Ming-Chih Ho

Heparanase inhibitor PI-88 as adjuvant therapy for hepatocellular carcinoma after curative resection: A randomized phase II trial for safety and optimal dosage

BACKGROUND/AIMS Hepatocellular carcinoma recurrence after curative treatment adversely influences clinical outcome. It is important to explore adjuvant therapies. This phase II/stage 1 multi-center, randomized trial investigated the safety, optimal dosage and preliminary efficacy of PI-88, a novel heparanase inhibitor, in the setting of post-operative recurrence of HCC according to a Simons 2-stage design. METHODS Three groups were included: one untreated arm (Group A) and two PI-88 arms (Group B: 160 mg/day; Group C: 250 mg/day). Treatment groups received PI-88 over nine 4-week treatment cycles, followed by a 12-week treatment-free period. Safety and optimal dosage were assessed. RESULTS Overall, 172 patients were randomized and 168 were included in the intention-to-treat (ITT) population. Treatment-related adverse effects included cytopenia, injection site hemorrhage, PT prolongation, etc. Four serious adverse events were possibly related to PI-88 treatment. One (1.8%) group B patients and six (10.5%) group C had hepatotoxicity-related withdrawals. Among the ITT population, 29 patients (50%) in Group A, 35 (63%) in Group B, and 22 (41%) in Group C remained recurrence-free at completion. Calculated T(1) value suggested 160 mg/day treatment satisfied the criteria for the next stage of the trial. CONCLUSIONS PI-88 at 160 mg/day is optimal and safe, and shows preliminary efficacy as an adjunct therapy for post-operative HCC.

Long-term prognosis of patients with biliary atresia: a 25 year summary.

Objective: The purpose of this study was to delineate the long-term prognosis of biliary atresia (BA) in Taiwan. Study Design: From 1976 to 2000, 185 children were diagnosed with BA, 22 underwent exploratory laparotomy without Kasai operation, and 163 underwent Kasai operation, of which 141 cases had long-term follow-up and formed the basis of this study. The outcome was analyzed. Results: Among the 141 BA children studied who underwent Kasai operation, 115 (81.6%) had recoloration of stools, and 86 (61.0%) became jaundice-free (bilirubin <20 μmol/L). The resolution of jaundice and the absence of repeated cholangitis contributed to better outcome. Five and 10 year survival rates with native liver were 35% and 31%, respectively. Liver transplantation was performed in 19 patients (all but 2 with a living-related donor), and 15 (79%) survived. Five and 10 year overall survival rates for BA patients were 41.9% and 40.2%, respectively. Conclusions: The study delineated the long-term outcome of BA in an Asian country other than Japan. Survival with native liver after a Kasai operation in Taiwan was similar to that in the American and European series. Limited donors for liver transplantation in the years of the study accounted for the poor overall prognosis of BA patients in this series.

Expression of Hepatocyte Transporters and Nuclear Receptors in Children With Early and Late-Stage Biliary Atresia

To investigate how the liver adapts to chronic obstructive cholestasis, liver samples from infants with early- and late-stage cholestasis were analyzed for changes in the levels of hepatocyte transporters and nuclear receptors. At early-stage cholestasis, most canalicular transporters and sinusoidal uptake transporters were downregulated, including bile salt export pump (BSEP, ABCB11), multidrug resistant protein 3 (MDR3, ABCB4), multidrug-resistant associated protein 2 (MRP2, ABCC2), sodium-dependent taurocholate cotransporting polypeptide (NTCP, SLC10A1), organic anion transporter (OATP, SLCO1A2), and nuclear receptor farnesoid X receptor (FXR, NR1H4). At late-stage cholestasis, FXR-BSEP levels returned to normal, MDR3 and MDR1 (ABCB1) were upregulated, and MRP-2 was downregulated. In addition, alternative sinusoidal efflux transporters, organic solute transporter alpha/beta (OSTα/β) and MRP4 were upregulated, and pregnane X receptor (PXR, NR1I2) levels decreased. Cytochrome enzyme P450 7A1 was markedly downregulated at both early and late-stage cholestasis. An analysis of the long-term prognosis of 18 patients revealed lower PXR and constitutive androstane receptor (CAR, NR1I3) levels in the poor prognosis group. In conclusion, at long-term cholestasis, hepatocyte bile efflux was through sinusoidal and canalicular transporters, with FXR-BSEP levels maintained and PXR downregulated. Low PXR and CAR levels were associated with poor prognosis.

A planar interdigitated ring electrode array via dielectrophoresis for uniform patterning of cells

Uniform patterning of cells is highly desirable for most cellular studies involving cell-cell interactions but is often difficult in an in vitro environment. This paper presents the development of a collagen-coated planar interdigitated ring electrode (PIRE) array utilizing positive dielectrophoresis to pattern cells uniformly. Key features of the PIRE design include: (1) maximizing length along the edges where the localized maximum in the electric field exists; (2) making the inner gap slightly smaller than the outer gap in causing the electric field strength near the center of a PIRE being generally stronger than that near the outer edge of the same PIRE. Results of human hepatocellular carcinoma cells, HepG2, adhered on a 6x6 PIRE array show that cells patterned within minutes with good uniformity (48+/-6 cells per PIRE). Cell viability test revealed healthy patterned cells after 24h that were still confined to the collagen-coated PIREs. Furthermore, quantification of fluorescence intensity of living cells shows an acceptable reproducibility of cell viability among PIREs (mean normalized intensity per PIRE was 1+/-0.138). The results suggest that the PIRE array would benefit applications that desire uniform cellular patterning, and improve both response and reproducibility of cell-based biosensors.

Clinical Practice Guidelines for Hepatocellular Carcinoma Differ between Japan, United States, and Europe

Hepatocellular carcinoma (HCC) is a malignant tumor that is the fifth most common type of cancer and the third leading cause of cancer-related death globally. Although HCC was once thought to be a special type of cancer prevalent only in Southeast Asia and Africa, it has rapidly become more common in other regions, particularly Europe and the United States, which has led to greater interest in the diagnosis and treatment of HCC worldwide. Consequently, the American Association for the Study of Liver Diseases (AASLD) [1] and the European Association for the Study of the Liver and the European Organisation for Research and Treatment of Cancer (EASL-EORTC) [2] have published clinical practice guidelines for liver cancer. In Japan, the first edition of evidence-based clinical practice guidelines was published in 2005 [3, 4], followed by a revised edition in 2009 and a third revision in 2013 [5, 6]. In addition, 1 or 2 years after the publication of each revised edition of the evidence-based treatment guidelines, The Japan Society of Hepatology (JSH) has also published consensusbased clinical practice manuals for HCC. The first edition was published in 2007 and the second edition in 2010 [7, 8]. A third edition will be published in 2015. In this article, differences between the aforementioned European and American clinical practice guidelines and Japanese clinical practice guidelines will be discussed. Specifically, as these guidelines primarily consist of both a surveillance and diagnostic algorithm and a treatment algorithm, each component of the algorithms will be explained in detail.

Using ultrasound Nakagami imaging to assess liver fibrosis in rats

This study explored the feasibility of using the ultrasound Nakagami image to assess the degree of liver fibrosis in rats. The rat has been widely used as a model in investigations of liver fibrosis. Ultrasound grayscale imaging makes it possible to observe fibrotic rat livers in real time. Statistical analysis of the envelopes of signals backscattered from rat livers may provide useful clues about the degree of liver fibrosis. The Nakagami-model-based image has been shown to be useful for characterizing scatterers in tissues by reflecting the echo statistics, and hence the Nakagami image may serve as a functional imaging tool for quantifying rat liver fibrosis. To validate this idea, fibrosis was induced in each rat liver (n=21) by an intraperitoneal injection of 0.5% dimethylnitrosamine. Livers were excised from rats for in vitro ultrasound scanning using a single-element transducer. The backscattered-signal envelopes of the acquired raw ultrasound signals were used for Nakagami imaging. The Metavir score determined by a pathologist was used to histologically quantify the degree of liver fibrosis. It was found that the Nakagami image could be used to distinguish different degrees of liver fibrosis in rats, since the average Nakagami parameter increased from 0.55 to 0.83 as the fibrosis score increased from 0 (i.e., normal) to 4. This correlation may be due to liver fibrosis in rats involving an increase in the concentration of local scatterers and the appearance of the periodic structures or clustering of scatterers that would change the backscattering statistics. The current findings indicate that the ultrasound Nakagami image has great potential as a functional imaging tool to complement the use of the conventional B-scan in animal studies of liver fibrosis.

Survival in patients with recurrent hepatocellular carcinoma after primary hepatectomy: Comparative effectiveness of treatment modalities

BACKGROUND Insufficient data are available on the survival of recurrent hepatocellular carcinoma after primary hepatectomy in patients receiving different treatments. We evaluated retrospectively the effects of treatment modalities on long-term survival. METHODS Between 2001 and 2007, 435 posthepatectomy hepatocellular carcinoma patients who developed recurrence were grouped by treatment modality into re-resection, radiofrequency ablation, transarterial chemoembolization, and supportive treatment groups. Treatment strategies for both primary hepatocellular carcinoma and its recurrence were selected using the same criteria. Postrecurrence survival was estimated using the Kaplan-Meier method and compared using the Cox proportional hazard model with adjusted independent prognostic factors. Survival rates after primary resection without recurrence were also compared. RESULTS In re-resection, radiofrequency ablation, transarterial chemoembolization, and supportive treatment groups, the 2-year postrecurrence survival rates were 90%, 96%, 75%, and 20%, respectively, and the 5-year survival rates were 72%, 83%, 56%, and 0%, respectively. The adjusted hazard of death was less for the re-resection and radiofrequency ablation groups than for the transarterial chemoembolization group, and the adjusted hazard ratios for the re-resection and radiofrequency ablation groups were 0.45 (95% confidence interval, 0.20-0.98) and 0.25 (0.08-0.81), respectively. The adjusted hazard ratio (95% confidence interval) of death for the radiofrequency ablation group compared to the re-resection group was 0.64 (0.19-2.19). Survival in the single resection group did not differ from that in the re-resection and radiofrequency ablation groups. CONCLUSION Postrecurrence survival in the re-resection and radiofrequency ablation groups was significantly better than that in the transarterial chemoembolization group and similar to that of patients in the primary resection without recurrence group.

Health-Related Quality of Life in Patients With Hepatocellular Carcinoma: A Systematic Review

BACKGROUND & AIMS This systematic review was conducted to identify the following: (1) generic and disease-specific measures used to assess health-related quality of life (HRQOL) in patients with hepatocellular carcinoma (HCC); (2) HRQOL in patients with HCC compared with those with chronic liver disease and the general population; (3) effects of treatment (liver surgery, hepatic artery transcatheter treatment, and radiotherapy) on HRQOL; (4) relationships between physical variables, symptoms, and HRQOL; (5) relationships between demographic characteristics, psychological variables, and HRQOL; and (6) effects of psychological interventions on HRQOL. METHODS Computerized databases including British Nursing Index, Cumulative Index to Nursing and Allied Health Literature, Cochrane library, PsychoINFO, and Pubmed were searched. RESULTS Thirty-six articles were identified. The results suggested the following. Four original articles described the development of standardized measures to assess liver cancer-specific HRQOL. Patients with HCC reported worse physical, emotional, and functional HRQOL, but better social/family HRQOL compared with the general population. HRQOL improved after liver surgery, hepatic artery transcatheter treatment, and radiotherapy. Better liver function, early stage of disease, and no recurrence were correlated positively with better HRQOL; and pain, fatigue, nausea, and performance status were associated with worse HRQOL. HRQOL was correlated negatively with depression, uncertainty, chance health locus of control, and positively with satisfaction with medical services. Psychosocial interventions may reduce negative feelings and enhance HRQOL. CONCLUSIONS Future work should explore the effects of psychological variables on HRQOL and the interaction between physical and psychological variables in relation to HRQOL.

S1P5 is required for sphingosine 1-phosphate-induced autophagy in human prostate cancer PC-3 cells

Sphingosine 1-phosphate (S1P) is a platelet- and endothelial cell-released lysophospholipid that regulates various cellular functions through activating a specific family of G protein-coupled receptors. Both platelet activation and angiogenesis play important roles in cancer development, implying that cancer cells might encounter a large amount of S1P during these processes. Cancer cells, in the meantime, may experience nutrient deprivation and rely on autophagy for early development. Whether extracellular S1P regulates autophagy remains to be tested. In the present work, we investigated whether autophagy is regulated by S1P in PC-3 cells. Through monitoring the modification patterns of LC3 by Western blotting, we demonstrated that autophagy was induced by exogenously applied S1P in PC-3 cells. This observation was further confirmed by fluorescence microscopy using PC-3 cells stably expressing enhanced green fluorescent protein-LC3. By applying small interfering RNA and dihydro-S1P, S1P(5) activation was found to be involved in this process. Besides, mammalian target of rapamycin signaling was inhibited upon S1P treatment. Taken together, our results suggest that, under serum-starved conditions, S1P further upregulates autophagic activity through S1P(5)-dependent pathways in PC-3 cells.

High-Titer Antibody to Hepatitis B Surface Antigen Before Liver Transplantation Can Prevent De Novo Hepatitis B Infection

Objective: De novo hepatitis B virus (HBV) infection is defined as infection occurring in HBV surface antigen (HBsAg)–negative patients who become HbsAg positive after organ transplantation. We assessed the incidence and risk factors of de novo HBV infection in pediatric liver transplant recipients. Patients and Methods: From 1996 to 2006, 71 Taiwanese children with non-HBV-related liver diseases underwent orthotopic liver transplantation (OLT) at the National Taiwan University Hospital. All of the surviving recipients were tested regularly for liver function, serum levels of immunosuppressant, HBsAg, titers of antibodies to hepatitis B surface antigen (anti-HBs), antibodies to hepatitis B core antigen (anti-HBc), and antibodies to hepatitis C virus (anti-HCV). HBV vaccination histories and the anti-HBs titers before OLT were recorded. No regular prophylaxis was given. Results: Fifty-nine patients (33 girls and 26 boys) were followed up for a median of 4.4 years (range 1.0–10.0). Of those, 36 (61.0%) received allografts from anti-HBc-positive and HBsAg-negative donors. De novo HBV infection was found in 9 (15.3%) patients after OLT, 8 of whom received allografts from HBsAg-negative and anti-HBc-positive donors. Forty-eight (81.4%) patients received 3 or more doses of HBV vaccine before OLT. Pre-OLT anti-HBs titers were available for 49 recipients. Of the 9 de novo HBV-infected recipients, 8 had anti-HBs titers <200 mIU/mL. No graft loss or fulminant hepatitis was noted. Conclusions: In the absence of adequate prophylaxis, the incidence of de novo HBV infection in pediatric OLT recipients is 15.3%. An anti-HBs titer of >200 mIU/mL before OLT may be sufficient to prevent de novo HBV infection in HBsAg-negative recipients.