Chee-Kiat Tan

Thermoresponsive core–shell magnetic nanoparticles for combined modalities of cancer therapy

Thermoresponsive polymer-coated magnetic nanoparticles loaded with anti-cancer drugs are of considerable interest for novel multi-modal cancer therapies. Such nanoparticles can be used for magnetic drug targeting followed by simultaneous hyperthermia and drug release. Gamma-Fe(2)O(3) iron oxide magnetic nanoparticles (MNP) with average sizes of 14, 19 and 43 nm were synthesized by high temperature decomposition. Composite magnetic nanoparticles (CNP) of 43 nm MNP coated with the thermoresponsive polymer poly-n-isopropylacrylamide (PNIPAM) were prepared by dispersion polymerization of n-isopropylacrylamide monomer in the presence of the MNP. In vitro drug release of doxorubicin-(dox) loaded dehydrated CNP at temperatures below and above the lower critical solution temperature of PNIPAM (34 degrees C) revealed a weak dependence of drug release on swelling behavior. The particles displayed Fickian diffusion release kinetics; the maximum dox release at 42 degrees C after 101 h was 41%. In vitro simultaneous hyperthermia and drug release of therapeutically relevant quantities of dox was achieved, 14.7% of loaded dox was released in 47 min at hyperthermia temperatures. In vivo magnetic targeting of dox-loaded CNP to hepatocellular carcinoma (HCC) in a buffalo rat model was studied by magnetic resonance imaging (MRI) and histology. In summary, the good in vitro and in vivo performance of the doxorubicin-loaded thermoresponsive polymer-coated magnetic nanoparticles suggests considerable promise for applications in multi-modal treatment of cancer.

Prospective evaluation of transient elastography for the diagnosis of hepatic fibrosis in Asians : comparison with liver biopsy and aspartate transaminase platelet ratio index

Background  Transient elastography (TE) is a reliable non‐invasive predictor of hepatic fibrosis, but data on TE in Asians are limited.

Efficacy of entecavir in chronic hepatitis B patients with mildly elevated alanine aminotransferase and biopsy‐proven histological damage

Current guidelines for management of chronic hepatitis B recommend treatment for patients presenting with elevated hepatitis B virus (HBV) DNA and alanine aminotransferase (ALT) >2 × upper limit of normal (ULN) or histological evidence of liver disease. Retrospective analyses have demonstrated that significant hepatic necroinflammation and fibrosis were present in a substantial proportion of patients with ALT 1 to 2 × ULN. To assess therapeutic efficacy in this clinical setting, we retrospectively examined treatment endpoints among the subset of nucleoside‐naïve chronic hepatitis B (CHB) patients treated in phase 3 clinical trials of entecavir who had both screening and baseline serum ALT 1.3 to 2 × ULN. A total of 1347 patients were randomized to treatment with entecavir or lamivudine. Three hundred thirty‐six patients, constituting 25% of the total study population, had screening and baseline ALT 1.3 to 2 × ULN. Clinically significant necroinflammation (Knodell necroinflammation score ≥7) was observed in 60% and 72% of hepatitis B e antigen (HBeAg)‐positive and HBeAg‐negative patients, respectively, whereas marked fibrosis (Ishak fibrosis score ≥4) was observed in 8% and 15% of HBeAg‐positive and HBeAg‐negative patients, respectively. Among entecavir‐treated HBeAg‐negative patients, the proportions of patients achieving histological improvement, HBV DNA <300 copies/mL, and ALT normalization were similar between patients with mildly elevated ALT and those with ALT >2 × ULN. However, entecavir‐treated HBeAg‐positive patients with mildly elevated ALT had lower response rates for histological improvement, HBV DNA less than 300 copies/mL, ALT normalization, and HBeAg seroconversion than those with ALT greater than 2 × ULN. Conclusion: This retrospective analysis demonstrated that HBeAg‐negative CHB patients treated with entecavir responded similarly irrespective of baseline ALT level. However, HBeAg‐positive patients with mildly elevated ALT responded less well to treatment with entecavir than did those with ALT greater than 2 × ULN. (HEPATOLOGY 2010.)

Is the prognosis of young patients with hepatocellular carcinoma poorer than the prognosis of older patients? A comparative analysis of clinical characteristics, prognostic features, and survival outcome

BackgroundHepatocellular carcinoma (HCC) is uncommon in young adults. This study examined the clinical characteristics and survival outcome of young HCC patients compared with those in older patients.MethodsData were prospectively collected from 638 patients diagnosed with HCC over a 9-year period. Patients aged ≤40 years at diagnosis of HCC were defined as young HCC patients. Their clinical characteristics and survival was compared with those aged >40 years.ResultsThe prevalence of young HCC was 8.6% (55/638). Young HCC patients had a significantly higher rate of hepatitis B-related disease (HBsAg positivity: 85.5% vs. 59.7%, P = 0.003), better Child-Pugh status (Child-Pugh class A: 69.1% vs. 43.9%, P = 0.002), and lower rates of cirrhosis (12.7% vs. 34.3%, P = 0.001) compared with the older group. They had more advanced disease at diagnosis, with higher α-fetoprotein levels (>12 000 μg/l: 45.4% vs. 30.5%, P = 0.026), a higher incidence of portal vein involvement (63.6% vs. 40%, P = 0.003), and a more advanced TNM stage (TNM IV: 83.6% vs. 66.4%, P = 0.018). More young patients were eligible for surgical resection (18.2% vs. 8.2%, P = 0.014). The overall survival between the two groups was similar, but when the patients were stratified for stage of disease, the median survival of young patients with early disease was superior to that of older patients (51.2 vs. 11.6 months, P = 0.025).ConclusionsHCC in young adults occurs mainly in hepatitis B carriers and is often diagnosed at an advanced stage. Their survival outcome is not different from that of older patients because the advanced disease at presentation offsets the advantages of better liver function and a higher resection rate. However, there is a distinct survival advantage for young patients diagnosed with early disease. These results support the importance of extending HCC surveillance to young hepatitis B carriers.

Rates of cirrhosis and hepatocellular carcinoma in chronic hepatitis B and the role of surveillance: a 10-year follow-up of 673 patients.

Background and objectives Development of cirrhosis and hepatocellular carcinoma (HCC) are critical milestones in the natural history of chronic hepatitis B virus (HBV) infection. There are no prospective data on the risk of these critical milestones in HBV patients in Singapore. The efficacy and justification of HCC surveillance is determined by the rate of HCC development. Our study aims to determine the rates of cirrhosis and HCC in HBV patients in Singapore and hence the appropriateness of HCC surveillance. Materials and methods A total of 673 HBV patients were enrolled between March 2003 and March 2004 and followed up for 10 years with regular surveillance for HCC using &agr;-fetoprotein and abdominal ultrasound. Results Overall, 62.6% of the patients were men, mean age 56.4 years. In all, 31% were hepatitis B e antigen-positive and 14.9% had cirrhosis at baseline. Seventy-four patients developed cirrhosis and 42 patients developed HCC after 10 years. The overall 10-year incidence of cirrhosis and HCC was 16.2% (1.6%/year) and 7.8% (0.8%/year), respectively. The overall incidence of HCC in cirrhotics was 29.7% (3.0%/year), highest within a year of diagnosis of cirrhosis (7.9%). The rate of cirrhosis was significantly higher in those aged more than 55 years (P=0.001). Sex and hepatitis B e antigen status did not affect the rate of cirrhosis. Factors with significantly higher overall rates of HCC were age 55 years or more (P=0.001), male sex (P=0.001), and baseline &agr;-fetoprotein of 4.1 µg/l or more (P<0.0001). However, age more than 55 years was not significant in the development of HCC in cirrhotics. Conclusion The rate of cirrhosis in HBV patients in Singapore is about 1.6% per year. The rate of HCC is about 0.8% per year overall and 3.0% per year in cirrhotics, which justifies HCC surveillance.

Treatment of Chronic Hepatitis C in Patients with End-Stage Renal Disease and Hemophilia – The Singapore Experience

Objective: The aim of this study was to determine the response to treatment with interferon-alpha (IFN-α) in patients with chronic hepatitis C who had end-stage renal disease (ESRD) or hemophilia in Singapore. Methods: Treatment-naive hepatitis patients with ESRD or hemophilia were given IFN-α2a 3 million units three times per week for 12 months in an open-label study. Hepatitis C virus RNA was determined before treatment, at the end of treatment and 6 months thereafter. Regular clinical examinations including blood counts and biochemistry were carried out during and after the treatment. Results: Nine consecutive patients with ESRD (8 men and 1 woman) and 6 consecutive male patients with hemophilia, with a mean age of 43 and 40 years, received treatment. Patients in both groups were predominantly infected with hepatitis C virus genotype 1 and had significant cytopenia affecting all three cell lines during the treatment; only 1 patient developed serious neutropenia, temporarily demanding a reduction of his IFN dose. Biochemical and virological responses at the end of treatment were accomplished by 8 of the 9 (89%) patients with ESRD and 4 of the 6 (67%) patients with hemophilia; however, 1 patient with ESRD and 2 with hemophilia relapsed after the treatment. Four of the 7 patients with ESRD who had sustained virological response underwent successful kidney transplantation later on. Conclusion: Monotherapy with IFN-α for 12 months is safe for treatment of the patients with chronic hepatitis C who had ESRD or those with hemophilia. A higher sustained virological response rate was observed in patients with ESRD than in those with hemophilia (78 vs. 33%).

MARS therapy in critically ill patients with advanced malignancy: a clinical and technical report

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Chronic Hepatitis E Infection Resulting in Graft Failure in a Liver Transplant Tourist

Hepatitis E, usually an acute hepatitis in the immunocompetent, has a chronic form described in immunocompromised hosts. We report the clinical course and outcome of an adult liver transplant recipient whose posttransplant period was complicated by chronic hepatitis E, Epstein-Barr virus infection, and cellular rejection of the graft.

Paraneoplastic erythrocytosis as a primary presentation of hepatocellular carcinoma

Sir, A 55-year-old man with hypertension, diabetes mellitus and gout presented with generalized lethargy and weight loss. He was diagnosed as a hepatitis B carrier 5 years ago but was not on regular follow-up and did not undergo regular liver function tests or ultrasound examinations. He smoked 20 cigarettes per day for the past 30 years. Clinical examination revealed facial plethora, mild scleral icterus and conjunctival suffusion. He had hepatomegaly with a hard, irregular liver. The patient was fully orientated with no asterixis. He had minimal ascites, numerous spider nevi (>6) and palmar erythema.

Peretinoin as an adjuvant therapy for hepatocellular carcinoma

ABSTRACT Introduction: The current curative treatment modalities for hepatocellular carcinoma (HCC) are unfortunately fraught with high rates of HCC recurrence. Hence there is a need to prevent or reduce HCC recurrence after initial curative therapy. Peretinoin is a synthetic oral retinoid showing significant reduction in the incidence of recurrent or new HCC in patients who had received curative HCC therapy. Areas covered: Peretinoin is analysed against the background of molecular pathogenesis of the different causes of HCC. Publications related to peretinoin since 1996 are reviewed, covering clinical characteristics, safety and tolerance profile as well as the current status of clinical development. Expert commentary: Early phase studies are promising but we need to await the results of the ongoing phase III study of peretinoin in hepatitis C related HCC. Long term impact of peretinoin may be diminished by the foreseeable near eradication of hepatitis C by the direct acting antivirals.