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Summary of Patients and Clinical Data.

Supplementary Figure 1. Unsupervised Clustering on CCA samples. Supplementary Figure 2. Alterations Found in CCA Clusters. Supplementary Figure 3. MAP2K4 Homozygous Deletions and ERBB2 Amplifications. Supplementary Figure 4. Alterations Related to Structural Variations Found in CCAs. Supplementary Figure 5. FIREFLY Analysis of Pathways Systematically Dysregulated by Somatic Promoter Mutations that Alter Transcription Factor Binding. Supplementary Figure 6. Epigenetic Clusters and Mutation Signatures.

Structural Variations across 71 WGS CCAs.

Summary of CCA Alterations.

Further details of methods, in addition to the supplementary figure and table legends.

Alterations in CCA Clusters.

Coverage Statistics and List of Genes for Targeted Sequencing.

Supplemental Figure S2 to S11

RTK expression profiles in normal, early HCC, and advanced HCC tissues.

Purpose:Hepatitis promotes the development and recurrence of hepatocellular carcinoma (HCC). Receptor tyrosine kinases (RTK) play critical roles in the development of many cancers. We explored the potential roles of RTKs in hepatitis-related liver cancers.Experimental Design:We conducted loss-of-function screening to elucidate the roles of RTKs in the development of HCC in vitro and in vivo.Results:Many RTKs were coexpressed in HCC and were involved in tumor development and growth. Of these, TYRO3 promoted tumor growth and was clinically associated with hepatitis activity and poor prognosis. In mice, chemical-induced hepatitis transcriptionally activated Tyro3 expression via IL-6/IL6R–STAT3 signaling. Moreover, hepatitis-associated apoptotic cells facilitated the presentation of GAS6, a TYRO3 ligand, to further activate TYRO3-mediated signaling. Furthermore, TYRO3 activation elicited intracellular SRC- and STAT3 signaling. In mice, hepatitis and Tyro3 synergistically promoted HCC development. Silencing TYRO3 expression or inhibiting its kinase activity suppressed xenograft HCC growth in nude mice.Conclusions:Many RTKs are simultaneously involved in HCC development. Hepatitis exerts dual effects on the activation of TYRO3-mediated signaling in HCC cells, which further elicits the “TYRO3–STAT3–TYRO3” signaling loop to facilitate tumor growth. Our findings unveil a previously unrecognized link between RTKs and hepatitis-associated HCC and suggest TYRO3 as a marker and therapeutic target for the HCCs with higher hepatitis activity.

Supplemental information of Materials and Methods

Background/purpose Cirrhosis is the primary risk factor for hepatocellular carcinoma (HCC) and gastrointestinal bleeding (GI). We aimed to assess the efficacy and safety of daily aspirin on HCC occurrence, overall survival, and GI bleeding in cirrhotic patients. Methods 35898 eligible cases were enrolled for analyses from an initial 40603 cirrhotic patients without tumor history. Patients continuously treated with aspirin for at least 84 days were in the therapy group, whereas those without treatment were controls. A 1:2 propensity score matching by age, sex, comorbidities, drugs, and significant clinical laboratory tests with covariate assessment was used. Results Multivariate regression analyses revealed that daily aspirin use was independently associated with a reduced risk of HCC (three-year HR 0.567; 95% CI 0.371–0.869; P = 0.0091; five-year HR 0.629, 95% CI 0.449–0.882; P = 0.0072) inversely correlated with the treatment duration [3–12 months: HR 0·88 (95% CI 0.576–1.344); 12–36 months: HR 0.56 (0.311–0.996); and ≥ 36 months: HR 0.37 (0.178–0.764)]. Overall mortality rates were significantly lower among aspirin users compared with untreated controls [three-year HR 0.43 (0.33–0.57); five-year HR 0.51 (0.42–0.63)]. The risk for gastrointestinal bleeding was not increased among aspirin users whether with [three-year HR 0.507 (0.360–0.712); five-year HR 0.511 (0.362–0.720)] or without previous gastrointestinal bleeding [three-year HR .664 (0.489–0.902); five-year HR 0.656 (0.500–0.860)]. Consistent results were obtained when the laboratory data were included in the propensity score for matching. Conclusion Long-term aspirin use significantly reduced the incidence of HCC and overall mortality without increasing gastrointestinal bleeding in cirrhotic patients.

BACKGROUND Genome-wide association studies from Asia indicate that HLA-DP and HLA-DQ loci are important in persistent hepatitis B virus (HBV) infections. One of the key elements for HBV-related carcinogenesis is persistent viral replication and inflammation. AIM To examine genetic and nongenetic factors with persistent HBV infection and viral load in families with hepatocellular carcinoma (HCC). METHODS The HCC families included 301 hepatitis B surface antigen (HBsAg) carriers and 424 noncarriers born before the nationwide vaccination program was initiated in 1984. Five HBV-related single nucleotide polymorphisms (SNPs) — rs477515, rs9272105, rs9276370, rs7756516, and rs9277535 — were genotyped. Factors associated with persistent HBV infection and viral load were analyzed by a generalized estimating equation. RESULTS In the first-stage persistent HBV study, all SNPs except rs9272105 were associated with persistent infection. A significantly higher area under the reciprocal operating characteristic curve for nongenetic factors vs genetic factors (P < 0.001) suggests that the former play a major role in persistent HBV infection. In the second-stage viral load study, we added 8 HBsAg carriers born after 1984. The 309 HBsAg carriers were divided into low (n = 162) and high viral load (n = 147) groups with an HBV DNA cutoff of 105 cps/mL. Sex, relationship to the index case, rs477515, rs9272105, and rs7756516 were associated with viral load. Based on the receiver operating characteristic curve analysis, genetic and nongenetic factors affected viral load equally in the HCC family cohort (P = 0.3117). CONCLUSION In these east Asian adults, the mechanism of persistent HBV infection-related SNPs was a prolonged viral replication phase.

ObjectivesChronic hepatitis B virus (HBV) infection is a leading cause of liver disease and hepatocellular carcinoma. A key feature of HBV replication is the synthesis of the covalently close circular (ccc)DNA, not targeted by current treatments and whose elimination would be crucial for viral cure. To date, little is known about cccDNA formation. One major challenge to address this urgent question is the absence of robust models for the study of cccDNA biology.DesignWe established a cell-based HBV cccDNA reporter assay and performed a loss-of-function screen targeting 239 genes encoding the human DNA damage response machinery.ResultsOvercoming the limitations of current models, the reporter assay enables to quantity cccDNA levels using a robust ELISA as a readout. A loss-of-function screen identified 27 candidate cccDNA host factors, including Y box binding protein 1 (YBX1), a DNA binding protein regulating transcription and translation. Validation studies in authentic infection models revealed a robust decrease in HBV cccDNA levels following silencing, providing proof-of-concept for the importance of YBX1 in the early steps of the HBV life cycle. In patients,YBX1expression robustly correlates with both HBV load and liver disease progression.ConclusionOur cell-based reporter assay enables the discovery of HBV cccDNA host factors including YBX1 and is suitable for the characterisation of cccDNA-related host factors, antiviral targets and compounds.

Ulcerative colitis (UC), a subtype of inflammatory bowel disease, is characterized by repetitive remission and relapse. Gut microbiome is critically involved in pathogenesis of UC. The shifts in microbiome profile during disease remission remain under-investigated. Recent studies revealed that UC pathogenesis is likely to originate in the mucosal barrier. Therefore, we investigated the effectiveness of mucosal tissue microbiomes to differentiate patients with subclinical UC from healthy individuals. The microbiomes of cecal and rectal biopsies and feces were characterized from 13 healthy individuals and 45 patients with subclinical UC. Total genomic DNA was extracted from the samples, and their microbial communities determined using next-generation sequencing. We found that changes in relative abundance of subclinical UC were marked by a decrease in Proteobacteria and an increase in Bacteroidetes phyla in microbiome derived from rectal tissues but not cecal tissue nor feces. Only in the microbiome of rectal tissue had significantly higher community richness and evenness in subclinical UC patients than controls. Twenty-seven operational taxonomic units were enriched in subclinical UC cohort with majority of the taxa from the Firmicutes phylum. Inference of putative microbial functional pathways from rectal biopsy microbiome suggested a differential increase in interleukin-17 signaling and T-helper cell differentiation pathways. Rectal biopsy tissue was suggested to be more suitable than fecal samples for microbiome assays to distinguish patients with subclinical UC from healthy adults. Assessment of the rectal biopsy microbiome may offer clinical insight into UC disease progression and predict relapse of the diseases.

Human kinome/phosphatome screen identified CAMK2N1 genes suppressing the development of human hepatocellular carcinoma (HCC). CAMK2N1 downregulation was found in 47% HCCs and associated with poor prognosis. The downregulation was mainly attributed to its genome deletion (28.4%) and DNA hypermethylation of its promoter (12.5%). Silencing and ectopic expression of CAMK2N1 respectively enhanced and suppressed cell proliferation, colony formation, and xenograft tumor growth in nude mice. Comparative proteomics revealed that CAMK2N1 silencing transcriptionally deregulated the genes regulated by E2F1 (89 out of the 114 E2F-signaling targets, P = 8.8E-240). The promoter assays revealed that CAMK2N1 suppressed E2F1-mediated transcriptional activities. CAMK2N1 silencing induced cyclins D/E expression, whereas its ectopic expression induced P27/KIP1 expression and suppressed the cell cycle. CAMK2N1 was translocated from the nuclei to the cytoplasm when cell proliferation reached the stationary phase, where its functions as an endogenous inhibitor of CAMK2. In conclusion, CAMK2NA is a novel 1p36 tumor suppressor gene that inhibits E2F1 transcriptional activities and induces P27/KIP1 expression. CAMK2N1-CAMK2 signaling forms a mechanism that restricts the cell cycle progression. Its deregulation could lead to tumorigenesis and might serve as promising therapeutic targets.

Caustic substance ingestion is frequently life-threatening, and its pathological mechanisms of tissue damage are well documented. However, few studies have assessed the combined effects of pH and the ingested dose on patient outcomes. Additionally, the miscellaneous chemical properties are not immediately available for providing predictive insights to physicians. This study aimed to provide a new perspective of the risk assessment of caustic substance ingestion based on the pH and dose.The retrospective study analyzed adults treated for caustic substance ingestion at Chang Gung Memorial Hospital between January 1999 and December 2018. Uniformly strict inclusion/exclusion criteria and a double-checked process during chart review were adopted. All patients underwent urgent esophagogastroduodenoscopy (EGD) within 24 h. Caustic mucosal damage was graded using Zargar's modified endoscopic classification. The pH and ingested dose of caustic substances were clearly recorded. Statistical analyses were conducted using IBM SPSS, version 22.Based on the 468 enrolled cases, the pH and dose were valuable predictors of the extent of gastrointestinal tract injury, commonly encountered complications, and long-term overall survival outcomes. Risks of mortality and perforation were dose-dependent for acids and pH-dependent for alkalis. The severe EGD findings (grade ≥ 2b) in this study were pH-dependent for both substances and additionally dose-dependent for acids.Combining pH and dose, we proposed a new perspective for the risk assessment of caustic substance ingestion. Such findings may provide predictive insights for resolving clinical uncertainty before the availability of examination results. "Large doses of acids" and "high pH of alkalis" deserve special attention. This new perspective with a retrospective nature requires further validation.

Purpose High prevalence of psychiatric comorbidities (PCs) has been widely documented in caustic substance ingestion cases. However, their effect on the clinical features and prognostic outcomes remains unclear due to the paucity of discussion. We report on detailed clinical courses with long-term multifaceted outcomes and review the association between caustic ingestion and each specific PC. Patients and methods The retrospective chart review included 396 adults (median follow-up, 16.6 months) with and 377 without (control group) PCs treated between 1999 and 2018 at Chang Gung Memorial Hospital. All PCs were diagnosed/confirmed by psychiatrists through face-to-face interviews. Results The PCs predicted serious esophagogastroduodenoscopy grading, higher rates of admission/surgery/intensive care unit stay, increments of systemic/gastrointestinal complications, and poorer 5-year overall survival rates. The poor survival among patients with PCs was highly consistent with their baseline characteristics. Significantly advanced age, more non-PCs, alcoholism, illicit drug abuse, and baseline unhealthy status resulted in statistically higher risks of severe complications and limited recovery. Conclusion PCs changed clinical patterns and had critical roles in the survival outcomes of caustic injury victims. Clinical awareness achieves benefit by limiting injuries in mild cases or allowing emergent interventions in severe cases. Future studies based on worldwide populations are essential for realizing geographic differences.

The overexpression of SOX4 in various kinds of cancer cells was associated with poor prognosis for patients. The role of SOX4 in angiogenesis and tumor microenvironment modulation was recently documented in breast cancer but remains unclear in hepatocellular carcinoma (HCC). In our study, the clinical relevance of SOX4 overexpression in HCC and its role in the tumor microenvironment were investigated. The overexpression of SOX4 (SOX4high) in tumor lesions was associated with higher microvessel density (P = 0.012), tumor thrombosis formation (P = 0.012), distant metastasis (P

Background: Hepatocellular carcinoma (HCC) tends to recur after curative treatment. This study aimed to identify the clinical factors associated with HCC recurrence after initial curative therapy. Methods: We retrospectively included patients with early stage HCC Barcelona Clinic Liver Cancer (BCLC) stages 0 and A who received curative surgical resection or local ablation at three different Chang Gung Memorial Hospitals in Taiwan (527 patients from Linkou, 150 patients from Keelung, and 127 patients from Chiayi) from 2000 to 2009. Pretreatment clinical data were subjected to univariate and multivariate logistic analyses to identify the risk factors for HCC recurrence within five years after the primary curative treatment. Recurrence and survival rates were assessed using Kaplan–Meier curves and log-rank tests. Results: Patients with a history of nucleoside analog or peg-interferon treatment for hepatitis B or hepatitis C infection had lower HCC recurrence rates than did those without such treatment. By contrast, alcohol drinking habits (p = 0.0049, hazard ratio (HR): 1.508, 95%CI: 1.133–2.009), a platelet count of < 14 × 104/μL (p = 0.003, HR: 1.533, 95%CI: 1.155–2.035), and a serum alanine aminotransferase level > 40 U/L (p = 0.0450, HR: 1.305, 95%CI: 1.006–1.694) were independent risk factors for HCC recurrence. The five-year HCC recurrence rates did not differ between patients who received either local radiofrequency ablation or surgical resection at BCLC stages 0 and A. Conclusions: Factors contributing to persistent hepatitis activity and advanced fibrosis precipitate tumor recurrence. Active intervention to discontinue liver injury or hepatitis could reduce HCC recurrence.

Long-term use of gastric-acid-suppressive drugs is known to be associated with several adverse effects. However, the association between enteric infection and acid suppression therapy is still uncertain. This study aimed to evaluate the association between gastric acid suppression and the risk of enteric infection. Materials and Methods: We conducted a population-based case-control study using the data from Chang Gung Research Database (CGRD) in Taiwan. Between January 2008 and December 2017, a total of 154,590 adult inpatients (age &gt, 18) were identified. A pool of potential eligible controls according to four propensity scores matching by sex, age, and index year were extracted (n = 89,925). Subjects with missing data or who received less than 7 days of proton pump inhibitors (PPIs) and/or H2-receptor antagonists (H2RAs) were excluded. Finally, 17,186 cases and 69,708 corresponding controls were selected for analysis. The use of PPIs and H2RAs, the result of microbiological samples, and co-morbidity conditions have been analyzed. Confounders were controlled by conditional logistic regression. Results: 32.84% of patients in the case group used PPIs, compared with 7.48% in the control group. Of patients in the case group, 9.9% used H2RAs, compared with 6.9% in the control group. Of patients in the case group, 8.3% used a combination of PPIs and H2RAs, compared with 2.7% in the control group. The most common etiological pathogens were Enterococcus (44.8%), Clostridioides difficile (34.5%), and Salmonella spp. (10.2%). The adjusted odds ratio (OR) for PPI use with enteric infection was 5.526 (95% confidence interval [CI], 5.274–5.791). For H2RAs, the adjusted odds ratio was 1.339 (95% confidence interval [CI], 1.261–1.424). Compared to the control group, persons with enteric infection had more frequent acid-suppressive agent usage. Conclusions: This study demonstrates that gastric-acid-suppressive drug use is associated with an increased risk of enteric infection after adjusting for potential biases and confounders.

Membrane protrusion and adhesion to the extracellular matrix, which involves the extension of actin filaments and formation of adhesion complexes, are the fundamental processes for cell migration, tumor invasion, and metastasis. How cancer cells efficiently coordinate these processes remains unclear. Here, we showed that membrane-targeted chloride intracellular channel 1 (CLIC1) spatiotemporally regulates the formation of cell-matrix adhesions and membrane protrusions through the recruitment of PIP5Ks to the plasma membrane. Comparative proteomics identified CLIC1 upregulated in human hepatocellular carcinoma (HCC) and associated with tumor invasiveness, metastasis, and poor prognosis. In response to migration-related stimuli, CLIC1 recruited PIP5K1A and PIP5K1C from the cytoplasm to the leading edge of the plasma membrane, where PIP5Ks generate a phosphatidylinositol 4,5-bisphosphate–rich (PIP(2)-rich) microdomain to induce the formation of integrin-mediated cell-matrix adhesions and the signaling for cytoskeleon extension. CLIC1 silencing inhibited the attachment of tumor cells to culture plates and the adherence and extravasation in the lung alveoli, resulting in suppressed lung metastasis in mice. This study reveals what we believe is an unrecognized mechanism that spatiotemporally coordinates the formation of both lamellipodium/invadopodia and nascent cell-matrix adhesions for directional migration and tumor invasion/metastasis. The unique traits of upregulation and membrane targeting of CLIC1 in cancer cells make it an excellent therapeutic target for tumor metastasis.

Background: Caustic ingestion has gained increasing attention worldwide. However, the insight into whether to use esophagogastroduodenoscopy (EGD) or computed tomography (CT) for first-line investigation remains controversial. This study aimed to evaluate a diagnostic and management algorithm that combines EGD and CT for rapid triage. Methods: We established an algorithm for our hospital in 2013, aiming to maximize the benefits and minimize the limitations of EGD and CT. Then, we retrospectively analyzed the 163 enrolled patients treated between 2014 and 2019 and categorized them into 4 groups: A = 3 (1.8%): with perforation signs and directly confirmed by CT, B = 10 (6.1%): clinically suspected perforation but not initially proven by CT, C = 91 (55.8%): initial perforation less favored but with EGD grade ≥ 2b or GI/systemic complications, and D = 59 (36.2%): clinically stable with EGD grade ≤ 2a, according to initial signs/symptoms and EGD/CT grading. The morbidity and mortality of each group were analyzed. The predictive values of EGD and CT were examined by logistic regression analyses and receiver operating characteristic (ROC) curves. Results: The outcomes of such algorithm were reported. CT was imperative for patients with toxic signs and suspected perforation. For non-emergent operations, additional EGD was safe and helpful in identifying surgical necessity. For patients with an initially low perforation risk, EGD alone sufficiently determined admission necessity. Among inpatients, EGD provided excellent discrimination for predicting the risk for signs/symptoms’ deterioration. Routine additional CT was only beneficial for those with deteriorating signs/symptoms. Conclusions: According to the analyses, initial signs/symptoms help to choose EGD or CT as the first-line investigative tool in caustic patients. CT is necessary for seriously injured patients, but it cannot replace EGD for moderate/mild injuries. The severity stratification and patient categorization help to simplify complex scenarios, accelerate decision-making, and prevent unnecessary intervention/therapy. External validation in a larger sample size is further indicated for this algorithm.

Background and Aim Extrahepatic metastasis (EHM) of hepatocellular carcinoma (HCC) leads to a worse prognosis. We aimed to develop a nomogram based on noninvasive pretreatment clinical data to predict EHM of HCC sooner. Methods Three cohorts containing 1820, 479, and 988 HCC patients were enrolled from three hospitals in different regions in Taiwan and served as the training and validation cohorts. Pretreatment clinical data were analyzed by Cox regression modeling for independent risk factors of EHM. Results Platelet count ≥ 200 × 103/μL, serum alfa-fetoprotein ≥ 100 ng/dL, tumor size ≥ 3 cm, tumor number > 1, and macrovascular invasion were independent risk factors for EHM and were used to develop a nomogram. This nomogram had concordance indices of 0.733 (95% confidence interval [CI]: 0.688-0.778) and 0.739 (95% CI: 0.692-0.787) for the prediction of EHM during a 5-year follow-up duration in the training and validation cohorts, respectively. A nomogram score > 61 implied a high risk of EHM (hazard ratio [HR] = 3.83; 95% CI: 2.77-5.31, P

Background and Aim Extrahepatic metastasis (EHM) of hepatocellular carcinoma (HCC) leads to a worse prognosis. We aimed to develop a nomogram based on noninvasive pretreatment clinical data to predict EHM of HCC sooner. Methods Three cohorts containing 1820, 479, and 988 HCC patients were enrolled from three hospitals in different regions in Taiwan and served as the training and validation cohorts. Pretreatment clinical data were analyzed by Cox regression modeling for independent risk factors of EHM. Results Platelet count ≥ 200 × 103/μL, serum alfa‐fetoprotein ≥ 100 ng/dL, tumor size ≥ 3 cm, tumor number > 1, and macrovascular invasion were independent risk factors for EHM and were used to develop a nomogram. This nomogram had concordance indices of 0.733 (95% confidence interval [CI]: 0.688–0.778) and 0.739 (95% CI: 0.692–0.787) for the prediction of EHM during a 5‐year follow‐up duration in the training and validation cohorts, respectively. A nomogram score > 61 implied a high risk of EHM (hazard ratio [HR] = 3.83; 95% CI: 2.77–5.31, P

High invasiveness is a hallmark of human hepatocellular carcinoma (HCC). Large tumors predict invasion and metastasis. Epithelial-mesenchymal transition (EMT) is crucial for cancer invasion and metastasis. However, the mechanisms whereby large tumors tend to undergo EMT remain unclear. We conducted a subgenome-wide screen and identified KLHL23 as an HCC invasion suppressor by inhibiting EMT. KLHL23 binds to actin and suppresses actin polymerization. KLHL23 silencing induced filopodium and lamellipodium formation. Moreover, EMT was suppressed by KLHL23 through its action on actin dynamics. Traditionally, actin cytoskeleton remodeling is downstream of EMT reprogramming. It is therefore intriguing to ask why and how KLHL23 inversely regulates EMT. Activation of actin cytoskeleton remodeling by either KLHL23 silencing or treatment with actin cytoskeleton modulators augmented cellular hypoxic responses in a cell-density-dependent manner, resulting in hypoxia-inducible factor (HIF) and Notch signals and subsequent EMT. Environmental hypoxia did not induce EMT unless actin cytoskeleton remodeling was simultaneously activated and only when cells were at high density. The resulting EMT was reversed by either adenosine 5'-triphosphate supplementation or actin polymerization inhibitors. Down-regulation of KLHL23 was associated with invasion, metastasis, and poor prognosis of HCC and pancreatic cancer. Correlations of tumor size with EMT and inverse association of expression of KLHL23 with HIF/Notch signals were further validated in patient-derived xenograft HCCs in mice. Conclusion Simultaneously activation of actin cytoskeleton remodeling by intrinsic (such as KLHL23 down-regulation) or microenvironment cues is crucial for cell-density-dependent and hypoxia-mediated EMT, providing a mechanistic link between large tumor size and invasion/metastasis. Our findings provide a means of developing the prevention and treatment strategies for tumor invasion and metastasis. (Hepatology 2018;67:2226-2243).

Background: Aristolochic acids (AAs) are potent mutagens commonly found in herbal plant-based remedies widely used throughout Asian countries. Patients and Methods: To understand whether AA is involved in the tumorigenesis of the oro-gastrointestinal tract, we used whole-exome sequencing to profile 54 cases of four distinct types of oro-gastrointestinal tract cancer (OGITC) from Taiwan. Results: A diverse landscape of mutational signatures including those from DNA mismatch repair and reactive oxygen species was observed. APOBEC mutational signatures were observed in 60% of oral squamous cell carcinomas. Only one sample harbored AA mutational signatures, contradictory to prior reports of cancers from Taiwan. The metabolism of AA in the liver and urinary tract, transient exposure time, and high cell turnover rates at OGITC sites may explain our findings. Conclusion: AA signatures in OGITCs are rare and unlikely to be a major contributing factor in oro-gastrointestinal tract tumorigenesis.

// Chern-Horng Lee 1 , Sen-Yung Hsieh 2 , Chih-Chun Chang 3 , I-Kuan Wang 4 , Wen-Hung Huang 5,6 , Cheng-Hao Weng 5,6 , Ching-Wei Hsu 5,6 and Tzung-Hai Yen 5,6,7 1 Department of General Internal Medicine and Geriatrics, Chang Gung Memorial Hospital, Linkou, Taiwan 2 Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital and College of Medicine, Chang Gung University, Linkou, Taiwan 3 Department of Clinical Pathology, Far Eastern Memorial Hospital, Banciao, New Taipei City, Taiwan 4 Department of Nephrology, China Medical University Hospital and College of Medicine, China Medical University, Taichung, Taiwan 5 Department of Nephrology, Chang Gung Memorial Hospital and College of Medicine, Chang Gung University, Linkou, Taiwan 6 Kidney Research Center, Chang Gung Memorial Hospital, Linkou, Taiwan 7 Center for Tissue Engineering, Chang Gung Memorial Hospital, Linkou, Taiwan Correspondence to: Tzung-Hai Yen, email: // Keywords : hepatocellular carcinoma, end-stage renal disease, hemodialysis, liver cirrhosis, tumor stage Received : October 24, 2016 Accepted : April 01, 2017 Published : April 16, 2017 Abstract We investigated the rates and predictors of mortality in hepatocellular carcinoma (HCC) patients who were or were not undergoing long-term hemodialysis. The participants in this retrospective observational study were 1298 HCC patients (60.0 ± 12.1 years old, 72% male), of whom 172 were undergoing hemodialysis and 1126 were not. HCC patients on hemodialysis exhibited a higher hepatitis C virus carrier rate (49.4% versus 39.3%, P = 0.012), lower hepatitis B virus carrier rate (37.2% versus 58.3%, P < 0.001) and lower hepatitis B or C virus carrier rate (77.9% versus 89.3%, P < 0.001) than those not on hemodialysis. Serum alkaline phosphatase levels were higher in the hemodialysis than non-hemodialysis group (162.8 ± 141.1 u/l versus 124.6 ± 102.5 u/l, P < 0.001). By the end of the analysis, 32.0% of HCC patients on hemodialysis and 28.0% of those not on hemodialysis had died. Kaplan-Meier analysis confirmed that cumulative survival was poorer in HCC patients on hemodialysis ( P = 0.004). In a multivariate Cox regression model, hemodialysis ( P < 0.001), older age ( P < 0.001) and advanced tumor stages ( P < 0.001) were found to be risk factors for mortality. HCC patients on hemodialysis had a 2.036-fold greater chance of death than HCC patients not on hemodialysis. Prospective studies with longer follow-ups and larger samples are warranted.

The expanding use of novel targeted anticancer agents such as sorafenib has led to an increasing number of dermatologic adverse events. Although cutaneous adverse events are commonly described in patients taking sorafenib, there are few reports describing psoriasis secondary to this medication. In this report, we describe 3 patients with sorafenib-induced psoriasiform drug eruption and review the available literature of similar patient cases. Our findings highlight shared characteristics among affected patients and potential treatment options for patients in whom sorafenib cannot be discontinued. Increased awareness of such drug eruptions and management options is critical to prevent suboptimal dosing and decreased quality of life.

Background Hepatocellular carcinoma (HCC) may arise from genomic instability and has dismal outcome. Sorafenib is the first-line treatment for advanced stage HCC, but its therapeutic efficacy is less than 50%. Biomarkers for predicting the therapeutic efficacy of sorafenib administration to patients with advanced HCC are required. Here, we evaluated the role of chromosomal copy number aberrations (CNAs) in patients with advanced HCC who were treated with sorafenib along with their drug response. Methods The response to sorafenib treatment of twenty-three HCC patients who developed advanced recurrence after partial hepatectomy was analyzed using the modified Response Evaluation Criteria in Solid Tumors (mRECIST). Formalin fixed paraffin embedded (FFPE) tissue specimens obtained after tumor resection were analyzed using the Affymetrix OncoScan® FFPE assay. Results From the 23 patients analyzed in this study, 7 (30.4%) had complete/partial response to sorafenib (CR/PR), 7 (30.4%) had stable disease (SD), and 9 (39.1%) had progressive disease (PD). The mean genome-wide percentage of genome change acquisition via the OncoScan platform was 19.8% for patients with CR/PR/SD and 50.02% in the PD group (P = 0.055). Percentage of genome change above 33% was associated with adverse outcomes for sorafenib treatment in the time-to-progression analysis (P = 0.007) and overall survival (P = 0.096). Among these CNAs, amplification of chromosome 7q, containing the multidrug resistance gene ATP Binding Cassette Subfamily B Member 1 (ACBC1), significantly associated with poor overall survival (P = 0.004) and time-to-progression (P Conclusions Higher percentage genome change and amplification of chromosome 7q in advanced HCC is associated with sorafenib resistance.

Air pollution is a severe public health problem in Taiwan. Moreover, Taiwan is an endemic area for hepatocellular carcinoma (HCC). This study examined the effect of particulate matter 2.5 (PM2.5) exposure on mortality in this population. A total of 1003 patients with HCC treated at Chang Gung Memorial Hospital between 2000 and 2009 were included in this study. At the end of the analysis, 288 (28.7%) patients had died. Patients with HCC living in environments with PM2.5 concentrations of &ge, 36 &micro, g/m3 had a higher mortality rate than patients living in environments with PM2.5 concentrations of &lt, g/m3 (36.8% versus 27.5%, p = 0.034). The multivariate Cox regression analysis confirmed that PM2.5 &ge, g/m3 was a significant risk factor for mortality (1.584 (1.162&ndash, 2.160), p = 0.004). A nonlinear relationship was observed between the odds ratio and PM2.5. The odds ratio was 1.137 (1.015&ndash, 1.264) for each increment of 5 &micro, g/m3 in PM2.5 or 1.292 (1.030&ndash, 1.598) for each increment of 10 &micro, g/m3 in PM2.5. Therefore, patients with HCC exposed to ambient PM2.5 concentrations of &ge, g/m3 had a 1.584-fold higher risk of death than those exposed to PM2.5 concentrations of &lt, g/m3. Further studies are warranted.

The overexpression of SOX4 in various kinds of cancer cells was associated with poor prognosis for patients. The role of SOX4 in angiogenesis and tumor microenvironment modulation was recently documented in breast cancer but remains unclear in hepatocellular carcinoma (HCC). In our study, the clinical relevance of SOX4 overexpression in HCC and its role in the tumor microenvironment were investigated. The overexpression of SOX4 (SOX4

Classification of cirrhosis based on clinical stages is rapid and based on five stages at present. Two other relevant events, hepatic encephalopathy (HE) and spontaneous bacterial peritonitis (SBP), can be considered in a clinical perspective but no study has implemented a seven-stage classification and confirmed its value before. In addition, long-term validation of the Model for End-Stage Liver Disease (MELD) in large cohorts of patients with cirrhosis and comparison with clinical findings are insufficient. Therefore, we performed a study to address these items. From the Chang-Gung Research Database (CGRD), 20,782 patients with cirrhosis were enrolled for an historical survival study. The MELD score, the five-stage clinical score (i.e., occurrence of esophageal varices (EV), EV bleeding, ascites, sepsis) and a novel seven-stage clinical score (i.e., occurrence of EV, EV bleeding, ascites, sepsis, HE, SBP) were compared with their Cox models by receiver operating characteristic (ROC) analysis. The addition of HE and SBP to the seven-stage model had a 5% better prediction result than the five-stage model did in the survival ROC analysis. The result showed that the seven clinical stages are associated with an increased risk for mortality. However, the predicted performances of the seven-stage model and MELD system are likely equivalent. In conclusion, the study (i) proved that clinical staging of cirrhosis based on seven items/stages had higher prognostic value than the five-stage model and (ii) confirmed the validity of the MELD criteria vs. clinical assessment.