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Background & Aims: Hepatocellular carcinoma (HCC) is a fatal disease characterized by vast molecular heterogeneity. Although major advances in tumour genetics has led to the identification of new biomarkers, the prognosis of patients with HCC remains dismal. Methods: Quantitative reverse‐transcription polymerase chain reaction (qRT‐PCR) and western blot (WB) were used to evaluate meiosis‐specific nuclear structural 1 (MNS1) expression in HCC cells. Immunohistochemistry staining was used to evaluate MNS1 expression in HCC tissues. Clinical significance of MNS1 was evaluated by Cox regression analysis. Transwell assays were conducted to assess cells migration ability. Cell counting kit‐8 and colony formation assays were performed to detect cells proliferation ability. NOD/SCID/γc(null) (NOG) mice model was adopted to investigate functions of MNS1 in vivo. Results: The expression of MNS1, which is elevated in most HCC tissues, correlated with poor survival in HCC patients. Functional experiments revealed the oncogenic role of MNS1, which promotes HCC growth and metastasis through AKT‐dependent modulation of β‐catenin. β‐Catenin expression was crucial for MNS1's oncogenic effects. MNS1 indirectly translocated β‐catenin from the cytoplasm to the nucleus via the MNS1‐GSK3β axis. Conclusions: MNS1 promotes HCC growth and metastasis via activating PI3K/AKT signalling and may serve as an important prognostic biomarker as well as potential novel therapeutic target for HCC. [ABSTRACT FROM AUTHOR]

Background: Postoperative extrahepatic metastases (EHM) contribute to a grim outcome in patients with hepatocellular carcinoma (HCC) who are undergoing curative surgical resection. The current study investigated the clinical value of circulating tumor cells (CTCs) in predicting EHM after curative surgery. Methods: A total of 197 patients with HCC who were undergoing curative surgical resection were assigned to a retrospective training cohort (144 patients) or a prospective validation cohort (53 patients). The CELLSEARCH system was used for the detection of CTCs prior to surgical resection and 1 month thereafter. The cutoff value of CTCs was estimated using receiver operating characteristic analysis. Bonferroni correction was applied for multiple testing in a Cox proportional hazards regression model. Results: In the training cohort, EHM was found to be associated with a higher postoperative CTC burden compared with no EHM (mean: 4.33 vs 0.52; P <.001). Receiver operating characteristic analysis demonstrated a postoperative CTC count ≥3 as the optimal cutoff value for the prediction of EHM. Patients with a postoperative CTC count ≥3 experienced a higher EHM risk (56.3% vs 5.5%) and a shorter median overall survival (31.25 months vs not reached) (all P <.001). The prognostic significance of a postoperative CTC count ≥3 also applied to patient subgroups with a low EHM risk, such as those with an α‐fetoprotein level ≤400 ng/mL, absence of vascular invasion, well differentiation, and early tumor stage, and its predictive value was retained in patients with a continuous normal α‐fetoprotein level during postoperative follow‐up (all P <.05). The results were confirmed in the validation cohort. Conclusions: A postoperative CTC count ≥3 appears to be a surrogate marker for the prediction of EHM after curative surgical resection of HCC. More careful surveillance should be recommended to patients with a high CTC load to ensure the greater possibility of early interventions for postoperative EHM. A postoperative circulating tumor cell (CTC) count ≥3 is a surrogate marker for the prediction of extrahepatic metastases after curative surgical resection of hepatocellular carcinoma. A more careful surveillance of metastatic spread should be recommended to patients with a high CTC load after hepatectomy. [ABSTRACT FROM AUTHOR]

Using a method optimized in hepatocellular carcinoma (HCC), we established patient‐derived xenograft (PDX) models with an increased take rate (42.2%) and demonstrated that FBS +10% dimethyl sulfoxide exhibited the highest tumor take rate efficacy. Among 254 HCC patients, 103 stably transplantable xenograft lines that could be serially passaged, cryopreserved and revived were established. These lines maintained the diversity of HCC and the essential features of the original specimens at the histological, transcriptome, proteomic and genomic levels. Tumor engraftment was associated with lack of encapsulation, poor tumor differentiation, large size and overexpression of cancer stem cell biomarkers, and was an independent predictor for overall survival and tumor recurrence after resection. To confirm the preclinical value of the PDX model in HCC treatment, several antitumor agents were tested in 16 selected PDX models. The results revealed a high degree of pharmacologic heterogeneity in the cohort, as well as heterogeneity to different agents in the same individual. The sorafenib responses observed between HCC patients and the corresponding PDXs were also consistent. After molecular characterization of the PDX models, we explored the predictive markers for sorafenib response and found that mitogen‐activated protein kinase kinase kinase 1 (MAP3K1) might play an important role in sorafenib resistance and sorafenib response is impaired in patients with MAP3K1 downexpression. Our results indicated that PDX models could accurately reproduce patient tumors biology and could aid in the discovery of new treatments to advance in precision medicine. What's new? Patient‐derived xenografts (PDX) models offer a promising preclinical tool. Here, the authors established the largest bank of hepatocellular carcinoma (HCC) PDX models with a high and stable tumor take rate that recapitulated the key clinical and molecular characteristics of primary tumors. The tumor take rate was associated with expression of cancer stem cell proteins, lack of tumor encapsulation, poor differentiation, advanced stage, overall survival, and time to recurrence in patients. The models were used to identify MAP3K1 expression as an indicator of patient response to sorafenib treatment. PDX models are valuable surrogates for HCC patients and could facilitate translational research. [ABSTRACT FROM AUTHOR]

Background: Portal vein tumor thrombus (PVTT) is a common complication in hepatocellular carcinoma (HCC), signaling dismal outcomes. This study was conducted to evaluate the survival benefit of postoperative portal vein perfusion chemotherapy (PVC) in patients with HCC and PVTT. Methods: A retrospective review was conducted in 401 consecutive patients with HCC and PVTT who underwent hepatic resection between January 2009 and December 2015 and 67 patients received adjuvant postoperative PVC. A propensity score matching (PSM) was used to match patients with and without PVC at a ratio of 1:1. Results: After PSM, the median time to recurrence (TTR) and overall survival (OS) were significantly longer in PVC group compared with control group (12.3 vs 5.8 months, P = .001; 19.0 vs 13.4 months, P = .037; respectively). At 1, 2, 3, and 5 years, the cumulative recurrence rates in PVC group were 48.1%, 86.5%, 92.3% ,96.2%, respectively, with OS rates of 63.8%, 37.9%, 24.4%, 18.3%, respectively; whereas cumulative recurrence rates of 76.6%, 91.5%, 94.3%, and 97.2%, respectively and OS rates of 55.4%, 23.0%, 12.4%, and 12.4%, respectively were recorded for the control group. In multivariate analysis, postoperative PVC emerged as a significant predictor for TTR (hazard ratio [HR], 0.523; P = .001) and OS (HR, 0.591; P = .010). PVC could reduce early recurrence (≤1 year) rate after surgical resection (40.3% vs 64.2%, P = .006) and clinical outcomes were further enhanced by adding sorafenib to postoperative PVC. Conclusions: Compared with surgical resection alone, postoperative adjuvant PVC treatment boosts survival and reduces early tumor recurrences in patients surgically treated for HCC and PVTT. [ABSTRACT FROM AUTHOR]

Interleukin‐35 (IL‐35) is implicated in tumorigenesis, but its exact impact on intrahepatic cholangiocarcinoma (ICC) is not clear. The aim of the present study was to explore the specific effect of IL‐35 on patient prognosis. Additionally, we formulated an effective prognostic nomogram for ICC patients after curative resection. Immunohistochemistry was applied to explore IL‐35 expression as well as IL‐35 receptor (IL‐35R) in 102 ICC patients. Results showed that IL‐35 was highly expressed in ICC tumor tissues and was positively associated with lymph node metastasis (LNM), TNM stage and vascular invasion and was an independent prognostic factor for patients' overall survival (OS) and recurrence‐free survival (RFS). High expression of IL‐35R (gp130 and IL‐12Rβ2) was also observed in ICC cancer tissues, but only gp130 was an independent prognostic factor for OS and RFS and was indispensable in IL‐35‐mediated ICC clinical prognosis. The nomogram comprising carcinoembryonic antigen, LNM, IL‐35 and gp130 expression achieved better predictive accuracy compared with TNM stage for OS. Our data support that high IL‐35 expression correlates with ICC aggressiveness and emerges as a valuable biomarker for evaluating ICC progression and prognosis in clinical work. [ABSTRACT FROM AUTHOR]

Aim Myeloid-derived suppressor cells (MDSCs) play an important role in tumor progression. The aim of the present study was to investigate the prognostic value of MDSCs for early recurrence of hepatocellular carcinoma (HCC) in patients undergoing curative resection. Methods Myeloid-derived suppressor cells were measured by flow cytometry. The correlation between MDSCs and tumor recurrence was analyzed using a cohort of 183 patients who underwent curative resection between February 2014 and July 2015. Prognostic significance was further assessed using Kaplan-Meier survival estimates and log-rank tests. Results In vivo, CD14+HLA-DR−/low MDSCs inhibit T cell proliferation and secretion. The frequency of CD14+HLA-DR−/low MDSCs was significantly higher in HCC patients (3.7 ± 5.3%, n = 183) than in chronic hepatitis patients (1.4 ± 0.6%, n = 25) and healthy controls (1.1 ± 0.5%, n = 50). High frequency of MDSCs was significantly correlated with recurrence (time to recurrence) ( P < 0.001) and overall survival ( P = 0.034). Patients with HCC in the high MDSC group were prone to more vascular invasion ( P = 0.018) and high systemic immune-inflammation index (SII) ( P = 0.009) than those in the low MDSC group. Scatter-plot analyses revealed a significant positive correlation between the SII level and the frequency of MDSCs ( r = 0.188, P = 0.011). Patients with HCC with a high MDSC frequency and high SII level had significantly shorter time to recurrence ( P < 0.001) and overall survival ( P = 0.028) than those with a low MDSC frequency and low SII. Conclusions An increased frequency of MDSCs was correlated with early recurrence and predicted the prognosis of patients with HCC undergoing curative resection. The HCC patients with high frequency of MDSCs should be provided more advanced management and frequent monitoring. [ABSTRACT FROM AUTHOR]

Background & Aims Previous studies predicted the prognosis of hepatocellular carcinoma ( HCC) mainly based on tumour-related factors, whereas the impacts of hepatitis B virus ( HBV)-related factors are usually ignored. The objective of this exploratory study was to investigate the prognostic role of hepatitis B core antibody ( HBcAb) on post-operative survival and recurrence of HCC. Methods A retrospective analysis of 3388 HBsAg positive ( HBV-related) HCC patients treated by curative resection was performed. Multivariate analysis of independent prognostic factors was performed by Cox proportional hazards regression model. Results HBcAb positivity was an independent prognostic factor for recurrence-free survival ( RFS) of HBV-related patients ( P < 0.001, HR: 1.723, 95% CI: 1.278-2.324), and the 1-, 3-, 5-year RFS rates for HBcAb-negative patients were significantly better than those of HBcAb-positive patients (92.5%, 72.1% and 65.9% vs 77.9%, 58.6% and 46.9%, P < 0.001). HBcAb-positive HCC was much bigger ( P = 0.006), more often involved with vascular invasion ( P = 0.001), elevated AFP ( P = 0.001) and ALT ( P = 0.046) levels, but less often involved with capsule formation ( P = 0.034). Besides vascular invasion, tumour size, interferon-α treatment, AFP and GGT level, HBcAb positivity was an independent prognostic factor for early intrahepatic recurrence of HBV-related patients ( P = 0.025, HR: 1.766, 95% CI: 1.073-2.907) and the majority of HBcAb-positive recurrence were early recurrence while most of HBcAb-negative recurrence were late recurrence ( P = 0.004). Conclusion Positive HBcAb may represent a more invasive phenotype of HBV-related HCC, and is associated with a higher risk of early intrahepatic recurrence and poorer RFS of HBV-related patients after curative resection. [ABSTRACT FROM AUTHOR]

Atypical chemokine receptors ( ACRs) have been discovered to participate in the regulation of tumour behaviour. Here we report a tumour-suppressive role of a novel ACR member, CC chemokine receptor like 1 ( CCRL1), in human hepatocellular carcinoma ( HCC). Both mRNA and protein expressions of CCRL1 correlated with the malignant phenotype of HCC cells and were significantly down-regulated in tumour tissue compared with paired normal liver tissue. In both the initial and validation cohorts ( n = 240 and n = 384, respectively), CCRL1 deficiency was associated with advanced tumour stage and was an independent index for worse survival and increased recurrence. Furthermore, knock-down or forced expression of CCRL1 revealed that CCRL1 suppressed the proliferation and invasion of HCC cells in vitro and reduced tumour growth and lung metastasis in vivo, with depressed levels of CCL19 and CCL21. By sequestrating CCL19 and CCL21, CCRL1 reduced their binding to CCR7 and consequently mitigated the detrimental impact of CCR7, including Akt- GSK3β pathway activation and nuclear accumulation of β-catenin in tumour cells. Clinically, the prognostic value of the CCR7 expression in HCC depended on the expression level of CCRL1, suggesting that CCRL1 may serve as an upstream switch for the CCR7 signalling cascade. Together, our findings suggest that CCRL1 impairs chemotactic events associated with CCR7 in the progression and metastasis of HCC. Our results also show a potential interplay between typical and atypical chemokine receptors in human cancer. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Circulating microRNAs are promising biomarkers for non-invasive testing and dynamic monitoring in cancer patients. However, no consensus exists regarding the normalization of circulating microRNAs in the quantification, making the results incomparable. We investigated global circulating microRNA profiles to identify a stable endogenous control for quantifying circulating microRNAs using three cohorts ( n = 544), including 168 control individuals (healthy subjects and those with chronic hepatitis B and cirrhosis) and 376 cancer patients (hepatocellular, colorectal, lung, esophageal, gastric, renal, prostate, and breast cancer patients). GeNorm, NormFinder, and coefficient of variability (CV) were used to select the most stable endogenous control, whereas Ingenuity Pathway Analysis (IPA) was adopted to explore its signaling pathways. Seven candidates (miR-1225-3p, miR-1228, miR-30d, miR-939, miR-940, miR-188-5p, and miR-134) from microarray analysis and four commonly used controls (miR-16, miR-223, let-7a, and RNU6B) from literature were subjected to real-time quantitative reverse transcription-polymerase chain reaction validation using independent cohorts. MiR-1228 (CV = 5.4%) with minimum M value and S value presented as the most stable endogenous control across eight cancer types and three controls. IPA showed miR-1228 to be involved extensively in metabolism-related signal pathways and organ morphology, implying that miR-1228 functions as a housekeeping gene. Functional network analysis found that 'hematological system development' was on the list of the top networks that associate with miR-1228, implying that miR-1228 plays an important role in the hematological system. The results explained the steady expression of miR-1228 in the blood. In conclusion, miR-1228 is a promising stable endogenous control for quantifying circulating microRNAs in cancer patients. [ABSTRACT FROM AUTHOR]

Background & Aims Prognostic factors and adjuvant therapy of intrahepatic cholangiocarcinoma ( ICC) after curative resection were not clear. We aim to analyse prognostic factors after curative resection and evaluate adjuvant therapy and survival based on the new staging system. Methods A retrospective analysis of 283 patients who underwent surgical exploration for ICC was performed. Staging was performed according to the 7th edition AJCC staging manual. Univariate and multivariate analyses were used to evaluate independent prognostic factors. Results The difference for OS at different TNM stages after R0 resection was significant ( P < 0.001). Despite regional lymph node metastasis, tumour number and vascular invasion, serum GGT level was also an independent prognostic factor for OS of patients after R0 resection. The incidence of biliary and vascular invasion was significantly higher in high GGT group than in normal GGT group. Factors predictive of recurrence were multiple tumours and regional lymph node metastasis. After R0 resection, adjuvant TACE not only did not improve the OS of patients at TNM stage I ( P = 0.508), but significantly promoted recurrence of these patients ( P = 0.006). Only patients at TNM stage II, III and IV benefited from adjuvant TACE for longer survival, while the recurrence rates were not affected. Conclusions The new staging system can predict the survival of ICC patients after R0 resection. High GGT level may be suggestive of biliary and vascular invasion and was an independent risk factor for OS after R0 resection. Adjuvant TACE may be indicated only for patients at advanced stages for better survival. [ABSTRACT FROM AUTHOR]

Background and Aim Regulatory T cells ( Treg) play a vital role in immunosuppressive crosstalk; however, Tregs from different locations lead to different clinical outcomes. Our aim was, therefore, to compare the prevalences and suppressive phenotypes of Tregs in the peripheral blood, peritumor, and intratumor of patients with hepatocellular carcinoma ( HCC). Methods The frequencies and phenotypes of CD4+ CD25+ CD127low/− CD49d− Tregs in the periphery, peritumor, and intratumor of 78 HCC patients and 12 healthy controls were evaluated by flow cytometry. Treg-cell suppressive activity was determined using an in vitro CD154 expression assay. Tregs from tumor and paired peritumor were then hybridized using an Agilent whole genome oligo microarray, and selected genes were validated by real-time polymerase chain reaction. Functional analysis of the microarray data was performed using Kyoto Encyclopedia of Genes and Genomes and Gene Ontology analyses. Results Intratumoral Tregs exhibited higher frequencies and more suppressive phenotypic functions than those in peritumor and periphery, whereas there was no difference between the latter two. Functional analysis showed that complement cascades, p53, and glycosylphosphatidylinositol-anchor biosynthesis pathways were significantly upregulated in intratumoral Tregs; the salivary secretion pathway was significantly downregulated in intratumoral Tregs, and immune cells and tumor-immuno-related Gene Ontology terms were significantly affected. Conclusions Tregs in different locations exhibited different functional statuses. A higher prevalence and more suppressive phenotype suggested a critical role for intratumoral Tregs in the formation of multicellular immunosuppressive networks. HCC immunotherapy may be improved, therefore, by specific locational Tregs elimination or suppression. [ABSTRACT FROM AUTHOR]

BACKGROUND: Dickkopf-related protein 1 (DKK1) has been reported involved in metastasis and invasion in several tumors. This study sought to investigate the prognostic value of DKK1 in intrahepatic cholangiocarcinoma (ICC) and its role in promoting ICC metastasis. METHODS: Tissue microarrays of 138 ICC patient samples were employed to detect DKK1, vascular endothelial growth factor C (VEGF-C), and matrix metalloproteinase 9 (MMP9) expression using immunohistochemistry. The prognostic significances were assessed by Kaplan-Meier survival estimates. DKK1 expression was measured in an ICC cell line (HCCC-9810) and ICC tissues by immunofluorescence assay, quantitative real-time polymerase chain reaction, and western blot. Serum levels of DKK1 from 37 ICC patients were tested by enzyme-linked immunosorbent assay. The role of DKK1 in proliferation, migration, invasion, and gene expression regulation was assessed by DKK1 depletion using small interfering RNA. RESULTS: Multivariate analyses revealed that DKK1 was an unfavorable predictor for overall survival and time to recurrence. The prognostic significance was retained in ICC patients with low recurrence risk ( P < .05). DKK1 expression was elevated in an ICC cell line, tumor samples, and patient sera. High levels of DKK1 in ICC tissues correlated with elevated MMP9, VEGF-C, and metastasis of hepatic hilar lymph nodes. DKK1 depletion caused a decrease in cell migration and invasiveness, and down-regulation of MMP9 and VEGF-C expression. CONCLUSIONS: DKK1 is a novel prognostic biomarker for ICC, and it enhances tumor cell invasion and promotes lymph node metastasis of ICC through the induction of MMP9 and VEGF-C. DKK1 may be a potential therapeutic target for ICC. Cancer 2013. © 2012 American Cancer Society. [ABSTRACT FROM AUTHOR]

BACKGROUND: Although the incidence of hepatitis B virus surface antigen (HBsAg)-negative/hepatitis C virus antibody (HCVAb)-negative hepatocellular carcinoma (NBNC-HCC) is gradually increasing, it has been mostly ignored in previous studies. The objective of this exploratory study was to investigate the clinicopathologic characteristics and prognostic factors that influence recurrence and survival in patients with NBNC-HCC. METHODS: A retrospective analysis was performed of 675 patients with NBNC-HCC and 3529 patients with HBsAg-positive/HCVAb-negative HCC (BNC-HCC) who underwent curative resection between 1997 and 2009. Intrahepatic recurrences were classified into early (≤1 year) and late (>1 year) recurrences. Multivariate competing risks analyses with Bonferroni correction were used to evaluate independent prognostic factors. RESULTS: There were no significant differences between the NBNC-HCC and BNC-HCC groups regarding overall survival, cumulative incidence of HCC-specific death, and recurrence. However, the patients with NBNC-HCC were much older ( P < .001), were associated less often with cirrhosis or elevated α-fetoprotein levels ( P < .001), and had a much lower ratio of men to women ( P < .001). NBNC-HCC tumors were larger ( P < .001), but were involved less often with vascular invasion ( P = .004). Women, serum γ-glutamyl transpeptidase level, tumor size, tumor capsule, and tumor differentiation were identified as independent risk factors for HCC-specific survival in patients with NBNC-HCC. The cumulative incidence of HCC-specific death for women with NBNC-HCC was significantly greater than for men with NBNC-HCC ( P < .001).Tumor capsule and vascular invasion were identified as independent risk factors for early recurrence of NBNC-HCC, whereas tumor differentiation was identified as the only significant risk factor for late recurrence. CONCLUSIONS: Patients who had NBNC-HCC had characteristics and prognostic factors that differed from those in patients who had BNC-HCC. Women with NBNC-HCC should be more closely monitored, and it may be worthwhile to evaluate estrogen administration for the maintenance of sex hormone balance and to improve these poor outcomes. Cancer 2013. © 2012 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background and Aim: The high expression of the galectin-1 predicts poor patient outcome in several tumors. The aim of this study was to investigate its prognostic value in patients with hepatocellular carcinoma (HCC) after resection. Methods: Galectin-1 and tumor-infiltrating FoxP3+ regulatory T cells (Tregs) were validated by tissue microarrays from HCC patients ( n = 386) and statistically assessed for correlations with the clinical profiles and the prognosis of the patients. Results: We found that galectin-1, which was prevalently upregulated in HCC, was significantly associated with tumor invasive characteristics (such as vascular invasion, incomplete encapsulation, poor differentiation, multiple number, and large tumor size). Patients with high galectin-1 expression had a significantly poorer tumor recurrence ( P = 0.025) and overall survival ( P = 0.021) than those with low galectin-1 expression. Even in early-stage disease, high galectin-1 expression was also independently associated with shortened survival ( P < 0.001) and increased tumor recurrence ( P = 0.005). Multivariate Cox proportional hazards analysis showed that galectin-1 was an independent marker for predicting the poor prognosis of HCC. The galectin-1 level was positively related to the number of tumor-infiltrating FoxP3+ Tregs ( r = 0.416, P < 0.001), and their combination served as a better prognosticator. The postoperative tumor recurrence and survival of HCC patients with galectin-1high and FoxP3high were significantly poorer than the other groups (both P < 0.001). Conclusions: Galectin-1 might be a new prognostic factor for HCC after resection and could potentially be a high-priority therapeutic target. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma ( HCC) is a typical inflammation-related malignancy characterized by high postoperative recurrence and metastasis. Although several inflammatory cells and inflammatory signatures have been linked to poor prognosis, the inflammation-associated molecular mechanisms of HCC development and progression are largely unknown. Here we show that triggering receptor expressed in myeloid cells ( TREM)-1, a transmembrane receptor expressing in myeloid cells, was also expressed in tumor-activated hepatic stellate cells ( HSCs) and associated with the aggressive behavior of HCC cells. Enzyme-linked immunosorbent assay was used to measure the expression levels of soluble TREM-1 (s TREM-1) in activated hepatic stellate cells supernatant and 92 preoperative and postoperative plasmas of patients with malignancy and/or benign liver tumor/disease, respectively. Expression levels of TREM-1 were assessed by immunohistochemistry in tissue microarray from 240 patients with HCC. As a result, increased secretion of s TREM-1 from activated HSCs was observed after co-culture with HCC cell lines ( P < 0.001), and conditioned medium collected from activated HSCs/cancer associated myofibroblasts (CAMFs) with or without agonist/inhibitor of TREM-1 significantly changed the migratory ability of HCC cells. The levels of s TREM-1 were significantly higher in patients with HCC than those with benign liver tumors ( P < 0.005). Peritumoral density of TREM-1 was shown to be an independent prognosis predictor according to univariate ( P < 0.001 for both overall survival and time to recurrence) and multivariate analysis ( P = 0.008 for overall survival; P = 0.005 for time to recurrence). Thus, these observations suggest that TREM-1 is related to the aggressive tumor behavior and has potential value as a prognostic factor for HCC. ( Cancer Sci 2012; 103: 984-992) [ABSTRACT FROM AUTHOR]

The tumor stroma is a source of many potential new tumor biomarkers, in which the immune response is of major importance. Little is known regarding how changes in stromal gene expression affect hepatocellular carcinoma (HCC) progression. We analyzed the expression of 28 stroma-related genes using quantitative RT-PCR in 122 HCC samples, and related the results to patient prognosis. Hierarchical clustering based on expression of the 28 genes, or the 6-Th1 cell markers, can classify HCC patients into prognostically different subgroups. We further identified a five-gene classifier (protective genes IRF1 and GZMB and risk genes CRTH2, VEGF, and MMP7) as a significant independent prognosticator for recurrence (hazard ratio [HR], 4.80; 95% confidence interval [CI], 2.31-9.96; P = 2.6 × 10−5) by multivariate analyses. Importantly, the classifier was further validated in an independent set of 172 HCC samples (HR, 2.21; 95% CI, 1.20-3.00; P = 0.002). The predictive ability of the classifier, as measured by area under the curve (0.713 and 0.613 for original and validation cohorts, respectively), was comparable to those of vascular invasion, Barcelona Clinic Liver Cancer stage, and TNM stage. The densities of various tumor stromal cells were analyzed by immunostaining. Comparing the immunostaining and gene expression data showed significant association of the gene classifier with the amount of reactive stroma in both cohorts. Thus, the signature reveals the strong prognostic capacity of immune responses, angiogenic activity, and ECM remodeling, highlighting the importance of stromal biology in HCC progression. Contained in this novel predictor may be targets suitable for new therapeutic interventions, or for use as independent prognosticators. ( Cancer Sci 2011; 102: 1522-1531) [ABSTRACT FROM AUTHOR]

The peritumoral inflammatory environment is critical for the progression of intrahepatic recurrence of hepatocellular carcinoma (HCC) after curative resections. Here, we investigated the relevance of peritumoral mast cells (MCs) to HCC outcomes. Peritumoral tryptase+ MCs in addition to Foxp3+ T-regulatory cells (Tregs) were evaluated using immunohistochemistry enumeration in tissue microarrays containing 207 randomly selected HCC patients. Clinicopathological factors and postoperative outcomes were compared between high and low subgroups of MCs or Tregs. Compared to low denstiy, higher peritumoral MCs were associated with poorer clinical outcomes, and independently related to elevated 5-year recurrence incidence (54.1% vs 39.2%, P = 0.026). High-dense MCs were especially related to increased probability of early recurrence (within 2 years) ( P = 0.004). We also found that peritumoral Tregs were positively correlated with MCs in density ( r = 0.353, P < 0.001) and reversely related to HCC outcomes. Notably, MCs in combination with Tregs displayed better prognostic performances than MCs alone (area under curve [AUC]survival = 0.629 vs 0.589, AUCrecurrence = 0.632 vs 0.591). Moreover, MCs were positively correlated to alanine aminotransferase, a serum inflammatory marker ( P = 0.014). Therefore, peritumoral MCs are promising prognostic parameters for HCC mainly through inflammation response–related mechanisms, and we propose that MCs and Tregs may cooperate with each other and result in poorer prognosis. ( Cancer Sci 2009; 100: 1267–1274) [ABSTRACT FROM AUTHOR]