Early and late recurrence of surgically resected hepatitis B virus-related hepatocellular carcinoma on nucleos(t)ide analogues therapy.

BACKGROUND/PURPOSE: Hepatocellular carcinoma (HCC) is a highly recurrent tumor. Antiviral therapy with nucleos(t)ide analogues (NUCs) may reduce the risk of recurrence in hepatitis B virus (HBV)-related HCC. The risk factors associated with recurrence in HCC patients after surgical resection and with NUCs treatment should be delineated. METHODS: Consecutive 339 HBV-related HCC patients receiving surgical resection of HCC with NUCs therapy (including 256 entecavir, 36 tenofovir, and 18 lamivudine) after the surgery were retrospectively reviewed. Factors related to the recurrence-free survival (RFS) and overall survival (OS) were evaluated. RESULTS: After a median of 48.5 months of follow-up, 183 (54%) patients developed HCC recurrence, with the 5-year RFS of 42.8% and OS of 79%. Male gender (HR = 1.736, p = 0.037), baseline HBsAg level >200 IU/ml (HR = 1.748, p = 0.008), platelet count ≦100 (109/L) (HR = 1.592, p = 0.023), presence of microscopic vascular invasion (MVI) (HR = 1.499, p = 0.026), safety cut margin of ≦0.5 cm (HR = 1.507, p = 0.013), and Ishak fibrosis score 5-6 (HR = 1.579, p = 0.009) were independent factors associated with RFS in multivariate analysis. While tumor burden, platelet count, MVI, and safety cut margin were factors associated with early recurrence; baseline HBsAg level, and platelet count were independent factors associated with late recurrence. Ishak fibrosis score 5-6, poor differentiation, MVI, diabetes mellitus were factors associated with OS in multivariate analysis. CONCLUSION: For HBV-HCC patients on NUCs treatment, tumor factors are associated with early recurrence, while HBsAg level and thrombocytopenia determines late recurrence. For patient with a high baseline HBsAg level, warning of higher risk of recurrence is required even under NUCs treatment.

Consensus report from the 8th International Forum for Liver Magnetic Resonance Imaging.

OBJECTIVES: The 8th International Forum for Liver Magnetic Resonance Imaging (MRI), held in Basel, Switzerland, in October 2017, brought together clinical and academic radiologists from around the world to discuss developments in and reach consensus on key issues in the field of gadoxetic acid-enhanced liver MRI since the previous Forum held in 2013. METHODS: Two main themes in liver MRI were considered in detail at the Forum: the use of gadoxetic acid for contrast-enhanced MRI in patients with liver cirrhosis and the technical performance of gadoxetic acid-enhanced liver MRI, both opportunities and challenges. This article summarises the expert presentations and the delegate voting on consensus statements discussed at the Forum. RESULTS AND CONCLUSIONS: It was concluded that gadoxetic acid-enhanced MRI has higher sensitivity for the diagnosis of hepatocellular carcinoma (HCC), when compared with multidetector CT, by utilising features of hyperenhancement in the arterial phase and hypointensity in the hepatobiliary phase (HBP). Recent HCC management guidelines recognise an increasing role for gadoxetic acid-enhanced MRI in early diagnosis and monitoring post-resection. Additional research is needed to define the role of HBP in predicting microvascular invasion, to better define washout during the transitional phase in gadoxetic acid-enhanced MRI for HCC diagnosis, and to reduce the artefacts encountered in the arterial phase. Technical developments are being directed to shortening the MRI protocol for reducing time and patient discomfort and toward utilising faster imaging and non-Cartesian free-breathing approaches that have the potential to improve multiphasic dynamic imaging. KEY POINTS: • Gadoxetic acid-enhanced MRI provides higher diagnostic sensitivity than CT for diagnosing HCC. • Gadoxetic acid-enhanced MRI has roles in early-HCC diagnosis and monitoring post-resection response. • Faster imaging and free-breathing approaches have potential to improve multiphasic dynamic imaging.

Radiological features and outcomes of combined hepatocellular-cholangiocarcinoma in patients undergoing surgical resection.

BACKGROUND/PURPOSE: Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a rare primary liver cancer. Preoperative diagnosis of cHCC-CCA is difficult, and outcome of cHCC-CCA is obscured. Our study aimed to investigate the clinicopathological and radiological features of cHCC-CCA and compare their outcomes with hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). METHODS: From August 2010 to December 2017, 891 patients undergoing liver tumor resection in Taipei Veterans General Hospital, including 30 patients with pathology-proven cHCC-CCA, 819 HCC, and 42 ICC were retrospectively reviewed. Radiological features of contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) in patients with cHCC-CCA were reevaluated by a radiologist. Factors association with disease-free survival (DFS) and overall survival (OS) were analyzed. RESULTS: The mean age of cHCC-CCA, HCC and ICC was similar. Hepatitis B virus infection was prevalent in patients with cHCC-CCA (22/30, 73.3%). Most (70%) of the cHCC-CCA had atypical radiological pattern of HCC and belonged to classic type in pathological features. cHCC-CCA and ICC had worse DFS, but the 5-year OS of cHCC-CCA was substantial adequate after surgery. Of the 891 patients, male gender, advanced T stage, multiple tumor number, alpha-fetoprotein (AFP) level >20 ng/ml, cHCC-CCA, and ICC were factors associated with poor DFS in multivariable analysis. Older age, T stage 3 or 4, presence of macrovascular invasion, AFP >20 ng/mL, cHCC-CCA, and ICC were factors significantly associated with OS. CONCLUSION: cHCC-CCA is associated with high risk of recurrence following surgical resection as compared with HCC. Closely post-operative monitoring is highly recommended.

Aspirin is associated with low recurrent risk in hepatitis B virus-related hepatocellular carcinoma patients after curative resection.

BACKGROUND/PURPOSE: The risk of recurrence after resection of hepatocellular carcinoma (HCC) is high. Apart from nucleos(t)ide analogues therapy, population-based studies suggest statin, nonsteroidal anti-inflammatory drugs (NSAIDs) and aspirin have chemopreventive effect on recurrence. The role of those drugs on HCC recurrence should be delineated. METHODS: Consecutive 430 hepatitis B surface antigen (HBsAg)-positive patients undergoing curative resection of HCC were enrolled. The detailed medical records including the use of statin, NSAID and aspirin were reviewed. All the patients had regular image study surveillance after the surgery. Predictors associated with recurrence were analyzed by Cox's proportional hazards models. RESULTS: There were 58.8% patients in Barcelona Clinic Liver Cancer (BCLC) stage A, and 37.6% had severe liver fibrosis or cirrhosis. Of them, 47 (10.9%) patients had received potential chemoprophylactic agents either at the time of HCC diagnosis or before their HCC recurrence. During a median 50.3 months of follow-up, 54.7% patients experienced recurrence. The median time to recurrence was 15.4 months. In the univariate analysis, aspirin and statins use were significantly associated a low risk of recurrence (hazard ratio [HR]: 0.18; p = 0.016, and HR: 0.50; p = 0.031, respectively). After adjusting competing factors, large tumor size, severe liver fibrosis, and high alpha-fetoprotein (AFP) level were significantly associated with recurrence. Importantly, aspirin use was found to significantly decrease the risk for HCC recurrence with the adjusted HRs of 0.22-0.24 based on the models. CONCLUSION: Aspirin use may have chemo-preventive effect on recurrence of hepatitis B virus-related HCC after curative resection.

Molecular predictors of prevention of recurrence in HCC with sorafenib as adjuvant treatment and prognostic factors in the phase 3 STORM trial.

OBJECTIVE: Sorafenib is the standard systemic therapy for advanced hepatocellular carcinoma (HCC). Survival benefits of resection/local ablation for early HCC are compromised by 70% 5-year recurrence rates. The phase 3 STORM trial comparing sorafenib with placebo as adjuvant treatment did not achieve its primary endpoint of improving recurrence-free survival (RFS). The biomarker companion study BIOSTORM aims to define (A) predictors of recurrence prevention with sorafenib and (B) prognostic factors with B level of evidence. DESIGN: Tumour tissue from 188 patients randomised to receive sorafenib (83) or placebo (105) in the STORM trial was collected. Analyses included gene expression profiling, targeted exome sequencing (19 known oncodrivers), immunohistochemistry (pERK, pVEGFR2, Ki67), fluorescence in situ hybridisation (VEGFA) and immunome. A gene signature capturing improved RFS in sorafenib-treated patients was generated. All 70 RFS events were recurrences, thus time to recurrence equalled RFS. Predictive and prognostic value was assessed using Cox regression models and interaction test. RESULTS: BIOSTORM recapitulates clinicopathological characteristics of STORM. None of the biomarkers tested (related to angiogenesis and proliferation) or previously proposed gene signatures, or mutations predicted sorafenib benefit or recurrence. A newly generated 146-gene signature identifying 30% of patients captured benefit to sorafenib in terms of RFS (p of interaction=0.04). These sorafenib RFS responders were significantly enriched in CD4+ T, B and cytolytic natural killer cells, and lacked activated adaptive immune components. Hepatocytic pERK (HR=2.41; p=0.012) and microvascular invasion (HR=2.09; p=0.017) were independent prognostic factors. CONCLUSION: In BIOSTORM, only hepatocytic pERK and microvascular invasion predicted poor RFS. No mutation, gene amplification or previously proposed gene signatures predicted sorafenib benefit. A newly generated multigene signature associated with improved RFS on sorafenib warrants further validation. TRIAL REGISTRATION NUMBER: NCT00692770.

Ethanol-metabolizing activities and isozyme protein contents of alcohol and aldehyde dehydrogenases in human liver: phenotypic traits of the ADH1B*2 and ALDH2*2 variant gene alleles.

OBJECTIVE: Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) are principal enzymes responsible for the metabolism of ethanol. East Asian populations are unique in that they carry both a prevalent ADH1B*2 and a dominant-negative ALDH2*2 allele. A systematic investigation of ethanol-metabolizing activities in normal livers correlated with the corresponding functional allelic variations and protein contents of the relevant isozymes in respective enzyme families has been lacking. MATERIALS AND METHODS: To obtain a reasonable sample size encompassing all possible genetic allelotypes of the ADH1B and ALDH2, 141 surgical liver specimens from adult Han Chinese were studied. Expression patterns and activities of ADH and ALDH were determined with stratification of the genetic phenotypes. Absolute protein contents as well as cellular localization of the activity and protein of ADH/ALDH isozymes were also investigated. RESULTS: The activities of ADH1B*1/*2 and ADH1B*2/*2 allelic phenotypes were 5-6-fold those of the ADH1B*1/*1, suggesting that ADH1B*2 allele-encoded subunits are dominant over expression of hepatic ADH activity. The activities of the ALDH2-active phenotype were 90% higher than those of the ALDH2-inactive phenotype. Sex and age did not significantly influence the hepatic ADH and ALDH activities with specified genetic phenotypes. The isozyme protein contents were as follows in decreasing order: ADH1, ADH2, ALDH1A1, ALDH2, and ADH3. Both ADH1, but not ADH2/3, and ALDH1A1/2 showed a preferential expression in perivenular hepatocytes. CONCLUSION: Functional correlations of ADH1B*2 and ALDH2*2 variant alleles in the liver provide a biochemical genetic basis suggesting their contribution toward variability in ethanol metabolism as well as susceptibility to alcoholism and alcohol-related diseases in East Asians.

Sorafenib or placebo plus TACE with doxorubicin-eluting beads for intermediate stage HCC: The SPACE trial.

BACKGROUND & AIMS: Transarterial chemoembolization with doxorubicin-eluting beads (DC Bead®; DEB-TACE) is effective in patients with Barcelona clinic liver cancer stage B hepatocellular carcinoma (HCC). The multikinase inhibitor sorafenib enhances overall survival (OS) and time-to-tumor progression (TTP) in patients with advanced HCC. This exploratory phase II trial tested the efficacy and safety of DEB-TACE plus sorafenib in patients with intermediate stage HCC. METHODS: Patients with intermediate stage multinodular HCC without macrovascular invasion (MVI) or extrahepatic spread (EHS) were randomized 1:1 to DEB-TACE (150 mg doxorubicin) plus sorafenib 400 mg twice daily or placebo. The primary endpoint was TTP by blinded central review. Secondary endpoints included time to MVI/EHS, OS, overall response rate (ORR) using modified response evaluation criteria in solid tumors, disease control rate (DCR), time to unTACEable progression (TTUP), and safety. RESULTS: Of 307 patients randomized, 154 received sorafenib and 153 received placebo. Median TTP for subjects receiving sorafenib plus DEB-TACE or placebo plus DEB-TACE was similar (169 vs. 166 days, respectively; hazard ratio (HR) 0.797, p=0.072). Median time to MVI/EHS (HR 0.621, p=0.076) and OS (HR 0.898, p=0.29) had not been reached. The ORRs for patients in the sorafenib and placebo groups with post-baseline scans were 55.9% and 41.3%, respectively, and the DCRs were 89.2% and 76.1%, respectively. TTUP was lower with sorafenib than with placebo (HR 1.586; 95% confidence intervals, 1.200-2.096; median 95 vs. 224 days). No unexpected adverse events related to sorafenib were observed. CONCLUSION: Sorafenib plus DEB-TACE was technically feasible, but the combination did not improve TTP in a clinically meaningful manner compared with DEB-TACE alone.

Adjuvant sorafenib for hepatocellular carcinoma after resection or ablation (STORM): a phase 3, randomised, double-blind, placebo-controlled trial.

BACKGROUND: There is no standard of care for adjuvant therapy for patients with hepatocellular carcinoma. This trial was designed to assess the efficacy and safety of sorafenib versus placebo as adjuvant therapy in patients with hepatocellular carcinoma after surgical resection or local ablation. METHODS: We undertook this phase 3, double-blind, placebo-controlled study of patients with hepatocellular carcinoma with a complete radiological response after surgical resection (n=900) or local ablation (n=214) in 202 sites (hospitals and research centres) in 28 countries. Patients were randomly assigned (1:1) to receive 400 mg oral sorafenib or placebo twice a day, for a maximum of 4 years, according to a block randomisation scheme (block size of four) using an interactive voice-response system. Patients were stratified by curative treatment, geography, Child-Pugh status, and recurrence risk. The primary outcome was recurrence-free survival assessed after database cut-off on Nov 29, 2013. We analysed efficacy in the intention-to-treat population and safety in randomly assigned patients receiving at least one study dose. The final analysis is reported. This study is registered with ClinicalTrials.gov, number NCT00692770. FINDINGS: We screened 1602 patients between Aug 15, 2008, and Nov 17, 2010, and randomly assigned 1114 patients. Of 556 patients in the sorafenib group, 553 (>99%) received the study treatment and 471 (85%) terminated treatment. Of 558 patients in the placebo group, 554 (99%) received the study treatment and 447 (80%) terminated treatment. Median duration of treatment and mean daily dose were 12·5 months (IQR 2·6-35·8) and 577 mg per day (SD 212·8) for sorafenib, compared with 22·2 months (8·1-38·8) and 778·0 mg per day (79·8) for placebo. Dose modification was reported for 497 (89%) of 559 patients in the sorafenib group and 206 (38%) of 548 patients in the placebo group. At final analysis, 464 recurrence-free survival events had occurred (270 in the placebo group and 194 in the sorafenib group). Median follow-up for recurrence-free survival was 8·5 months (IQR 2·9-19·5) in the sorafenib group and 8·4 months (2·9-19·8) in the placebo group. We noted no difference in median recurrence-free survival between the two groups (33·3 months in the sorafenib group vs 33·7 months in the placebo group; hazard ratio [HR] 0·940; 95% CI 0·780-1·134; one-sided p=0·26). The most common grade 3 or 4 adverse events were hand-foot skin reaction (154 [28%] of 559 patients in the sorafenib group vs four [<1%] of 548 patients in the placebo group) and diarrhoea (36 [6%] vs five [<1%] in the placebo group). Sorafenib-related serious adverse events included hand-foot skin reaction (ten [2%]), abnormal hepatic function (four [<1%]), and fatigue (three [<1%]). There were four (<1%) drug-related deaths in the sorafenib group and two (<1%) in the placebo group. INTERPRETATION: Our data indicate that sorafenib is not an effective intervention in the adjuvant setting for hepatocellular carcinoma following resection or ablation.

Impact of Steatosis on Prognosis of Patients with Early-Stage Hepatocellular Carcinoma After Hepatic Resection.

BACKGROUND: It is still unclear whether steatosis determines the prognosis of patients with hepatocellular carcinoma (HCC). This study aimed to compare the clinical manifestations and outcomes between early-stage HCC patients with and without steatosis after hepatic resection. METHODS: We enrolled 188 patients who underwent hepatic resection for HCC within the Milan criteria. After surgery, fibrosis, steatosis, lobular inflammation, portal inflammation, and ballooning in the background liver were assessed. Factors related to prognosis after surgery were analyzed by multivariate analysis. RESULTS: Seventy-four patients (39.4 %) had steatosis. Patients with steatosis had larger body mass index, higher fasting glucose levels, and higher rates of ballooning than those without steatosis. After a median follow-up period of 69.8 months, 73 patients died. The cumulative survival rates at 5 years were 57.8 and 75.6 % for patients with and without steatosis, respectively (p = 0.008). Multivariate analysis disclosed that an age of > 65 years [hazard ratio (HR) 1.996, p = 0.009], platelet count of <10(5)/mm(3) (HR 2.198, p = 0.005), indocyanine green retention rate at 15 min of >10 % (HR 2.037, p = 0.022), multinodularity (HR 2.389, p = 0.004), and steatosis (HR 1.773, p = 0.023) were independent risk factors associated with poor overall survival after resection. The impact of steatosis on postsurgical prognosis was more apparent in patients without cirrhosis. CONCLUSIONS: The presence of steatosis in the background liver was associated with a poor prognosis in early-stage HCC patients after hepatic resection, especially for noncirrhotic patients.

Analysis of protein-protein interactions in cross-talk pathways reveals CRKL protein as a novel prognostic marker in hepatocellular carcinoma.

Deciphering the network of signaling pathways in cancer via protein-protein interactions (PPIs) at the cellular level is a promising approach but remains incomplete. We used an in situ proximity ligation assay to identify and quantify 67 endogenous PPIs among 21 interlinked pathways in two hepatocellular carcinoma (HCC) cells, Huh7 (minimally migratory cells) and Mahlavu (highly migratory cells). We then applied a differential network biology analysis and determined that the novel interaction, CRKL-FLT1, has a high centrality ranking, and the expression of this interaction is strongly correlated with the migratory ability of HCC and other cancer cell lines. Knockdown of CRKL and FLT1 in HCC cells leads to a decrease in cell migration via ERK signaling and the epithelial-mesenchymal transition process. Our immunohistochemical analysis shows high expression levels of the CRKL and CRKL-FLT1 pair that strongly correlate with reduced disease-free and overall survival in HCC patient samples, and a multivariate analysis further established CRKL and the CRKL-FLT1 as novel prognosis markers. This study demonstrated that functional exploration of a disease network with interlinked pathways via PPIs can be used to discover novel biomarkers.

Dominance of the inactive Asian variant over activity and protein contents of mitochondrial aldehyde dehydrogenase 2 in human liver.

BACKGROUND: It has been well documented that a variant allele of mitochondrial aldehyde dehydrogenase 2 (ALDH2), ALDH2*2, commonly occurs in East Asians but rarely in other ethnic populations. This unique allelic variation significantly influences drinking behavior and susceptibility to development of alcoholism. Previous structural, functional, and cellular studies indicate that the resulting variant polypeptide subunit K (Lys-487) exerts dominance of null activity and shorter half-life over the tetrameric enzyme molecules in distinct manners. However, the in vivo evidence for the proposed dominance mechanisms remains lacking. METHODS: To address this question, we investigated 33 surgical liver samples identified to be normal homozygous ALDH2*1/*1 (n = 17), heterozygous ALDH2*1/*2 (n = 13), and variant homozygous ALDH2*2/*2 (n = 3). The ALDH2 activity was determined at a sufficient low acetaldehyde concentration (3 µM) and the isozyme protein amount by immunotitration using purified class-specific antibodies. RESULTS: The tissue ALDH2 activity in heterozygotes was 17% that of the ALDH2*1/*1 genotype (p < 0.001), whereas the activity of ALDH2*2/*2 was too low to be precisely determined. The protein amounts of tissue ALDH2 in variant homozygotes and heterozygotes were similar but only 30 to 40% that of normal homozygotes (p < 0.01). Linear regression analyses show that ALDH2 activities were significantly correlated with the protein contents in normal homozygotes and heterozygotes, respectively (p < 0.005). The specific activity of ALDH2 per enzyme protein in ALDH2*1/*2 was 38% that of ALDH2*1/*1 (p < 0.001). CONCLUSIONS: These results are in good agreement with those predicted by the model studies, thus providing in vivo evidence for differential impairments of hepatic acetaldehyde oxidation with alcohol metabolism in individuals carrying ALDH2*1/*2 and ALDH2*2/*2 genotypes.

Forfeited hepatogenesis program and increased embryonic stem cell traits in young hepatocellular carcinoma (HCC) comparing to elderly HCC.

BACKGROUND: Hepatocellular carcinoma (HCC) in young subjects is rare but more devastating. We hypothesize that genes and etiological pathways are unique to young HCC (yHCC; ≤ 40 years old at diagnosis) patients. We therefore compared the gene expression profiles between yHCCs and HCCs from elderly patients. RESULTS: All 44 young HCCs (≤ 40 years old at the diagnosis; 23 cases in the training set while another 21 in the validation cohort) were positive for serum hepatitis B surface antigen (HBsAg), but negative for antibodies to hepatitis C virus (anti-HCV). All 48 elderly (>40 years old; 38 in the training set while another 10 in the validation cohort) HCC patients enrolled were also serum HBsAg positive and anti-HCV negative. Comparative genomics analysis was further performed for elucidating enriched or suppressed biological activities in different HCC subtypes.The yHCC group showed more macroscopic venous invasions (60.9% vs. 10.5%, p < 0.001), fewer associated cirrhosis (17.4% vs. 63.2%, p < 0.001), and distinct profiles of expressed genes, especially those related to DNA replication and repair. yHCCs possessed increased embryonic stem cell (ESC) traits and were more dedifferentiated. A 309-gene signature was obtained from two training cohorts and validated in another independent data set. The ILF3 ESC gene, which was previously reported in poorly differentiated breast cancers and bladder carcinomas, was also present in yHCCs. Genes associated with HCC suppression, including AR and ADRA1A, were less abundant in yHCCs. ESC genes were also more enriched in advanced HCCs from elderly patients. CONCLUSION: This study revealed the molecular makeup of yHCC and the link between ESC traits and HCC subtypes. Findings in elderly tumors, therefore, cannot be simply extrapolated to young patients, and yHCC should be treated differently.

Serum interferon gamma level predicts recurrence in hepatocellular carcinoma patients after curative treatments.

Host immunity may have important role in the prognosis of hepatocellular carcinoma (HCC). The aim of this study was to evaluate the correlation between circulating immune regulators and clinical outcome in patients with HCC. Sixty-three HCC patients were prospectively enrolled. Serum levels of interleukin-10 (IL-10), transforming growth factor-beta (TGF-ß), interferon-gamma (IFN-γ) and interferon gamma-inducible protein 10 (IP-10) were measured, as well as the prevalence of regulatory T cells (Treg), NK(+) T cells, invariant natural killer T cells (iNKT), programmed cell death-1 (PD-1)(+) CD8(+) T cells, T helper 17 cells (Th17), CD69(+) and CD45RO(+) T cells in peripheral blood mononuclear cells (PBMC). Correlation between these immune regulators and clinical outcome were analyzed. A low serum IFN-γ level (<50 pg/mL) was significantly associated tumor stage (BCLC stage B: 61.25% vs. stage A: 25%, p = 0.010) and tumor size (>5 cm: 53.8% vs. <5 cm: 25%, p = 0.047). Recurrence-free survival was evaluated in 48 patients receiving curative treatment of HCC. By multivariate analysis, BCLC stage [hazard ratio (HR) = 32.180, p < 0.001], tumor size (HR = 15.373, p = 0.005), AST (HR = 3.796, p = 0.011) and IFN-γ (HR = 0.354, p = 0.018) levels were independent factors associated with recurrence-free survival. In conclusion, serum IFN-γ level correlates with tumor stage and tumor size in HCC patients. Patients with lower baseline IFN-γ levels have a higher risk of tumor recurrence after curative treatment. IFN-γ may reflect host anti-tumor immunity and may be a potential marker of HCC recurrence after curative treatment.

Expression of GOLM1 correlates with prognosis in human hepatocellular carcinoma.

BACKGROUND: Serum Golgi membrane protein 1 (GOLM1) is a novel biomarker for hepatocellular carcinoma (HCC). However, few studies have investigated the relationship between GOLM1 protein expression and clinicopathologic features in HCC patients. The aim of this study was to investigate the expression of GOLM1 in human HCC and its correlation with clinicopathologic parameters. METHODS: Clinicopathologic data were obtained through a detailed retrospective review of the medical records of 193 patients with HCC who had undergone surgical resection between 1990 and 2006 at the Taipei Veterans General Hospital. Another 120 HCC tissue samples provided by the Taiwan Liver Cancer Network were used as validation cohort. Immunohistochemical staining was used to determine the expression of GOLM1 in archived formalin-fixed, paraffin-embedded tissue specimens. RESULTS: GOLM1 expression was significantly higher in resected HCC tumor tissues than in corresponding normal liver tissues (p < 0.01). After a median follow-up of 51 months, multivariate analysis showed that portal vein invasion (hazard ratio [HR], 1.515; 95 % confidence interval [95 % CI], 1.008-2.277; p = 0.046) and high GOLM1 protein expression (HR, 1.696; 95 % CI, 1.160-2.479; p = 0.006) were independent prognostic factors for poor overall survival. High GOLM1 protein expression still significantly correlates with worse overall survival as well as disease-free survival in the validation cohort (p < 0.001 and p = 0.002). CONCLUSIONS: Overexpression of GOLM1 is associated with poor prognosis in human HCC.

Significance of incorporation of model for end-stage liver disease score with TNM staging in patients with hepatocellular carcinoma undergoing hepatic resection.

BACKGROUND/AIMS: Currently, the tumor-node-metastasis (TNM) system is used in hepatectomy patients for tumor staging of HCC patients. However this can only evaluate the histopathological factor. MELD score is an objective measure for liver function widely used as a severity index for priority on the waiting list for liver transplantation. Here we suggest a modified TNM staging system based on the MELD score and test its relation with post-operative outcome of HCC. METHODOLOGY: We retrospectively collected 922 HCC patients undergoing hepatic resection, with TNM stage I (n=239), stage II (n=375) and stage III (n=308); giving points 0 to 2 for each stage (from I to III). Pre-operative MELD score was calculated and assigned 0 points for MELD <6; 1 for 6-8; 2 for >8. The two scores were added together to form a modified MELD-base TNM stage score and tested the correlation of this new scoring system with outcome after liver resection. RESULTS: The modified MELD-base TNM stage score resulted in score 0 (n=114), score 1 (n=247), score 2 (n=335), score 3 (n=164), and score 4 (n=62). The disease-free survival in each group showed significant difference (p<0.05), the lower the score, the better the outcome. CONCLUSIONS: The MELD-based TNM staging system reliably separates patients with HCC into homogeneous groups with respect to post-resectional prognosis. Further prospective validation studies are required to confirm the feasibility of this strategy.

Early cholecystectomy following percutaneous transhepatic gallbladder drainage is effective for moderate to severe acute cholecystitis in the octogenarians.

BACKGROUND: Acute cholecystitis (AC) is a life-threatening infectious/inflammatory disease in older patients. This study aimed to investigate the safety and optimal timing of surgery in patients aged ≥ 80 years with moderate to severe AC who received percutaneous transhepatic gallbladder drainage (PTGBD). METHODS: From January 2008 to February 2021, 152 patients were retrospectively enrolled. Clinical outcomes were compared among patients who received laparoscopic cholecystectomy (LC), open cholecystectomy (OC), and conversion surgery, and between those who received early (< 6 weeks after PTGBD) and delayed cholecystectomy (≥ 6 weeks after PTGBD). Logistic regression analysis was used to identify risk factors for recurrent AC, further biliary events, conversion, and perioperative complications. RESULTS: Sixty-seven patients underwent LC, 62 underwent OC, and 23 underwent conversion surgery. Operation-related complications and mortality rates did not differ among the types of surgery; however, LC group had shorter operative time than the other groups. Eighty-two patients underwent early cholecystectomy, while 70 underwent delayed cholecystectomy. There were no differences in operative time, operation-related complications, and mortality rates between the groups. However, higher rates of recurrent AC and biliary events were observed in the delayed cholecystectomy group (52.9% vs. 4.9% and 57.1% vs. 8.5%, p < 0.001). On multivariate analysis, delayed cholecystectomy was a significant risk factor for recurrent AC (odds ratio [OR] = 19.42, p < 0.001) and further biliary events (OR = 15.95, p < 0.001). CONCLUSIONS: Early cholecystectomy is recommended for patients aged ≥ 80 years with moderate to severe AC following PTGBD.

Surgical strategy for colorectal cancer with synchronous liver and extrahepatic metastases: A scoring system and decision tree model.

BACKGROUND: The role of hepatectomy in a specific group of patients with synchronous colorectal cancer with liver metastases (SCRLM) and synchronous extrahepatic disease (SEHD) is still unclear. The aim of this study was to evaluate the efficacy of liver surgery and define the selection criteria for surgical candidates in patients with SCRLM + SEHD. METHODS: Between July 2007 and October 2018, 475 patients with colorectal cancer with liver metastases (CRLM) who underwent liver resection were retrospectively reviewed. Sixty-five patients with SCRLM + SEHD were identified and included in the study. Clinical pathological data of these patients were analyzed to evaluate the influence on survival. Important prognostic factors were identified by univariate and multivariate analyses. The risk score system and decision tree analysis were generated according to the important prognostic factors for better patient selection. RESULTS: The 5-year survival rate of patients with SCRLM + SEHD was 21.9%. The most important prognostic factors were SCRLM number of more than five, site of SEHD other than the lung only, inability to achieve SCRLM + SEHD R0 resection, and BRAF mutation of cancer cells. The proposed risk score system and decision tree model easily discriminated between patients with different survival rates and identified the profile of suitable surgical patients. CONCLUSION: Liver surgery should not be a contraindication for patients with SCRLM + SEHD. Patients with complete SCRLM + SEHD R0 resection, SCRLM number less than or equal to five, SEHD confined to the lung only, and wild-type BRAF could have favorable survival outcomes. The proposed scoring system and decision tree model may be beneficial to patient selection in clinical use.

Long-term results of a randomized, observation-controlled, phase III trial of adjuvant interferon Alfa-2b in hepatocellular carcinoma after curative resection.

OBJECTIVE: To investigate the clinical efficacy of adjuvant interferon alfa-2b (IFNα-2b) therapy on recurrence-free survival (RFS) of patients with postoperative viral hepatitis-related hepatocellular carcinoma (HCC). BACKGROUND: Despite most individual trials have failed to meet their primary endpoint, recent pooled-data meta-analyses suggest that adjuvant IFN therapy may significantly reduce the incidence of recurrence in curatively ablated HCC. METHODS: Patients with curative resection of viral hepatitis-related HCC were eligible, and were stratified by underlying viral etiology and randomly allocated to receive either 53 weeks of adjuvant IFNα-2b treatment or observation alone. The primary endpoint of this study was RFS. RESULTS: A total of 268 patients were enrolled with 133 in the IFNα-2b arm and 135 in the control arm. Eighty percent of them were hepatitis B surface antigen seropositive. At a median follow-up of 63.8 months, 154 (57.5%) patients had tumor recurrence and 84 (31.3%) were deceased. The cumulative 5-year recurrence-free and overall survival rates of intent-to-treat cohort were 44.2% and 73.9%, respectively. The median RFS in the IFNα-2b and control arms were 42.2 (95% confidence interval [CI], 28.1-87.1) and 48.6 (95% CI, 25.5 to infinity) months, respectively (P = 0.828, log-rank test). Adjuvant IFNα-2b treatment was associated with a significantly higher incidence of leucopenia and thrombocytopenia. Thirty-four (24.8%) of treated patients required dose reduction, and 5 (3.8%) of these patients subsequently withdrew from therapy because of excessive toxicity. Adjuvant IFNα-2b only temporarily suppressed viral replication during treatment period. CONCLUSIONS: In this study, adjuvant IFNα-2b did not reduce the postoperative recurrence of viral hepatitis-related HCC. More potent antiviral therapy deserves to be explored for this patient population. This study is registered at ClinicalTrials.gov and carries the identifier NCT00149565.