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Magnetic resonance elastography (MRE) is a noninvasive tool for diagnosing hepatic fibrosis with high accuracy. We investigated the preoperative clinical and imaging predictors of intrahepatic recurrence after curative resection of hepatocellular carcinoma (HCC), and evaluated MRE as a predictor of intrahepatic recurrence. We retrospectively evaluated 80 patients who underwent preoperative contrast-enhanced magnetic resonance imaging (MRI) with two-dimensional MRE and curative resection for treatment-naïve HCC between May 2019 and December 2021. Liver stiffness (LS) was measured on the elastograms, and the optimal cutoff of LS for predicting intrahepatic recurrence was obtained using receiver operating characteristic (ROC) analysis. An LS above this cutoff was defined as MRE-recurrence. Preoperative imaging features of the tumor were assessed on MRI, including features in the Liver Imaging Reporting and Data System and microvascular invasion (MVI). Recurrence-free survival (RFS) rates were estimated using the Kaplan-Meier method, and differences were compared using the log-rank test. Using a Cox proportional hazards model, we conducted a multivariable analysis to investigate the factors affecting recurrence-free survival. During a median follow-up period of 32 months (range, 4–52 months), thirteen patients (16.3%) developed intrahepatic recurrence. ROC analysis determined an LS cutoff of ≥4.35 kPa to define MRE-recurrence. The 4-year RFS rate was significantly higher in patients without MRE-recurrence than in those with MRE-recurrence (93.4% vs. 48.9%; p = 0.001). In multivariable analysis, MRE-recurrence (Hazard ratio [HR], 5.9; 95% confidence interval [CI], 1.5–23.1) and MVI (HR, 3.4; 95% CI, 1.0–11.3) were independent predictors of intrahepatic recurrence. Patients without MRE-recurrence had significantly higher RFS rates than those with MRE-recurrence. MRE-recurrence and MVI were independent predictors of intrahepatic recurrence in patients after curative resection for HCC. • In at-risk patients after HCC resection, liver stiffness ≥4.35 kPa from pre-op MRE could predict intrahepatic recurrence. • Preoperative MRE may predict late recurrence >2 years after surgery and is associated with the occurrence of de novo HCC. • Preoperative MRE could help establish individualized treatment strategies and plans for recurrence surveillance. [ABSTRACT FROM AUTHOR]

As an effective locoregional therapy, transarterial chemoembolization (TACE) can induce vascular endothelial growth factor and PD-1/PDL-1 upregulation, accompanied by a reduction in tumor burden. The present study aimed to compare the efficacy of TACE combined with tyrosine kinase inhibitors (TKIs) plus immune checkpoint inhibitors (ICIs) (TACE-TKI-ICIs) versus TKIs plus ICIs (TKI-ICIs) in patients with unresectable hepatocellular carcinoma (HCC). The clinical data of 198 patients diagnosed with unresectable HCC who received a TKI (lenvatinib or sorafenib) plus an ICI (sintilimab or camrelizumab) with or without TACE were retrospectively reviewed between October 2019 and April 2022. Baseline characteristics of the TACE-TKI-ICI group and the TKI-ICI group were matched by propensity score matching in a 1:1 ratio. The tumor response, progression-free survival (PFS), and overall survival (OS) were evaluated and compared between the two groups. After matching, 54 patients were enrolled in each group. The objective response rate (ORR) and disease control rate (DCR) were higher in the TACE-TKI-ICI group (ORR: 63.0% vs. 29.6%, P < 0.001; DCR: 85.2% vs. 53.7%, P < 0.001). The median PFS was significantly longer in the TACE-TKI-ICI group (9.9 vs. 5.8 months; P = 0.026). The median OS between the two groups also reached a significant difference (not reached vs. 18.5 months; P = 0.003). In this retrospective study, the results indicated that the addition of TACE to TKI-ICI therapy could contribute to better tumor control, PFS, and OS benefits in patients with unresectable HCC. [ABSTRACT FROM AUTHOR]

Objective: Our meta-analysis was performed to explore the prognostic factors for overall survival among post-hepatectomy patients with spontaneous ruptured hepatocellular carcinoma (SRHCC). Methods: PubMed, EMBASE, the Cochrane Library, and Web of Science were all searched up for relevant studies regarding prognostic factors with SRHCC. RevMan5.3 software and Stata 14.0 software were used for statistical analysis. Results: A total of nineteen studies with 1876 resected SRHCC patients were finally identified. Pooled results indicated that preoperative AFP (high vs low) (P = 0.003), concurrent liver cirrhosis (yes vs no) (P = 0.02), preoperative liver function (child A vs non-child A) (P = 0.0007), tumor size (large vs small) (P < 0.00001), tumor number (solitary vs multiple) (P = 0.002), satellite foci (yes vs no) (P = 0.0006), micro-vascular invasion (yes vs no) (P < 0.00001), type of hepatectomy (major or minor) (P = 0.04), surgical margin (R + vs R −) (P < 0.00001), and type of hepatectomy (emergency hepatectomy vs staged hepatectomy) (P = 0.005) were prognostic factors for overall survival among post-hepatectomy SRHCC patients. Conclusion: Apart from some conventional prognostic factors identified in resected patients with SRHCC, numerous prognostic factors have also been unmasked, which might provide clinical reference to stratify patients with different therapeutic regimes. [ABSTRACT FROM AUTHOR]

The aim of the work described here was to evaluate the diagnostic performance of perfluorobutane (PFB)-enhanced ultrasound in differentiating hepatocellular carcinoma (HCC) from non-HCC malignancies and other benign lesions using different acquisition methods. This prospective study included 69 patients with solid liver lesions larger than 1 cm who were scheduled for biopsy or radiofrequency ablation between September 2020 and March 2021. Lesion diagnosis was designated by three blinded radiologists after reviewing three different sets of acquired images selected according to the following presumed acquisition methods: (i) method A, acquisition up to 5 min after contrast injection; (ii) method B, acquisition up to 1 min after contrast injection with additional Kupffer phase; and (iii) method C, acquisition up to 5 min after contrast injection with additional Kupffer phase. After excluding 7 technical failures, 62 patients with liver lesions (mean size: 24.2 ± 14.8 mm), which consisted of 7 benign lesions, 37 non-HCC malignancies and 18 HCCs. For the HCC diagnosis, method C had the highest sensitivity (75.9%), followed by method B (72.2%) and method A (68.5%), but failed to exhibit statistical significance (p = 0.12). There was no significant difference with respect to the pooled specificity between the three methods (p = 0.28). Diagnostic accuracy was the highest with method C (87.1%) but failed to exhibit statistical significance (p = 0.24). Image acquisition up to 5 min after contrast injection with additional Kupffer phase could potentially result in high accuracy and sensitivity without loss of specificity in diagnosing HCC with PFB-enhanced ultrasound. [ABSTRACT FROM AUTHOR]

Oxaliplatin is currently used for chemotherapy in patients with hepatocellular carcinoma, but its increasing tolerance to tumours over time limits its clinical application. Studies have shown that high PD-L1 expression promotes the polarization of M2 macrophages. The increased infiltration of M2 macrophages, including those in HCC, is positively correlated with poor prognosis in various solid tumours. We found that oxaliplatin promoted the expression of PD-L1 in liver cancer cells, which might be attributed partly to the tolerance of tumours to oxaliplatin. Therefore, in this study, we explored the antitumour effect of attenuated Salmonella carrying siRNA-PD-L1 combined with oxaliplatin via Western blotting, immunohistochemistry, immunofluorescence, and flow cytometry. The results revealed that attenuated Salmonella carrying siRNA-PD-L1 combined with oxaliplatin more significantly inhibited tumour growth in tumour-bearing mice, suppressed the expression of PD-L1 in tumour tissue, increased the apoptosis of tumour cells and the expression of the tumour-related protein cleaved-caspase3, and increased the infiltration of M1 macrophages and T lymphocytes in tumour tissues. Moreover, the combination therapy increased the activation of T cells and the number of T lymphocytes and NK cells in the spleens of the mice and improved the overall antitumour immune response in the mice. Our results confirmed that attenuated Salmonella harbouring siRNA-PD-L1 combined with oxaliplatin had a significant antitumour effect and did not increase the incidence of toxic side effects, providing a theoretical reference for addressing oxaliplatin tolerance in the treatment of hepatocellular carcinoma. [ABSTRACT FROM AUTHOR]

Nanomaterials (NMs)-based cancer-targeted drug delivery systems have been promoted as a promising therapy. Using silk fibroin (SF), Ru(II)-modified selenium (Ru@Se), Nivolumab (NMB), and heptapeptide (HP), we designed a pH-response innovative Nanomaterials for the drug delivery framework. The constructed NMB@HP/SF-Ru@Se-NMs were nanospheres of ∼100 nm, contributing to enhanced permeability and retention (EPR) in tumor sites. The NMB was released from the pH-dependent nanocarriers, and in an acidic environment, the release of NMB was accelerated. NMB@HP/SF-Ru@Se-NMs demonstrated improved cellular uptake and anticancer efficacy for hepatocellular carcinoma. In addition, the flow cytometry results demonstrated that NMB@HP/SF-Ru@Se-NMs could efficiently destroy cancer cells. Further, histochemical investigations revealed that NMB@HP/SF-Ru@Se-NMs exhibited less toxicity to the primary organs, suggesting that the constructed NMs are biocompatible in vivo. Overall, the findings imply that the nanomaterials-based delivery framework (NMB@HP/SF-Ru@Se-NMs) is a novel treatment for hepatocellular carcinoma. [Display omitted] • We have designed a pH-response Ru(II)-modified selenium nanomaterials for cancer therapy. • The Nivolumab (NMB) was released from the pH-dependent nanocarriers in an acidic environment. • Nanomaterials demonstrated improved cellular uptake and hepatocellular anticancer efficacy. • Flow cytometry results demonstrated that nanomaterials could efficiently destroy cancer cells. • Nanomaterials exhibited less toxicity to the primary organs. [ABSTRACT FROM AUTHOR]

A 13-year-old male neutered Cocker Spaniel mixed-breed dog developed a subcutaneous mass 2 years after undergoing surgery to remove a hepatocellular carcinoma. An approximately 4 × 3 cm subcutaneous mass was found on the ventral abdomen at the cranial end of the abdominal incision from the previous surgery. The subcutaneous mass was surgically removed and histopathological examination determined that it was an implantation of the previously excised hepatocellular carcinoma. The diagnosis was confirmed by immunohistochemical labelling with hepatocyte paraffin 1 antibody and pancytokeratin. Based on the location of the subcutaneous mass at the cranial end of the abdominal incision associated with the previous hepatocellular carcinoma resection, it is likely there was iatrogenic metastasis from the primary tumour excision. Subcutaneous iatrogenic metastasis of hepatocellular carcinoma is well recognized in humans but has apparently never been reported in dogs. Clinicians should be aware of this potential surgical complication. [ABSTRACT FROM AUTHOR]

The CELESTIAL trial (NCT01908426) demonstrated overall survival benefit for cabozantinib versus placebo in patients with advanced hepatocellular carcinoma (aHCC) who had received prior sorafenib treatment. This analysis of CELESTIAL compared the impact of cabozantinib versus placebo on health-related quality of life (HRQoL). Health status was assessed using the EuroQol five-dimension five-level (EQ-5D-5L) questionnaire over the 800-day follow-up period. EQ-5D-5L health states were mapped to health utility scores using reference values for the UK population. Quality-adjusted life years (QALYs) were calculated for each treatment group as the area under the curve for the plot of health utility score over time. The between-treatment group difference in restricted mean QALYs was calculated by generalized linear models and adjusted for baseline differences. A difference of 0.08 in health utility score (or in QALY) was deemed a minimally important difference and to be clinically significant. At week 5, the difference in mean health utility score between cabozantinib and placebo was −0.097 (95% confidence interval [95% CI]: −0.126, −0.067; p ≤ 0.001). Between-group differences in health utility scores diminished over time and were generally non-significant. The cabozantinib group accrued more QALYs than the placebo group over follow-up. Differences in mean QALYs (cabozantinib minus placebo) were statistically and clinically significant, ranging from +0.092 (95% CI: 0.016, 0.169) to +0.185 (95% CI: 0.126, 0.243) in favour of cabozantinib, depending on the reference value set used. These HRQoL findings support a positive benefit–risk profile for cabozantinib in previously treated patients with aHCC. • This analysis of CELESTIAL compared the impact of cabozantinib vs placebo on HRQoL • Randomisation to cabozantinib led to a small short-term decrement in HRQoL • Cabozantinib accrued greater HRQoL vs placebo over follow-up to 3 years • This result adds to a positive benefit–risk profile for cabozantinib [ABSTRACT FROM AUTHOR]

Introduction: Although hepatectomy is a curative treatment modality for hepatocellular carcinoma (HCC), the associated 10-year long-term actual survival are rarely reported. This study aims to develop and validate a predictive nomogram for 10-year actual survivors with HCC.Materials and Methods: From 2004 to 2009, 753 patients with curative hepatectomy for HCC (development set, n = 325; validation set, n = 428) were included. In development set, comparison of clinic-pathological data was made between patients surviving ≥10 years and those surviving <10 years. Good independent prognostic factors identified by multivariate analysis were involved in a nomogram development, which was validated internally and externally using validation set.Results: On multivariate analysis, five independent good prognostic factors for 10-year survival were identified, including young age (OR = 0.943), good ASA status (≤2) (OR = 2.794), higher albumin level (OR = 1.116), solitary tumor (OR = 2.531) and absence of microvascular invasion (OR = 3.367). A novel nomogram was constructed with C-index of 0.801 (95% CI 0.762-0.864). A cut-off point of 167.5 had a sensitivity of 0.794 and specificity of 0.730. Internal validation using bootstrap sampling and external validation using validation set revealed C-index of 0.792 (95% CI, 0.741-0.853) and 0.761 (95% CI, 0.718-0.817).Conclusion: A novel nomogram for 10-year HCC survivor using age, ASA status, preoperative albumin, tumor number and presence of microvascular tumor invasion was developed and validated with high accuracy. [ABSTRACT FROM AUTHOR]

Background: Surgical and oncological outcomes in ruptured hepatocellular carcinoma (HCC) are not well known. The objective of this study was to review and compare survival outcomes and recurrence rates between ruptured and unruptured HCC. Methods: Data of patients with ruptured HCC who underwent curative surgical resection between January 2000 and December 2016 were retrospectively reviewed. To compare survival outcomes between ruptured and unruptured HCC, 1:2 individual matching was conducted. Results: The 1-, 3-, and 5-year overall survival (OS) rates were 88.8%, 67.0%, and 51.9%, respectively. The 1-, 3-, and 5-year disease-free survival (DFS) rates were 51.7%, 32.8%, and 25.0%, respectively. OS and DFS rates were significantly lower in the ruptured HCC group than the matched unruptured HCC group. HCC recurred in 63 patients (70.8%), 33 (52.4%) of whom presented with both intrahepatic and extrahepatic recurrences. Mean recurrence interval was 12.6 ± 13.8 months. The 1-, 3-, and 5-year survival rates after recurrence were 61.6%, 40.2%, and 33.6%, respectively. Mean survival time after recurrence was 26.4 ± 29.5 months. Incidence of peritoneal seeding (PS) was 18.0%, and eight of them demonstrated solitary lesion. Mean recurrence interval was 5.9 ± 8.2 months. The 1-, 3-, and 5-year OS rates after recurrence were significantly lower in patients with PS (49.7%, 18.7%, and 9.3%, respectively) than in patients without PS. Conclusions: Hepatectomy in ruptured HCC did show worse survival outcome compared with unruptured HCC and bear a high risk of PS. However, surgical resection combined with transcatheter arterial chemoembolization could help in achieving acceptable oncological outcomes. [ABSTRACT FROM AUTHOR]

Background: Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and the third cause of cancer-related death. Current clinical/pathological criteria contribute to risk stratification, but are far from the desired on individualized medicine. Recently, HCC classifications have been published based on immunohistochemical and morphological features. Methods: A retrospective review of patients submitted to surgical treatment—partial hepatectomy (PH) or liver transplantation (LT), with pathological diagnosis of HCC, in a 9-year period (2007–2015) was performed. Results: Applying the classification of Srivastava et al. (#1), based on the expression of CD31, p53, AFP and CD44, tumour size and presence of vascular invasion, HCC were categorized as low- and high-risk HCC. With the classification of Tsujikawa et al. (#2), HCC were classified into biliary/stem cell marker positive, Wnt signalling positive and the "all negative" HCC, according to the expression of CK19, SALL4, β-catenin glutamine synthetase, EpCAM and p53. There were sixty-six patients (53 males; 13 females), with median age of 64.5 ± 9.46 years (range 38–86), with solitary HCC, comprehending 37 PH (56.1%) and 29 LT (43.9%). The mean overall survival (OS) was 75.4 ± 6.9 months. Biliary/stem cell type of HCC was a predictive factor of worse OS on the overall population (24.4 versus 78.3 months, p = 0.032) and in PH cohort (11.5 versus 64.01 months, p = 0.016), on uni- and multivariate analyses. Conclusion: These results support the relevance of a risk stratification classification of HCC. Classification #2 seems adequate to our reality demonstrating OS impact, allowing its application in future biopsies, prompting individualized medicine. [ABSTRACT FROM AUTHOR]

There are uncertainties about the epidemic patterns of HDV infection and its contribution to the burden of liver disease. We estimated the global prevalence of HDV infection and explored its contribution to the development of cirrhosis and hepatocellular carcinoma (HCC) among HBsAg-positive people. We searched Pubmed, EMBASE and Scopus for studies reporting on total or IgG anti-HDV among HBsAg-positive people. Anti-HDV prevalence was estimated using a binomial mixed model, weighting for study quality and population size. The population attributable fraction (PAF) of HDV to cirrhosis and HCC among HBsAg-positive people was estimated using random effects models. We included 282 studies, comprising 376 population samples from 95 countries, which together tested 120,293 HBsAg-positive people for anti-HDV. The estimated anti-HDV prevalence was 4.5% (95% CI 3.6–5.7) among all HBsAg-positive people and 16.4% (14.6–18.6) among those attending hepatology clinics. Worldwide, 0.16% (0.11–0.25) of the general population, totalling 12.0 (8.7–18.7) million people, were estimated to be anti-HDV positive. Prevalence among HBsAg-positive people was highest in Mongolia, the Republic of Moldova and countries in Western and Middle Africa, and was higher in injecting drug users, haemodialysis recipients, men who have sex with men, commercial sex workers, and those with HCV or HIV. Among HBsAg-positive people, preliminary PAF estimates of HDV were 18% (10–26) for cirrhosis and 20% (8–33) for HCC. An estimated 12 million people worldwide have experienced HDV infection, with higher prevalence in certain geographic areas and populations. HDV is a significant contributor to HBV-associated liver disease. More quality data are needed to improve the precision of burden estimates. We combined all available studies to estimate how many people with hepatitis B also have hepatitis D, a viral infection that only affects people with hepatitis B. About 1 in 22 people with hepatitis B also have hepatitis D, increasing to 1 in 6 when considering people with liver disease. Hepatitis D may cause about 1 in 6 of the cases of cirrhosis and 1 in 5 of the cases of liver cancer that occur in people with hepatitis B. Hepatitis D is an important contributor to the global burden of liver disease. • HDV infection is common among HBsAg-positive people worldwide. • Among HBsAg-positive people, estimated HDV prevalence is 4.5% (95% CI 3.6–5.7). • HDV prevalence in HBsAg-positive hepatology clinic attendees is 16.4% (14.6–18.6). • HDV prevalence is higher in people who inject drugs and who have HCV or HIV. • HDV causes an estimated 18% of cirrhosis and 20% of HCC associated with hepatitis B. [ABSTRACT FROM AUTHOR]

• The risk of liver abscess after DEB-TACE increased as treatment interval of DEB-TACE and ICIs was less than one month. • Though with higher incidence, liver abscess after DEB-TACE as in combination with ICIs didn't show more aggressive course. • Receiving ICIs before DEB-TACE exhibited a trend toward liver abscess formation compared with receiving DEB-TACE before ICIs. To analyze the safety of combination treatment comprising drug-eluting bead transarterial chemoembolization (DEB-TACE) and immune checkpoint inhibitors (ICIs) in hepatocellular carcinoma (HCC). In total, 208 HCC patients receiving DEB-TACE were enrolled for this retrospective single-institution study. Among them, 50 patients who received ICIs at an interval less than one month from DEB-TACE were categorized into the DEB-ICI group; the remaining 158 patients were categorized into the DEB group. Albumin-bilirubin (ALBI) score before and at three months after DEB-TACE were recorded to evaluate liver function changes. Adverse events within three months after DEB-TACE were considered TACE-related and were compared between the two groups. The DEB-ICI group had significantly higher incidence of liver abscess than the DEB group (14.0 % versus 5.1 %, p -value = 0.0337). No significant difference in the other TACE-related adverse events and change of ALBI score between the groups. Univariate logistic regression confirmed that combination with ICIs was an independent risk factor for liver abscess after DEB-TACE (odds ratio = 3.0523, 95 % confidence interval: 1.0474–8.8947, p -value = 0.0409); other parameters including subjective angiographic chemoembolization endpoint scale and combined targeted therapy were nonsignificant risk factors in this study population. In the DEB-ICI group, patients who received ICIs before DEB-TACE exhibited a trend toward liver abscess formation compared with those who received DEB-TACE before ICIs (23.8 % versus 6.9 %, p -value = 0.0922). Combination treatment involving DEB-TACE and ICIs at an interval less than one month increased the risk of liver abscess after DEB-TACE. Greater caution is therefore warranted for HCC patients who receive ICIs and DEB-TACE with this short interval. [ABSTRACT FROM AUTHOR]

Background: Opioid receptors are implicated in cancer progression and long-term patient outcomes. However, the prognostic significance, underlying mechanisms, and therapeutic value of mu-opioid receptor (MOP) in hepatocellular carcinoma (HCC) remain unclear.Methods: MOP expression in human biopsy HCC samples was evaluated using RNA microarrays, quantitative real-time polymerase chain reaction (qRT-PCR), and immunochemical analyses. Molecular and cellular techniques, including siRNA-mediated depletion and lentiviral vector-mediated overexpression, were used to elucidate the functions and mechanisms of MOP. The effect of the MOP agonist morphine in HCC was evaluated both in vitro and in vivo. The therapeutic value of MOP inhibitors in HCC progression and metastasis was investigated with in vitro experiments and subcutaneous and orthotopic HCC mouse models in vivo.Results: Through microarray analysis and qRT-PCR, we identified that MOP is highly expressed in human HCC tumours. High MOP expression in HCC tumours was confirmed by immunocytochemistry and correlated with aggressive clinicopathological features and a worse prognosis. Depletion of MOP suppressed cell proliferation, migration, and invasion, whereas overexpression of MOP promoted cell growth and metastasis in human HCC cell lines. Both clinical and biological evidence revealed that MOP-mediated epithelial-mesenchymal transition promotes HCC metastasis and poor prognosis. Morphine promotes cell proliferation, migration, and invasion in vitro and in vivo in mouse models. More importantly, MOP inhibitors suppressed cell growth, invasion, and metastasis in vitro and in the subcutaneous and orthotopic xenograft models.Conclusions: MOP plays a key oncogenic function in hepatocarcinogenesis. Its overexpression is associated with poor prognosis in patients with HCC. Furthermore, MOP inhibitors may be a promising strategy for HCC therapy. [ABSTRACT FROM AUTHOR]

• Combination with siRNA-CD24 and oxaliplatin reduced protein expression associated with tumor invasion, migration, and proliferation, and increased cell apoptosis. • The combination therapy of siRNA-CD24 and oxaliplatin raised the infiltration of macrophages and T cells. • The combination therapy of siRNA-CD24 and oxaliplatin enhanced the activation of T cells. Oxaliplatin is a chemotherapy drug currently utilized in the treatment of advanced cancer patients. However, its tolerability poses a limitation to its clinical application. Studies have demonstrated that the presence of tumor-associated macrophages is positively correlated with poor prognosis in various solid tumors, including hepatocellular carcinoma (HCC), and is a significant factor contributing to oxaliplatin resistance. Therefore, targeting tumor-associated macrophages may be an effective strategy to improve the efficacy of oxaliplatin in the treatment of HCC patients. CD24 is a novel target for tumor therapy that can interact with the inhibitory receptor Siglec-10 on tumor-associated macrophages, transmitting immune inhibitory signals and inhibiting macrophage phagocytosis function. In this study, we utilized RNAi technology to inhibit the expression of CD24 in tumor cells and combined it with oxaliplatin, resulting in reduced tumor invasion, migration, and proliferation, as well as increased cell apoptosis. Furthermore, immunofluorescence and flow cytometry results indicated that both the single treatment group and combination treatment group enhanced the infiltration of immune cells. This study presents a novel approach to identifying combination therapy and targets for the clinical treatment of HCC with oxaliplatin. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • MiR-133a is downregulated in HCC tissues and HCC cell lines. • Overexpression of miR-133a suppresses HCC cell growth, proliferation, migration, invasion and promotes cell apoptosis. • FOSL2 is a target of miR-133a and overexpression of FOSL2 reverses the role of miR-133a in HCC cells. • MiR-133a suppresses HCC cell biological behaviors through TGF-β/Smad3 signaling pathway. • MiR-133a inhibits the growth of tumor cell xenografts in nude mice. Abstract Hepatocellular carcinoma (HCC), one of the most common maligant cancers in the world, is difficult to diagnose in the early time. MicroRNAs (miRNAs), small non-coding RNAs, perform vital functions in cellular differentiation, metabolism and physiological processes. MiR-133a acts as a tumor suppressor in breast, lung and gastric cancer, while the molecular circadian mechanism has not been clear in HCC. In the present study, we certified that the expression of miR-133a decreased in HCC tissues and cell lines and that miR-133a inhibited proliferation, migration and invasion of hepatocellular carcinoma cells. Fos-related antigen 2 (FOSL2), also named FRA-2, was predicted to be a downstream target of miR-133a based on bioinformatic analysis and the prediction was verified by Western Blot, qRT-PCR and luciferase reporter assay. In addition, there was a negative correlation between miR-133a and FOSL2 expression in HCC samples. Furthermore, we verified that overexpression of miR-133a suppressed biological behaviour of HCC through TGF-β/Smad3 signaling pathway. In brief, miR-133a may be a potential prognostic biomarker and may thus be a new therapy in HCC. [ABSTRACT FROM AUTHOR]

Objective The relative benefit of anatomic resection (AR) versus non-anatomic resection (NAR) of HCC remains poorly defined. We sought to evaluate the available evidence on oncologic outcomes, as well as the clinical efficacy and safety of AR versus NAR performed as the primary treatment for HCC patients. Material and methods A systematic review and meta-analysis was conducted using Medline, ClinicalTrials.gov and Cochrane library through April 15th, 2017. Only clinical studies comparing AR versus NAR were deemed eligible. Results A total of 43 studies were considered eligible (total 12,429 patients: AR, n = 6839 (55%) versus NAR, n = 5590 (45%)). Blood loss was higher among patients undergoing AR (mean difference: +229.74 ml, 95% CI: 97.09–362.38, p = 0.0007), whereas resection margin was slightly wider following AR versus NAR (mean difference: +0.29 cm, 95% CI: 0.15–0.44, p < 0.0001). No difference was noted for perioperative complications (RR: 0.95, 95% CI: 0.81–1.11, p = 0.49) and perioperative mortality (RR: 0.91, 95% CI: 0.43–1.95, p = 0.82). AR was associated with a disease-free survival (DFS) benefit at 1- (HR: 0.79, 95% CI: 0.68–0.92, p = 0.002), 3- (HR: 0.87, 95% CI: 0.78–0.95, p = 0.004) and 5-years (HR: 0.87, 95% CI: 0.82–0.93, p < 0.0001). AR also was associated with a decreased risk of death at 5-years (HR: 0.88, 95% CI: 0.79–0.97, p = 0.01). Conclusion Despite the high heterogeneity among studies, the data demonstrated that AR had comparable perioperative morbidity and mortality versus NAR. AR seemed to offer an advantage versus NAR in terms of DFS and OS among patients undergoing resection of HCC – especially among patients without cirrhosis. Thus, AR should be considered the preferred surgical option for patients with HCC when feasible. [ABSTRACT FROM AUTHOR]

Background Postoperative liver failure remains the main complication and predominant cause of hepatectomy-related mortality for patients undergoing liver resection. Aim Our aim is to investigate whether immediate postoperative Fibrosis-4 could predict postoperative liver failure. Methods We retrospectively enrolled 1353 consecutive hepatocellular carcinoma patients undergoing radical resection. The characteristics and clinical outcomes were compared between patients with high and low immediate postoperative Fibrosis-4. Risk factors for hepatic failure were evaluated by univariate and multivariate analysis. Results Using a receiver operating characteristic curve, immediate postoperative Fibrosis-4 showed good prediction ability for postoperative liver failure (AUROC = 0.647, P < 0.001). With the optimal cut-off value of 5.9, the high postoperative Fibrosis-4 group (Fibrosis-4 < 5.9) had higher postoperative complication (39.1% vs 28.6%, P < 0.001), mortality (2.8% vs 0.6%, P < 0.001) and liver failure (13.9% vs 6.2%, P < 0.001). In addition, patients with high Fibrosis-4 had worse and delayed recovery of liver function. By univariate and multivariate analysis, Fibrosis-4, as well as liver removed volume, total bilirubin and albumin was identified as independent risk factor for postoperative liver failure. Conclusions Immediate postoperative Fibrosis-4 showed good prediction ability for postoperative liver failure, and required measure should be taken to prevent liver failure when high postoperative Fibrosis-4 appeared. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is a primary liver malignancy, and is now the six most common in between malignancies. Early diagnosis of HCC with prompt treatment increases the opportunity of patients to survive. With the advances in understanding the molecular biology of HCC, new therapeutic strategies to treat HCC have emerged. There is a growing consensus that vitamins are important for the control of various cancers. Biochemical evidence clearly indicates that HCC cells are responsive to the inhibitory effect of vitamin D, vitamin D analogues and vitamin K. In this review, we summarize the mechanisms used by vitamin D and K to influence the development of HCC and the latest development of vitamin analogues for potential HCC therapy. [ABSTRACT FROM AUTHOR]

Background & Aims Patients chronically infected with the hepatitis B virus (HBV) and receiving long-term treatment with nucleoside or nucleotide analogues are at risk of selecting HBV strains with complex mutational patterns. We herein report two cases of HBV-infected patients with insufficient viral suppression, despite dual antiviral therapy with entecavir (ETV) and tenofovir (TDF). One patient died from aggressive hepatocellular carcinoma (HCC). Methods Serum samples from the two patients at different time points were analyzed using ultra-deep pyrosequencing analysis. HBV mutations were identified and transiently transfected into hepatoma cells in vitro using replication-competent HBV vectors, and functionally analyzed. We assessed replication efficacy, resistance to antivirals and potential impact on HBV secretion (viral particles, exosomes). Results Sequencing analyses revealed the selection of the rtS78T HBV polymerase mutation in both cases that simultaneously creates a premature stop codon at sC69 and thereby deletes almost the entire small HBV surface protein. One of the patients had an additional 261 bp deletion in the preS1/S2 region. Functional analyses of the mutations in vitro revealed that the rtS78T/sC69∗ mutation, but not the preS1/S2 deletion, significantly enhanced viral replication and conferred reduced susceptibility to ETV and TDF. The sC69∗ mutation caused truncation of HBs protein, leading to impaired detection by commercial HBsAg assay, without causing intracellular HBsAg retention or affecting HBV secretion. Conclusions The rtS78T/sC69∗ HBV mutation, associated with enhanced replication and insufficient response to antiviral treatment, may favor long-term persistence of these isolates. In addition to the increased production of HBV transcripts and the sustained secretion of viral particles in the absence of antigenic domains of S protein, this HBV mutation may predispose patients to carcinogenic effects. Lay summary Long-term treatment with antiviral drugs carries the risk of selecting mutations in the hepatitis B virus (HBV). We herein report two cases of patients with insufficient response to dual tenofovir and entecavir therapy. Molecular analyses identified a distinct mutation, rtS78T/sC69∗, that abolishes HBsAg detection, enhances replication, sustains exosome-mediated virion secretion and decreases susceptibility to antivirals, thereby representing a potentially high-risk mutation for HBV-infected individuals. [ABSTRACT FROM AUTHOR]

Development of targeted, selective, and noninvasive fluorescent probes for in vivo visualization of tumor-associated overexpressed enzymes are highly anticipated for cancer diagnosis and therapy. Herein, we developed a noninvasive fluorescent probe ( DCDHF- β gal ) for the sensitive detection, and in vivo visualization of β-galactosidase in hepatocyte HepG2 cells and its xenograft model. As a model system for in vivo targeted imaging, DCDHF- β gal possessing galactose unit selectively target hepatocyte and monitor the β-galactosidase activity with deep tissue penetration, and low background interference. DCDHF- β gal was activated by intracellular β-galactosidases as the driving force for the release of NIR fluorophore, thereby exhibiting ratiometric optical response. Initial fluorescence emission measured at 615 nm was changed to fluorescence at 665 nm upon activation of DCDHF- β gal with β-galactosidase. Ratiometric fluorescence detection of β-galactosidase was also observed in hepatocellular carcinoma cells and tumor xenograft. The noninvasive in vivo optical imaging facilitated by targeted and enzyme-activated imaging agent would be useful in various biomedical and diagnostic applications. [ABSTRACT FROM AUTHOR]

Background & Aims Overall survival (OS) is a composite clinical endpoint in hepatocellular carcinoma (HCC) due to the mutual influence of cirrhosis and active malignancy in dictating patient’s mortality. The ALBI grade is a recently described index of liver dysfunction in hepatocellular carcinoma, based solely on albumin and bilirubin levels. Whilst accurate, this score lacks cross-validation, especially in intermediate stage HCC, where OS is highly heterogeneous. Methods We evaluated the prognostic accuracy of the ALBI grade in estimating OS in a large, multi-centre study of 2426 patients, including a large proportion of intermediate stage patients treated with chemoembolization (n = 1461) accrued from Europe, the United States and Asia. Results Analysis of survival by primary treatment modality confirmed the ALBI grade as a significant predictor of patient OS after surgical resection ( p <0.001), transarterial chemoembolization ( p <0.001) and sorafenib ( p <0.001). Stratification by Barcelona Clinic Liver Cancer stage confirmed the independent prognostic value of the ALBI across the diverse stages of the disease, geographical regions of origin and time of recruitment to the study ( p <0.001). Conclusions In this large, multi-centre retrospective study, the ALBI grade satisfied the criteria for accuracy and reproducibility following statistical validation in Eastern and Western HCC patients, including those treated with chemoembolization. Consideration should be given to the ALBI grade as a stratifying biomarker of liver reserve in routine clinical practice. Lay summary Liver failure is a key determinant influencing the natural history of hepatocellular carcinoma (HCC). In this large multi-centre study we externally validate a novel biomarker of liver functional reserve, the ALBI grade, across all the stages of HCC. [ABSTRACT FROM AUTHOR]

Keywords: Liver neoplasms; Carcinoma; Hepatocellular; Liver transplantation; Canada; Tumour burden; Health policy UCSF[5] = Maximum tumour size <6.5 cm, maximum of 3 total tumors with none >4.5 cm, and cumulative tumor size <8 cm). Liver neoplasms, Carcinoma, Hepatocellular, Liver transplantation, Canada, Tumour burden, Health policy. [Extracted from the article]

A 15-year-old intact female sugar glider ( Petaurus breviceps ) presented for a 3-day history of diarrhea and weight loss despite an excellent appetite. Upon physical examination under manual restraint, the animal was determined to be emaciated with a palpable l cm diameter, firm, and irregular abdominal mass. Following 72 hours of supportive and palliative treatment (including oral antibiotics and glucocorticoids) with no clinical response, the owner elected euthanasia and approved antemortem diagnostics for teaching purposes. A complete blood count revealed a moderate regenerative anemia, mild leukopenia, and thrombocytopenia. A significant number of sideroleukocytes were noted upon examination of a blood smear, along with platelet clumps. Plasma biochemical analysis showed moderate hypoproteinemia, moderate hypoalbuminemia, mild hypokalemia, and elevated total bilirubin. Mild hypernatremia and hyperchloremia were also present. An abdominal ultrasound confirmed the presence of a large hypoechoic abdominal mass, which appeared to be associated with the liver. Whole-body radiographs did not assist in reaching an antemortem diagnosis because of poor abdominal serosal detail secondary to severe emaciation. Postmortem examination and histopathology provided a definitive diagnosis of concurrent hepatocellular carcinoma and adrenocortical carcinoma with no evidence of metastases. Hemosiderin pigment accumulation was noted within macrophages and hepatocytes. [ABSTRACT FROM AUTHOR]

Introduction Hepatocellular carcinoma (HCC) in ectopic liver tissue is extremely rare. Presentation of case A 64-year-old woman presented initially with abdominal complaints. Computed tomography (CT) revealed a tumor in the diaphragm and laparoscopic resection of the tumor was performed. Histology showed HCC. During the next 4 years four more tumors, all of which showed HCC on histology and were located extrahepatically, was treated with laparoscopic resection. During this course the patient was followed with regular thoracoabdominal CT and measurement of serum alpha-fetoprotein (AFP). A negative magnetic resonance imaging (MRI) examination of the liver excluded a primary intrahepatic tumor. Discussion The literature available on ectopic HCC and the guidelines for management of HCC do not address the postoperative surveillance of patients undergoing curative treatment. A follow-up regime has been proposed by Hatzaras et al. (2014) to include cross-sectional imaging of the liver and measurement of serum AFP levels [1] . CT would be the preferred study of choice in a total radiologic investigation of the abdomen. While MRI is prone to artifacts due to movements, CT scans allows so rapid recordings that this no longer is an issue. An early investigation of the liver for intrahepatic HCC should nevertheless be performed early to exclude primary intrahepatic HCC. Conclusion We recommend that patients with ectopic HCC should be followed every 6 months with measurement of AFP and abdominal CT imaging. MRI of the liver should be performed early to exclude primary intrahepatic HCC. [ABSTRACT FROM AUTHOR]

The liver is more prone to infections that cause fibrosis, such as steatosis, non-alcoholic steatohepatitis, hepatotoxicity, cirrhosis, and hepatocellular carcinoma. Also, Viral hepatitis is a common condition worldwide it worsens into chronic inflammation of the liver. One of the healthiest fruits is the pomegranate for the body and health, as it contains a high nutritional value of minerals, vitamins, antioxidants, so we worked on this investigation to magnify the therapeutic applications of pomegranate fruits (POF) and peel (POP) in carbon tetrachloride-injected rats (Ccl4). The experiment was carried out in a caged animal. All rats were fed a basal diet for one week before the study, and they were divided into seven groups, each with six rats. As a control negative group (C–ve), the first group sample was fed only the basal diet for 28 days. The remaining rats (n = 36) were injected with carbon tetrachloride (Ccl4). Five groups were fed varying concentrations of (5 %, 10 %, 15 % POF, 5 %, and 10 % pomegranate peel (POP)), whereas one group was diagnosed with the illness and disease, and didn't even feed the experimental diet. The results revealed significant increases in T.BIL, D.BIL, and BIL in the serum of rats injected by CC14 to induce hepatopathy compared to the healthy group (normal rats). Also, the best treatment considering the serum D.BIL was recorded for the 5 % POF. [ABSTRACT FROM AUTHOR]

Objective To identify predictors of intrahepatic cholangiocarcinoma in cirrhotic patients scanned by gadobenate dimeglumine (Gd-BOPTA)-enhanced magnetic resonance (MR) imaging. Methods Fifty cirrhotic patients with 120 nodules, including 10 mass-forming intrahepatic cholangiocarcinomas and two combined hepatocellular carcinoma–cholangiocarcinomas, were scanned by Gd-BOPTA-enhanced MR imaging. Results T1 hypointensity [odds ratio (OR), 20.12], peripheral hyperintense rim at hepatic arterial phase (OR, 13.5), and iso -hyperintensity at hepatobiliary phase (OR 21.32) were found to be independent predictors of intrahepatic cholangiocarcinoma. Conclusions T1 hypointensity, peripheral hyperintense rim at hepatic arterial phase, and iso -hyperintensity at hepatobiliary phase are independent predictors of intrahepatic cholangiocarcinoma diagnosis in patients with liver cirrhosis. [ABSTRACT FROM AUTHOR]

Objectives: The objective was to evaluate time-trend bias in the context of a series of studies reporting that a national hepatitis B virus vaccination program (launched in mid-1980s) substantially reduced childhood hepatocellular carcinoma (HCC) incidence. Study Design and Setting: We applied an age-period-cohort model to evaluate the relative importance of age, time-trend (period), and vaccination (cohort) effect, respectively, on the incidence and mortality rate of HCC in boys and girls in Taiwan from 1980 to 2009. Results: HCC incidence increased with age. The period effect analysis revealed that the incidence of HCC started to decrease in 1980s, leveled off in mid-1990s, and declined again in mid-2000s among boys. The period effect was flat among girls. Cohort effect analysis demonstrated that among boys, the incidence of HCC started to decrease by those born in 2000-2004, which was 15 years later than the first vaccinated cohort. Among girls, the incidence rate started to decline before the mass vaccination program was initiated. The analysis showed a decline in mortality for boys and girls born in 1980s. Conclusion: Time trend may play a more important role than the universal vaccination program in interpretation of the observed early decreasing trend in HCC in children, especially among boys. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is the major malignant tumour of the liver. Its rupture is a serious and fatal complication. Its diagnosis and management are a major challenge in sub-Saharan Africa. The peri-hepatic packing: the only alternative for the management of hepatic tumour ruptures in resource-constrained hospitals. We are reporting the case of a 45 years old man, carrier of viral hepatitis B and poorly followed up, who presented a sudden picture of hemodynamic instability. A laparotomy allowed finding a hepatic tumour rupture. He benefited from a damage control by peri hepatic packing. Peri hepatic packing is a major solution in the management of ruptured liver tumour in Africa. • Tumour ruptures are very serious and life-threatening. • Their management is complex and requires an adapted technical platform. • This management is difficult in developing countries. • The alternative of packing is not negligible. [ABSTRACT FROM AUTHOR]

Background & Aims Liver transplantation from marginal donors is associated with ischemia/reperfusion (I/R) lesions, which may increase the risk of post-transplant hepatocellular carcinoma (HCC) recurrence. Graft reperfusion prior to retrieval (as for extracorporeal membrane oxygenation - ECMO) can prevent I/R lesions. The impact of I/R on the risk of cancer recurrence was assessed on a syngeneic Fischer-rat liver transplantation model. Methods HCC cells were injected into the vena porta of all recipients at the end of an orthotopic liver transplantation (OLT). Control donors were standard heart-beating, ischemic ones (ISC), underwent 10min or 30min inflow liver clamping prior to retrieval, and ischemic/reperfused (ISC/R) donors underwent 2h liver reperfusion after the clamping. Results I/R lesions were confirmed in the ISC group, with the presence of endothelial and hepatocyte injury, and increased liver function tests. These lesions were in part reversed by the 2h reperfusion in the ISC/R group. HCC growth was higher in the 10min and 30min ISC recipients (p=0.018 and 0.004 vs. control, as assessed by MRI difference between weeks one and two), and was prevented in the ISC/Rs (p=0.04 and 0.01 vs. ISC). These observations were associated with a stronger pro-inflammatory cytokine profile in the ISC recipients only, and the expression of hypoxia and HCC growth-enhancer genes, including Hmox1, Hif1a and Serpine1. Conclusions This experiment suggests that ischemia/reperfusion lesions lead to an increased risk of post-transplant HCC recurrence and growth. This observation can be reversed by graft reperfusion prior to retrieval. [ABSTRACT FROM AUTHOR]

Background and Aim To explore the expression and role of activating transcription factor 3 in human hepatocellular carcinoma. Methods Immunohistochemistry, Western blot assay and Real-time PCR were used to evaluate activating transcription factor 3 protein and gene level in HCC clinical samples. Results Activating transcription factor 3 expression is lowest in HCC, and the protein level is lower in patients with capsule invasion, while there is no association with other main clinical pathological features. Conclusions Low expression of ATF3 may function as a tumor suppressor during human hepatocellular oncogenesis and targeting ATF3 pathway might be beneficial for anti-HCC therapy. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is one of the most lethal and chemo-refractory cancers, clearly, alternative treatment strategies are needed. We utilized 10 nm gold nanoparticles as a scaffold to synthesize nanoconjugates bearing a targeting antibody (cetuximab, C225) and gemcitabine. Loading efficiency of gemcitabine on the gold nanoconjugates was 30%. Targeted gold nanoconjugates in combination with RF were selectively cytotoxic to EGFR expressing Hep3B and SNU449 cells when compared to isotype particles with/without RF (P < 0.05). In animal experiments, targeted gold nanoconjugates halted the growth of subcutaneous Hep3B xenografts in combination with RF exposure (P < 0.05). These xenografts also demonstrated increased apoptosis, necrosis and decreased proliferation compared to controls. Normal tissues were unharmed. We have demonstrated that non-invasive RF-induced hyperthermia when combined with targeted delivery of gemcitabine is more effective and safe at dosages ~ 275-fold lower than the current clinically-delivered systemic dose of gemcitabine. [ABSTRACT FROM AUTHOR]

Abstract: Hepatocellular adenomas (HCA) are benign neoplasms that rarely affect men. However, male subjects are more likely to develop a subset of β-catenin activated HCAs which are associated with a higher risk of malignant transformation. Moreover, glycogen storage disease is a known risk factor for the development of HCA. We report an unusual case of hepatocellular carcinoma arising in the background of multiple hepatic adenomas and glycogen storage disease type 2 in which a targeted liver biopsy failed to demonstrate the malignant component of the hepatocellular tumor. We discuss the main diagnostic criteria of HCA and its management implications. [Copyright &y& Elsevier]

Abstract: Objective: Hepatitis C virus (HCV) infection is the leading cause of liver disease, and Taiwan has among the highest prevalence of HCV infection in the general population in Northeast Asia, estimated at between 2% and 4%. The aim of this study was to estimate the number of patients living with chronic HCV infection in Taiwan and quantify the expected numbers in each of the five Metavir fibrosis stages. Methods: We applied a back-projection approach, using observed hepatocellular carcinoma incidence between 1979 and 2008 and a smoothed Expectation-Maximization algorithm to maximize a Poisson likelihood to estimate the previous incidence of HCV infection. The algorithm was coded in Excel and combined with the MOdelling the NAtural histoRy and Cost-effectiveness of Hepatitis model (a hepatitis C natural history markov model) to predict the past and future numbers in each Metavir fibrosis stage. Results: Incident cases were predicted to have peaked in 1972 at 56,634 annually, with the prevalence peaking in 1986 at 763,737 infections and falling to 578,203 infections in 2012. It was estimated that in 2012, 127,795 (23.0%), 105,545 (19.0%), 81,211 (14.6%), 123,939 (22.3%), and 116,823 (21.1%) subjects were in fibrosis stages F0, F1, F2, F3, and F4, respectively. Discussion: Our study provides HCV infection prevalence estimates, stratified by Metavir fibrosis stage, in Taiwan for 2012. This has potential implications for budget planning, particularly with the availability of emerging therapies because fibrosis stage is predictive of both rapid and sustained virological response; therefore, planning expected treatment response in a given population could be enhanced with this additional information. [Copyright &y& Elsevier]

Background The prognosis for patients with hepatocellular cancer (HCC) undergoing transarterial therapy (TACE/TAE) is variable. Methods We carried out Cox regression analysis of prognostic factors using a training dataset of 114 patients treated with TACE/TAE. A simple prognostic score (PS) was developed, validated using an independent dataset of 167 patients and compared with Child–Pugh, CLIP, Okuda, Barcelona Clinic Liver Cancer (BCLC) and MELD. Results Low albumin, high bilirubin or α-fetoprotein (AFP) and large tumour size were associated with a two- to threefold increase in the risk of death. Patients were assigned one point if albumin <36 g/dl, bilirubin >17 μmol/l, AFP >400 ng/ml or size of dominant tumour >7 cm. The Hepatoma arterial-embolisation prognostic (HAP) score was calculated by summing these points. Patients were divided into four risk groups based on their HAP scores; HAP A, B, C and D (scores 0, 1, 2 and >2, respectively). The median survival for the groups A, B, C and D was 27.6, 18.5, 9.0 and 3.6 months, respectively. The HAP score validated well with the independent dataset and performed better than other scoring systems in differentiating high- and low-risk groups. Conclusions The HAP score predicts outcomes in patients with HCC undergoing TACE/TAE and may help guide treatment selection, allow stratification in clinical trials and facilitate meaningful comparisons across reported series. [ABSTRACT FROM PUBLISHER]

Background: Management of hepatocellular carcinoma (HCC) often involves many subspecialist providers, as well as a broad range of treatment options. This study sought to evaluate referral and treatment patterns among patients with HCC at a large academic medical center. Methods: Data from our cancer registry between 2003-2011 were abstracted on 394 patients who were primarily diagnosed/treated for HCC at Johns Hopkins Hospital (JHH); data on patients who were diagnosed/treated with HCC elsewhere and who received secondary treatment at JHH ( n = 391) were also abstracted for comparison purposes. Results: Among the main cohort, the most common specialties to be consulted were surgery ( n = 225, 57.1 %), gastroenterology ( n = 225, 57.1 %), and interventional radiologist ( n = 206, 52.3 %), while only 96 (24.4 %) were referred to medical oncology. Factors associated with surgical consultation included younger age (odds ratio (OR) 3.35, 95 % CI 1.62-6.92), tumor size <5 cm (OR 1.82, 1.09-3.02), and unilobar disease (OR 2.94, 1.31-6.59) (all P < 0.05). Patients initially diagnosed/treated elsewhere had larger tumors (4 vs. 6 cm), bilateral disease (19.2 vs. 26.8 %), and were more likely to be seen by interventional radiology (all P < 0.05) Conclusions: Most patients were seen by surgeons, gastroenterologists, or interventional radiologists, with only a minority being seen by medical oncologists. Referral patterns depended on patient-level factors, as well as extent of disease. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: Fibrolamellar hepatocellular carcinoma (FL-HCC) and conventional hepatocellular carcinoma (HCC) cases in two consecutive paediatric HCC trials were analysed to compare outcome and derive treatment implications. Patients and methods: Data of 24 FL-HCC (24% PRETEXT IV) and 38 HCC (42% PRETEXT IV) cases from SIOPEL-2 and -3 (1995–1998, 1998–2006) were analysed. Patients were treated according to SIOPEL-2 and -3 high-risk protocol (carboplatin+doxorubicin alternating with cisplatin; seven preoperative, three postoperative cycles) or with primary surgery followed by chemotherapy as indicated. Results: Thirteen of 24 FL-HCC (54%) and 32/38 HCC (84%) were initially treated with chemotherapy. Eight FL-HCC (33%) and five HCC patients (13%) had primary surgery. Partial response was observed in 31% of FL-HCC versus 53% of HCC patients (p =0.17). Complete resection was achieved in ten FL-HCC and seven HCC patients (p =0.08). Three-year event free survival (EFS) was 22% for FL-HCC versus 28% for HCC. Overall survival (OS) was not significantly different at 3 years follow up (42% for FL-HCC versus 33% for HCC, p =0.24). EFS/OS Kaplan–Meier curves did not differ significantly, with median follow up of 43 (FL-HCC) and 60 (HCC) months. No significant correlation was found between potential prognostic factors and OS. In the entire cohort nine out of 23 (39%) patients with complete resection or orthotopic liver transplantation versus 34/39 (87%) without successful surgical treatment, died. Conclusions: Long-term OS in FL-HCC and HCC is similar. With low response rates, complete resection remains the treatment of choice. [Copyright &y& Elsevier]

BACKGROUND: Hepatocellular carcinoma arises in an environment of chronic injury, and woundhealing responses may vary by treatment. METHODS: Peripheral blood myeloid populations were quantified in 39 patients with hepatocellular carcinoma treated with surgical or endoluminal therapy. Macrophages were quantified in tissue when available. RESULTS: There was a similar expansion of myeloid populations after operative procedures compared with endoluminal treatments. Immunostaining for CD68 revealed no significant differences in the number of macrophages within benign versus malignant tumors and when tumors were compared with nontumor liver. Cytotoxic CD81 T cells were rare within tumors compared with the surrounding liver (P <.0001). Progression-free survival was reduced in patients with preoperative peripheral blood monocyte expansion (P <.05). CONCLUSIONS: These data provide preliminary evidence of poor prognostic significance of elevated peripheral blood monocyte counts. We propose that the inflammatory environment of hepatocellular carcinoma may represent a consistent feature to both predict and alter the course of disease. [ABSTRACT FROM AUTHOR]

Background Sorafenib has shown survival benefits in patients with advanced hepatocellular carcinoma (HCC) and Child-Pugh (CP) class A liver function. There are few prospective data on sorafenib in patients with HCC and CP class B. Patients and methods A consecutive prospective series of 300 patients with CP class A or B HCC were enrolled in a dual-phase trial to determine survival and safety data according to liver function (class A or B) in patients receiving oral sorafenib 800 mg daily. [Results of this study were presented in part at the ASCO 2012 Gastrointestinal Cancers Symposium, 19–21 January 2012. J Clin Oncol 2012; 30 (Suppl 4): abstract 306.] Results Overall progression-free survival (PFS), time to progression (TTP) and overall survival (OS) were 3.9, 4.1 and 9.1 months, respectively. For patients with CP class A versus B status, PFS was 4.3 versus 2.1 months, TTP was 4.2 versus 3.8 months and OS was 10.0 versus 3. 8 months. Extrahepatic spread was associated with worse outcomes but taken together with CP class, liver function played a greater role in reducing survival. Adverse events for the two CP groups were similar. Conclusion Although patients with HCC and CP class B liver function have poorer outcomes than those with CP class A function, data suggest that patients with CP class B liver function can tolerate treatment and may still benefit from sorafenib. [ABSTRACT FROM PUBLISHER]

Abstract: With increased understanding of cancer biology, a multitude of pathological, genetic, and molecular events that drive hepatocarcinogenesis, including angiogenesis, invasion, and metastasis, has been identified. Lately, they are being aggressively evaluated due to challenges involved in establishing early diagnosis, optimizing therapy for cancer inducing hepatotrophic viruses, minimizing the emergence of new tumors, and preventing recurrence after surgical resection or liver transplantation. This comprehensive review examines and critiques the evidence from published manuscripts reporting various tissue and serum biomarkers involved in hepatocellular carcinoma. These markers not only help in prediction of prognosis or recurrence, but may also assist in deciding appropriate modality of therapy and represent novel targets for potential therapeutic agents. [Copyright &y& Elsevier]

Summary: Hepatocellular cancer is a significant global health problem yet the prognosis for the majority of patients has not changed significantly over the past few decades. For patients with advanced disease, sorafenib is currently the standard of care providing a survival advantage of 2–3months in selected patients. Cytotoxic chemotherapy has been used for over 30years but definite evidence that it prolongs survival has been lacking. Resistance remains a significant barrier for both targeted and cytotoxic agents and an understanding of the underlying mechanisms is critical if outcomes are to be improved. Here, we summarise the past and current data that constitute the evidence base for chemotherapy in HCC, review the causes of chemoresistance and suggest strategies to overcome these barriers. [Copyright &y& Elsevier]

Abstract: Purpose: To implement a reliable, practical and reproducible treatment procedure, based on in-room kV-image guidance and respiratory control, for liver cancer patients treated with high dose conformal radiotherapy using a commercially available treatment system. Materials and methods: CT stimulation was conducted under voluntary breath hold or gating using the Varian Real-time Position Management™ (RPM) System. Treatments were delivered daily under kV image guidance to verify the diaphragmatic or lipiodol-defined tumor position. Results: Thirty-three patients with liver confined hepatocellular carcinoma were treated between May 2006 and Dec 2009. After a median follow-up period of 16.5months (range: 3.5–40.7), all but 2 patients demonstrated radiological tumor regression. Eight patients (24%) achieved complete remission. The median tumor shrinkage was 42% (27–100%). Subsequent in-field tumor progression was observed in only three patients (10%). For the 23 patients with abnormal alpha fetoprotein level, 22 of them showed biochemical response with a median AFP level drop of 78%. The treatment was well tolerated: Grade 3 toxicities occurred in 5 patients (1 leucopenia, 1 elevated liver enzyme and 3 elevated bilirubin level) but there was no grade 4 toxicity or treatment related death. The 1year overall survival rate is 71.7% and median survival time is 17.2months (3.5–40.7months). Conclusions: Excellent treatment results with minimal toxicities could be achieved in a clinical environment with a commercially available highly sophisticated radiotherapy system. [Copyright &y& Elsevier]

Introduction: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. It is traditionally difficult to cure, especially when discovered at later stages, making early diagnosis and intervention of paramount importance. HCC typically arises in the background of chronic liver disease and can have various morphologic appearances. One of the most difficult of these to recognize on early surveillance imaging is the infiltrative subtype, which can account for up to 13% of all HCC cases, and may be more closely associated with background hepatitis B infection.Discussion: Certain imaging characteristics can provide vital clues, including differing signal intensity on the T1 and T2 sequences of magnetic resonance imaging (MRI) and the presence/appearance of portal vein thrombus. Owing to the diffuse and infiltrating properties of this tumor, surgical resection and transplantation are rarely if ever viable therapeutic options. Other forms of liver-directed therapy have been attempted with limited success, having minimal efficacy and high morbidity. To date, there is no data available to determine if the various HCC subtypes respond to systemic therapy differently, so this may be the most reasonable approach. Left untreated, observed patients commonly progress to hepatic failure fairly rapidly.Conclusion: Infiltrative HCC can be extremely subtle, and therefore difficult to detect, especially in the background of cirrhosis. Providers caring for patients with hepatitis, chronic liver disease, and cirrhosis must be extremely vigilant in the evaluation of surveillance imaging in order to potentially discover this HCC subtype as early as possible and initiate a multidisciplinary treatment plan. [ABSTRACT FROM AUTHOR]

Summary: The incidence of hepatocellular carcinoma has shown an alarming increase in North America and Europe since 1980, as has the incidence of reported metastases to the oral region. Consequently, it is important that head and neck health care specialists be familiar with recent epidemiological trends and the histologic and recent immunohistochemical advances in the diagnosis of this deadly malignancy. Histologic features are reviewed, and recent advances in the immunohistochemical differential diagnosis are detailed and illustrated in two cases. A panel of immunohistochemical stains is recommended, some or all of which may be useful to differentiate poorly differentiated or pseudoglandular hepatocellular carcinoma from other metastatic adenocarcinomas to the oral and maxillofacial region. [ABSTRACT FROM AUTHOR]