Assessing the periprocedural magnitude of platelet count change in response to lusutrombopag.

BACKGROUND & AIMS: Despite limitations, platelet transfusion has been used to minimise bleeding risk in patients with thrombocytopaenia. Lusutrombopag is an oral, thrombopoietin receptor agonist approved for treatment of thrombocytopaenia associated with chronic liver disease in patients undergoing planned invasive procedures. This post-hoc analysis assessed the magnitude of platelet count change based on the integrated per-protocol population from 2 similar phase III multicentre, randomised, double-blind, placebo-controlled trials. METHODS: Adults with chronic liver disease-induced thrombocytopaenia and platelet count <50 (× 109/L) received lusutrombopag 3 mg or placebo ≤7 days before invasive procedure scheduled 9-14 days after randomisation. Platelet transfusion was required per protocol if the platelet count remained <50 no more than 2 days before the planned invasive procedure. Post-hoc analysis included: proportion of patients with platelet count ≥50, ≥1.5-fold increase, and a doubling of platelet count; maximum and maximum change in platelet count; and platelet count time course. RESULTS: Platelet count ≥50, a platelet count increase ≥1.5-fold, and at least a doubling in platelet count were achieved in 88.3%, 86.9%, and 52.6% of patients in the lusutrombopag group (n = 137) vs. 58.6%, 32.3%, and 6.0% of patients in the placebo group (n = 133), respectively. In the lusutrombopag group, median maximum platelet count across baseline platelet counts of <30, ≥30 to <40, and ≥40 was 46, 76, and 87, respectively. Median maximum change in platelet count by baseline platelet count was +24, +42, and +40, respectively. Patients who received lusutrombopag without platelet transfusion achieved a median platelet count ≥50 for 3 weeks. CONCLUSIONS: Patients treated with lusutrombopag experienced a clinically relevant response in platelet count for a substantial duration of time. LAY SUMMARY: Patients with low platelet counts caused by chronic liver disease may not receive planned invasive procedures or surgeries because of an increased risk of bleeding. Lusutrombopag has previously demonstrated efficacy in raising platelet counts and is approved to treat chronic liver disease patients with low platelet counts in advance of a planned surgery. Physicians need to understand more clearly what to expect in terms of platelet count change when using lusutrombopag; this integrated analysis provides data to help guide its clinical application.

Is platelet monitoring during 7-day lusutrombopag treatment necessary in chronic liver disease patients with thrombocytopenia undergoing planned invasive procedures? A phase IIIb open-label study.

AIM: Lusutrombopag is approved for thrombocytopenia in chronic liver disease patients planned to undergo invasive procedures. In previous clinical studies, lusutrombopag treatment was stopped in patients with an increase in platelet count (PC) of ≥20 × 109 /L from baseline and whose PC was ≥50 × 109 /L (discontinuation criteria). We assessed the influence of platelet monitoring during lusutrombopag treatment in lusutrombopag-naïve patients. METHODS: In this open-label study, Child-Pugh class A and B (A/B) patients were enrolled and treated with lusutrombopag (3 mg/day) for 7 days. In the treatment-naïve A/B-1 group, the discontinuation criteria were applied on day 6. In the treatment-naïve A/B-2 group, the criteria were not applied. In a non-naïve A/B group, the criteria were applied on days 3 and 5-7. The main efficacy end-point was the proportion of patients without platelet transfusion (PT) before the primary invasive procedure. RESULTS: In the A/B-1, A/B-2, and non-naïve A/B groups, the proportions of patients without PT were 80.9% (38/47), 83.0% (39/47), and 75.0% (6/8), respectively. The mean durations of PC ≥ 50 × 109 /L without PT were 20.7, 20.3, and 22.8 days, respectively. Excessive PC increases (≥200 × 109 /L) were not detected in any group. Treatment-related adverse events occurred in 4.3%, 6.4%, and 0% of A/B-1, A/B-2, and non-naïve A/B patients, respectively. Severe portal vein thrombosis occurred in one A/B-2 patient (PC 75 × 109 /L at onset). CONCLUSIONS: No meaningful efficacy and safety differences were observed among the groups with or without discontinuation criteria and the non-naïve group. These findings support lusutrombopag treatment without platelet monitoring and retreatment with lusutrombopag.

Lusutrombopag Is Safe and Efficacious for Treatment of Thrombocytopenia in Patients With and Without Hepatocellular Carcinoma.

BACKGROUND & AIMS: Patients with hepatocellular carcinoma (HCC) secondary to chronic liver disease often require invasive procedures but frequently have thrombocytopenia. Lusutrombopag is an agonist of the thrombopoietin receptor that activates platelet production. METHODS: We performed an integrated analysis of data from 2 phase 3 trials (L-PLUS 1, Japan, October 2013 to May 2014, and L-PLUS 2, global, June 2015 to April 2017) that compared the efficacy and safety of lusutrombopag with placebo in patients with chronic liver disease, with and without HCC. Our analysis included patients with Eastern Cooperative Oncology Group grades of 0 or 1, Child-Pugh classes A or B, and a platelet count less than 50 × 109/L who were scheduled to undergo invasive procedures in 9 to 14 days. Patients received lusutrombopag (3 mg) or placebo daily for 7 days or fewer before an invasive procedure. Imaging studies assessed treatment-emergent adverse events, including asymptomatic portal vein thrombosis. The primary end point was no requirement for platelet transfusion before the invasive procedure and rescue therapies for bleeding 7 days or fewer after the invasive procedure. RESULTS: The per-protocol population included 270 patients (95 with HCC). A significantly higher proportion of patients with HCC who received lusutrombopag achieved the primary end point (68.0%) vs patients who received placebo (8.9%) (P < .0001); in patients without HCC, these proportions were 77.0% vs 21.6% (P < .0001). Lusutrombopag reduced the need for platelet transfusions, increased platelet counts for 3 weeks, and reduced the number of bleeding events in patients with and without HCC compared with placebo. Risk of thrombosis was similar to that of placebo. CONCLUSIONS: Patients with and without HCC receiving lusutrombopag had a reduction in the number of platelet transfusions before invasive procedures compared with patients receiving placebo, with no increase in thrombosis or bleeding. L-PLUS 1: JapicCTI-132323; L-PLUS 2: ClinicalTrials.gov number no: NCT02389621.

Hepatitis B Virus Genotype-Dependent Vulnerability of Infected Cells to Immune Reaction in the Early Phase of Infection.

Infection with hepatitis B virus (HBV) genotype (GT)-A has been reported to predispose patients to chronic infection. To explore the immune responses in infection with different HBV genotypes and clarify the genotype-dependent pathogenicity, a system mimicking the immune reaction during the early phase of HBV infection is indispensable. To this end, we established a coculture system with the replication-competent HBV molecular clone-transfected HepG2 cells and immortalized human natural killer (NK) cells, NK-92MI. Using this system, we evaluated HBV genotype dependency in NK functions and cell death of HBV positive HepG2 cells induced by NK cells or administration of tumor necrosis factor (TNF) by use of flow cytometry. After coculture with NK cells, we found that GT-A-positive HepG2 cells exhibited lower susceptibility to NK cell-induced cell death than GT-B- or GT-C-positive HepG2 cells. The NK responses of degranulation and cytokine production were not different among transfected HBV genotypes in cocultured cells. The expression levels of death receptors in HBV-transfected HepG2 cells were not different. In GT-A-positive cells, a similar low susceptibility was detected by the external administration of TNF, although relatively higher susceptibility was observed in GT-B- and GT-C-positive cells than in GT-A-positive cells. The activation of caspase signaling was revealed to be responsible for this genotype-dependent susceptibility. In conclusion, our results indicate that the HBV genotype does not influence the NK cell function itself but rather cell vulnerability through the TNF signal pathway. This observation may explain the high chronicity rate of HBV GT-A strains even in adult infections.

Safety and effectiveness of lusutrombopag in Japanese chronic liver disease patients with thrombocytopenia undergoing invasive procedures: Interim results of a postmarketing surveillance.

AIM: Lusutrombopag is approved for the treatment of thrombocytopenia in chronic liver disease patients undergoing invasive procedures. This real-world surveillance assesses the safety and effectiveness of lusutrombopag in Japan. METHODS: This ongoing, multicenter, prospective, real-world surveillance is collecting data from case report forms between October 2016 and May 2021. Interim data up to September 2018 were used to evaluate safety (adverse events and adverse drug reactions [ADRs]) and effectiveness (proportion of patients avoiding preoperative platelet transfusion and change in platelet count from baseline). RESULTS: The safety analysis set included 331 patients. The mean baseline platelet count was 46.2 ± 13.7 × 109 /L. Of 377 invasive procedures, radiofrequency ablation (110 procedures, 29.2%) was the most frequent. The mean time from starting lusutrombopag treatment to invasive procedure was 12.3 days. Incidences of serious adverse events and ADRs were 8.76% and 3.32%, respectively. Six cases (1.81%) of portal vein thrombosis were considered serious adverse events; of these, four cases (1.21%) were classified as serious ADRs. Of 300 patients who underwent an invasive procedure (excluding those with platelet transfusion refractoriness), 282 (94.0%) avoided preoperative platelet transfusion. In patients with platelet measurements before and after lusutrombopag administration who did not undergo platelet transfusion, the mean maximum change in platelet count from baseline was 41.7 ± 31.4 × 109 /L (range, -6 to 276; n = 286). All patients receiving second (n = 20) and third (n = 1) treatments avoided preoperative platelet transfusion without developing any ADRs. CONCLUSIONS: This real-world surveillance further supports the safety and effectiveness of lusutrombopag in patients with chronic liver disease undergoing invasive procedures.

Lusutrombopag Reduces Need for Platelet Transfusion in Patients With Thrombocytopenia Undergoing Invasive Procedures.

BACKGROUND & AIMS: Platelet transfusion is used to prevent hemorrhagic events in patients with thrombocytopenia undergoing invasive procedures, but there are many disadvantages. We evaluated the efficacy and safety of lusutrombopag in patients with chronic liver disease and thrombocytopenia undergoing invasive procedures. METHODS: We performed a double-blind, parallel-group, phase 3 study of 96 patients with chronic liver disease and thrombocytopenia (platelet counts below 50,000/µL) undergoing invasive procedures from October 2013 to May 2014 at 81 centers in Japan. Patients were randomly assigned (1:1) to groups given once-daily lusutrombopag (3 mg) or placebo for up to 7 days. The primary efficacy endpoint was the proportion of patients not requiring platelet transfusion before the invasive procedure. The protocol-defined response (platelet count 50,000/µL or more with an increase of 20,000/µL or more from baseline) and the time course of the change in platelet count were also evaluated. Adverse events were recorded. RESULTS: The proportions of patients who did not require preoperative platelet transfusion were 79.2% (38/48) in the lusutrombopag group and 12.5% (6/48) in the placebo group (P < .0001). A response was observed in 77.1% (37/48) of patients in the lusutrombopag group and 6.3% (3/48) of patients in the placebo group (P < .0001). In the lusutrombopag group without platelet transfusion, the median platelet count was 50,000/µL or more after 5 days; the mean time to reach the maximum platelet count was 13.4 days; and the number of days (adjusted mean) during which the platelet count was 50,000/µL or more was 21.09 days. Adverse drug reactions were reported in 8.3% of patients in the lusutrombopag group and 2.1% of patients in the placebo group. Two patients (1 per group) had a thrombotic event, but neither were associated with an excessive increase in platelet count (200,000/µL or more). CONCLUSION: In a placebo-controlled trial, lusutrombopag was effective in achieving and maintaining the target platelet count in patients with chronic liver disease and thrombocytopenia undergoing invasive procedures. No significant safety concerns were raised. Japanese clinical trial registration no: JapicCTI-132323.

A randomized controlled trial of lusutrombopag in Japanese patients with chronic liver disease undergoing radiofrequency ablation.

BACKGROUND: Thrombocytopenia represents an obstacle for invasive procedures in chronic liver disease (CLD) patients. We aimed to estimate the appropriate dose and evaluate the efficacy and safety of lusutrombopag for the treatment of thrombocytopenia before percutaneous liver radiofrequency ablation (RFA) for primary hepatic cancer in patients with CLD. METHODS: In this multicenter, randomized, double-blind, placebo-controlled study conducted in Japan, 61 CLD patients with platelet count < 50 × 103/µL at screening were randomized to placebo or lusutrombopag 2, 3, or 4 mg once daily for 7 days, followed by a 28-day post-treatment assessment period. The primary efficacy endpoint was the proportion of patients who did not require platelet transfusion before RFA. The pre-specified key secondary efficacy endpoint was the proportion of responders. Adverse events (AEs) and thrombosis-related AEs were evaluated. RESULTS: The proportion of patients who did not require platelet transfusion before RFA and that of responders were significantly higher (p < 0.01) in the 2-mg (80.0, 66.7%), 3-mg (81.3, 68.8%), and 4-mg groups (93.3, 80.0%) compared with the placebo group (20.0, 6.7%) and showed a dose-dependent effect. The incidence of AEs was 97.8 and 100% in the lusutrombopag (all groups) and placebo groups, respectively; no dose-related increase was observed. Four patients experienced thrombosis-related events (one each in the placebo and 2-mg groups, and two in the 4-mg group). A total of 16 (18%) adverse drug reactions occurred in the safety analysis set. CONCLUSIONS: Lusutrombopag 3 mg once daily for 7 days was effective without raising concerns about excessive increases in platelet count. CLINICAL TRIAL REGISTRATION: The study is registered at JapicCTI-121944.

Vitamin D derivatives inhibit hepatitis C virus production through the suppression of apolipoprotein.

Supplementation with vitamin D (VD) has been reported to improve the efficacy of interferon-based therapy for chronic hepatitis C. We found that 25-hydroxyvitamin D3 (25-(OH)D3), one of the metabolites of VD, has antiviral effects by inhibiting the infectious virus production of the hepatitis C virus (HCV). In this study, to clarify the underlying mechanisms of the anti-HCV effects, we searched VD derivatives that have anti-HCV effects and identified the common target molecule in the HCV life cycle by using an HCV cell culture system. After infection of Huh-7.5.1 cells with cell culture-generated HCV, VD derivatives were added to culture media, and the propagation of HCV was assessed by measuring the HCV core antigen levels in culture media and cell lysates. To determine the step in the HCV life cycle affected by these compounds, the single-cycle virus production assay was used with a CD81-negative cell line. Of the 14 structural derivatives of VD, an anti-HCV effect was detected in 9 compounds. Cell viability was not affected by these effective compounds. The 2 representative VD derivatives inhibited the infectious virus production in the single-cycle virus production assay. Treatment with these compounds and 25-(OH)D3 suppressed the expression of apolipoprotein A1 and C3, which are known to be involved in infectious virus production of HCV, and the knockdown of these apolipoproteins reduced infectious virus production. In conclusion, we identified several compounds with anti-HCV activity by screening VD derivatives. These compounds reduce the infectious virus production of HCV by suppressing the expression of apolipoproteins in host cells.

One case that developed bile duct cancer all over the progress of repeated cholangitis.

A 65-year-old man was referred to our department due to repeated episodes of cholangitis in the past five years. Endoscopic retrograde cholangiopancreatography was performed, and a stricture of the lower bile duct was detected. At a later date, an irregular mucosa of the bile duct was confirmed using nasal endoscopy. Based on the biopsy results, the patient was diagnosed with bile duct cancer and subsequently underwent surgery. Postoperative histopathology did not show lymph node metastasis, and the condition was determined to be early-stage bile duct cancer. In the present case, it was presumed that the cancer had developed due to chronic cholangitis. Therefore, in patients with repeated episodes of cholangitis, attention should be focused on the possible and concomitant development of cancer.

Relationship of aging and nutritional status to innate immunity in tube-fed bedridden patients.

BACKGROUND AND OBJECTIVES: Aging and malnutrition are known to influence immune functions. The aim of this study was to investigate the relationship of aging and malnutrition to innate immune functions in tube-fed bedridden patients. METHODS AND STUDY DESIGN: A cross-sectional survey was performed in 71 tube-fed bedridden patients aged 50-95 years (mean age±SD, 80.2±8.5 years) with serum albumin concentrations between 2.5 and 3.5 g/dL. We evaluated associations of age and nutritional variables with natural-killer cell activity, neutrophilphagocytic activity, and neutrophil-sterilizing activity. Nutritional variables included body mass index, weightadjusted energy intake, total lymphocyte count, and serum concentrations of albumin, transferrin, prealbumin, total cholesterol, C-reactive protein, and zinc. RESULTS: Natural-killer cell activity, neutrophil-phagocytic activity, and neutrophil-sterilizing activity were normal or increased in 67 (94%), 63 (89%), and 69 (97%) patients, respectively. Multiple linear regression analysis with a backward elimination method showed that natural-killer cell activity correlated negatively with aging and lymphocyte counts (p<0.01 for both) but positively with body mass index and transferrin (p<0.01 for both). Neutrophil-phagocytic and neutrophil-sterilizing activities were not associated with any variables. CONCLUSIONS: In tube-fed bedridden patients with hypo-albuminemia, natural-killer cell activity may be associated with aging, body mass index, transferrin, and lymphocyte counts.

Antimicrobial peptide LL-37 attenuates infection of hepatitis C virus.

AIM: Although recent studies indicate that supplementation with vitamin D (VD) potentiates a sustained viral response by interferon-based therapy to chronic hepatitis C, detailed mechanisms are not fully defined. The production of cathelicidin, an antimicrobial peptide, has been demonstrated to be part of the VD-dependent antimicrobial pathway in innate immunity. Cathelicidin is known to directly kill or inhibit the growth of microbial pathogens including mycobacteria and viruses. METHODS: We used a hepatitis C virus (HCV) cell culture system to clarify the anti-HCV effects of the human cathelicidin, LL-37. HuH-7 cells were administrated with LL-37 and infected with cell culture-generated HCV (HCVcc). HCV propagation was estimated by measuring the level of HCV core antigen (Ag). RESULTS: Treatment with LL-37 resulted in decreased intra- and extracellular levels of HCV core Ag, suggesting inhibition of HCV propagation. To assess the effects of LL-37 on HCV replication, JFH-1 subgenomic replicon RNA-transfected cells were treated with LL-37. However, inhibition of HCV replication was not detected by this assay. To clarify the effects on HCV infection, we treated HCVcc with LL-37 and removed the antimicrobial peptide prior to use of the virus in infection. This exposure of HCVcc to LL-37 diminished the infectivity titers in a dose-dependent fashion. Iodixanol density gradient analysis revealed that the peak fraction of infectivity titer was eliminated by LL-37 treatment. CONCLUSION: The VD-associated antimicrobial peptide LL-37 attenuated the infectivity of HCV. This anti-HCV effect of LL-37 may explain the contribution of VD to the improved efficacy of interferon-based therapy.

Restoration of natural killer cell activity by pegylated interferon-alpha/ribavirin therapy in chronic hepatitis C patient.

AIM: The combination therapy of pegylated interferon-α and ribavirin (PEG IFN/RBV) is one of the effective treatments for chronic hepatitis C (CHC) patients. Natural killer (NK)-cell activity was reported to be impaired in patients with hepatitis C virus (HCV). The aim of this study was to examine whether PEG IFN/RBV therapy could restore NK activity in CHC patients. METHODS: In 19 CHC patients, PEG IFN/RBV therapy was performed. Just before (0M), at 3 months of the therapy (3M) and at 6 months after completion of the therapy (6M), NK activity and the frequency of NK cells, CD56(dim) NK cells and CD56(bright) NK cells in peripheral blood was estimated by creatinine release assay and flow cytometry. Statistical analysis was performed by anova and Mann-Whitney U-test. RESULTS: anova showed that NK activity significantly improved at 6M (vs 0M, P < 0.05) in the patients studied and in the patients with sustained virological response (SVR). It also showed that frequency of CD56(bright) NK cells was significantly increased at 6M (vs 0M, P < 0.05) in the patients studied and in the SVR group. However, no significant change in NK activity and frequency of CD56(bright) NK cells were detected in non-SVR group. Furthermore, NK activity ratio (6M/0M) in the SVR group was revealed to be higher compared with that in the non-SVR group by analysis using Mann-Whitney U-test (P < 0.05). CONCLUSION: PEG IFN/RBV therapy in CHC patients could improve NK activity by increasing the frequency of CD56(bright) NK cells in SVR patients. Our study also revealed that eradication of HCV could restore NK-cell activity.

Multicenter study of pegylated interferon α-2a monotherapy for hepatitis C virus-infected patients on hemodialysis: REACH study.

Many studies have reported poor vital prognosis in hepatitis C virus (HCV)-infected dialysis patients. The rate of HCV-infected dialysis patients in Japan is as high as 9.8%, and antiviral therapy is believed to be important for improving vital prognosis. We conducted a multicenter study to examine the administration method for pegylated interferon α-2a (PEG-IFNα-2a) monotherapy in HCV-infected dialysis. We studied 56 patients: 14 with low viral loads (HCV RNA < 5.0 log IU/mL) were treated with 90 µg PEG-IFNα-2a weekly, 42 with high viral loads (HCV RNA ≥ 5.0 log IU/mL) were treated with 135 µg PEG-IFNα-2a weekly. We examined the sustained virological response (SVR), factors affecting the SVR, and treatment safety. The overall SVR rate was 39% (22/56); that for genotype 1, genotype 2, low viral loads, and high viral loads was 29%, 67%, 93%, and 21%, respectively. From receiver operating characteristic (ROC) analysis, the HCV RNA cutoff values likely to achieve SVR for genotypes 1 and 2 were <5.7 log IU/mL (SVR rate: 64% 9/14) and <6.5 log IU/mL (SVR rate: 88% 7/8), respectively. If there was HCV RNA negativation at 4 weeks (rapid virological response), the SVR rate was 94% (16/17), whereas it was 6% (1/16) if there was HCV RNA positivity at 24 weeks. The rate of treatment discontinuation from adverse events or aggravated complications was 25% (14/56). High SVR rates can potentially be achieved with PEG-IFN monotherapy by identifying the target patients, based on virus type and viral load before initiating treatment and by modifying therapy during treatment according to responsiveness.

Distinct molecular features of different macroscopic subtypes of colorectal neoplasms.

BACKGROUND: Colorectal adenoma develops into cancer with the accumulation of genetic and epigenetic changes. We studied the underlying molecular and clinicopathological features to better understand the heterogeneity of colorectal neoplasms (CRNs). METHODS: We evaluated both genetic (mutations of KRAS, BRAF, TP53, and PIK3CA, and microsatellite instability [MSI]) and epigenetic (methylation status of nine genes or sequences, including the CpG island methylator phenotype [CIMP] markers) alterations in 158 CRNs including 56 polypoid neoplasms (PNs), 25 granular type laterally spreading tumors (LST-Gs), 48 non-granular type LSTs (LST-NGs), 19 depressed neoplasms (DNs) and 10 small flat-elevated neoplasms (S-FNs) on the basis of macroscopic appearance. RESULTS: S-FNs showed few molecular changes except SFRP1 methylation. Significant differences in the frequency of KRAS mutations were observed among subtypes (68% for LST-Gs, 36% for PNs, 16% for DNs and 6% for LST-NGs) (P<0.001). By contrast, the frequency of TP53 mutation was higher in DNs than PNs or LST-Gs (32% vs. 5% or 0%, respectively) (P<0.007). We also observed significant differences in the frequency of CIMP between LST-Gs and LST-NGs or PNs (32% vs. 6% or 5%, respectively) (P<0.005). Moreover, the methylation level of LINE-1 was significantly lower in DNs or LST-Gs than in PNs (58.3% or 60.5% vs. 63.2%, P<0.05). PIK3CA mutations were detected only in LSTs. Finally, multivariate analyses showed that macroscopic morphologies were significantly associated with an increased risk of molecular changes (PN or LST-G for KRAS mutation, odds ratio [OR] 9.11; LST-NG or DN for TP53 mutation, OR 5.30; LST-G for PIK3CA mutation, OR 26.53; LST-G or DN for LINE-1 hypomethylation, OR 3.41). CONCLUSION: We demonstrated that CRNs could be classified into five macroscopic subtypes according to clinicopathological and molecular differences, suggesting that different mechanisms are involved in the pathogenesis of colorectal tumorigenesis.

Contribution of diuretic therapy with human serum albumin to the management of ascites in patients with advanced liver cirrhosis: A prospective cohort study.

The number of available studies on the role of human serum albumin (HSA) in the treatment of cirrhotic ascites is currently limited. In this study, we aimed to investigated the parameters associated with diuretic therapy with HSA in patients with advanced cirrhotic ascites. The patient inclusion criteria were cirrhotic ascites and a serum albumin (Alb) concentration of <3.5 g/dl. A total of 49 patients registered and 38 patients were ultimately included in this study. The enrolled patients were mainly treated with oral spironolactone and furosemide, which were not specified; the HSA amount was also not specified, although the administration period was set to a maximum of 7 days. Our results demonstrated that the administration of HSA significantly increased the serum levels of Alb [0.97 g/dl; two-sided 95% confidence interval (CI): 0.83-1.11 g/dl] and decreased body weight (-2.24 kg; 95% CI: -3.06 to -1.43 kg), hematocrit ratio (0.96; 95% CI: 0.94-0.98) and plasma renin concentration (day 4; geometric mean fold change, -0.1528; 95% CI: -0.2510 to -0.0545; log-transformed data) in patients with advanced cirrhotic ascites. The observed weight loss was found to be correlated with the total amount of HSA administered (P=0.0012), as indicated by the results of the multiple linear regression analysis. In conclusion, this study confirmed the efficacy of HSA in patients with advanced cirrhotic ascites.

In vivo immunological antitumor effect of OK-432-stimulated dendritic cell transfer after radiofrequency ablation.

Radiofrequency ablation therapy (RFA) is a radical treatment for liver cancers and induces tumor antigen-specific immune responses. In the present study, we examined the antitumor effects of focal OK-432-stimulated dendritic cell (DC) transfer combined with RFA and analyzed the functional mechanisms involved using a murine model. C57BL/6 mice were injected subcutaneously with colon cancer cells (MC38) in their bilateral flanks. After the establishment of tumors, the subcutaneous tumor on one flank was treated using RFA, and then OK-432-stimulated DCs were injected locally. The antitumor effect of the treatment was evaluated by measuring the size of the tumor on the opposite flank, and the immunological responses were assessed using tumor-infiltrating lymphocytes, splenocytes and draining lymph nodes. Tumor growth was strongly inhibited in mice that exhibited efficient DC migration after RFA and OK-432-stimulated DC transfer, as compared to mice treated with RFA alone or treatment involving immature DC transfer. We also demonstrated that the antitumor effect of this treatment depended on both CD8-positive and CD4-positive cells. On the basis of our findings, we believe that combination therapy for metastatic liver cancer consisting of OK-432-stimulated DCs in combination with RFA can proceed to clinical trials, and it is anticipated to be markedly superior to RFA single therapy.