A survey of herbal medicines as tumor microenvironment-modulating agents.

The tumor microenvironment (TME) is extremely complex, involving extensive interactions among stromal cells, immune cells, and signaling molecules. Therefore, an approach targeting the TME has emerged as a promising therapeutic strategy. Herbal medicines consist of multiple active compounds, which have multi-target effects. Therefore, they have been regarded as potential anticancer agents; multiple studies have explored their effects on the TME. In this review, we report the effects of 29 single herb medicines or herbal formulas on the TME, based on the findings of 64 published studies. Specifically, we describe the effects of these herbal medicines on cancer-associated fibroblasts/tumor-associated fibroblasts, tumor-associated endothelial cells, myeloid-derived suppressor cells, and tumor-associated macrophages. Among the reviewed herbal medicines, the most promising TME-modulating effects were exhibited by curcumin, DHA, EGCG, resveratrol, and silibinin; these medicines showed the ability to regulate two or more components of the TME. The findings of this review support the notion that the combination of herbal medicines with conventional anticancer therapies are likely to exhibit a clinical benefit, which should be further explored in clinical trials.

Clinical outcomes after the introduction of direct antiviral agents for patients infected with genotype 1b hepatitis C virus depending on the regimens: A multicenter study in Korea.

BACKGROUND: A real-life study is essential outside clinical trials. The aim is to evaluate the clinical outcomes of direct acting agents (DAA) for patients with chronic hepatitis C (CHC) in real practice. METHODS: We analyzed 590 consecutively enrolled patients with CHC-1b who received DAAs since 2015, when DAAs were introduced in Korea. The patients were checked for resistance-associated variants (RAV) against nonstructural protein 5A inhibitors and then daclatasvir/asunaprevir or sofosbuvir based regimens were chosen. RESULTS: The frequency of patients with cirrhosis and prior hepatocellular carcinoma (HCC) was 29.2% and 4.7%, respectively. For the RAV test, 10% were positive and in 3.6% the result was "indeterminate." Overall, 518 patients were treated with a 24-week regimen of daclatasvir/asunaprevir, 72 patients (RAV positive 75%) were treated with 12 weeks regimen of ledipasvir/sofosbuvir or daclatasvir/sofosbuvir. The SVR12 was 94.0% in the daclatasvir/asunaprevir, 98.2% in the ledipasvir/sofosbuvir, and 100% in the daclatasvir/sofosbuvir group. A total of 93.3% of SVR12 in the RAV-"indeterminate" patients was not difference 95.0% in the RAV-negative patients. Up to 1 year, de novo HCC occurrence and recurrence developed in 2.6% and 17.8%, respectively. HCC was more frequent in cirrhotic patients than in noncirrhotic patients (P = 0.000). α Fetoprotein (AFP) level at the end of treatment was a predicting factor for de novo HCC. CONCLUSIONS: Optimizing the choice of DAAs according to RAV test resulted in high SVR among CHC-1b Korean patients. This real practice multicenter cohort study suggests the importance of AFP and HCC surveillance in cirrhotic patients even after successful HCV therapy.

Efficacy and Safety of Tenofovir Disoproxil Fumarate in Treatment-Naïve Patients with Chronic Hepatitis B in Korea.

AIMS: To evaluate the efficacy and safety of 144-week tenofovir disoproxil fumarate (TDF) therapy in treatment-naïve chronic hepatitis B (CHB) patients in Korean. METHODS: In total, 579 treatment-naïve CHB patients at 11 medical centers were enrolled retrospective and prospective from September 2015 to January 2016 by design (NCT02533544). We evaluated the complete virologic response (CVR) rate and the renal safety of TDF. RESULTS: The overall CVR rate was 69.4%, 87.0%, and 89.7% at weeks 48, 96, and 144, respectively. In the HBeAg-positive CHB patients, the CVR rate at weeks 48, 96, and 144 was 61.4%, 83.1%, and 89.6%, respectively. The rates of HBeAg loss and seroconversion at weeks 48, 96, and 144 were 16.6%, 23.5%, 34.1%, and 7.6%, 8.9%, 13.3%, respectively. In HBeAg-negative CHB patients, the CVR rate at weeks 48, 96, and 144 was 82.5%, 93.2%, and 90.0%, respectively. The rate of alanine aminotransferase normalization was 36.9%, 45.4%, and 46.8% at weeks 48, 96, and 144, respectively. Of the CHB patients, 0.9% showed an elevated creatinine (> 0.5 mg/dL from baseline). Age (≥ 60 years) was significantly associated with a decline in renal function at week 144 (P < 0.0001). Comorbidities (diabetes or hypertension) showed the tendency to reduce renal function (P = 0.0624). Hepatocellular carcinoma developed in 10 (1.7%) patients and was related to cirrhosis. CONCLUSIONS: TDF therapy induced sustained viral suppression and had a favorable safety profile over a 3-year period. However, close monitoring of renal function should be mandatory in treating CHB patients receiving TDF, particularly older patients.

The role of diacylglycerol kinase ζ and phosphatidic acid in the mechanical activation of mammalian target of rapamycin (mTOR) signaling and skeletal muscle hypertrophy.

The activation of mTOR signaling is essential for mechanically induced changes in skeletal muscle mass, and previous studies have suggested that mechanical stimuli activate mTOR (mammalian target of rapamycin) signaling through a phospholipase D (PLD)-dependent increase in the concentration of phosphatidic acid (PA). Consistent with this conclusion, we obtained evidence which further suggests that mechanical stimuli utilize PA as a direct upstream activator of mTOR signaling. Unexpectedly though, we found that the activation of PLD is not necessary for the mechanically induced increases in PA or mTOR signaling. Motivated by this observation, we performed experiments that were aimed at identifying the enzyme(s) that promotes the increase in PA. These experiments revealed that mechanical stimulation increases the concentration of diacylglycerol (DAG) and the activity of DAG kinases (DGKs) in membranous structures. Furthermore, using knock-out mice, we determined that the ζ isoform of DGK (DGKζ) is necessary for the mechanically induced increase in PA. We also determined that DGKζ significantly contributes to the mechanical activation of mTOR signaling, and this is likely driven by an enhanced binding of PA to mTOR. Last, we found that the overexpression of DGKζ is sufficient to induce muscle fiber hypertrophy through an mTOR-dependent mechanism, and this event requires DGKζ kinase activity (i.e. the synthesis of PA). Combined, these results indicate that DGKζ, but not PLD, plays an important role in mechanically induced increases in PA and mTOR signaling. Furthermore, this study suggests that DGKζ could be a fundamental component of the mechanism(s) through which mechanical stimuli regulate skeletal muscle mass.

Safety and immunogenicity of therapeutic DNA vaccine with antiviral drug in chronic HBV patients and its immunogenicity in mice.

BACKGROUND & AIMS: Here, we evaluated the safety and immunogenicity of hepatitis B virus (HBV) DNA vaccine, HB-110, in mice and Korean patients with chronic hepatitis B (CHB) undergoing adefovir dipivoxil (ADV) treatment. METHODS: For animal study, mice (BALB/c or HBV transgenic) were immunized with mHB-110, and T-cell and antibody responses were evaluated. For clinical study, 27 patients randomly received either ADV alone or ADV in combination with HB-110. Liver function tests, serum HBV DNA levels and the presence of HBeAg/anti-HBe were analysed. T-cell responses were estimated by ELISPOT and FACS analysis. RESULTS: mHB-110 induced higher T-cell and antibody responses than mHB-100 in mice. No adverse effects were observed by HB-110 cotreated with ADV. HBV-specific T-cell responses were induced in a portion of patients in medium to high dose of HB-110. Interestingly, HB-110 exhibited positive effects on ALT normalization and maintenance of HBeAg seroconversion. One patient, who received high dose of HB-110 exhibited HBeAg seroconversion during vaccination, which correlated with vaccine-induced T-cell responses without ALT elevation. CONCLUSIONS: HB-110 was safe and tolerable in CHB patients. In contrast to results in animal models, HB-110 in Korean patients exhibited weaker capability of inducing HBV-specific T-cell responses and HBeAg seroconversion than HB-100 in Caucasian patients. As Asian patients, who are generally infected via vertical transmission, appeared to have higher level of immune tolerance than Caucasian, novel approaches for breaking immune tolerance rather than enhancing immunogenicity may be more urgently demanded to develop effective therapeutic HBV DNA vaccines.

Prognostic value of C-reactive protein and neutrophil-to-lymphocyte ratio in patients with hepatocellular carcinoma.

BACKGROUND: Accumulating evidence indicates that components of the systemic inflammatory response, such as C-reactive protein (CRP) and neutrophil-to-lymphocyte ratio (NLR), have been associated with prognosis of various cancers. We aimed to elucidate whether CRP and NLR could serve as potential surrogate markers for response and survival in patients with hepatocellular carcinoma (HCC). METHODS: The study population consisted of 318 consecutive patients with HCC. CRP and NLR were measured at baseline with follow-up measurements. RESULTS: With the mean follow-up of 13.9 months, the median survival time was 13.8 months. Child-Pugh class, tumor size > 5 cm, tumor multiplicity, presence of portal vein thrombosis, α-fetoprotein > 200 ng/mL, CRP > 6.3 mg/L and NLR > 2.3 were identified as independent factors for worse survival of HCC (all p < 0.05). Patients with elevated CRP (> 6.3 mg/L) and elevated NLR (> 2.3) had a significantly shorter overall survival than those with low CRP and low NLR (all p < 0.001). The combined use of CRP and NLR provided incremental prognostic information. With significant inter-correlations, levels of CRP and NLR escalated with aggravating Child-Pugh class from A to C or progressing tumor stage from I to IV. CRP and NLR on baseline and serial measurements were well predictive of treatment response (p < 0.001). CONCLUSIONS: CRP and NLR are independent indicators for survival in HCC patients, reflecting tumor burden and hepatic reserve. Their role in predicting tumor response and survival is more enhanced when used in combination. This study suggests that CRP and NLR are important prognostic biomarkers for HCC.

Feasibility of combination of Gun-Chil-Jung and cytokine-induced killer cells-based immunotherapy for terminal hepatocellular carcinoma patient: a case report.

Introduction: Terminal-stage hepatocellular carcinoma (HCC) is inoperable and currently has no form of adjuvant therapy. This study examined the anticancer herbal extract Gun-Chil-Jung (GCJ) combined with cytokine-induced killer (CIK)-cell-based immunotherapy as a palliative therapy for terminal HCC. We report the case of an HCC patient with extended overall survival and improved symptoms and tumor marker levels following combination therapy with GCJ and CIK cell-based immunotherapy. Baseline Characteristics: From March to July 2020, a 57-year-old man who had been diagnosed with HCC underwent combination treatment with GCJ and CIK cell-based immunotherapy. By August 2021, he was prescribed GCJ. After treatment, the patient's condition was evaluated with respect to overall survival, tumor markers, symptoms, abdominal computed tomography findings, chest x-ray results, and Eastern Cooperative Oncology Group (ECOG) grade. Results: The patient's overall survival, tumor marker levels, ECOG grade, and symptoms, including ascites, lower limb edema, jaundice, pleural effusion, and fatigue, were largely alleviated. Conclusion: We expect that this combination therapy may be an option for palliative therapy of terminal HCC.

Serum interleukin-6 and C-reactive protein as a prognostic indicator in hepatocellular carcinoma.

The development of hepatocellular carcinoma (HCC) is often associated with chronic inflammation, suggesting a strong relationship between inflammation and carcinogenesis. This study evaluated the prognostic values of inflammatory and T-helper (Th) cytokines in the clinical outcome and survival of HCC. The study included 110 patients with HCC undergoing loco-regional therapy and 24 healthy controls. Five Th1/Th2 cytokines and C-reactive protein (CRP) were quantified before and after loco-regional treatment, using enzyme-linked immunosorbent assays. Levels of CRP, interleukin (IL)-4, and IL-6 were higher in patients with HCC than those in healthy subjects. Tumor characteristics, Child-Pugh class, and CRP, IL-6, and IL-10 levels were associated with HCC survival (all P<0.05). With multivariate analysis, higher IL-6 levels were identified as the independent cytokine for shorter survival (P=0.010). Higher CRP and IL-6 levels correlated well with larger tumor size, poor Child-Pugh function, and shorter survival, with a significant inter-correlation (r=0.667). On serial measurements, the association of CRP with tumor response was stronger than that of α-fetoprotein or other cytokines. IL-6 and CRP are strong inflammatory indicators predictive of outcome in patients with HCC receiving loco-regional therapy. This study suggests that inflammatory activation of the IL-6/CRP network may be a potential therapeutic target and biomarker for HCC.

Role of intrahepatic tumor control in the prognosis of patients with hepatocellular carcinoma and extrahepatic metastases.

BACKGROUND AND AIM: There has been little information about the long-term outcome and prognostic factors in patients with hepatocellular carcinoma (HCC) and extrahepatic metastases. The purpose of this study was to investigate the clinical factors affecting survival after extrahepatic metastasis and to determine the survival benefit of controlling intrahepatic HCC. METHODS: Between 2004 and 2009, a total of 240 consecutive patients with HCC and extrahepatic metastasis were recruited. Based on tumor extent, performance, and hepatic function, the patients underwent locoregional and/or systemic treatments. The treatment response of the intrahepatic tumor after extrahepatic metastasis and other prognostic parameters were analyzed retrospectively. RESULTS: During the mean follow up of 276 days, 222 patients died; the median survival time was 146 days. Multivariate analysis revealed that Child-Pugh class A, smaller hepatic tumor size, absence of portal venous invasion, single metastatic organ involvement, and objective treatment response of the intrahepatic tumor were the favorable prognostic factors for survival. Of the 183 evaluable patients, 24 achieved complete or partial response for intrahepatic tumors after treatment. The overall survival for the 24 responders was significantly improved, with a median of 521 days, as compared to 170 days for the remaining 159 patients without objective tumor response. The leading cause of death was progressive intrahepatic tumor. CONCLUSIONS: Intrahepatic tumor status and hepatic reserve are among the significant predictors of survival in patients with HCC and extrahepatic metastases. This study indicates that even in patients with metastases from advanced HCC, therapeutic approaches to control intrahepatic tumors are important in improving patient survival.

Frequency of killer cell immunoglobulin-like receptors (KIRs) in Korean patients with chronic HCV infection.

Natural killer (NK) cells play an important role in innate immunity, especially in the response to viral infections, such as hepatitis C virus (HCV). Killer cell immunoglobulin-like receptors (KIRs) are the primary receptors of NK cells that mediate innate immunity. KIRs are also involved in acquired immunity, because some KIRs are expressed on the surface of certain subsets of T cells. In this study, the frequency of KIR genes, HLA-C allotypes, and combinations of KIR genes with their HLA-C ligands were evaluated in two different groups of the Korean population: controls and patients with chronic HCV infection. The study population consisted of 147 Korean patients with chronic HCV infection. The frequency of KIR2DS2 in patients with chronic HCV infection was 9.5% which was significantly lower than 19.5% of the control (P < 0.01). However, there were no significant differences in the frequency of other KIR genes, HLA-C allotypes or different combinations of KIR genes with their HLA-C ligands. This study can contribute to the further prospective study with a larger scale, suggesting the assumption that KIR2DS2 might aid in HCV clearance by enhancing both the innate and acquired immune responses of people in Korea.

Risk levels of herb-induced liver injury in Korea: from a meta-analysis.

BACKGROUND: As the use of herbal medicines increased worldwide, there has been concern about the risk of herb-induced liver injury (HILI). Many clinical studies have assessed the risk of HILI in Korea. METHODS: Therefore, we conducted a meta-analysis of the incidence of HILI in Korea, by analyzing nine clinical studies. These involved 8625 participants (3274 males; 5351 females), including 436 outpatients (three studies) and 8189 inpatients (six studies). RESULTS: As a result, the overall incidence of HILI in Korea was 0.49% (95% CI 0.33-0.74%), and it was 0.57% in males and 0.30% in females. We found a similar incidence of HILI in prospective (0.51%) and retrospective (0.50%) studies. The incidence of HILI was higher in inpatients (0.62%) than outpatients (0.03%). CONCLUSION: Although there are limitations regarding study quality and the number of participants, we systematically estimated the risk of HILI in Korea. We anticipate this study would be a helpful information for prescribing herbal medicines and researching the safety of herbs.

Tumor doubling time after initial response to transarterial chemoembolization in patients with hepatocellular carcinoma.

OBJECTIVE: Following initial transarterial chemoembolization (TACE) of hepatocellular carcinoma (HCC), these tumors can frequently recur, making it important to determine the appropriate follow-up interval after initial response to TACE. We therefore assessed the time taken by new recurrent HCCs to double in volume after an initial response to TACE. MATERIAL AND METHODS: This retrospective cohort study included 73 patients who achieved an initial response after TACE. After intrahepatic distant recurrence of HCC, dynamic CT scans were reviewed by two radiologists without clinical information, and the doubling time of new recurrent nodules was determined. The relationship between doubling time and clinical factors was also analyzed. RESULTS: In 32 of the 73 patients, 40 intrahepatic distant recurrent (IDR) nodules were detected over a median period of 14 months (range 4-46 months). The 1-, 2- and 3-year cumulative IDR rates of patients were 27%, 45% and 65%, respectively. The doubling time of IDR HCC ranged from 20 to 104 days, with a median of 46 days. Over 90% of IDR HCCs had a doubling time of less than 3 months. The doubling time (median 108 days; range 51-129 days) of primary HCC in five patients for whom we had information regarding primary tumors was longer than that of recurrent nodules (median 28 days; range 24-90 days) in the same five patients (P = 0.022). CONCLUSIONS: The median doubling time of IDR HCCs after an initial response was 47 days (range 20-104 days). These findings indicate that the appropriate follow-up interval for dynamic CT in patients with an initial response after TACE is less than 3 months.

Impact of adherence to peginterferon-ribavirin combination therapy in chronic hepatitis C patients on achieving a sustained virologic response.

BACKGROUND/AIMS: Various predictive factors for peginterferon alpha and ribavirin therapy in chronic hepatitis C have been reported, but the effect of adherence to therapy has not been established. We investigated how adherence affects the sustained virologic response (SVR). METHODS: We analyzed 92 chronic hepatitis C patients receiving peginterferon alpha and ribavirin combination therapy. Patients were first identified as having either genotype 1 or genotype non-1 infection and then categorized into three groups according to their adherence to the treatment protocol: (1) patients who received >/=80% of the recommended dosage of both peginterferon alpha and ribavirin for > or =80% of the intended duration of therapy, (2) patients who received <60% of the recommended dosage of both peginterferon alpha and ribavirin for <60% of the intended duration of therapy, and (3) patients who were not included in either group 1 or 2. RESULTS: The rates of early virologic response, end of treatment response, and SVR differed significantly with the degree of adherence to the treatment. The SVRs of genotype 1 patients were 86.7%, 26.7%, and 66.7% in groups 1, 2, and 3, respectively (P=0.003), and those of genotype non-1 were 100%, 16.7%, and 88.9%, respectively (P<0.001). CONCLUSIONS: Adherence to therapy is a key factor in achieving an SVR. Supportive strategies to improve adherence will increase overall SVR rates.

[The value of serum retinol-binding protein 4 levels for determining disease severity in patients with chronic liver disease].

BACKGROUNDS/AIMS: Serum retinol-binding protein 4 (RBP4) is known to be a specific transport protein for retinol, and has recently been reported to be associated with insulin resistance. Hyaluronic acid (HA) is a well-known marker of liver fibrosis. In this study, the degree to which serum RBP4 levels can be used to predict disease severity in patients with chronic liver disease (CLD) was evaluated. METHODS: Serum levels of RBP4 and HA were measured in 573 CLD patients [235 with chronic hepatitis (CH), 230 with liver cirrhosis Child-Pugh grade (Child) A, and 108 with liver cirrhosis with Child B and C] and 40 normal controls. RESULTS: The mean age of the whole cohort was 53.1 years and the causes of CLD were hepatitis B virus (61.9%), hepatitis C virus (9.8%), alcohol (9.0%), and nonalcoholic steatohepatitis (3.8%). Serum levels of RBP4 significantly reduced and HA increased with disease condition, from none (normal controls) to advanced cirrhosis (normal control: RBP4 4.3+/-0.1 mg/dL, HA 25.3+/-28.1 ng/mL; CH: RBP4 3.6+/-0.1 mg/dL, HA 75.5+/-7.8 ng/mL; cirrhosis with Child A: RBP4 2.6+/-0.1 mg/dL, HA 184.4+/-14.5 ng/mL; and cirrhosis with Child B and C: RBP4 1.6+/-0.1 mg/dL, HA 656.5+/-86.7 ng/mL; P<0.001, respectively). Serum RBP4 level was a distinguishing factor at the early stage of CLD between CH and Child A cirrhosis (post-hoc test; P<0.001) and was correlated with histological fibrosis score (n=80, P<0.05) and several biochemical factors. Antiviral therapy (n=45, median interval 1,205 days) resulted in an improvement in serum RBP4 levels (P=0.001). CONCLUSIONS: The results of our study suggest that RBP4 is a serologic marker for disease severity in patients with CLD. It could also be useful as an early marker of CLD and of the relative success of antiviral therapy.

Recovery from hepatitis A after Korean medicine-based treatment : a case report.

BACKGROUND: Many studies reported that Korean medicine (KM) is effective for treating liver disease, including hepatitis A. However, KM, specifically with herbal medicine (Chungganplus, CGP) has not been reported yet. We aimed to report a patient with hepatitis A who was treated with KM including CGP, acupuncture, and moxibustion for 12 days. METHODS: A 39-year-old man with hepatitis A who was hospitalized for 12 days after being admitted to our hospital with abdominal pain, diarrhea and vomiting. We prescribed CGP three times a day, with acupuncture performed twice daily and moxibustion at conception vessel (CV)-12 once a day. Follow-up blood tests have been done 4 times during the admission in order to access the effect of the treatment. RESULTS: In 12 days the symptoms had disappeared and the blood test results improved steadily. His AST level have declined from 1,189 IU/L to 44 IU/L, ALT from 2,423 IU/L to 127 IU/L, r-GTP from 1,347 IU/L to 339 IU/L, ALP from 384 IU/L to 205 IU/L, and total bilirubin from 3.6 mg/dL to 0.89 mg/dL. CONLCUSIONS: This case suggests that KM-based treatment using CGP may be effective for hepatitis A with no adverse effect. Further research and clinical trial on CGP would be needed to make the basis more valid.

Prediction model for hepatocellular carcinoma risk in treatment-naive chronic hepatitis B patients receiving entecavir/tenofovir.

BACKGROUND/AIM: Accurate assessment of hepatocellular carcinoma (HCC) risk in chronic hepatitis B (CHB) patients receiving entecavir (ETV)/tenofovir disoproxil fumarate (TDF) is likely to play a pivotal role in post-treatment follow-up strategy. We aimed to develop a simple and reliable predictive model for HCC risk in these patients. PATIENTS AND METHODS: A database of 1242 consecutive treatment-naive CHB patients who initially underwent ETV/TDF between February 2007 and January 2017 at four referral hospitals in South Korea was analyzed. The HCC risk model was constructed on the basis of a multivariable Cox proportional hazards model in the derivation dataset (n=944) and was validated using Harrell's C-statistic in a validation dataset (n=298). RESULTS: The 3/5-year cumulative incidence rates of HCC were 3.9/6.5 and 4.2/11.6% in the derivation and the validation dataset, respectively (P=0.08). In the derivation dataset, we identified four factors associated with HCC, namely, age, albumin, sex, and liver cirrhosis. The AASL (age, albumin, sex, liver cirrhosis)-HCC scoring system was developed on the basis of these factors, and simplified to an integer scoring system. AASL-HCC scores were found to have high discriminating performance for the prediction of HCC development at 5 years in the derivation (C-statistics=0.802, 95% confidence interval: 0.716-0.888) and validation dataset (C-statistics=0.805, 95% confidence interval: 0.671-0.939). When AASL-HCC scores were classified as 5 or less, 6-19, and at least 20 (low-risk, intermediate-risk, and high-risk groups, respectively), the 5-year cumulative incidence rates of HCC were 0, 4.2, and 17.6%, respectively, in the derivation dataset. CONCLUSIONS: The AASL-HCC model was simple and reliable for HCC risk prediction in treatment-naive CHB patients receiving ETV/TDF, and is easily applicable in the clinical setting.

Role of long-term lamivudine treatment of hepatitis B virus recurrence after liver transplantation.

In this study, the long-term (>3 years) efficacy of combination therapy for hepatitis B virus (HBV) recurrence and the associated factors were investigated. One hundred and sixty-five consecutive HBsAg-positive patients (92 with liver cirrhosis, 73 with hepatocellular carcinoma; HCC) who underwent liver transplantation were assessed with a median follow-up time of 40 months. One hundred and twenty-one patients (121/165, 73.3%) were treated with lamivudine before transplantation for a mean of 8.4 months (range 0.1-72 months). The post-transplantation treatment protocol consisted of a high dose intravenous hepatitis B immunoglobulin (HBIg) followed by a low dose intramuscular HBIg and lamivudine combination therapy. Seven (4.2%, 7/165) recipients experienced HBV recurrence at a median time of 19 months (range 5-36 months) following transplantation. Six of seven cases of HBV recurrence were treated with lamivudine before transplantation for a median period of 15 months (range 0.6-30 months). Eighteen (24.6%, 18/73) patients had HCC recurrences after transplantation. Of the four patients with both HCC and HBV recurrence, three experienced HBV recurrence after recurrence of HCC. The clinical factor associated with HBV recurrence in the total cohort (n = 165) was the duration of antiviral treatment (over 6 months) before transplantation (P = 0.004). In the HCC group, HCC recurrence after transplantation (P = 0.002), tumor burden before transplantation (P = 0.005), and postoperative adjuvant chemotherapy (P = 0.002), were additional factors for HBV recurrence. Combination therapy of HBIg and antiviral drugs was effective over 3 years regardless of the pretransplantation viral load. However, the possible recurrence of HBV needs to be monitored cautiously in patients treated with long-term (over 6 months) lamivudine.

Living donor liver transplantation in hepatocellular carcinoma beyond the Milan criteria.

BACKGROUND/AIMS: In patients with hepatocellular carcinoma (HCC) exceeding the Milan criteria, the recurrence rate after liver transplantation is over 50%. We investigated pretransplant factor(s) that could predict recurrence after living donor liver transplantation (LDLT) in patients with HCC exceeding the Milan criteria. METHODS: Pre-operative imaging showed that, of the 111 HCC patients who underwent LDLT between June 1995 and January 2006, 37 exceeded the Milan criteria. Clinical factors before LDLT were evaluated. RESULTS: The 1- and 3-year cumulative recurrence rates were 35 and 55% respectively. Pretransplant risk factors for HCC recurrence were large tumour size (>6 cm, P=0.001), tumour exposed to the liver surface (P=0.014) and progressive disease after pretransplant treatment (P=0.038). The 2-year HCC recurrence rates in patients with 0, 1, 2 and 3 factors were 0% (0/4), 9% (1/16), 80% (8/10) and 100% (7/7) respectively (P<0.001). The 2-year survival rate was significantly higher in patients with 0 or 1 factor than in patients with two or more factors (P=0.022). CONCLUSIONS: In patients with HCC exceeding the Milan criteria, the three pretransplant factors that may be useful for identifying those with high HCC recurrence potential after LDLT are tumour size >6 cm, progressive disease after pretransplant treatment and tumour exposed to the liver surface.

Severe thrombocytopenia before liver transplantation is associated with delayed recovery of thrombocytopenia regardless of donor type.

AIM: To compare the recovery of thrombocytopenia and splenomegaly during long-term follow-up after liver transplantation in patients receiving a living donor transplant or a cadaveric donor transplant. METHODS: This was a retrospective cohort study of 216 consecutive liver transplant patients who survived for > 6 mo after transplantation; 169 received a liver transplant from a living donor and 47 from a cadaveric donor. The platelet counts or spleen volumes were examined before transplant, 1, 6, and 12 mo after transplant, and then annually until 5 years after transplant. RESULTS: The mean follow-up period was 49 mo (range, 21-66). Platelet counts increased continuously for 5 years after orthotopic liver transplant. The restoration of platelet counts after transplant was significantly slower in patients with severe pretransplant thrombocytopenia (< 50,000/microL) until 4 years after transplant (P = 0.005). Donor type did not significantly affect the recovery of platelet count and spleen volume in either patient group. In multivariate analysis, pretransplant severe thrombocytopenia (< 50,000/microL) was an independent factor associated with sustained thrombocytopenia (P < 0.001, odds ratio 6.314; confidence interval, 2.828-14.095). Thrombocytopenia reappeared after transplant in seven patients with portal flow disturbance near the anastomosis site. CONCLUSION: Our study suggests that severe thrombocytopenia before transplant is closely associated with delayed recovery of platelet count after transplant and donor type did not affect the recovery of thrombocytopenia. The reappearance of thrombocytopenia after transplant should be considered a possible indicator of flow disturbance in the portal vein.

[A case report of treatment with pegylated interferon alpha for lamivudine-resistant chronic hepatitis B virus infection].

The wide use of lamivudine in chronic hepatitis B has produced a monotonic increase in patients with lamivudine resistance. Therefore, treating lamivudine resistance in chronic hepatitis B is a major concern in clinical practice for the treatment of hepatitis B virus (HBV). There is conflicting evidence on the outcome of pegylated interferon alpha (PEG-IFN alpha) therapy against lamivudine-resistant HBV, which is due to mutations in the YMDD motif. We experienced a patient with chronic hepatitis B who was successfully treated with PEG-IFN alpha-2a after the development of virologic and biochemical breakthrough during lamivudine therapy. Virologic breakthrough was associated with the emergence of YMDD mutants 48 months after starting lamivudine therapy. Treatment with PEG-IFN alpha-2a for 12 months resulted in an undetectable serum level of HBV DNA and the resolution of hepatitis, and the virologic response was maintained over 16 months after cessation of PEG-IFN alpha-2a.