37.5%) and lymph node metastases (33.3%). Among 33 patients with intrahepatic tumors and MVTT, 18 had differential responses in each site, including 13 with a better response in MVTT versus intrahepatic lesions. Among 18 patients whose MVTT achieved a radiographic CR or PR, six underwent surgical resection: 4/6 achieved a pathological CR in MVTT and 2/6 in the intrahepatic tumor. CONCLUSIONS: First-line lenvatinib plus anti-PD-1 antibodies resulted in better tumor responses in MVTT versus intrahepatic lesions. Complete MVTT necrosis may allow downstaging and subsequent eligibility for surgical resection in a proportion of patients with advanced HCC.

Hepatic Arterial Infusion Chemotherapy with Modified FOLFOX as an Alternative Treatment Option in Advanced Hepatocellular Carcinoma Patients with Failed or Unsuitability for Transarterial Chemoembolization.

OBJECTIVE: This study aimed to assess the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC) with modified FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin) as an alternative treatment option in advanced hepatocellular carcinoma (HCC) patients with failed or unsuitability for transarterial chemoembolization (TACE). MATERIALS AND METHODS: From September 2018 to January 2020, 87 advanced HCC patients who progressed on TACE or were not eligible for TACE received HAIC treatment with modified FOLFOX. The primary endpoint was overall survival (OS) and secondary endpoints included progression-free survival (PFS), tumor response assessed by Response Evaluation Criteria in Solid Tumors 1.1, and adverse events graded according to CTCAE 5.0. Based on prognostic factors determined by multivariate analysis, a nomogram was developed to predict patient survival. RESULTS: The median OS and PFS were 9.0 months (95%CI 7.6-10.4) and 3.7 months (95%CI 3.1-4.3), respectively. The objective response rate was 13.8%, with a disease control rate of 48.3%. Grade 3 adverse events were observed, such as infection (9.2%), thrombocytopenia (5.7%), hyperbilirubinemia (3.4%), abdominal pain (2.3%) and alanine aminotransferase increase (2.3%). Albumin, AST, and extrahepatic metastasis were incorporated to construct a new nomogram that could stratify patients into three prognostic subgroups, including low-, intermediate-, and high-risk groups, with significant differences in 9-month OS rates (71%, 42% and 6%, respectively; p< 0.001). The nomogram was better than the Okuda, AJCC, and CLIP staging systems for OS prediction. CONCLUSION: These findings support the feasibility of HAIC with modified FOLFOX as an alternative treatment strategy for advanced HCC when TACE is ineffective or unsuitable.

A new prediction model for prognosis of patients with intermediate-stage HCC after conventional transarterial chemoembolization: an internally validated study.

Purpose: The prognosis of patients with intermediate-stage hepatocellular carcinoma (HCC) treated by conventional TACE (cTACE) is greatly heterogeneous. This study aimed to develop a new survival prediction model to help select patients who would benefit better from cTACE treatment. Methods: We collected data of 848 treatment-naïve patients with BCLC B HCC who received cTACE as first-line therapy. The prognostic model's variables were derived from univariate and multivariate Cox regression analyses. The concordance index (C-statistic) calculated through cross-validation and bootstrap resampling was used for the model selection. The calibration of our final prediction model was also assessed. Results: The model showed a better discrimination ability than Bolondi's BCLC B1-B4 subclassification to predict the prognosis of BCLC B patients (C-statistic, 0.66 vs. 0.60; difference, 0.05, 95% CI, 0.03-0.07). In cross-validation, bootstrap resampling demonstrated that the model maintained sufficiently discriminant (an average of C-statistic, 0.66; 95% CI, 0.65-0.68). The model calibration was accurate in predicting survival of patients matched well with the observed outcomes. On the basis of the improved survival of 18 months or more as the responding patient, the observations of patients in each response category (responder and non-responder) were fair-moderately matched with those predicted by the model (κ=0.40, P<0.001). Conclusions: Based on clinically available features of patient, tumor and liver function, we developed an alternative prediction model with better performance than the Bolondi's substaging system for intermediate HCC patients after cTACE, which could help define the distinct subgroup of BCLC B patients who are suitable for cTACE treatment.

Adjuvant Transarterial Chemoembolization for HBV-Related Hepatocellular Carcinoma After Resection: A Randomized Controlled Study.

Purpose: The survival of patients with hepatocellular carcinoma (HCC) recurrence after curative resection is usually poor. We sought to evaluate the safety and efficacy of adjuvant transarterial chemoembolization (TACE) in HBV-related HCC patients with an intermediate (a single tumor larger than 5 cm without microvascular invasion) or high risk (a single tumor with microvascular invasion, or two or three tumors) of recurrence.Experimental Design: In this randomized phase 3 trial, 280 eligible patients were assigned to adjuvant TACE (n = 140) or no adjuvant treatment (control; n = 140) groups. The primary endpoint was recurrence-free survival (RFS); secondary endpoints included overall survival (OS) and safety. Multivariable Cox-proportional hazards model was used to determine the independent impact of TACE on patients' outcomes.Results: Patients who received adjuvant TACE had a significantly longer RFS than those in the control group [56.0% vs. 42.1%, P = 0.01; HR, 0.68; 95% confidence interval (CI), 0.49-0.93]. Patients in the adjuvant TACE group had 7.8% higher 3-year OS rate than the control group (85.2% vs. 77.4%; P = 0.04; HR, 0.59; 95% CI, 0.36-0.97). The impact of adjuvant TACE on RFS and OS remained significant after controlling for other known prognostic factors (HR, 0.67; P = 0.01 for RFS; and HR, 0.59; P = 0.04 for OS). There was no grade 3 or 4 toxicity after adjuvant TACE.Conclusions: For patients with HBV-related HCC who had an intermediate or high risk of recurrence after curative hepatectomy, our study showed adjuvant TACE significantly reduced tumor recurrence, improved RFS and OS, and the procedure was well tolerated. Clin Cancer Res; 24(9); 2074-81. ©2018 AACR.

Hepatitis B surface antigen predicts recurrence after radiofrequency ablation in patients with low hepatitis B virus loads.

Radiofrequency ablation (RFA) is a first-line option for the treatment of small liver cancers, but the recurrence remains a problem affecting long-term survival. Hepatitis B virus (HBV) activity is associated with the prognosis of hepatocellular carcinoma (HCC). We investigated the significance of hepatitis B surface antigen (HBsAg) in HCC recurrence after curative RFA treatment in HBV-related small HCC.We enrolled 404 HBV-related patients with small HCC (≤3 cm) who underwent curative RFA. We used univariate and multivariate analyses to investigate the baseline levels of HBsAg, in addition to other known risk factors for HCC recurrence, for association with HCC tumor recurrence after curative RFA.The overall 1-, 2-, and 3-year recurrence-free survival (RFS) rates were 75%, 50%, and 34%, respectively. The median recurrence-free time was 25 months. The level of HBsAg was an independent risk factor for recurrence in patients with lower HBV-DNA levels. In hepatitis Be antigen (HBeAg)-negative patients, the 1-, 2-, and 3-year RFS rates were 79%, 64%, and 44%, respectively, for that with low HBsAg levels, compared with 73%, 50%, and 37%, respectively, for that with high HBsAg levels (P = .039).HBsAg might serve as a valuable marker to evaluate the risk of HCC recurrence in HBeAg-negative patients with low HBV viral load.

High platelet counts increase metastatic risk in huge hepatocellular carcinoma undergoing transarterial chemoembolization.

AIM: Accumulating evidence suggests platelets play critical roles in tumor metastasis. Moreover, the role of platelets in metastasis is partially correlated with inflammation. However, evidence regarding the contribution of platelets to hepatocellular carcinoma (HCC) metastasis is lacking. This study investigated the association between platelets and metastatic risk in HCC. METHODS: We used huge HCC (diameter over 10 cm), a tumor subgroup with a strong inflammatory background, as a model to evaluate the potential predictive role of platelets and platelet-related biomarkers for metastasis in HCC patients undergoing transarterial chemoembolization. A logistic regression model was used to analyze risk factors for metastasis. RESULTS: Patients with huge HCC (n = 178) were enrolled, and 24.7% (44/178) of patients had remote metastases after treatment. Univariate analyses showed high platelet counts (P = 0.012), pretreatment platelet-to-lymphocyte ratios (pre-PLR) of 100 or more (P = 0.018) and post-PLR of 100 or more (P = 0.013) were potential risk factors for metastasis. Furthermore, multivariate analyses showed high platelet counts (odds ratio, 2.18; 95% confidence interval, 1.074-4.443; P = 0.031) and platelet-related biomarkers were independent risk factors for HCC metastasis. Particularly, the risk of metastasis in patients with high post-PLR values was significantly greater than patients with low post-PLR values. For tumor response and survival, patients with high platelet counts had faster disease progression (P = 0.002) and worse survival (P < 0.0001). CONCLUSION: High platelet counts increase the extrahepatic metastasis risk of huge HCC undergoing chemoembolization, which supply clinical verification of the association between high platelet counts and HCC metastasis.

Caveolin-1 Confers Resistance of Hepatoma Cells to Anoikis by Activating IGF-1 Pathway.

BACKGROUND/AIMS: Anoikis resistance is a prerequisite for hepatocellular carcinoma (HCC) metastasis. The role of Caveolin-1 (CAV1) in anoikis resistance of HCC remains unclear. METHODS: The oncogenic effect of CAV1 on anchor-independent growth and anoikis resistance was investigated by overexpression and knockdown of CAV1 in hepatoma cells. IGF-1 pathway and its downstream signals were detected by immunoblot analysis. Caveolae invagination and IGF-1R internalization was studied by electron microscopy and (125)I-IGF1 internalization assay, respectively. The role of IGF-1R and tyrosine-14 residue (Y-14) of CAV1 was explored by deletion experiment and mutation experiment, respectively. The correlation of CAV1 and IGF-1R was further examined by immunochemical analysis in 120 HCC specimens. RESULTS: CAV1 could promote anchor-independent growth and anoikis resistance in hepatoma cells. CAV1-overexpression increased the expression of IGF-1R and subsequently activated PI3K/Akt and RAF/MEK/ERK pathway, while CAV1 knockdown showed the opposite effect. The mechanism study revealed that CAV1 facilitated caveolae invagination and (125)I-IGF1 internalization. IGF-1R deletion or Y-14 mutation reversed CAV1 mediated anchor-independent growth and anoikis resistance. In addition, CAV1 expression was positively related to IGF-1R expression in human HCC tissues. CONCLUSION: CAV1 confers resistance of hepatoma cells to anoikis by activating IGF-1 pathway, providing a potential therapeutic target for HCC metastasis.

Imbalance in systemic inflammation and immune response following transarterial chemoembolization potentially increases metastatic risk in huge hepatocellular carcinoma.

Inflammation plays a critical role in tumor metastasis. However, few inflammation-related biomarkers are currently available to predict the risk of metastasis for advanced hepatocellular carcinoma (HCC). Using huge tumors (diameter >10 cm) as a model, we evaluated the potential risk of pre- and post-treatment inflammatory responses in the development of metastasis of HCC patients undergoing transarterial chemoembolization (TACE). A logistic regression model was used to analyze the risk factors. One hundred and sixty-five patients with huge HCC were enrolled in the study. Metastases were identified in 25.5% (42/165) patients by imaging evaluation post-TACE. Neutrophils increased, whereas lymphocytes decreased significantly post-TACE. Univariate analysis showed that high post-treatment neutrophil-to-lymphocyte ratio (NLR; p = 0.003), low post-treatment lymphocyte count (p = 0.047), and high baseline NLR (p = 0.100) were potential risk factors for metastasis. Further, multivariate analysis showed that high post-treatment NLR, but not pre-treatment NLR, was an independent risk factor for metastasis; this was confirmed by receiver operating characteristic curve analysis. Post-treatment NLR, however, had no correlation to tumor response and overall survival of patients. In conclusion, post-treatment NLR but not pre-treatment NLR independently increases the risk of metastasis in huge HCC. Our findings suggest the potential contribution of treatment-related inflammation to metastasis in advanced HCC.

Oxaliplatin and 5-fluorouracil hepatic infusion with lipiodolized chemoembolization in large hepatocellular carcinoma.

AIM: To investigate transarterial chemoembolization (TACE) with hepatic infusion of oxaliplatin and 5-fluorouracil and Lipiodol chemoembolization in large hepatocellular carcinoma (HCC). METHODS: In this retrospective study, 132 patients with unresectable HCCs larger than 10 cm were treated with hepatic infusion of oxaliplatin and 5-fluorouracil followed by Lipiodol chemoembolization. The primary endpoint was overall survival (OS). Sixteen-week disease-control rate, time to progression (TTP), and major complications were also studied. Univariate and multivariate analyses were performed to identify prognostic factors affecting OS and TTP. RESULTS: A total of 319 procedures were performed in the 132 patients. Eleven (8.3%) patients received radical resection following TACE treatment (median time to initial TACE 4.3 ± 2.3 mo). The median OS and TTP were 10.3 and 3.0 mo respectively, with a 50.0% 16-wk disease-control rate. Major complications were encountered in 6.0% (8/132) of patients following TACE and included serious jaundice in 1.5% (2/132) patients, aleukia in 1.5% (2/132), and hepatic failure in 3.0% (4/132). One patient died within one month due to serious hepatic failure and severe sepsis after receiving the second TACE. The risk factor associated with TTP was baseline alpha-fetoprotein level, and vascular invasion was an independent factor related to OS. CONCLUSION: Hepatic infusion of oxaliplatin and 5-fluorouracil followed by lipiodolized-chemoembolization is a safe and promising treatment for patients with HCCs larger than 10 cm in diameter.

The platelet-to-lymphocyte ratio predicts poor survival in patients with huge hepatocellular carcinoma that received transarterial chemoembolization.

Inflammation is particularly strong in huge hepatocellular carcinoma (HCC). However, it is unclear whether the platelet-to-lymphocyte ratio (PLR), as an inflammatory-related marker, can predict survival of patients with huge HCC. In this study, we enrolled 291 patients with huge HCC (diameter over 10 cm) who were undergoing repeated transarterial chemoembolization (TACE) at our institute. The baseline PLR was calculated from complete serum blood counts before the first chemoembolization. We found that a baseline PLR cutoff value over 150 best predicted huge HCC survival. The 12, 24, and 36 months survival rates in the high PLR group (22.6, 8.1, and 4.1 %, respectively) were significantly lower than in the low PLR group (35.6, 22.4, and 14 %, respectively). Thus, a significant difference was found in overall survival (log-rank test, p < 0.0001). Univariate analyses indicated a high PLR (p < 0.0001) was predictor of poor survival, and multivariate Cox analyses further showed that a high PLR (p = 0.002) was an independent factor that predicted worse survival. In conclusion, for patients with huge HCC, a high baseline PLR is a useful predictor of poor survival in patients undergoing chemoembolization. Additional anti-inflammatory or anti-platelet treatments, in combination with TACE, may improve survival in HCC patients with high PLR.