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ABSTRACT Background & Aims Methods Results Conclusions Hepatocellular carcinoma (HCC) is the third leading cause of cancer‐related death worldwide. Liver transplantation (LT) is a curative treatment option. We investigated survival outcomes based on recipient‐donor sex constellation (RDSC) following LT.We performed a European Liver Transplant Registry analysis, including patients from 1988 to December 2022. The cohort was split into four RDSC groups: female donor female recipient (FDFR), female donor male recipient (FDMR), male donor female recipient (MDFR) and male donor male recipient (MDMR). Survival analysis, including death with recurrence, was performed.In 7601 LT for HCC with an overall median follow‐up of 22.6 months (5.8, 60.7), death was registered in 25.1% and, as primary cause of death, HCC tumour recurrence in 26.0%. There was no statistically significant difference on crude survival estimates among the different RDSC groups (log‐rank p = 0.66) with 10‐year overall survival (OS) of 54.5% in FDFR, 54.6% in FDMR, 59.1% in MDFR and 56.9% in MDMR. On multivariable analysis, RDSC showed a significant effect on OS (FDFR as reference): MDFR (aHR 0.72, p = 0.023). No significant difference was found for FDMR (aHR 0.98, p = 0.821) and MDMR (aHR 0.90, p= 0.288). Regarding overall registered causes of death, differences between RDSC groups were found in rejection (p = 0.017) and cardiovascular (p = 0.046) associated deaths.In female recipients undergoing LT for HCC, male donor grafts were associated with a 28% reduction of mortality compared to female donor grafts. [ABSTRACT FROM AUTHOR]

Background: Highly aggressive hepatocellular carcinoma (HCC) is characterized by high tumor recurrence and poor outcomes, but its definition and imaging characteristics have not been clearly described. Purpose: To develop and validate a fusion model on gadobenate dimeglumine‐enhanced MRI for identifying highly aggressive HCC. Study Type: Retrospective. Population: 341 patients (M/F = 294/47) with surgically resected HCC, divided into a training cohort (n = 177), temporal validation cohort (n = 77), and multiscanner validation cohort (n = 87). Field Strength/Sequence: 3T, dynamic contrast‐enhanced MRI with T1‐weighted volumetric interpolated breath‐hold examination gradient‐echo sequences, especially arterial phase (AP) and hepatobiliary phase (HBP, 80–100 min). Assessment: Clinical factors and diagnosis assessment based on radiologic morphology characteristics associated with highly aggressive HCCs were evaluated. The radiomics signatures were extracted from AP and HBP. Multivariable logistic regression was performed to construct clinical‐radiologic morphology (CR) model and clinical‐radiologic morphology‐radiomics (CRR) model. A nomogram based on the optimal model was established. Early recurrence‐free survival (RFS) was evaluated in actual groups and risk groups calculated by the nomogram. Statistical Tests: The performance was evaluated by receiver operating characteristic curve (ROC) analysis, calibration curves analysis, and decision curves. Early RFS was evaluated by using Kaplan–Meier analysis. A P value <0.05 was considered statistically significant. Results: The CRR model incorporating corona enhancement, cloud‐like hyperintensity on HBP, and radiomics signatures showed the highest diagnostic performance. The area under the curves (AUCs) of CRR were significantly higher than those of the CR model (AUC = 0.883 vs. 0.815, respectively, for the training cohort), 0.874 vs. 0.769 for temporal validation, and 0.892 vs. 0.792 for multiscanner validation. In both actual and risk groups, highly and low aggressive HCCs showed statistically significant differences in early recurrence. Data Conclusion: The clinical‐radiologic morphology‐radiomics model on gadobenate dimeglumine‐enhanced MRI has potential to identify highly aggressive HCCs and non‐invasively obtain prognostic information. Level of Evidence: 4 Technical Efficacy: Stage 2 [ABSTRACT FROM AUTHOR]

Background and aims: Second‐generation direct‐acting antivirals (2G DAA) to cure HCV have led to dramatic clinical improvements. HCV‐associated hepatocellular carcinoma (HCC), however, remains common. Impaired immune tumor surveillance may play a role in HCC development. Our cohort evaluated the effects of innate immune types and clinical variables on outcomes including HCC. Methods: Participants underwent full HLA class I/KIR typing and long‐term HCV follow‐up. Results: A total of 353 HCV+ participants were followed for a mean of 7 years. Cirrhosis: 25% at baseline, developed in 12% during follow‐up. 158 participants received 2G DAA therapy. HCC developed without HCV therapy in 20 subjects, 24 HCC after HCV therapy, and 10 of these after 2G DAA. Two predictors of HCC among 2G DAA‐treated patients: cirrhosis (OR, 10.0, p = 0.002) and HLA/KIR profiles predicting weak natural killer (NK) cell‐mediated immunity (NK cell complementation groups 6, 9, 11, 12, OR of 5.1, p = 0.02). Without 2G DAA therapy: cirrhosis was the main clinical predictor of HCC (OR, 30.8, p < 0.0001), and weak NK‐cell‐mediated immunity did not predict HCC. Conclusion: Cirrhosis is the main risk state predisposing to HCC, but weak NK‐cell‐mediated immunity may predispose to post‐2G DAA HCC more than intermediate or strong NK‐cell‐mediated immunity. [ABSTRACT FROM AUTHOR]

Background and Aims: The World Health Assembly recommends integration of palliative care into treatment of patients with any life‐limiting condition, yet patients with non‐malignant disease are less likely to receive specialist palliative care (SPC). This study compares SPC offered to patients with hepatocellular carcinoma (HCC) versus patients with chronic liver disease without HCC (CLD without HCC). Methods: Patients who died from CLD or HCC over 5 years (2013–2017) in England were identified using a dataset linking national data on all hospital admissions (Hospital Episode Statistics – HES) with national mortality data from the Office for National Statistics (HES – ONS). The primary outcome was the proportion of patients who received inpatient SPC in their last year of life (LYOL). Secondary outcomes were (1) early inpatient SPC input and (2) the proportion dying in a hospice. The outcomes were compared between patients with HCC and CLD without HCC. Results: 29 669 patients were identified, 8143 of whom had HCC. Patients with HCC were significantly more likely to receive inpatient SPC input—adjusted OR 3.74 (95% CI 3.52–3.97) and early inpatient SPC input—adjusted OR 7.26 (95% CI 6.38–8.25) and die in a hospice OR 8.23 (95% CI 7.33–9.24) than patients with CLD without HCC. Conclusions: These data highlight the stark inequity in access to SPC services between patients with HCC and patients with CLD without HCC in England. Addressing these inequities will improve end‐of‐life care for patients with CLD. [ABSTRACT FROM AUTHOR]

There is scant literature on primary nonhematopoietic malignant liver tumours (PMLT) in cats. In this retrospective study, medical data of 40 cats diagnosed with PMLT were reviewed over a period of 22 years (2000–2021). The most frequent epithelial tumours were hepatocellular (42.5%) and bile duct carcinomas (32.5%), only six (15%) cats had mesenchymal tumours. The median age was 13 years and clinical signs commonly included ano‐/hyporexia (62.5%), apathy/lethargy (52.5%), weight loss (42.5%) and vomiting (35%). At initial diagnosis, metastases were confirmed in 1 (2.5%) and suspected in three (7.5%) cats. Massive was the most frequent morphology (75%). Most intrahepatic tumours were left‐sided (54.2%) with the left medial lobe being primarily affected (25%). Extrahepatic tumours were rare (5%). In 34 (85%) cats, liver lobectomy was performed (surgery group), four (10%) were treated palliatively (non‐surgery group), and two (5%) received no treatment. Intraoperative complications occurred in 11.8% with four (15.4%) postoperative deaths. Recurrence was detected in 28.6% at a median of 151 days (range, 79–684 days), while postoperative metastases were suspected in 21.4% at a median of 186 days (range, 79–479 days). The median survival time (MST) was significantly longer in cats of the surgery group (375 days) than in the non‐surgery group (16 days) (p =.002). MST was 868 days for hepatocellular compared to 270 days for bile duct carcinomas (p =.06). In summary, liver lobectomy is associated with prolonged survival times and good prognosis in cats with hepatocellular, and an acceptable prognosis in cats with bile duct carcinoma. [ABSTRACT FROM AUTHOR]

Aim: Cabozantinib showed a favorable benefit–risk profile in Japanese patients with advanced hepatocellular carcinoma (HCC) in an open‐label, phase II study (NCT03586973). This analysis presents cumulative data to final database lock. Methods: Patients with previously treated, advanced HCC received cabozantinib 60 mg/day. Progression‐free survival (PFS) and tumor response rates in prior‐sorafenib and sorafenib‐naïve cohorts were assessed by independent radiology committee (IRC) and an investigator. Liver function was evaluated by albumin–bilirubin (ALBI) score. Results: Median cabozantinib exposure was 5.6 months. In the prior‐sorafenib cohort (n = 20), median PFS was 7.4 months per IRC assessment and 5.6 months per investigator assessment. In the sorafenib‐naïve cohort (n = 14), median PFS was 3.6 and 4.4 months per IRC and investigator assessment, respectively. Six‐month PFS rate per IRC and investigator assessment in the prior‐sorafenib cohort was 59.8% and 49.5%, respectively, and in the sorafenib‐naïve cohort was 16.7% and 35.7%, respectively. Disease control rate by both IRC and investigator assessment was 85.0% in the prior‐sorafenib cohort and 64.3% in the sorafenib‐naïve cohort. Median overall survival (Kaplan–Meier estimate) was 19.3 and 9.9 months in the prior‐sorafenib and sorafenib‐naïve cohort, respectively. Mean ALBI score remained relatively constant in patients able to continue treatment. The most frequent adverse events were palmar–plantar erythrodysesthesia syndrome, diarrhea, hypertension, and decreased appetite. No new safety concerns were identified. Conclusions: Cabozantinib showed efficacy and a manageable safety profile in Japanese patients with advanced HCC. [ABSTRACT FROM AUTHOR]

Background: Stereotactic body radiotherapy (SBRT) has been established as a safe and effective treatment for hepatocellular carcinoma (HCC). Currently, there are no consensus guidelines to advise optimal patient selection and radiotherapy planning parameters to minimise the risk of surgical and medical complications after liver transplant (LT) in patients who have had prior SBRT for HCC, whilst optimising treatment benefit. Methods: We performed a retrospective analysis of all adult patients who received liver SBRT as a bridge to LT at a tertiary institution between 2017 and 2019. Results: Nine patients received SBRT as bridging therapy to LT. HCC location varied from peripheral to central/hilar regions and HCC diameter was 13–54 mm. Median time between SBRT and LT was 141 days (range 27–461 days). Median operating time was 360 min (range 270–480 min). Four patients (44%) had visible SBRT reaction or fibrosis at the time of LT. SBRT reaction resulted in clinical impact in one patient (11%) only, where vascular clamping of the IVC was required for 10 min. Conclusion: SBRT is a safe and effective treatment for HCC enabling patients to remain within LT criteria, even for lesions not amenable to other more conventional bridging therapies. We describe a preliminary decision pathway to guide the optimal use of SBRT as a bridge to LT developed in our institution. [ABSTRACT FROM AUTHOR]

Aims: To investigate the efficacy and safety of lenvatinib and idarubicin‐loaded drug‐eluting beads transarterial chemoembolization (IDADEB‐TACE) in primary advanced hepatocellular carcinoma (HCC). Methods: This retrospective study included patients with primary advanced HCC who received either lenvatinib monotherapy or lenvatinib plus IDADEB‐TACE as first‐line treatment from September 2019 to September 2020 at three institutes. Overall survival (OS), time to progression (TTP), objective response rate (ORR), and adverse events were compared. Propensity score‐matching was used to reduce the influence of confounding factors on the outcomes. Results: The study reviewed 118 patients who received lenvatinib plus IDADEB‐TACE (LIDA group) and 182 who received lenvatinib alone (LEN group). After propensity score‐matching, 78 pairs of patients remained. Compared to patients in the LEN group, those in the LIDA group had better post‐treatment ORR (57.7% vs. 25.6%, p < 0.001, respectively), median OS and TTP (15.7 vs. 11.3 months, hazard ratio [HR] = 0.50, p < 0.001; 8.0 vs. 5.0 months, HR = 0.60, p = 0.003, respectively), 6‐ and 12‐month OS rates (88.5% vs. 71.4%; 67.6% vs. 43.4%, respectively), and progression‐free rates at 6 and 12 months (60.3% vs. 42.3%; 21.1% vs. 10.3%, respectively). Vascular invasion, α‐fetoprotein level, and treatment type were independent OS predictors, and vascular invasion and treatment type were independent TTP predictors. Incidences of nausea/vomiting, fever, abdominal pain, and increased ALT/AST were higher in the LIDA group than in the LEN group. Conclusions: Lenvatinib plus IDADEB‐TACE is well‐tolerated and more effective than lenvatinib monotherapy in patients with advanced HCC. [ABSTRACT FROM AUTHOR]

Organophosphate flame retardants (OPFRs) have been widely used due to their unique properties. The OPFRs are mainly metabolized in the liver. However, whether the plasma level of OPFRs was involved in the progression of liver cancer remains unclear. Triphenyl phosphate (TPP) is one of the OPFRs that are mostly detected in environment. In this study, we performed CCK8, ATP, and EdU analyses to evaluate the effect of TPP at the concentrations at 0.025–12.8 μM on the proliferation, invasion, and migration of Hep3B, a hepatocellular carcinoma (HCC) cell line. Tumor‐bearing mouse model was used for in vivo validation. The results showed that low concentrations of TPP at (0.025–0.1 μM), which are obtained in the plasma of patients with cancers, remarkably promoted cell invasion and migration of Hep3B cells. Animal experiments confirmed that TPP treatment significantly enhanced tumor growth in the xenograft HCC model. To explore the possible molecular mechanisms that might mediate the actions of TPP on Hep3B cells, we profiled gene expression in groups treated with or without TPP at the concentrations of 0.05 and 0.1 μM using transcriptional sequencing. Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, and Protein–protein interaction (PPI) analyses demonstrated that pathways affected by differentially expressed genes (DEGs) were mainly in nuclear‐transcribed mRNA catabolic processes, cytosolic ribosome, and ATPase activity. A 0.05 and 0.1 μM TPP led to up‐regulation of a series of genes including EREG, DNPH1, SAMD9, DUSP5, PFN1, CKB, MICAL2, SCUBE3, and CXCL8, but suppressed the expression of MCC. These genes have been shown to be associated with proliferation and movement of cells. Taken together, our findings suggest that low concentration of TPP could fuel the proliferation, invasion, and migration of HCC cells. Thus, TPP is a risk factor in the progression of HCC in human beings. [ABSTRACT FROM AUTHOR]

Aim: Tyrosine kinase inhibitors target transarterial chemoembolization (TACE)‐mediated vascular endothelial growth factor to inhibit tumor revascularization and to slow tumor progression. The present study aimed to compare the clinical outcomes of TACE combined with lenvatinib (TACE‐lenvatinib) and TACE combined with sorafenib (TACE‐sorafenib) in patients with unresectable hepatocellular carcinoma (HCC). Methods: The clinical data of patients diagnosed with unresectable HCC who received TACE‐lenvatinib or TACE‐sorafenib between January 2018 and April 2021 were retrospectively reviewed. The tumor response, progression‐free survival (PFS), overall survival (OS), and adverse events (AEs) were evaluated and compared between the two groups. Results: A total of 112 patients were enrolled and classified into the TACE‐lenvatinib group (n = 53) and the TACE‐sorafenib group (n = 59). The objective response rates of patients in the TACE‐lenvatinib and TACE‐sorafenib groups were 54.7% and 44.1%, respectively (p = 0.260), and the disease control rates (DCRs) were 81.1% and 61.0% (p = 0.020). The median PFS time was significantly longer in the TACE‐lenvatinib group than in the TACE‐sorafenib group (10.7 vs. 6.0 months; p = 0.002). The median OS time between the TACE‐lenvatinib and TACE‐sorafenib groups also showed a significant difference (30.5 vs. 20.5 months, p = 0.018). All treatment‐related AEs and grade 3/4 AEs were comparable between the two groups (p > 0.05). Conclusion: Compared to TACE‐sorafenib, TACE‐lenvatinib was associated with better DCR, PFS and OS outcomes in patients with unresectable HCC. In subgroups of Barcelona Clinic Liver Cancer B stage or TACE‐refractory patients, TACE‐lenvatinib also showed a trend of superiority. [ABSTRACT FROM AUTHOR]

Background and Aims: Radiological prediction of microvascular invasion (MVI) of hepatocellular carcinoma (HCC) is essential but few models were clinically implemented because of limited interpretability and generalizability. Methods: Based on 2096 patients in three independent HCC cohorts, we established and validated an MVI predicting model. First, we used data from the primary cohort to train a 3D‐ResNet network for MVI prediction and then optimised the model with "expert‐inspired training" for model construction. Second, we implemented the model to the other two cohorts using three implementation strategies, the original model implementation, data sharing model implementation and skeleton sharing model implementation, the latter two of which used part of the cohorts' data for fine‐tuning. The areas under the receiver operating characteristic curve (AUCs) were calculated to compare the performances of different models. Results: For the MVI predicting model, the AUC of the expert‐inspired model was 0.83 (95% CI: 0.77–0.88) compared to 0.54 (95% CI: 0.46–0.62) of model before expert‐inspiring. Taking this model as an original model, AUC on the second cohort was 0.76 (95% CI: 0.67–0.84). The AUC was improved to 0.83 (95% CI: 0.77–0.90) with the data‐sharing model, and further improved to 0.85 (95% CI: 0.79–0.92) with the skeleton sharing model. The trend that the skeleton sharing model had an advantage in performance was similar in the third cohort. Conclusions: We established an expert‐inspired model with better predictive performance and interpretability than the traditional constructed model. Skeleton sharing process is superior to data sharing and direct model implementation in model implementation. [ABSTRACT FROM AUTHOR]

Background: Current major guidelines for diagnosis of hepatocellular carcinoma (HCC) based on imaging findings are different from each other and do not include clinical risk factors as a diagnostic criteria. Purpose: To developed and validated a new diagnostic score system using MRI and clinical features as applied in chronic hepatitis B patients. Study Type: Retrospective observational study. Subject: A total of 418 treatment‐naïve patients (out of 902 patients) with chronic hepatitis B having 556 lesions suspected for HCC which were eligible for curative treatment. Field Strength/sequence: T1W GRE in‐ and opposed‐phase, T2W FSE, DWI, and T1W 3D‐GRE dynamic contrast‐enhanced sequences at 1.5 T and 3 T. Assessment: Six radiologists with 7–22 years of experience independently evaluated MR images based on Liver Imaging Reporting and Data System (LI‐RADS) version 2018. Statistical Tests: Based on logistic regression analysis of MRI features and clinical factors, a risk score system was devised in derivation cohorts (268 patients, 352 lesions) and externally validated (150 patients, 204 lesions). The performance of the new score system was assessed by Harell's c‐index. Using cutoff value of 12, maintaining positive predictive value ≥95%, the diagnostic performances of the score system were compared with those of LR‐5. Results: The 15‐point diagnostic scoring system used MRI features (lesion size, nonrim arterial phase hyperenhancement, portal venous phase hypointensity, hepatobiliary phase hypointensity, and diffusion restriction) and clinical factors (alpha‐fetoprotein and platelet). It showed good discrimination in the derivation (c‐index, 0.946) and validation cohorts (c‐index, 0.907). Using a risk score of 12 as a cut‐off, this system yielded higher sensitivity than LR‐5 (derivation cohort, 76.8% vs. 52.1%; validation cohort, 73.4% vs. 49.5%) without significant decrease in specificity (derivation cohort, 93.1% vs. 97.2%, P = 0.074; validation cohort, 91.7% vs. 96.1%, P = 0.299). Data Conclusion: A new score system showed improved sensitivity in chronic hepatitis B patients compared to LI‐RADS without significant compromise in specificity. Evidence Level: 3 Technical Efficacy: Stage 2. [ABSTRACT FROM AUTHOR]

Background and Aims: Sequential therapy with molecular‐targeted agents (MTAs) is considered effective for unresectable hepatocellular carcinoma (HCC) patients. This study purposed to evaluate the efficacy of sequential therapy with sorafenib (SORA) as a first‐line therapy and to investigate the therapeutic impact of SORA in nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steato hepatitis (NASH)‐related HCC. Methods: We evaluated 504 HCC patients treated with SORA (Study‐1). The times of administration for sorafenib from 2009 to 2015, 2016 to 2017, and 2018 and later were defined as the early‐, mid‐, and late‐term periods, respectively. Among them, 180 HCC patients treated with SORA in addition to MTAs in the mid‐ and late‐term periods were divided into groups based on disease etiology (NAFLD or NASH [n = 37] and viral or alcohol [n = 143]), and outcomes were compared after inverse probability weighting (IPW) (Study‐2). Results: Overall survival (OS) of HCC patients who received sequential MTA therapy after first‐line SORA was significantly longer. The median survival times (MST) were 12.6 versus 17.6 versus 17.4 months in the early‐term group, mid‐term group, and the later‐time group (early vs. mid, p = 0.014, early vs. later. p = 0.045), respectively. (Study‐1). In Study‐2, there was no significant differences in OS between the Virus/alcohol group and the NAFLD/NASH group in patients who received sequential therapy (MST was 23.4 and 27.0 months p = 0.173, respectively). The NAFLD or NASH, female sex, albumin‐bilirubin (ALBI) grade 2b, and major Vp (Vp3/Vp4) were significant factors for OS treated with SORA. Conclusions: Sequential therapy with SORA as the first‐line treatment improved the prognosis of unresectable HCC patients and was effective regardless of HCC etiology. [ABSTRACT FROM AUTHOR]

Aim: We investigated effects of direct‐acting antiviral (DAA)–induced sustained virological response (SVR) after liver resection in patients with hepatitis C virus (HCV)–related hepatocellular carcinoma (HCC) for postoperative recurrence and survival. Methods: Surgical outcomes in 18 patients with postoperative DAA‐induced SVR (HCC‐DAA group) were compared with those in 23 patients with preoperative DAA‐induced SVR (DAA‐HCC group) and those in 10 patients who did not receive DAA therapy (control group). Patients who received DAA therapy >1 year after surgery and those with recurrence <1 year after surgery were excluded. Results: Serum concentrations of aminotransferases improved 1 year after surgery in both the HCC‐DAA and DAA‐HCC groups. The number of HCC‐DAA patients with albumin‐bilirubin (ALBI) grade 1 increased from 11 to 15. The disease‐free survival rate did not differ between HCC‐DAA group (3 years, 60%) and the other two groups (DAA‐HCC group, 92% and control group, 60%). The 3‐year overall survival rates were better in the DAA‐HCC group (84%) and HCC‐DAA group (100%) than in the control group (46%; all ps < 0.05 according to Holm's test). Multivariable analysis revealed that tumor stage was an independent risk factor for postoperative recurrence, and ALBI grade at 1 year after surgery was predictive of postoperative survival, but DAA‐induced SVR was neither. Conclusions: Although postoperative DAA‐induced SVR itself may not suppress postoperative recurrence, improvement in liver function as a result of DAA administration after surgery may prolong postoperative survival. [ABSTRACT FROM AUTHOR]

Background: Inflammation and the immune system significantly impact the development, progression, and treatment response of hepatocellular carcinoma (HCC). This retrospective study investigated the neutrophil-to-lymphocyte ratio (NLR) as a prognostic biomarker in Western patients with HCC in the setting of chronic viral hepatitis. Methods: Patients diagnosed with HCC from 2005 to 2016 were selected from a tertiary care institution. NLR was calculated within 30 days prior to treatment and dichotomized at the median. Kaplan–Meier overall survival (OS) curves and Cox hazard proportional models were utilized. Tumor and liver reserve parameters were included in multivariable analyses (MVA). Results: A total of 581 patients met inclusion criteria (median age 61.0 yr; 78.3% male; 66.3% Caucasian) with median OS = 34.9 mo. 371 patients (63.9%) had viral hepatitis, of which 350 had hepatitis C (94.3%). The low-NLR group (

Background and Aim: Percutaneous radiofrequency ablation (RFA) is a minimally invasive and curative local treatment for hepatocellular carcinoma (HCC). However, serious concerns remain regarding critical recurrences such as metastasis, dissemination, and/or seeding due to RFA. In August 2006, we introduced selective feeding artery ablation before tumor ablation to reduce the risk of critical recurrence by blocking tumor blood flow. The aim of the present study was to clarify whether feeding artery ablation before tumor ablation can reduce the risk of critical recurrence after RFA. Methods: This study retrospectively analyzed 279 patients with primary, solitary, and hypervascular HCC ≤5 cm in diameter who were treated with RFA alone between April 2001 and August 2013. Critical recurrence was defined as intra‐ or extrahepatic metastasis, dissemination, or seeding that was difficult to treat radically. Results: Of the 279 HCC patients, 157 patients were treated with conventional RFA alone, and 122 patients underwent RFA with prior feeding artery ablation. Although no significant differences were seen in the rates of local tumor progression‐free survival, overall recurrence‐free survival, or overall survival between a conventional RFA group and a prior feeding artery ablation group, significant differences were seen in rates of critical recurrence‐free survival and cancer‐specific survival (5‐year, 69 vs 81%, P = 0.01 and 76 vs 88%, P = 0.03, respectively). On multivariate analysis, prior feeding artery ablation, tumor diameter, and alpha‐fetoprotein were independent factors related to critical recurrence. Conclusions: Feeding artery ablation before tumor ablation may reduce the risk of critical recurrence. [ABSTRACT FROM AUTHOR]

Liver damage is a rare side effect of clopidogrel. That is reversible in most cases. Considering the widespread use of this medication in cardiovascular diseases, the management of hepatotoxicity requires further meticulous investigation. [ABSTRACT FROM AUTHOR]

Background: To develop and validate nomograms that can be used to predict outcomes in individuals suffering alpha‐fetoprotein (AFP) negative hepatocellular carcinoma (HCC) after radical resection. Methods: A total of 509 AFP‐negative HCC patients who received hepatectomy between January 2009 and March 2013 in our center were randomized into training and validation cohorts. Nomograms for both overall and recurrence‐free survival (OS and RFS, respectively) were established based on the predictors in the training cohort. Nomograms performance and discriminative power were assessed with concordance index (C‐index) values and decision curve analyses (DCA). The results were validated in the validation cohort. Results: Alkaline phosphatase, liver cirrhosis, tumor size, satellite lesions, microvascular invasion, and Edmondson‐Steiner grade were significantly linked to OS and RFS. Sex and tumor number were additional predictors for RFS. The OS nomogram had a C‐index value of 0.742, which was better than that for the AJCC eighth edition (0.632), BCLC system (0.553), and JIS score (0.557) (all P <.001). The RFS nomogram C‐index was 0.669, which was also superior to that of the AJCC eighth (0.608), BCLC stage (0.554), JIS score (0.551), and model of Gan et al (0.636) (P <.05 for all). Calibration curves indicated a good agreement between observed actual outcomes and predicted values. Kaplan‐Meier curves and DCA indicated that nomograms were powerful in discrimination and clinical usefulness. These results were supported by the validation cohort. Conclusions: These nomograms presented more accurate prognostic prediction in patients with AFP‐negative HCC after hepatectomy. [ABSTRACT FROM AUTHOR]

Comparisons of time‐to‐event clinical outcomes between patients with or without a sustained virological response (SVR) after treatment of chronic hepatitis C infection have been repeatedly reported in emphasizing the potential clinical impact of treatment. Combining recently published data from different therapeutic eras with simple examples, we show that comparisons of incidence rates by SVR status between patients treated with interferon‐based and interferon‐free regimens are flawed through confounding by prognosis. The relevant analysis for evaluating and comparing the clinical impact of these regimens should be a comparison between randomized treatment groups, irrespective of the SVR status. [ABSTRACT FROM AUTHOR]

Hematologic and neurological expression 1 (HN1) has been reported to involved in certain cancers, but its role in hepatocellular carcinoma (HCC) is largely unknown. The contribution of HN1 to HCC progression was investigated in the present study. We found that HN1 was significantly up‐regulated in HCC tissues, compared with normal tissues, by analyzing the Oncomine and Human Protein Atlas database; and found that high expression of HN1 was markedly associated with worse overall survival, relapse‐free survival, progression‐ free survival and disease‐specific survival in HCC patients via exploring the Kaplan‐Meier plotter database. Functional assays revealed that HN1 knockdown by siRNA induced G1 cell cycle arrest, and inhibited the growth and migration of HCC cells; accordingly, HN1 over‐expression promoted HCC cells proliferation and migration. Further studies indicated that HN1 knockdown reduced the expression of cyclin D1 and CDK4, while upregulated the cell cycle inhibitor p21WAF1/Cip1. Moreover, HN1 knockdown decreased c‐Met (receptor tyrosine kinase of hepatocyte growth factor) expression, and suppressed ERK activation, which is a common downstream signaling pathway triggered by c‐Met; consistently, HN1 over‐expression reversed these effects. Meanwhile, down‐regulation of c‐Met partly eliminated the effect of HN1 over‐expression in HCC cells. Thus, the present findings suggested that HN1 promotes the progression of HCC to some extent by up‐regulating the expression of c‐Met, and may act as a potential biomarker and therapeutic target for the treatment of HCC. [ABSTRACT FROM AUTHOR]

Background and Aim: The study aims to assess the influence of pretreatment tumor growth rate (TGR) on modified response evaluation criteria in solid tumors (mRECIST) objective response (OR) after a first session of selective transarterial chemoembolization (TACE) for the treatment of hepatocellular carcinoma (HCC). Methods: One hundred fifteen patients (101 men [88%], mean 65.1 ± 10.5 years [range 26–87]) with 169 tumors (mean 34.2 ± 29.3 mm [10–160]), undergoing a first session of selective TACE for the treatment of HCC between 2011 and 2016, were included. TGR was calculated as the percentage change in tumor volume per month (%/month) on imaging before treatment. TGR cut‐off for prediction of OR was identified by receiver operating characteristic curve analysis. Results: Overall 88/189 (52%) and 46/189 (27%) tumors showed complete response (CR) and partial response (PR) (OR rate 79%), while 32/189 (19%) showed stable disease (SD), and 3/189 (2%) were progressive disease (PD) on computed tomography at 1‐month post‐TACE. The mean pretreatment TGR was 12.0 ± 15.4 (−3.2–90.4) %/month. TGR of tumors showing CR, PR, SD, and PD was a mean 13.2 ± 16.4%, 12.1 ± 15.1%, 5.3 ± 4.5%, and 44.8 ± 20.4%, respectively (P < 0.001). The three tumors showing PD had TGR values > 20%/month. TGR was significantly higher in tumors with OR (12.8 ± 15.9% vs 5.3 ± 4.5% in SD, P = 0.009). A cut‐off value of 6.5%/month had the highest predictive value of OR (AUROC 0.65 ± 0.05, P = 0.009). Conclusion: Pretreatment TGR is highly variable in HCC before TACE with a U‐shaped distribution for the prediction of tumor response. It provides insight into tumor biology that may be used during pretreatment workup to help stratify patients. [ABSTRACT FROM AUTHOR]

Background: Hepatocellular carcinoma (HCC) rarely involves the biliary tree and may be inadvertently sampled on bile duct brushings (BDBs). Methods: The pathology archives of 5 institutions were searched for BDBs with HCC involvement. Results: A total of 17 BDBs from 14 patients were obtained. There was a male:female ratio of 6:1; the median age of the patients was 59.5 years (range, 22‐80 years). The median hepatic tumor size was 6.2 cm (range, 2.2‐13.0 cm). HCC risk factors included viral hepatitis (5 patients), cirrhosis (5 patients), hemochromatosis (1 patient), and alcoholic steatohepatitis (1 patient). Jaundice with elevated bilirubin, liver enzymes, and α‐fetoprotein was common. Endoscopic retrograde cholangiopancreatography demonstrated bile duct dilatation, polypoid intraductal masses (5 samples), clots/debris (2 samples), or strictures (4 samples). All BDBs had single and clustered large cells with naked atypical nuclei, granular cytoplasm, high nuclear/cytoplasmic ratios, and nuclei with prominent macronucleoli. Less common findings included clear/microvesicular cytoplasm (35%), papillae (29%), and anisonucleosis (35%). Classic HCC features (widened trabeculae [35%], endothelial wrapping [24%], multinucleation [24%], and cytoplasmic bile pigment [35%]) were uncommon. A total of 11 BDBs were diagnosed as malignant (10 with HCC and 1 with cholangiocarcinoma), 2 were diagnosed as atypical, and 1 BDB was diagnosed as negative; approximately two‐thirds were found to have polysomy on fluorescence in situ hybridization. Approximately 71% of patients died of disease at a median of 3.5 months. Conclusions: HCC may extend into the intrahepatic and/or extrahepatic biliary tree, causing masses and/or strictures that may be sampled on BDB. Although cytologically malignant, the classic features of HCC are uncommon, which can cause misdiagnosis. Cytopathologists should be mindful of this differential when evaluating BDBs, particularly when concomitant liver masses and/or HCC risk factors are present. Because of the associated high mortality and rapid rate of death, its presence should be conveyed clearly in pathology reports. Biliary tree involvement by hepatocellular carcinoma (HCC) may result in tumor sampling by bile duct brushing. Cytopathologists should be mindful of this differential, particularly when concomitant liver masses and/or HCC risk factors are present. [ABSTRACT FROM AUTHOR]

Background: There are large variations in prognosis among hepatocellular carcinoma (HCC) patients undergoing radiofrequency ablation (RFA). However, current staging or scoring systems hardly discriminate the outcome of HCC patients treated with RFA. Methods: A total of 757 treatment‐naïve HCC patients undergoing RFA (derivation cohort) were analyzed to establish a nomogram for disease‐free survival (DFS) based on Cox proportional hazard regression model. Accuracy of the nomogram was assessed and compared with conventional staging or scoring systems. Furthermore, external validation was performed in an independent cohort including 208 patients (validation cohort). Results: Tumor size, tumor number, alpha‐fetoprotein, prothrombin induced by vitamin K absence‐II, lymphocyte count, albumin, and presence of ascites were adopted to construct the prognostic nomogram from the derivation cohort. Calibration curves to predict probability of DFS at 3 and 5 years after RFA showed good agreements between the nomogram and actual observations. The concordance index of the present nomogram was 0.759 (95% confidence interval 0.728‐0.790), which was superior to those of conventional staging or scoring systems (range 0.505‐0.683, all P < .001). These results were also reproduced in the validation cohort. Conclusion: Our simple‐to‐use nomogram optimized for treatment‐naïve HCC patients undergoing RFA provided better prognostic performance than conventional staging or scoring systems. [ABSTRACT FROM AUTHOR]

Aim: The clinical impact of serosal invasion by hepatocellular carcinoma (HCC) remains unclear. This study aimed to clarify the significance of serosal invasion as a prognostic factor for patients who underwent hepatectomy for HCC. Methods: This retrospective study investigated patients who underwent hepatectomy for HCC between October 2003 and September 2016 in Ehime University Hospital (Toon, Japan). A total of 161 cases were enrolled after excluding cases of concomitant distant metastasis, macroscopic tumor remnant, mixed HCC, and rehepatectomy. We classified these 161 patients into groups with serosal invasion detected (S[+]) and serosal invasion undetected (S[−]). We compared patient characteristics, perioperative data, pathological findings, and prognosis between S(+) and S(−) groups. Results: Serosal invasion was observed in 19 of the 161 patients (12%). The 5‐year recurrence‐free survival rate was lower for S(+) (13.0%) than for S(−) (28.7%, P = 0.006). The 5‐year overall survival (OS) rate was lower for S(+) (24.7%) than for S(−) (63.9%, P < 0.001). Regarding OS, serosal invasion, preoperative α‐fetoprotein value, presence of invasion to hepatic veins, and liver cirrhosis were independent predictors in multivariate analyses. The 3‐year OS rate after recurrence was poorer in the S(+) group (22.9%) than in the S(−) group (49.7%, P = 0.001). Conclusions: Serosal invasion was a strong predictor of worse outcomes after hepatectomy for HCC. Patients showing serosal invasion need close postoperative follow‐up or consideration of adjuvant treatment. [ABSTRACT FROM AUTHOR]

Optimal patient management benefits from comprehensive and accurate pathology reports that contribute to cancer staging and prognostication. Proforma reports are used in many countries, but these vary in their structure and implementation. The International Collaboration on Cancer Reporting (ICCR) is an alliance formed by the Royal College of Pathologists of Australasia, the Royal College of Pathologists of the United Kingdom, the College of American Pathologists, the Canadian Partnership Against Cancer the European Society of Pathology and the American Society of Clinical Pathology (ASCP), with the aim of developing an evidence‐based reporting data set for each cancer site. It is argued that this should reduce the global burden of cancer data set development and reduplication of effort by different international institutions that commission, publish and maintain standardised cancer reporting data sets. The resultant standardisation of cancer reporting will benefit not only those countries directly involved in the collaboration but also others not in a position to develop their own data sets. We describe the development of a cancer data set by the ICCR expert panel for the reporting of the main malignant liver tumours: intrahepatic cholangiocarcinoma, perihilar cholangiocarcinoma and hepatocellular carcinoma and present the ‘required’ and ‘recommended’ elements to be included in the report with an explanatory commentary. This data set incorporates definitions and classifications in the most recent World Health Organisation (WHO) publication on hepatic malignancies (4th edition) and the recently published tumour–node–metastasis (TNM)8 staging system. Widespread adoption and implementation of this data set will enable consistent and accurate data collection, comparison of epidemiological and pathological parameters between different populations, facilitate research and ultimately result in better patient outcomes. [ABSTRACT FROM AUTHOR]

Abstract: Background: Recently proposed by the International Consensus Conference on Laparoscopic Liver Resection, the Iwate criteria (IC) can be used by surgeons to predict the operative difficulty of laparoscopic liver resection (LLR) and were validated in patients with hepatocellular carcinoma (HCC), the most common indication for LLR. Methods: The IC comprise six preoperative factors that allow the grading of operative difficulty as low, intermediate, advanced, or expert. IC scores were validated in patients with HCC who underwent LLR (n = 77). Results: The median operative time was 212 min (range 57–461 min). The difficulty of the resections was categorized as low in 9% (n = 7), intermediate in 38% (n = 29), advanced in 36% (n = 28), and expert in 15% (n = 12) of the patients. IC score was significantly linked to operative time, length of stay and liver function (P < 0.05). The rates of postoperative complications (Clavien–Dindo >II) for low, intermediate, advanced and expert were 0% (n = 0), 10% (n = 3), 3.5% (n = 1) and 50% (n = 6), respectively (P = 0.04). Conclusion: The IC can be used to preoperatively assess difficulty of LLR and to predict postoperative complications in HCC patients. Thus, the IC score may be useful to differentiate easy procedures from difficult procedures and is ideal to build an LLR curriculum for upcoming surgeons. [ABSTRACT FROM AUTHOR]

Abstract: Background & Aims: Pain management in cirrhosis is a clinical challenge. Most analgesics are metabolized in the liver and cirrhosis may deeply alter their concentration, favouring the appearance of side effects. We aimed to assess the efficacy and safety of oral prolonged‐release association of oxycodone/naloxone tablets (OXN) in the treatment of moderate/severe cancer pain in cirrhotic patients with metastatic hepatocellular carcinoma (HCC). Methods: We enrolled n = 32 HCC patients with moderate/severe cancer pain unresponsive to paracetamol alone or associated with codeine or tramadol. All patients received an initial OXN dose of 5 mg bid to be gradually increased in case of insufficient analgesia. At baseline and follow‐up visits, we evaluated: pain intensity (using the Numerical Rating Scale, NRS), patients’ autonomy in daily activities (Barthel Functioning Index); bowel dysfunction (Bowel Function Index, BFI), signs of hepatic encephalopathy (HE) and other opioid‐induced side effects. Results: No clinically significant adverse effects were reported (median follow‐up 122 days). No significant worsening of the BFI score was noted and no cases of HE were detected. Two patients (6.3%) discontinued treatment before T14 because of mild nausea and dizziness. The remaining n = 30 patients were assessed for efficacy. Treatment led to a significant reduction in the mean of pain scores both at T14 (−37.1 ± 16.3%, P < .001) and at T28 (−55.6 ± 21.5%, P < .001); Barthel scores showed gradual and significant increase from T0 (81.6 ± 13.0) to T14 (86.5 ± 11.4, P = .001) and to T28 (88.3 ± 13.6, P = .009). Conclusions: OXN may be considered a safe and effective option in the fragile population of cirrhotic patients. [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate the association of 10 SNPs in different micro RNAs (mi RNAs) with susceptibility to hepatitis B virus ( HBV) infection, HBV clearance, persistence of chronic HBV infection, and progression to liver cirrhosis and hepatocellular carcinoma ( HCC). Patients were categorized into the following groups: inactive HBV carrier, active HBV carrier, HBV-cleared subject and cirrhosis+ HCC. Samples were analysed for 10 SNPs in micro RNAs using either PCR-based genotyping or the TaqMan assay. We found that rs1358379 was associated with susceptibility to HBV infection, HBV clearance, persistent chronic HBV infection and liver cirrhosis+ HCC. In addition, we found that rs2292832 and rs11614913 were associated with risk of HBV infection, viral clearance and cirrhosis+ HCC, whereas rs2910164 was associated with proneness to HBV infection, and ability to clear the virus. There was evidence of associations between rs6505162 and HBV clearance and the development of liver disease, whereas a single association was found between rs2289030 and HBV clearance. Similarly, rs7372209 and rs4919510 were specifically associated with the development of HBV-induced liver complications. SNPs in mi RNAs affect the susceptibility, clearance and progression of HBV infection in Saudi Arabian patients. We found, using Gene Ontology or pathway analyses, that these genes may contribute to the pathophysiology of HBV infection and related liver complications. However, differences in the association of examined SNPs with various clinical stages indicate variations in the respective functional roles of these polymorphisms and their mi RNAs, and thus, further investigation to fully explore their therapeutic potential is warranted. [ABSTRACT FROM AUTHOR]

Nucleotide-binding oligomerization domain ( NOD)-like receptor ( NLR)C and NLRX family proteins play a key role in the innate immune response. The relationship between these proteins and hepatocellular carcinoma ( HCC) remains unclear. This study investigated the prognostic significance of NLRC and NLRX family protein levels in HCC patients. Data from 360 HCC patients in The Cancer Genome Atlas database and 231 patients in the Gene Expression Omnibus database were analyzed. Kaplan-Meier analysis and a Cox regression model were used to determine median survival time ( MST) and overall and recurrence-free survival by calculating the hazard ratio ( HR) and 95% confidence interval ( CI). High NOD2 and low NLRX1 expression in tumor tissue was associated with short MST (P = 0.012 and 0.014, respectively). A joint-effects analysis of NOD2 and NLRX1 combined revealed that groups III and IV had reduced risk of death from HCC as compared to group I (adjusted P = 0.001, adjusted HR = 0.31, 95% CI = 0.16-0.61 and adjusted P = 0.043, adjusted HR = 0.63, 95%CI = 0.41-0.99, respectively). NOD2 and NLRX1 expression levels are potential prognostic markers in HCC following hepatectomy. [ABSTRACT FROM AUTHOR]

Aim Recent reports have indicated that aldo-keto reductase family 1 member B10 (AKR1B10), a cancer-related oxidoreductase, was upregulated in some chronic liver diseases. However, few studies have reported AKR1B10 expression in chronic hepatitis B virus (HBV)-infected patients. The aim of the present study was to analyze AKR1B10 expression and its relevance on hepatocellular carcinoma (HCC) development in patients with chronic HBV infection. Methods Expression of AKR1B10 in the liver of 119 chronic HBV-infected patients was assessed and quantified immunohistochemically. A multivariate Cox model was used to estimate the hazard ratios of AKR1B10 expression for HCC development. The cumulative incidences of HCC were evaluated using Kaplan-Meier analysis. Results Expression of AKR1B10 in the study cohort ranged from 0% to 84%. During the median follow-up time (6.2 years), 13 patients developed HCC. Multivariate analysis revealed that high AKR1B10 expression (≥15%) was an independent risk factor for HCC (hazard ratio, 10.8; 95% confidence interval, 3.0-38.6; P < 0.001). The 5-year cumulative incidences of HCC were 20.6% and 2.6% in patients with high and low AKR1B10 expression, respectively ( P < 0.001). Patients with high AKR1B10 expression had significantly higher alanine aminotransferase levels during follow-up than those with low expression, even though antiviral treatment decreased HBV-DNA levels in both groups. Conclusion Chronic HBV-infected patients with high hepatic AKR1B10 expression had an increased risk of HCC development. This suggests that AKR1B10 upregulation might play a role in the early stages of HBV-related hepatocarcinogenesis. [ABSTRACT FROM AUTHOR]

Aim Branched-chain amino acids (BCAA) are valuable in the treatment of liver cirrhosis because they increase serum albumin levels. Poor adherence to BCAA may adversely affect prognosis, but little is known about factors predicting adherence. We undertook a survey of patients prescribed BCAA for the treatment of cirrhosis. Methods Pharmacists carried out face-to-face interviews with patients (or their representatives) prescribed any of nine BCAA formulations. Question categories included patient characteristics, prescription of BCAA granules, and perceptions of BCAA administration, including adherence and possible factors that might impact adherence. 'Poor adherence' was defined as 'not taking the medication appropriately' or 'forgetting to take the medication'. Results Overall, 253 patients (or representatives) completed the survey, of whom 135 were men, 114 were women, and 148 were ≥70 years old. Most patients (163) were prescribed BCAA for ≥2 years and were using three packs per day. Thirty-two patients did not take their medication appropriately and 69 sometimes forgot to administer it. Weariness of taking the medication ( P < 0.001) and the perceived unpleasantness ( P = 0.023) of the medication in terms of its taste and volume were significantly associated with poor adherence. The patients reported that the most influential educators were general practitioners, followed by certified hepatologists, then pharmacists. Conclusion Most patients had good adherence to BCAA in clinical practice. Poor adherence was associated with weariness with taking medication, and the unpleasantness of the medication itself. Patient education from general practitioners and hepatologists combined with adherence counseling from pharmacists may help improve adherence. [ABSTRACT FROM AUTHOR]

Background iPS- ML are myeloid lineage cells with a proliferative capacity derived from induced pluripotent stem ( iPS) cells. This study aimed to examine therapeutic effect of iPS- ML producing interferon-β ( iPS- ML/ IFN-β) towards primary and metastatic liver cancer and investigate the mechanism of that effect. Methods We established a xenograft model of liver metastasis by injecting the spleen of SCID mice with MKN-45 human gastric cancer cells and also a primary liver cancer model by injecting SK- HEP-1 human hepatocellular carcinoma cells into the liver. After cancer lesions were established, iPS- ML/ IFN-β was administered by intraperitoneal injection, and therapeutic effect was evaluated. Results The i.p. injection of iPS- ML/ IFN-β resulted in a significant retardation of cancer progression and prolonged mouse survival. The infiltration of i.p. administered iPS- ML into tumor lesions located below the liver capsule was observed, suggesting tumor-directed migration and penetration of the liver capsule by iPS- ML. The IFN-β concentration in the liver was maintained at levels sufficient to exert an anti-cancer effect for at least 3 days post-injection, accounting for the potent therapeutic effect obtained by injection two to three times per week. Conclusions This study demonstrates the therapeutic potential of the iPS- ML/ IFN-β in patients with liver cancer. [ABSTRACT FROM AUTHOR]

Addressing the fragmentation of cancer care requires the strengthening of existing health systems and bridging the divide between low‐volume and high‐volume hospitals and non–safety net and safety net hospitals. This can be accomplished through restructuring, investment, and cross‐collaboration between institutions that promote multidisciplinary and multi‐institutional care. [ABSTRACT FROM AUTHOR]

Despite the widespread use of proton beam therapy (PBT) as locoregional therapy, there is currently a lack of histological evidence about the therapeutic effect of PBT for hepatocellular carcinoma (HCC). We present a case of hepatectomy and histological examination of HCC initially treated by PBT. A 76-year-old man with chronic hepatitis C underwent routine ultrasound surveillance, which revealed a 22-mm HCC in segment 4 of the liver. His hepatic reserve was adequate for surgical resection of the tumor; however, he chose to undergo PBT because of his cardiac disease. The patient received 66 Gy in 10 fractions with no toxicity exceeding grade 1. Six months after completion of PBT, contrast computed tomography showed that the tumor had increased in size to 27 mm, and the marginal part of the tumor, but not the central region, was enhanced. Additionally, two new hypervascular nodules were present in segments 5 and 6. The patient underwent surgical treatment 7 months after PBT. The operation and postoperative clinical course were uneventful. Nine months later, however, computed tomography demonstrated new, small, enhanced nodules in the remnant liver (segments 3, 5 and 6) and sacrum. In conclusion, PBT is a valuable treatment for HCC; however, it is difficult to evaluate therapeutic effect of HCC during the early post-irradiation period and provide an alternative treatment if PBT is not effective, especially in HCC cases with good liver function. [ABSTRACT FROM AUTHOR]

Introduction: Washout is an important diagnostic imaging feature of hepatocellular carcinoma (HCC) on computed tomography (CT). The primary aim of this study is to evaluate the prevalence and the interobserver variation in the detection of portal venous phase (PVP) washout of HCCs using CT in a transplant population. The secondary aim is to evaluate factors influencing the detection of PVP washout. Methods: Forty-five patients who underwent CT liver imaging within the 60 days before transplantation had viable HCCs confirmed on pathology. Two radiologists retrospectively reviewed the images for HCCs including features of arterial enhancement and PVP washout. Clinical data, peak kilovoltage, imaging features of portal hypertension, region of interest attenuation measurements of the individual lesions, background liver parenchyma and portal vein were obtained. Liver to lesion attenuation ratio was also calculated. Statistical analysis was performed. Results: The two readers identified 50 arterially enhancing HCCs in 45 patients. In consensus, the two readers identified washout in 60% of the HCCs with a substantial interobserver agreement (kappa = 0.633). PVP washout was associated with larger lesion size, increased background liver parenchyma attenuation, increased liver to lesion attenuation ratio, increased portal vein attenuation and hepatitis B viral status (P = 0.027, 0.008, 0.014, 0.017 and 0.037 respectively). Conclusion: In our transplant population, portal venous phase washout was seen in 60% of the hypervascular HCCs. Factors influencing the presence of PVP washout include lesion size as well as the liver and portal vein attenuation reflective of the portal haemodynamics. [ABSTRACT FROM AUTHOR]

Background & Aims Early age at infection with Hepatitis B virus ( HBV) increases the risk of chronic infection. Moreover, early HBV infection may further independently increase the risk of hepatocellular carcinoma ( HCC) beyond its effect on chronicity. Methods The distribution of birth order, a proxy for mode and timing of HBV transmission, was compared in The Gambia between hepatitis B surface antigen ( HBsAg)-positive HCC cases recruited from hospitals ( n = 72) and two HBsAg-positive control groups without HCC: population-based controls from a community HBV screening ( n = 392) and hospital-based controls ( n = 63). Results HCC risk decreased with increasing birth order in the population-based case -control analysis. Using first birth order as the reference, the odds ratios were 0.52 (95% CI: 0.20-1.36), 0.52 (0.17-1.56), 0.57 (0.16-2.05) and 0.14 (0.03-0.64) for second, third, fourth and greater than fourth birth order respectively ( P = 0.01). A similar inverse association was observed in the hospital-based case -control comparison ( P = 0.04). Conclusions Compared to controls, HCC cases had earlier birth order, a proxy for young maternal age and maternal HBV viraemia at birth. This finding suggests that in chronic HBV carriers perinatal mother-to-infant transmission may increase HCC risk more than horizontal transmission. Providing HBV vaccine within 24 h of birth to interrupt perinatal transmission might reduce the incidence of HCC in The Gambia. [ABSTRACT FROM AUTHOR]

Hepatocellular adenomas ( HCA) are rare, benign liver tumours that often occur in women of reproductive age. HCA has been associated with the use of oral contraceptives, but the increased incidence of the tumour in older women and in men has linked the tumour type to other diseases, including the metabolic syndrome. Genotypical classification of the adenomas has led to the identification of four subgroups that correlate genotype with phenotype: human hepatocyte nuclear factor-1 alpha ( HNF1α) inactivating HCA, β-catenin activating HCA, inflammatory HCA and unclassified HCA. HNF1α inactivating HCA is associated with bi-allelic mutations in the TCF1 gene and morphologically has marked steatosis. β-catenin activating HCA has increased activity of the Wnt/β-catenin pathway and is associated with possible malignant transformation. Inflammatory HCA is characterized by an oncogene-induced inflammation due to alterations in the Janus kinase/signal transducer and activator of transcription ( JAK/ STAT) pathway. In the diagnostic setting, sub classification of HCA is based primarily on immunohistochemical analyzes, and has had an increasing impact on choice of treatment and individual prognostic assessment. This review offers an overview of the reported gene mutations associated with hepatocellular adenomas together with a discussion of the diagnostic and prognostic value. [ABSTRACT FROM AUTHOR]

The article discusses a study on tilapia fish which is considered to be relatively disease-resistant animals, especially to many of the common pathogens that target intensively reared fish. Accordingly, this study describes an outbreak of severe mortality in young farmed tilapia, restricted largely to Oreochromis niloticus, a strain of the same species.

Purpose To determine the added value of 3 Tesla liver MR in patients with hepatocellular carcinoma (HCC) within the liver computed tomography (CT) -based Milan criteria. Materials and Methods Liver CT and MR images of 130 patients with HCC within the Milan criteria based on liver CT were retrospectively reviewed. The number of MR-diagnosed HCCs and that of high risk hypervascular nodules (HRHNs), the effect of obtaining MR on patient management and CT appearances of MR-diagnosed HCCs and those of HRHNs were evaluated. Independent predictor for diagnosing additional HCCs on liver MR was analyzed. Results A total of 18.5% (24/130) of patients had additional 39 HCCs on MR, with a 5.4% (7/130) dropout rate from the Milan criteria. 28.5% (37/130) of patients had additional 78 HRHNs. Overall, 39.2% (51/130) of patients required changes in management. The common CT appearances of MR-diagnosed HCCs were arterial enhancing lesions ≥ 0.5cm (38.4%, 15/39), low density nodules < 1.5 cm (30.8%, 12/39) and invisibility (28.2%, 11/39). For MR-diagnosed HRHNs, 55.1% (43/78) were invisible on CT. The presence of inconclusive lesions on CT was an independent predictor for diagnosing additional HCCs on MR. Conclusion For patients with HCCs within the Milan criteria on liver CT, liver MR may be necessary to detect additional HCCs and HRHNs. J. Magn. Reson. Imaging 2014;39:842-852. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Background and Aim Although tumor differentiation is a known prognostic factor after the treatment of hepatocellular carcinoma ( HCC), there have not been any studies on the prognostic significance of tumor differentiation in HCC with heterogeneous histologic grades. In this study, we attempted to ascertain whether the major or the worst grade in mixed histologic type HCC determines the prognosis after liver resection. Methods From January 1996 to March 2010, a total of 724 patients underwent curative resection of HCC at Yonsei University Health System, Korea. Of those, we excluded 99 patients who had total necrosis because of previous treatment. Among the remaining 625 patients, we compared the homogeneous moderately differentiated group ( HG2, n = 241), mixed histologic grades with the worst component as poorly differentiated group ( M2, n = 142), and homogeneous poorly differentiated group ( HG3, n = 156). The clinicopathologic features, disease-free survival ( DFS) and overall survival ( OS) in each group were analyzed. Results The DFS and OS were significantly lower in M2 than in HG2 ( P = 0.004 and 0.025, respectively) whereas those of M2 were not significantly different from HG3. There were no significant differences in the clinicopathologic features of each group except that microvascular invasion was more frequently observed in M2 than in HG2. On multivariate analysis, being in the worst histologic group ( M2 and HG3) was an independent poor prognostic factor for DFS and OS ( P = 0.028 and < 0.001, respectively). Conclusions In patients with advanced histologic grade, the worst histologic grade may determine the prognosis after curative resection of HCC. [ABSTRACT FROM AUTHOR]

This study aimed to analyze the clinical outcomes and factors influencing the outcome in the recurrence of hepatocellular carcinoma ( HCC) after living donor liver transplantation ( LDLT). Between October, 1997 and September, 2010, 25 (16.0%) of 156 patients who had undergone LDLT for HCC experienced recurrence. All patients with recurrence, with a single exception, were in the high-risk group. Among patients with recurrence, 76.0% of patients experienced recurrence within one yr after LDLT. One- and five-yr survival rates of recurred patients were 56.0% and 8.6%, respectively. Among them, 32% of patients were treated with curative-intent treatment, and their one- and five-yr survival rates were 62.5% and 25.0%, respectively. Beyond the Milan criteria at liver transplantation ( LT) (p = 0.032), multiple recurrence (p = 0.001), and palliative treatment for recurrent tumors (p = 0.049) were related to poor survival after recurrence. Additionally, the independent prognostic factors included multiple recurrence (p = 0.005) and the Milan criteria at LT (p = 0.047). Because almost all recurrent cases belonged to the high-risk group and recurred within two yr, the high-risk group should undergo close follow-up for early detection and be treated with liver-directed therapies. Although the prognosis of recurrent HCC after LDLT is poor, long-term survival can be expected on a single recurrence and curative treatment. [ABSTRACT FROM AUTHOR]

Sorafenib is the first and only p.o. administrated drug currently approved to treat advanced hepatocellular carcinoma ( HCC). However, concerns have been raised about sorafenib therapy, including acquired drug resistance. This review provides an overview of sorafenib in the treatment of HCC on the basis of data obtained in the laboratory and in clinical studies. Three underlying mechanisms have been found to support sorafenib therapy. First, sorafenib blocks HCC cell proliferation by inhibiting BRaf and Raf1/c- Raf serine/threonine kinase phosphorylation in the mitogen-activated protein kinase pathway. Second, sorafenib induces apoptosis by reducing el F4 E phosphorylation and downregulating Mcl-1 levels in tumor cells. Third, sorafenib prevents tumor-associated angiogenesis by inactivating vascular endothelial growth factor receptors ( VEGFR-2 and -3) and the platelet-derived growth factor receptor-β. Clinical trials have demonstrated the effectiveness and relative safety of sorafenib, and thus the drug is used in unresectable HCC. However, many patients may develop acquired resistance to sorafenib, so their response to sorafenib is eventually lost. Sorafenib may induce autophagy, which leads to apoptosis. However, autophagy can also cause drug resistance. Many studies have combined sorafenib with other treatments in an effort to increase its effects, reduce the necessary dose or overcome resistance. It is urgent to study the mechanisms underlying how sorafenib interacts with cellular molecules and other drugs to increase its efficacy and reduce resistance in HCC patients. [ABSTRACT FROM AUTHOR]

A reliable test for the detection of hepatocellular carcinoma (HCC) could improve disease management. Recent reports suggested a link between abnormalities in the ubiquitin-proteasome system (UPS) and HCC. We investigated the potential of using UPS markers, along with HCC markers, to differentiate HCC from chronic liver disease (CLD). Sera from 135 HCC and 262 CLD patients were retrospectively analyzed for levels of UPS markers (proteasome, ubiquitin, and proteasome enzymatic activities) and the conventional HCC markers alpha fetoprotein (AFP), AFP-L3, and des-gamma-carboxyprothrombin (DCP). Multivariate logistic regression analysis was used to develop a model for differentiating HCC from CLD. The model was developed using a subset of 98 HCC patients and 104 CLD patients with advanced fibrosis or cirrhosis (Metavir F3-4) and then validated using an independent set (37 HCC and 44 CLD (F3-4)). A UPS signature model incorporating six markers (trypsin-like, caspase-like, chymotrypsin-like, and normalized chymotrypsin-like activities of proteasomes; AFP; and DCP) accurately differentiated HCC from CLD (area under the curve = 0.938 [95% confidence interval, 0.884-0.991]). When analysis was restricted to patients with tumors ≤ 3 cm, the UPS model exhibited higher sensitivity (83.1% vs 51.8%) and specificity (90.2% vs 83.7%) than the three conventional markers, with good positive predictive values (34.2% vs 15.1%). These results were confirmed in the independent validation set. The UPS signature in combination with AFP and DCP provides sensitive and specific differentiation of HCC in patients with CLD. The importance of the UPS in HCC suggests that therapeutic approaches targeting the UPS should be explored. [ABSTRACT FROM AUTHOR]

The purpose of this study was to assess the diagnostic accuracy of our early experience with contrast-enhanced ultrasound (CEUS) in the characterisation of focal liver lesions (FLLs) using histopathology, contrast-enhanced computed tomography (CT), magnetic resonance imaging (MRI) or other imaging follow-up as the standard of reference. Seventy-three patients with 82 FLLs who underwent liver CEUS from January 2006 to December 2008 were retrospectively reviewed. CEUS was performed with up to 4.8 mL of SonoVue® (Bracco, Milan, Italy) using a low mechanical index mode. The CEUS findings were compared with histopathology, or where histopathology was not available, clinical and imaging follow-up over at least 12 months was used as the standard of reference. Of the 82 FLLs, 50 were malignant and 32 were benign at final diagnosis. CEUS correctly identified 43 malignant FLLs, with final diagnosis confirmed by histopathology in 13 lesions and clinico-radiological follow-up in 30 lesions. Twenty-nine lesions were correctly identified as benign on CEUS, with all these lesions confirmed on clinico-radiological follow-up. CEUS demonstrated a sensitivity of 86.0% and a specificity of 90.6% in the characterisation of liver lesions as malignant, with an overall accuracy of 87.8% ( P < 0.05). Our early experience has shown that CEUS can be accurate in differentiating malignant from benign FLLs and may become a useful first-line imaging tool where CT or MRI are not available or contra-indicated. [ABSTRACT FROM AUTHOR]

Orthotopic liver transplantation (OLT) is the best treatment option for selected patients with hepatocellular carcinoma (HCC) with the background of cirrhosis since this treatment modality can cure both diseases at once. Over the years, the applicability of OLT for HCC has evolved. In Asia, including Hong Kong, a shortage of deceased donor liver grafts is a universal problem having to be faced in all transplant centers. Living-donor liver transplant (LDLT) has therefore been developed to counteract organ shortage and the high prevalence of HCC. The application of LDLT for HCC is a complex process involving donor voluntarism, selection criteria for the recipient and justification with respect to long-term survival in comparison to the result of deceased donor liver transplant. This article reviews the authors' experience with OLT for HCC patients in Hong Kong, with emphasis on the applicability and outcome of LDLT for HCC. Donor voluntarism has a significant impact on the application of LDLT. 'Fast-track' LDLT in the setting of recurrence following curative treatment carries a high risk of recurrence even though the tumor stage fulfills the standard criteria. Although the survival outcome may be worse following LDLT than DDLT for HCC, LDLT is still the main treatment option for patients with transplantable HCC in Hong Kong, and a reasonable survival outcome can be achieved in selected patients with extended indications. It is particularly true that LDLT provides the only hope for patients with advanced HCC under the constricting problem of organ shortage. [ABSTRACT FROM AUTHOR]

Background: Activated hepatic stellate cells (HSC) and other fibrogenic cell types are frequently found around hepatocellular carcinoma. It is unknown whether hepatocarcinoma cells regulate the biological functions of HSC. Aims: This study aimed to investigate the paracrine effects of hepatocarcinoma cells on human HSC using a co-culture system. Methods: Huh7 or HepG2 cells, human hepatocarcinoma cell lines, were co-cultured with primary human HSC. Intracellular calcium mobilization, proliferation, migration, expression of pro-angiogenic and fibrogenic genes, smooth muscle α-actin (α-SMA) protein expression, inflammatory properties (nuclear factor kappa B activation and interleukin 8 secretion) and intracellular signalling pathways (AKT and ERK) were analysed in HSC. Results: Culture of HSC with Huh7 cells for 24 h stimulated HSC proliferation, migration and expression of pro-angiogenic genes. The migration effect was corroborated with HepG2 cells. The effects of Huh7 cells on cell proliferation and migration were mediated mainly by PI3K/AKT activation. Moreover, Huh7 cells reduced the expression of genes involved in fibrogenesis, while they did not modify the inflammatory properties of HSC. The expression of α-SMA was induced by Huh7 cells. Because hepatitis C virus (HCV) infection is a major cause of hepatocarcinoma, we next investigated whether these effects are regulated by the expression of HCV in hepatocarcinoma cells. Expression of a subgenomic replicon expressing HCV nonstructural proteins (NS3–NS5) in Huh7 cells did not affect paracrine actions in HSC (cell proliferation and migration). Conclusions: These results suggested that there is a cross-talk between hepatocarcinoma cells and HSC. Activated HSC may be stimulated by cancer cells to accumulate and express angiogenic genes. [ABSTRACT FROM AUTHOR]

The article presents a study which retrospectively assesses the effectiveness of percutaneous transhepatic portal vein stenting and transarterial chemoembolization (PTPVS-TACE) with, or without 3-dimensional conformal (3-DCRT) radiotherapy for hepatocellular carcinoma (HCC). The results reveal no severe complications associated with PTPVS-TACE and 3-DCRT. The findings indicate that PTPVS-TACE-3DCRT is and effective treatment modality for HCC complicated by main portal vein tumor thrombus.

Aim: Hepatocellular carcinoma (HCC) in otherwise normal liver is rare, its pathogenesis remains obscure and the literature on the subject is scarce. We investigated microsatellite instability (MSI) in eight elderly patients (median age 70.7, range 63–76 years) without a clinical history of liver disease and who underwent liver resection for HCC in otherwise normal background liver between 2001 and 2005 at King's College Hospital, London. Methods: Immunohistochemistry for mutL homolog 1 (MLH1), mutS homolog 2 (MSH2), mutS homolog 6 (MSH6) and post-meiotic segregation increased 2 (PMS2) was carried out on formalin-fixed and paraffin-embedded sections of tumor and background liver. MSI analysis was performed using a panel of monomorphic microsatellites markers: BAT-25, BAT-26, NR21, NR24 and NR27 and pentaplex PCR. Results: All HCC were solitary large tumors. Two also had satellite nodules. The background liver was usually unremarkable. There was nuclear expression of MLH1, MSH2, MSH6 and PMS2 in all tumors excluding a DNA mismatch repair defect. The same pattern of staining was noted in the hepatocytes of the background liver of all cases. No differences between microsatellite lengths in the background liver and in the tumor, as assessed in PCR products, were found for any of the five microsatellite markers in any patients. These findings provided no evidence for MSI. Conclusion: Our study showed that MSI is not implicated in the pathogenesis of a subset of HCC affecting elderly patients without chronic liver disease. Further studies are needed to clarify the pathogenesis of HCC in this particular setting. [ABSTRACT FROM AUTHOR]

Background and Aim: Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. However, there is no general consensus as to which staging system is the most reliable for predicting the survival of patients with HCC. The aims of this study were to compare commonly-used staging systems in a cohort of Chinese HCC patients undergoing curative resection. Methods: From January 1991 to June 2002, 234 Chinese patients undergoing curative resection for HCC from one medical center were evaluated. All patients were classified by the Okuda, Cancer of the Liver Italian Program (CLIP), tumor node metastasis (TNM) (6th edition) and the Chinese University Prognostic Index (CUPI) staging systems. Survival curves were calculated using the Kaplan–Meier method and were examined using log-rank testing. The overall predictive power for patient survival with each staging system was evaluated by the area under the receiver operating characteristic (ROC) curve. Results: The overall median survival of the entire cohort was 24.9 months (95% confidence interval (CI) 18.15–31.65 months) and the estimated survival rates at 1, 3, and 5 years were 69.66% ± 3.01%, 41.02% ± 3.31%, and 29.08% ± 3.55%, respectively. In our patient cohort, the log-rank test demonstrated that the TNM and Okuda staging systems gave better results than the other staging systems in the prognosis stratification. The prognostic predictive powers of the TNM staging for survival, evaluated by ROC curve areas, was also superior. Conclusions: For HCC patients undergoing curative resection, the TNM staging system (6th edition) proved the best for prognostic stratification and prognosis prediction. [ABSTRACT FROM AUTHOR]

The article presents a study which aimed to determine the proportion of hepatocellular carcinoma (HCC) patients treated with erlotinib who were alive and progression-free (PFS) at 16 weeks of continuous treatment. In the study, patients with unresectable HCC, no prior systemic therapy, performance status (PS) of 0, 1, or 2, and Childs-Pugh (CP) cirrhosis A or B received oral erlotinib 150 mg daily for 28-day cycles. The study showed no correlation between epidermal growth factor receptor (EGFR) expression and outcome.