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Purpose: Sorafenib has proved survival benefit for patients with advanced hepatocellular carcinoma (HCC). This study explored whether the efficacy of sorafenib can be improved by adding the mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK) inhibitor CI-1040 to vertically block the Raf/MEK/ERK pathway.Experimental Design: The growth inhibitory effects of sorafenib and CI-1040 were tested in HCC cell lines (Huh-7 and Hep3B) and human umbilical vascular endothelial cells (HUVEC). The potential synergistic growth inhibitory effects were measured by median effect analysis. Apoptosis was measured by flow cytometry. The effects on ERK phosphorylation and levels of apoptosis regulatory proteins were measured by Western blotting. The in vivo antitumor activity of sorafenib and CI-1040 were tested in xenograft HCC models.Results: Combination of sorafenib and CI-1040 synergistically inhibited ERK phosphorylation and cell growth and induced apoptosis in both HCC cells and HUVECs. Increased expression of Bim protein, which correlated with the extent of ERK inhibition, was found in both HCC cells and HUVECs. Knockdown of Bim expression by small interfering RNA partially abrogated the synergistic proapoptotic effects of sorafenib and CI-1040. Combination therapy inhibited tumor growth significantly better than either single agent in the xenograft models.Conclusion: The antitumor effects of sorafenib in HCC can be improved by vertical blockade of Raf/MEK/ERK signaling with CI-1040. (Clin Cancer Res 2009;15(18):5820–8)

Objectives To assess the respective diagnostic value of Sonazoid™ and SonoVue® for characterizing FLLs as benign or malignant and the corresponding safety. Methods This prospective Phase 3 study was conducted at 17 centres in China and Korea (May 2014 to April 2015); 424 patients (20 to 80 years) with at least 1 untreated focal liver lesion (FLL) ( Results Sonazoid-enhanced and SonoVue-enhanced ultrasound provided a statistically significant improvement in specificity for all 3 readers comparing to unenhanced ultrasound (for Sonazoid: p = 0.0093, p = 0.002, 0.03, 0.12, respectively). Difference in accuracy improvement between the 2 groups was within the pre-specified non-inferiority margin of 20% for all 3 readers (6.1%, 95% CI: − 5.0 to 17.2; − 7.5%, 95% CI: − 18.4 to 3.5; − 0.3%, 95% CI: − 11.3 to 10.7). The diagnostic confidence level for all 3 readers increased with post-contrast images relative to pre-contrast images. Both contrast agents were well tolerated. Conclusion Results showed a similar efficacy for Sonazoid™ and SonoVue® in diagnosing FLLs as benign or malignant, and underlined the benefit of CEUS imaging over unenhanced ultrasound imaging in reaching a confident diagnosis without having to refer patients for additional imaging exams.

The efficacy of treatment for advanced hepatocellular carcinoma (HCC) has remained limited. Polyinosinic-polycytidylic acid-poly-L-lysine carboxymethylcellulose (poly-ICLC) is a synthetic double-stranded RNA that serves as a viral mimic and induces an immune response. Intratumoral (IT) poly-ICLC injections can induce an autovaccination effect and prime the immune system, whereas intramuscular (IM) injection of poly-ICLC can attract and maintain antigen-specific cytotoxic T lymphocytes in tumors. We found that IT injection of poly-ICLC upregulated the expression of CD83 and CD86 on conventional type 1 dendritic cells in tumors. Combination therapy with IT followed by IM injections of poly-ICLC significantly inhibited tumor growth and increased the tumor-infiltrating CD8

To assess the respective diagnostic value of Sonazoid™ and SonoVue® for characterizing FLLs as benign or malignant and the corresponding safety.This prospective Phase 3 study was conducted at 17 centres in China and Korea (May 2014 to April 2015); 424 patients (20 to 80 years) with at least 1 untreated focal liver lesion (FLL) ( 10 cm in diameter) underwent a contrast-enhanced ultrasound (CEUS) examination (218 received Sonazoid of 0.12 μL microbubbles/kg; 206 received SonoVue of 2.4 mL). Three independent blinded readers evaluated pre- and post-contrast images characterising the FLLs as benign or malignant.Sonazoid-enhanced and SonoVue-enhanced ultrasound provided a statistically significant improvement in specificity for all 3 readers comparing to unenhanced ultrasound (for Sonazoid: p = 0.0093, 0.0001, 0.0011; for SonoVue: p = 0.002, 0.03, 0.12, respectively). Difference in accuracy improvement between the 2 groups was within the pre-specified non-inferiority margin of 20% for all 3 readers (6.1%, 95% CI: - 5.0 to 17.2; - 7.5%, 95% CI: - 18.4 to 3.5; - 0.3%, 95% CI: - 11.3 to 10.7). The diagnostic confidence level for all 3 readers increased with post-contrast images relative to pre-contrast images. Both contrast agents were well tolerated.Results showed a similar efficacy for Sonazoid™ and SonoVue® in diagnosing FLLs as benign or malignant, and underlined the benefit of CEUS imaging over unenhanced ultrasound imaging in reaching a confident diagnosis without having to refer patients for additional imaging exams.

Background/Aims: The core needle biopsy (CNB), fine needle aspiration cytology (FNAC) and touch imprint cytology (TIC) are commonly used tools for the diagnosis of hepatic malignancies. However, little is known about the benefits and criteria for selecting appropriate technique among them in clinical practice. We aimed to compare the sensitivity of ultrasound-guided CNB, FNAC, TIC as well as combinations for the diagnosis of hepatic malignancies, and to determine the factors associated with better sensitivity in each technique.Methods: From January 2018 to December 2019, a total of 634 consecutive patients who received ultrasound-guided liver biopsies at the National Taiwan University Hospital was collected, of whom 235 with confirmed malignant hepatic lesions receiving CNB, FNAC and TIC simultaneously were enrolled for analysis. The clinical and procedural data were compared.Results: The sensitivity of CNB, FNAC and TIC for the diagnosis of malignant hepatic lesions were 93.6%, 71.9%, and 85.1%, respectively. Add-on use of FNAC or TIC to CNB provided additional sensitivity of 2.1% and 0.4%, respectively. FNAC exhibited a significantly higher diagnostic rate in the metastatic cancers (P=0.011), hyperechoic lesions on ultrasound (P=0.028), and those with depth less than 4.5 cm from the site of needle insertion (P=0.036).Conclusions: The sensitivity of CNB is superior to that of FNAC and TIC for the diagnosis of hepatic malignancies. Nevertheless, for shallow (depth

459 Background: Suratadenoturev (OBP-301) is an oncolytic adenovirus that harbors a promoter of human telomerase reverse transcriptase ( hTERT) and is genetically modified to selectively replicate within and then lyse cancer cells. The aim of this study was to assess the safety and optimal dosage for intratumoral (IT) injection of OBP-301 in patients with advanced hepatocellular carcinoma (HCC). Methods: An open-label, non-comparative, phase I dose-escalation trial was performed in 20 patients who had refractory advanced HCC. OBP-301 was administered to the primary tumor using ultrasound guidance. A single IT injection of 1010 virus particles (VP) was administered to patients in the initial cohort (Cohort-1), and the subsequent single-dose cohorts received 1011 VP (Cohort-2), 1012 VP (Cohort-3), and 3×1012 VP (Cohort-4). A multiple dose cohort (Cohort-5) received 2×1012 VP × 3 times every 2 weeks. Each of the single-dose cohorts had 3 patients and there was a single escalating dose of OBP-301 from 1010 to 3×1012 VP. The multiple-dose cohort had 8 patients, and 6 of them received multiple escalating doses of 2×1012 VP ×3 times every 2 weeks. Results: There were 18 males and 2 females, and the median age was 59.39 years (range: 48.4–65.9). Patients had good tolerance of the single dose and multiple-dose regimens, and the maximum tolerated dose (MTD) was more than 6×1012 VP/patient. There was no evidence of toxicity with increasing dose, but there was a greater frequency of treatment-emergent adverse events (TEAEs) in Cohorts 4–5 than in Cohorts 1–3. The most common TEAEs related to OBP-301 were influenza-like illness (30%), pyrexia (15%), and fatigue, decreased platelet count, abdominal distension, and anemia (10% each). The overall intrahepatic mRECIST response occurred in 7 patients (39%) with confirmed stable disease (SD) and 11 (61%) with progressive disease (PD). The best target response occurred in 14 patients (78%) and 4 (22%) of them had PD. There was evidence of OBP-301 replication-dependent dissemination in the blood. Cohorts 4–5 had about 50% greater levels of CD8+ T cells in peripheral blood after OBP-301 injection. Conclusions: Multiple IT injections of OBP-301 are well-tolerated in advanced HCC. Although antitumor activity of the study medication alone would not be demonstrated obviously, SD observed as best local response was higher than as overall response. Improved anti-tumor efficacy can be achieved with adjusting viral injection volume to the target sites as well as with adopting the combination therapy with another immunothrapeutics in further study (JRCT ID: jRCT2033200223). Clinical trial information: NCT02293850.

BACKGROUND Age might affect the change in care needs in patients with hepatocellular carcinoma after treatment during their transition process from hospital to home. However, there have been no studies that focus on this. OBJECTIVE The aim of this study is to examine changes in unmet supportive care needs in young (

Few studies have been conducted to compare the efficacies of stereotactic body radiation therapy (SBRT) and radiofrequency ablation (RFA). Thus, in this multinational study, we compared the effectiveness of SBRT and RFA in patients with unresectable HCC.The retrospective study cohort included 2,064 patients treated in 7 hospitals: 1,568 and 496 in the RFA and SBRT groups, respectively. More than half of the patients (56.5%) developed recurrent tumors, mainly after transarterial chemoembolization (44.8%). Propensity score matching was performed to adjust for clinical factors (n = 313 in each group).At baseline, the SBRT group had unfavorable clinical features compared to the RFA group, including BCLC stage (B-C 65% vs. 16%), tumor size (median 3.0 cm vs. 1.9 cm), and frequent history of liver-directed treatment (81% vs. 49%, all p0.001). With a median follow-up of 27.7 months, the 3-year cumulative local recurrence rates in the SBRT and RFA groups were 21.2% and 27.9%, respectively (p0.001). After adjusting for clinical factors, SBRT was related to a significantly lower risk of local recurrence than RFA in both the entire (hazard ratio [HR] 0.45, p0.001) and matched (HR 0.36, p0.001) cohorts. In subgroup analysis, SBRT was associated with superior local control in small tumors (≤3 cm) irrespective of location, large tumors located in the subphrenic region, and those that progressed after transarterial chemoembolization. Acute grade ≥3 toxicities occurred in 1.6% and 2.6% of the SBRT and RFA patients, respectively (p = 0.268).SBRT could be an effective alternative to RFA for unresectable HCC, particularly for larger tumors (3 cm) in a subphrenic location and tumors that have progressed after transarterial chemoembolization.It is currently not known what the best treatment option is for patients with unresectable hepatocellular carcinoma. Here, we show that stereotactic body radiation therapy provides better local control than radiofrequency ablation, with comparable toxicities. Stereotactic body radiation therapy appears to be an effective alternative to radiofrequency ablation that should be considered when there is a higher risk of local recurrence or toxicity after radiofrequency ablation.

Background: Hepatocellular carcinoma (HCC) has been one of the leading causes of cancer death. Despite accurate diagnosis and effective treatments, the recurrence rate of HCC is still high. To build a recursive model by analyzing preoperative reports is helpful for follow-up and observing recurrence of tumor. Methods: Newly diagnosed HCC patients in National Taiwan University Hospital (NTUH) who received radiofrequency ablation (RFA) as the first treatment, were enrolled. Among 334 enrolled patients, 256 patients did not have recurrent HCC one year after RFA treatment and the other 78 patients had HCC recurrences. Data was processed with workflow of feature extraction and data imputation to acquire 16 features. We use different machine-learning methods to build the recurrence prediction model of HCC. The model performance among linear regression (LR), support vector machine (SVM), random forest (RF), and deep neural network (DNN) under a variety of experimental environment, including different parameters of models, data normalizations, and methods of data up-sampling were compared. Results: DNN model has the relatively best result that is the highest accuracy (82.65%) and second balanced accuracy (BAC=66.03%) among all models. SVM with feature selection according to importance in RF has the best BAC result (66.48%) with 10% lower accuracy (72.51%) compared with DNN. LR has the worst BAC (50.00%). Conclusion: Among all prediction models, DNN achieved the best results by considering both accuracy and balanced accuracy. Establishment of prediction model could identify the risk patients with close monitoring of tumor recurrence. Citation Format: Ja-Der Liang, Ta-Wei Yang, Po-When Chen, Cheng-Fu Chou, Yao-Ming Wu. Recurrence predictive models for patients with hepatocellular carcinoma after radiofrequency ablation based on machine learning algorithms [abstract]. In: Proceedings of the AACR Virtual Special Conference on Artificial Intelligence, Diagnosis, and Imaging; 2021 Jan 13-14. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(5_Suppl):Abstract nr PO-059.

Current novel imaging techniques in the diagnosis of hepatocellular carcinoma (HCC), with the latest evidence in this field, was discussed at the Asia-Pacific Primary Liver Cancer Expert (APPLE) meeting held in Taipei, Taiwan, in July 2014. Based on their expertise in a specific area of research, the novel imaging group comprised 12 participants from Japan, South Korea, Taiwan, and China and it included 10 abdominal radiologists, one hepatologist, and one pathologist. The expert participants discussed topics related to HCC imaging that were divided into four categories: (i) detection method, (ii) diagnostic method, (iii) evaluation method, and (iv) functional method. Consensus was reached on 10 statements; specific comments on each statement were provided to explain the rationale for the voting results and to suggest future research directions.

Learning Objectives: After completing this course, the reader will be able to: List the top 10 ranked symptoms after discharge suffered by patients with hepatocellular carcinoma (HCC) receiving transarterial chemoembolization (TACE) treatment.Identify the significant factors in the associations between quality of life (QOL) and demographic factors and clinical factors over a period of 2 months in patients with HCC receiving TACE.Design individualized education programs for newly diagnosed and recurrent HCC patients in order to maintain better QOL after treatment. CME This article is available for continuing medical education credit at CME.TheOncologist.com Objective. To (a) explore changes in physical and psychological distress and quality of life (QOL) and (b) identify the significant pre- and postdischarge factors related to changes in physical and mental domains of QOL over a period of 2 months in patients with hepatocellular carcinoma receiving one course of transarterial chemoembolization (TACE) treatment. Methods. A longitudinal prospective design was used, with participants recruited from a teaching hospital in Northern Taiwan. Data were collected three times: within 3 days prior to discharge (T0) and at the fourth (T1) and eighth (T2) weeks after discharge. A set of structured questionnaires was used to assess participants' QOL, symptom distress, anxiety, and depression. Changes in QOL and associated factors were examined using generalized estimating equations. Results. Eighty-nine patients were included in this study. Fatigue was reported to be the most distressful symptom after treatment. Overall QOL improved monthly after discharge. Change in physical QOL 2 months after TACE treatment was associated with age, diagnosis status, level of symptom distress, and depression after discharge. Change in mental QOL was significantly associated with gender, diagnosis status, and anxiety and depression after discharge. Conclusions. Health care providers should pay special attention to patients of older age, those who are male, and those who have higher levels of depression and anxiety after discharge. Designing personalized education programs before discharge for patients with newly diagnosed cancer versus those who have recurrent disease is suggested to help patients maintain a better QOL after discharge.

Background and Aim: Hepatocellular carcinoma (HCC) is the leading cause of cancer-related deaths in Taiwan. HCC with duodenal involvement are rare and are associated with a poor prognosis. The purpose of this retrospective study was to collect clinical information and data regarding survival following various treatments. Methods: Between 1996 and 2009, 21 cases (17 men) were diagnosed with HCC and duodenal invasion and metastases by diagnostic imaging, endoscopy with biopsy, or surgically collected specimens sent to pathology. The clinical course was analyzed from the patients' medical records. Results: Gastrointestinal bleeding was reported in 18/21 patients. Diagnostic imaging showed that the majority of cases involved direct tumor invasion (predominantly from the right liver lobe) and six cases from metastasis. Tumor mass and ulcerations were the most common features noted on endoscopy. In addition to the component therapy and medication treatment, panendoscopic hemostasis, surgery, transcatheter arterial embolization, and radiotherapy were performed for the management of duodenal involvement and gastrointestinal bleeding. Survival duration after duodenal involvement ranged from 0.2 to 57.8 months (mean 10.5 months). Conclusions: Gastrointestinal bleeding in advanced HCC should raise suspicions of duodenal involvement. HCC can involve the duodenum by direct invasion (from either the left or right liver lobes) or metastasis. The prognosis for HCC patients with duodenal involvement is poor, but is improved by supportive care and application of various treatment modalities.

Background: The purpose of this study was to report the safety of perfluorobutane (Sonazoid) as a vascular-phase imaging agent in characterizing focal liver lesions (FLLs). Materials and Methods: From May 2014 to April 2015, a total of 54 individuals who received Sonazoid contrast-enhanced ultrasound (CEUS) were enrolled at 5 hospitals of 4 medical centers. All individuals were included in safety evaluation. A prospective study to evaluate the adverse effect (AE) incidences after intravenous administration of Sonazoid. Results: Sonazoid was well tolerated. Treatment-emergent adverse events (TEAEs) representing AE were recorded for 13 (24.1%) patients. The most common AE was abdominal pain (9.3%), followed by heart rate irregularity (5.6%). The majority of these patients (69.2%) experienced TEAEs that were mild in intensity. Sonazoid causes no significant AEs after intravenous injection. The only noteworthy AEs are related to tolerable myalgia (3.7%), abdominal pain (1.9%), and headache (1.9%). None of the 54 patients showed serious adverse effects. Conclusion: Sonazoid shows good safety and tolerance of intravenous use during CEUS of the liver for evaluation of FLLs.

Hepatic tumor detection is an important issue in ultrasound (US) examination, especially in the screening of malignancy in countries with prevalent chronic hepatitis and cirrhosis. US, which developed from grayscale scanning into color-coded blood flow signaling, not only detects the existence of hepatic tumors, but color and power Doppler ultrasonography also provide information on vascular structures and patterns, which help in the differential diagnosis of hepatic tumors. In addition, the development of contrast media has led to effective visualization of tumor vasculature. According to the vascularity and vascular pattern of tumors, the differential diagnosis of hepatic tumors has become increasingly promising and feasible with the use of contrast-enhanced US. Three-dimensional ultrasonography comprehensively demonstrates tumor structure and its related vasculature and provides information for differential diagnosis. These advances in ultrasonography and US have led to comparable detection and differential diagnostic rates to that of other imaging modalities, such as computed tomography and magnetic resonance imaging.

In an attempt to discover cell markers for liver stem cells, a cDNA microarray analysis was carried out to compare the gene expression profiles between an adult liver stem cell line, Lig-8, and mature hepatocytes. Several genes in the categories of extracellular matrix, cell membrane, cell adhesion, transcription factor, signal molecule, transporter, and metabolic enzyme were shown to be differentially expressed in Lig-8 cells. Among them, epithelial membrane protein (EMP)-1 has been previously implicated with stem cell phenotypes. Antiserum to EMP-1 was produced to localize its expression. On monolayers of Lig-8 cells, EMP-1 was expressed along the intercellular border. In the liver harboring proliferating oval cells, the liver progenitors, EMP-1 was localized as ribbon bands, a staining pattern for epithelial junctions, all the way through bile duct epithelia, oval cell ductules, and into peri-hepatocytic regions. These peri-hepatocytic regions were proved to be bile canaliculi by co-localization of EMP-1 and dipeptidyl peptidase IV, an enzyme located on bile canaliculi. This report is the first to indicate EMP-1 to be a junctional protein in the liver.

A description of patient conditions should consist of the changes in and combination of clinical measures. Traditional data-processing method and classification algorithms might cause clinical information to disappear and reduce prediction performance. To improve the accuracy of clinical-outcome prediction by using multiple measurements, a new multiple-time-series data-processing algorithm with period merging is proposed. Clinical data from 83 hepatocellular carcinoma (HCC) patients were used in this research. Their clinical reports from a defined period were merged using the proposed merging algorithm, and statistical measures were also calculated. After data processing, multiple measurements support vector machine (MMSVM) with radial basis function (RBF) kernels was used as a classification method to predict HCC recurrence. A multiple measurements random forest regression (MMRF) was also used as an additional evaluation/classification method. To evaluate the data-merging algorithm, the performance of prediction using processed multiple measurements was compared to prediction using single measurements. The results of recurrence prediction by MMSVM with RBF using multiple measurements and a period of 120 days (accuracy 0.771, balanced accuracy 0.603) were optimal, and their superiority to the results obtained using single measurements was statistically significant (accuracy 0.626, balanced accuracy 0.459, P0.01). In the cases of MMRF, the prediction results obtained after applying the proposed merging algorithm were also better than single-measurement results (P0.05). The results show that the performance of HCC-recurrence prediction was significantly improved when the proposed data-processing algorithm was used, and that multiple measurements could be of greater value than single.

An appropriate liver-specific progenitor cell marker is a stepping stone in liver regenerative medicine. Here, we report brain isoform glycogen phosphorylase (GPBB) as a novel liver progenitor cell marker. GPBB was identified in a protein complex precipitated by a monoclonal antibody Ligab generated from a rat liver progenitor cell line Lig-8. Immunoblotting results show that GPBB was expressed in two liver progenitor cell lines Lig-8 and WB-F344. The levels of GPBB expression decreased in the WB-F344 cells under sodium butyrate (SB)-induced cell differentiation, consistent with roles of GPBB as a liver progenitor cell marker. Short hairpin RNA (shRNA)-mediated GPBB knockdown followed by glucose deprivation test shows that GPBB aids in liver progenitor cell survival under low glucose conditions. Furthermore, shRNA-mediated GPBB knockdown followed by SB-induced cell differentiation shows that reducing GPBB expression delayed liver progenitor cell differentiation. We conclude that GPBB is a novel liver progenitor cell marker, which facilitates liver progenitor cell survival under low glucose conditions and cell differentiation.

AIM: To investigate whether hepatitis B virus (HBV) and hepatitis C virus (HCV) increase risk of pancreatic ductal adenocarcinoma (PDAC). METHODS: We recruited 585 patients with cytological and/or pathologically confirmed PDAC in National Taiwan University Hospital from September 2000 to September 2013, and 1716 age-, sex-, and race-matched controls who received a screening program in a community located in Northern Taiwan. Blood samples were tested for the presence of HCV antibodies (anti-HCV), HBV surface antigen (HBsAg), antibodies against HBsAg (anti-HBs), and hepatitis B core antigen (anti-HBc) in all cases and controls. The odds ratio (OR) of PDAC was estimated by logistic regression analysis with adjustment diabetes mellitus (DM) and smoking. RESULTS: HBsAg was positive in 73 cases (12.5%) and 213 controls (12.4%). Anti-HCV was positive in 22 cases (3.8%) and 45 controls (2.6%). Anti-HBs was positive in 338 cases (57.8%) and 1047 controls (61.0%). The estimated ORs of PDAC in multivariate analysis were as follows: DM, 2.08 (95%CI: 1.56-2.76, P < 0.001), smoking, 1.36 (95%CI: 1.02-1.80, P = 0.035), HBsAg+/anti-HBc+/anti-HBs-, 0.89 (95%CI: 0.89-1.68, P = 0.219), HBsAg-/anti-HBc+/anti-HBs+, 1.03 (95%CI: 0.84-1.25, P = 0.802). CONCLUSION: HBV and HCV infection are not associated with risk of PDCA after adjustment for age, sex, DM and smoking, which were independent risk factors of PDAC.

BackgroundBecause of the increased adoption rate of electronic medical record (EMR) systems, more health care records have been increasingly accumulating in clinical data repositories. Therefore, querying the data stored in these repositories is crucial for retrieving the knowledge from such large volumes of clinical data. ObjectiveThe aim of this study is to develop a Web-based approach for enriching the capabilities of the data-querying system along the three following considerations: (1) the interface design used for query formulation, (2) the representation of query results, and (3) the models used for formulating query criteria. MethodsThe Guideline Interchange Format version 3.5 (GLIF3.5), an ontology-driven clinical guideline representation language, was used for formulating the query tasks based on the GLIF3.5 flowchart in the Protégé environment. The flowchart-based data-querying model (FBDQM) query execution engine was developed and implemented for executing queries and presenting the results through a visual and graphical interface. To examine a broad variety of patient data, the clinical data generator was implemented to automatically generate the clinical data in the repository, and the generated data, thereby, were employed to evaluate the system. The accuracy and time performance of the system for three medical query tasks relevant to liver cancer were evaluated based on the clinical data generator in the experiments with varying numbers of patients. ResultsIn this study, a prototype system was developed to test the feasibility of applying a methodology for building a query execution engine using FBDQMs by formulating query tasks using the existing GLIF. The FBDQM-based query execution engine was used to successfully retrieve the clinical data based on the query tasks formatted using the GLIF3.5 in the experiments with varying numbers of patients. The accuracy of the three queries (ie, “degree of liver damage,” “degree of liver damage when applying a mutually exclusive setting,” and “treatments for liver cancer”) was 100% for all four experiments (10 patients, 100 patients, 1000 patients, and 10,000 patients). Among the three measured query phases, (1) structured query language operations, (2) criteria verification, and (3) other, the first two had the longest execution time. ConclusionsThe ontology-driven FBDQM-based approach enriched the capabilities of the data-querying system. The adoption of the GLIF3.5 increased the potential for interoperability, shareability, and reusability of the query tasks.

To provide an efficient way for tracking patients' condition over long periods of time and to facilitate the collection of clinical data from different types of narrative reports, it is critical to develop an efficient method for smoothly analyzing the clinical data accumulated in narrative reports.To facilitate liver cancer clinical research, a method was developed for extracting clinical factors from various types of narrative clinical reports, including ultrasound reports, radiology reports, pathology reports, operation notes, admission notes, and discharge summaries. An information extraction (IE) module was developed for tracking disease progression in liver cancer patients over time, and a rule-based classifier was developed for answering whether patients met the clinical research eligibility criteria. The classifier provided the answers and direct/indirect evidence (evidence sentences) for the clinical questions. To evaluate the implemented IE module and the classifier, the gold-standard annotations and answers were developed manually, and the results of the implemented system were compared with the gold standard.The IE model achieved an F-score from 92.40% to 99.59%, and the classifier achieved accuracy from 96.15% to 100%.The application was successfully applied to the various types of narrative clinical reports. It might be applied to the key extraction for other types of cancer patients.

Hepatocellular carcinoma (HCC) is the leading cause of cancer-related deaths in Taiwan. HCC with duodenal involvement are rare and are associated with a poor prognosis. The purpose of this retrospective study was to collect clinical information and data regarding survival following various treatments.Between 1996 and 2009, 21 cases (17 men) were diagnosed with HCC and duodenal invasion and metastases by diagnostic imaging, endoscopy with biopsy, or surgically collected specimens sent to pathology. The clinical course was analyzed from the patients' medical records.Gastrointestinal bleeding was reported in 18/21 patients. Diagnostic imaging showed that the majority of cases involved direct tumor invasion (predominantly from the right liver lobe) and six cases from metastasis. Tumor mass and ulcerations were the most common features noted on endoscopy. In addition to the component therapy and medication treatment, panendoscopic hemostasis, surgery, transcatheter arterial embolization, and radiotherapy were performed for the management of duodenal involvement and gastrointestinal bleeding. Survival duration after duodenal involvement ranged from 0.2 to 57.8 months (mean 10.5 months).Gastrointestinal bleeding in advanced HCC should raise suspicions of duodenal involvement. HCC can involve the duodenum by direct invasion (from either the left or right liver lobes) or metastasis. The prognosis for HCC patients with duodenal involvement is poor, but is improved by supportive care and application of various treatment modalities.

Purpose: Sorafenib has proved survival benefit for patients with advanced hepatocellular carcinoma (HCC). This study explored whether the efficacy of sorafenib can be improved by adding the mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK) inhibitor CI-1040 to vertically block the Raf/MEK/ERK pathway. Experimental Design: The growth inhibitory effects of sorafenib and CI-1040 were tested in HCC cell lines (Huh-7 and Hep3B) and human umbilical vascular endothelial cells (HUVEC). The potential synergistic growth inhibitory effects were measured by median effect analysis. Apoptosis was measured by flow cytometry. The effects on ERK phosphorylation and levels of apoptosis regulatory proteins were measured by Western blotting. The in vivo antitumor activity of sorafenib and CI-1040 were tested in xenograft HCC models. Results: Combination of sorafenib and CI-1040 synergistically inhibited ERK phosphorylation and cell growth and induced apoptosis in both HCC cells and HUVECs. Increased expression of Bim protein, which correlated with the extent of ERK inhibition, was found in both HCC cells and HUVECs. Knockdown of Bim expression by small interfering RNA partially abrogated the synergistic proapoptotic effects of sorafenib and CI-1040. Combination therapy inhibited tumor growth significantly better than either single agent in the xenograft models. Conclusion: The antitumor effects of sorafenib in HCC can be improved by vertical blockade of Raf/MEK/ERK signaling with CI-1040. (Clin Cancer Res 2009;15(18):5820–8)

Gene inactivation through DNA hypermethylation plays a pivotal role in carcinogenesis. This study aimed to profile aberrant DNA methylation in different stages of liver disease, namely noncirrhosis, cirrhosis and hepatocellular carcinoma (HCC), and also to clarify the influence of hepatitis B virus (HBV) infection on the aberrant DNA methylation in HCCs. Promoter methylation in p14(ARF), p16(INK4a), O(6)-methylguanine-DNA methyltransferase (MGMT), glutathione S-transferase pi (GSTP1) and E-cadherin (E-Cad) genes of 58 HCCs paired with adjacent nontumorous tissues was assayed by methylation-specific PCR. HBV infection was determined using a hepatitis B virus surface antigen (HBsAg) serological assay. The frequency of p16(INK4a) promoter methylation increased from noncirrhotic, cirrhotic, to HCC tissues (noncirrhotic vs. HCC, p < 0.001), while that of GSTP1 promoter methylation increased in cirrhotic tissues compared to noncirrhotic ones (p = 0.029). The frequency of GSTP1 promoter hypermethylation is significantly higher in HCC than in nontumorous tissues (p = 0.022) from HBsAg-positive patients, but not the HBsAg-negative controls (p = 0.289). While the frequency of E-Cad promoter hypermethylation remained high in both nontumorous tissues and HCCs from HBsAg-positive patients (p = 0.438), it was lower in HCCs than in nontumorous tissues from HBsAg-negative patients (p = 0.002). In contrast, the frequency of p16(INK4a), MGMT and p14(ARF) promoter hypermethylation in HCCs was unrelated to HBsAg status. In conclusion, aberrant DNA methylation may begin at different stages of liver disease in a gene-dependent manner. Moreover, HBV infection may enhance or maintain GSTP1 and E-Cad promoter methylation and thereby affect hepatocarcinogenesis.

Percutaneous microwave coagulation therapy (PMCT) can effectively treat hepatocellular carcinomas (HCCs) smaller than 2 cm. However, for tumors 2 to 3 cm in size, combination of transarterial chemoembolization (TACE) or multiple insertions of electrodes may be more effective. This study investigated the treatment efficacy of PMCT for tumors 2 to 3 cm in size.Nineteen HCCs smaller than 3 cm in diameter (2 cm in 11, and 2-3 cm in 8) in 18 patients (including 14 previously treated patients) were treated by PMCT under ultrasound guidance. One or 2 PMCT electrodes were consecutively inserted either into the left and right portion, or into the distal and proximal portion of the tumor, according to the size, shape, and margin of tumors and puncture direction. Liver function tests and contrast-enhanced computed tomography were used to examine preoperative status and response to PMCT.After an average of 1.6 emissions of PMCT, 18 tumors (95%) were completely ablated. The only case of treatment failure was due to a tumor location which made the approach of the electrode difficult. Bacteremia developed after the procedure in 1 patient (5%) and local inflammatory reaction of the puncture wound in another (5%). During follow-up ranging from 5 to 19 months, no recurrence was noted at the site of the original tumors. Tumor recurrence was detected at another site 2-9 months after PMCT in 9 of the 14 previously treated patients.PMCT can effectively and safely treat HCCs smaller than 3 cm in size without combination of TACE or multiple insertions of electrodes.

Due to modern diagnostic imaging and the sensitive alpha-fetoprotein test, small hepatocellular carcinoma can now be detected at an early stage. Studies have shown that surgical resection of the tumors is a valuable treatment. Local treatment under ultrasound guidance was initially considered as an alternative when patients' liver reserves were not good enough for surgical resection; however, this technique has been improved and the results indicate that its survival rate can compete with that of surgical resection. In follow-up studies of patients with small hepatocellular carcinoma, a 5-year survival of 60% has been achieved after percutaneous ethanol injection therapy. Percutaneous microwave coagulation therapy and percutaneous radiofrequency ablation therapy have been shown to have some advantages over percutaneous ethanol injection therapy, although the follow-up durations of these studies were not long enough. Percutaneous ethanol injection therapy, percutaneous microwave coagulation therapy and percutaneous radiofrequency ablation therapy have become the 3 most widely used techniques for the treatment of hepatocellular carcinomas that are less than 5 cm in diameter and have a tumor number less than 3. In general, a tumor size of 3 to 5 cm is a good candidate for radiofrequency ablation and a tumor size of 2 to 3 cm is suitable for radiofrequency ablation or microwave coagulation. If the tumor size is around 2 cm or less, microwave coagulation or ethanol injection is often chosen due to the relatively low cost and similar efficacy. Ethanol injection also has the advantage of needing only a fine needle for injection. Informed selection of the appropriate technique, or combining a technique with transcatheter hepatic arterial embolization according to the tumor size and number, might provide the most effective treatment and achieve better results for hepatocellular carcinoma, even if the liver reserve is not good. However, large-scale, randomized, controlled trials are required before a definitive conclusion can be reached.

Although 2-dimensional (2D) ultrasonography (US) with conventional color and power Doppler US has been applied widely in the differential diagnosis of hepatic tumors and in the follow-up of treatment of hepatocellular carcinomas (HCCs), it has limited capabilities for demonstrating associated arteries of HCCs. Three-dimensional (3D) US can provide more accurate depiction of stereotypic vascular patterns than 2D US. This study investigated the efficacy of 3D power Doppler US versus angiography for demonstrating associated arteries of HCCs.A total of 24 HCCs with surrounding or intratumoral arteries detected by 2D power Doppler US were studied using a US machine equipped with power Doppler software and a built-in stereo image processing workstation. Serial 2D images were reconstructed into 3D images to analyze the distribution and routes of arteries associated with HCCs. These results were compared with angiographic findings.Three-dimensional US imaging of vasculature associated with HCCs in the 24 patients was categorized into 3 patterns: peripheral arteries around the tumor (pattern I, n = 9); no more than 4 intratumoral arteries with or without originating peripheral arteries (pattern II, n = 9); and prominent (more than 4) intratumoral arteries (pattern III, n = 6). Most feeding arteries shown in angiograms that could be demonstrated by 3D power Doppler US were in HCCs with pattern I and II vasculature. In HCCs with pattern III, the basket vascular pattern shown on angiograms could also be demonstrated on 3D power Doppler US. The vascular proficiency, including major feeding arteries and branches of feeding arteries,could be shown to significantly increase from pattern I to III on 3D power Doppler, but this method had a lower detection rate of smaller branches and neovascularization than angiographic study.Three-dimensional power Doppler US can effectively depict the associated arteries of HCCs, especially the major feeding arteries. Three vascularization patterns of HCCs were categorized in 3D images. There is a good correlation of the findings of 3D power Doppler US with angiographic study. These findings demonstrate the usefulness of 3D power Doppler as a non-invasive alternative to angiographic examination.

A 56-year-old woman, with underlying rheumatic heart disease status post mitral valve replacement, presented with fever, low back pain radiating to right leg, and congestive heart failure. Magnetic resonance imaging detected an L5-S1 spinal epidural abscess. A vegetation on prosthetic mitral valve was found by transesophageal echocardiography. Cultures of epidural aspirate, surgical specimen, and blood all grew Candida albicans. She received surgical drainage of the spinal epidural abscess and i.v. amphotericin B 1 mg/kg/day for eight weeks. Clinical symptoms improved gradually and she was discharged without neurologic sequelae. She remained well and continued to lead an active life two years after discharge.