Sorafenib use in hepatitis B virus- or hepatitis C virus-related hepatocellular carcinoma: A propensity score matching study.

Sorafenib is the recommended first-line treatment option for patients with advanced hepatocellular carcinoma (HCC). Hepatitis C virus (HCV)-related advanced HCC (HCV-HCC) seemed to have a better response than hepatitis B virus (HBV)-related HCC (HBV-HCC) in sorafenib use, but it was undetermined. Hence, we aimed to investigate the effect of sorafenib between HBV-HCC and HCV-HCC patients in Taiwan. From August 2012 to December 2016, 575 consecutive advanced HCC patients received sorafenib under the reimbursement of Taiwan national health insurance in our hospital. Radiologic assessment was performed at a 2-month interval. Those patients with tumor progression or liver function deterioration were disallowed for further sorafenib use. Patients with HBV or HCV infection were, retrospectively, enrolled and followed till December 2018. There were 277 (62.4%) HBV-HCC patients and 167 (37.6%) HCV-HCC patients. Before sorafenib, 192 (69.3%) HBV-HCC patients who had used nucleoside analogs (NAs) for HBV management, whereas only 5 (3%) HCV-HCC patients received interferon-based antiviral therapy. Overall survival (OS) of HCV-HCC patients was significantly superior to HBV-HCC patients without NAs (8.8 months vs. 4.9 months, p = 0.006), but was noninferior to HBV-HCC patients with NAs (8.8 months vs. 10.7 months, p = 0.54). Using propensity score matching, progression-free survival (2.0 months vs. 2.1 months, p = 0.374) and OS (10.5 months vs. 9.6 months, p = 0.746) between HBV-HCC and HCV-HCC groups were not different. Antiviral therapy might increase survival benefits of advanced HBV-HCC patients underwent sorafenib use, leading to a comparable OS to HCV-HCC patients in Taiwan.

Microalgal extract from thermotolerant Coelastrella sp. F50 retards the liver tumor progression by targeting hepatic cancer stem cells.

Microalgae extracts have shown antitumor activities. However, the antitumor mechanism of them is not yet completely clear, especially the effect on cancer stem cells (CSCs). This study aimed to elucidate the antitumor activity and mechanism of microalgal extract from thermotolerant Coelastrella sp. F50 (F50) in hepatocellular carcinoma (HCC). Oncogenic behaviors were analyzed using cell proliferation, colony formation, invasion, sphere formation, and side population cells (SPCs) assays in HCC cells after F50 treatment. The molecular mechanism was further studied by quantitative real-time PCR, immunoblot, and immunofluorescence analyses. The chemopreventive efficacy of F50 was evaluated in rat orthotopic hepatoma, and the hepatic pathologies were investigated by immunohistochemical, immunoblot, and immunofluorescence analyses. F50 specifically suppressed hepatic CSCs (tumor spheres, drug efflux, CD133/ABCG2 CSCs markers) with no cytotoxicity in vitro. In the animal experiments, prophylactic F50 administration significantly attenuated tumor progression and improved liver function in HCC-bearing rats. In the mechanistic analysis, F50 potentially inhibited cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2 ) axis in HCC cells and rat hepatoma, and exogenous PGE2 restored CSCs properties in F50-treated HCC cells. In summary, F50 extract inhibits hepatic CSCs by COX-2/PGE2 downregulation and may facilitate a novel phytotherapy for HCC prevention.

Real world clinical practice in treating advanced hepatocellular carcinoma: When East meets West.

BACKGROUND AND AIMS: The Barcelona Clinic Liver Cancer (BCLC) stage C (BCLC C) of hepatocellular carcinoma (HCC) includes a heterogeneous population for which sorafeninb is one of the recommended therapies. We aim to evaluate the real world clinical treatment and survival of BCLC stage C patients in an Asian cohort. METHODS: This is a retrospective cohort study that enrolled 427 consecutive BCLC stage C patients diagnosed between 2011 and 2017 by using the HCC registry data for our hospital. All patients were managed via a multidisciplinary team (MDT) approach. RESULTS: Hepatitis B surface antigen positive was noted in 50.6% of the patients. The patients were classified as performance status (PS)1 alone (n = 83; 19.4%), PS2 alone (n = 23; 5.4%), or macrovascular invasion (MVI) or extrahepatic spread (EHS) (n = 321; 75.2%). The median overall survival (OS) was 11.0 months in the whole cohort. The most frequent treatments were transcatheter arterial embolization (TAE) in the PS1 (45.8%) and PS2 patients (52.2%) and sorafenib (32.4%) in the MVI or EHS patients. The independent prognostic factors were the PS, Child-Pugh class, MVI or EHS, alpha fetoprotein levels, and treatment type. CONCLUSIONS: We reported the real world management in BCLC stage C patients in an Asian cohort through the use of personalized management via a MDT approach.

A 14 day esomeprazole- and amoxicillin-containing high-dose dual therapy regimen achieves a high eradication rate as first-line anti-Helicobacter pylori treatment in Taiwan: a prospective randomized trial.

BACKGROUND: The first-line eradication rate of standard triple therapy for Helicobacter pylori infection has declined to <80%, and alternative therapies with >90% success rates are needed. Inconsistent eradication rates were reported for proton pump inhibitor- and amoxicillin-containing high-dose dual therapy. OBJECTIVES: We performed a prospective, randomized controlled study to assess the efficacy of esomeprazole- and amoxicillin-containing high-dose dual therapy and investigated the influencing clinical factors. PATIENTS AND METHODS: We recruited 240/278 eligible H. pylori-infected patients after exclusion. They were randomly assigned to 14 day high-dose dual therapy (esomeprazole 40 mg three times daily and amoxicillin 750 mg four times daily for 14 days; EA group) or 7 day non-bismuth quadruple therapy (esomeprazole 40 mg twice daily, clarithromycin 500 mg twice daily, amoxicillin 1 g twice daily and metronidazole 500 mg twice daily for 7 days; EACM group). Urea breath tests were followed up 8 weeks later. RESULTS: The eradication rates for the EA and EACM groups were 91.7% (95% CI = 85.3%-96.0%) and 86.7% (95% CI = 79.3%-92.2%) (P = 0.21) in ITT analysis; and 95.7% (95% CI = 90.2%-98.6%) and 92.0% (95% CI = 85.4%-96.3%) (P = 0.26) in PP analysis. The adverse event rates were 9.6% versus 23.0% in the two groups (P = 0.01). The H. pylori culture positivity rate was 91.8%. The antibiotic resistance rates were amoxicillin, 0%; clarithromycin, 14.6%; and metronidazole, 33.7%. CONCLUSIONS: A 14 day esomeprazole- and amoxicillin-containing high-dose dual therapy achieves a high eradication rate as first-line anti-H. pylori therapy, comparable to that with 7 day non-bismuth quadruple therapy but with fewer adverse events.

Celecoxib enhances the therapeutic efficacy of epirubicin for Novikoff hepatoma in rats.

Epirubicin is a chemotherapy agent for hepatocellular carcinoma (HCC). However, the outcome of HCC patients receiving epirubicin remains unsatisfactory. Moreover, our previous study indicated that celecoxib suppresses HCC progression and liver cancer stemness. This study evaluated the potential of celecoxib to serve as a complementary therapy during epirubicin treatment. Cell proliferation, apoptosis, invasiveness, and anchorage-independent growth were analyzed in hepatoma cells. Therapeutic efficacy was validated in rat orthotopic Novikoff hepatoma. After animal sacrifice, the antitumor mechanism of celecoxib and epirubicin combined therapy was investigated by histological analysis. Celecoxib enhanced the cytotoxic activity of epirubicin in HCC cells by promoting apoptosis. Besides, celecoxib potentiated the antineoplastic function of epirubicin in inhibiting the invasiveness and anchorage-independent growth of HCC cells. Ultrasound monitoring showed that combined therapy was more potent than either therapy alone in perturbing HCC progression. Consistently, the size and weight of dissected HCC tissues from rats receiving combined therapy were smallest among all groups. HCC treated with combined therapy exhibited the highest prevalence of apoptotic cells, which was accompanied by reduced proliferating and angiogenic activities in tumor tissues. Moreover, the expression levels of cancer stemness markers (CD44 and CD133) and drug transporter MDR-1 were significantly diminished in rats receiving combined therapy. Besides, celecoxib treatment increased the infiltration of cytotoxic T lymphocytes (CTLs) and reduced the number of regulatory T cells (Tregs), tumor-associated macrophages (TAMs), and the expression of immune checkpoint PD-L1 in HCC tissues during epirubicin therapy. Celecoxib augmented the therapeutic efficacy while modulated cancer stemness and antitumor immunity. Thus, celecoxib may serve as complementary therapy to improve the outcome of patients with advanced HCC during epirubicin treatment.

The outcome of sorafenib monotherapy on hepatocellular carcinoma with portal vein tumor thrombosis.

Sorafenib is not recommended for advanced hepatocellular carcinoma (HCC) patients with Vp4 (portal invasion at the main trunk) by the Japan Society of Hepatology (JSH) due to a risk of hepatic failure. This study aimed to elucidate the safety and efficacy of sorafenib monotherapy on HCC with macro-vascular invasion (MVI). A total of 415 consecutive advanced HCC patients received sorafenib in our hospital. Patients with only MVI and sorafenib monotherapy were retrospectively enrolled. We enrolled 113 (27.2%) patients, including 56 (49.5%) Vp3 (portal invasion at the first branch) and 57 (50.5%) Vp4. Their median intervals of follow-up and sorafenib-use were 7.8 months and 2.7 months respectively. Using sorafenib, more Vp4 had hepatic decompensation (HD) (37% VS 18.2%, p = 0.028) than Vp3 patients. The multivariate analysis showed Vp4 (Odds ratio: 2.91; 95% CI: 1.02-8.3, p = 0.041) and baseline alpha-fetoprotein (AFP) ≥ 200 ng/ml were associated with HD. Dividing our patients into four subgroups as Vp3 + AFP < 200 ng/ml, Vp3 + AFP ≥ 200 ng/ml, Vp4 + AFP < 200 ng/ml and Vp4 + AFP ≥ 200 ng/ml, the proportions of HD were 16.7%, 19.4%, 16.7% and 55.2% respectively (p = 0.002). The overall survival rates were distributed with a significant decreasing trend as 10.2 ± 4.4 months, 6.5 ± 1.0 months, 6.0 ± 1.3 months and 2.5 ± 0.5 months (p = 0.001). We found only Vp4 plus AFP ≥ 200 ng/ml could induce more HD and a poorer prognosis than Vp3 patients. Hence, in Vp4 patients with higher AFP, sorafenib should not be the first-line treatment due to its limited survival benefit.

Albumin-Bilirubin grade predicts prognosis of HCC patients with sorafenib use.

BACKGROUND AND AIM: The Albumin-Bilirubin (ALBI) grade is a new index to assess objectively liver function and prognosis in patients with hepatocellular carcinoma (HCC). This study aimed to elucidate the application of ALBI grade in baseline and sorafenib-end in advanced HCC patients who received sorafenib. METHODS: A total of 415 consecutive advanced HCC patients in Child-Pugh A received sorafenib in our hospital. Sorafenib was terminated when radiologic tumor progression or clinical liver function deterioration (LD) occurred in the reassessment bimonthly. Patients who failed with sorafenib monotherapy were retrospectively analyzed. RESULTS: A total of 260 (62.6%) patients were enrolled, including 98 (37.7%) ALBI grade I and 162 (62.3%) grade II in baseline. More patients in ALBI grade II stopped sorafenib because of LD than in grade I (33.3% vs 14.3%, P < 0.001). Those who in baseline ALBI grade I had a superior overall survival than in grade II (8.5 months vs 4.4 months, P = 0.003). Cox regression analysis confirmed that baseline ALBI grade II (P < 0.001) and ALBI grade increase during treatment (P < 0.001) strongly contributed to the mortality of HCC patients who received sorafenib. After sorafenib failure, those with post-sorafenib treatment had a better post-sorafenib survival than those without (9.3 vs 1.6 months, P < 0.001). Logistic regression analysis indicated that sorafenib-end ALBI grade and LD occurrence were the only two predictors of post-sorafenib treatment after sorafenib failure. CONCLUSIONS: In clinical practice, we firstly demonstrated that not only ALBI grade in baseline but also ALBI grade change during treatment could predict the prognosis of advanced HCC patients who received sorafenib.

Five-year sequential changes in secondary antibiotic resistance of Helicobacter pylori in Taiwan.

AIM: To determine changes in the antibiotic resistance of Helicobacter pylori (H. pylori) in southern Taiwan after failure of first-line standard triple therapy. METHODS: We analyzed 137 H. pylori-infected isolates from patients who experienced eradication failure after standard first-line triple therapy from January 2010 to December 2014. The H. pylori strains were tested for susceptibility to amoxicillin, clarithromycin, levofloxacin, metronidazole and tetracycline using the E-test method. The minimal inhibitory concentration (MIC) was determined by the agar dilution test. MIC values of ≥ 0.5, ≥ 1, ≥ 1, ≥ 4 and ≥ 8 mg/L were considered to be the resistance breakpoints for amoxicillin, clarithromycin, levofloxacin, tetracycline and metronidazole, respectively. RESULTS: A high resistance rate was found for clarithromycin (65%-75%) and metronidazole (30%-40%) among patients who failed first-line standard therapy. The resistance levels to amoxicillin and tetracycline remained very low; however, levofloxacin resistance was as high as 37.5% in 2010 but did not increase any further during the past 5 years. The rates of resistance to these antibiotics did not show a statistically significant upward or downward trend. CONCLUSION: Antibiotic resistance of H. pylori remains a problem for the effective eradication of this pathogen and its associated diseases in Taiwan. High clarithromycin resistance indicated that this antibiotic should not be prescribed as a second-line H. pylori eradication therapy. Moreover, levofloxacin-based second-line therapy should be used cautiously, and the local resistance rates should be carefully monitored.

Brivanib versus sorafenib as first-line therapy in patients with unresectable, advanced hepatocellular carcinoma: results from the randomized phase III BRISK-FL study.

PURPOSE: Brivanib is a dual inhibitor of vascular-endothelial growth factor and fibroblast growth factor receptors that are implicated in the pathogenesis of hepatocellular carcinoma (HCC). Our multinational, randomized, double-blind, phase III trial compared brivanib with sorafenib as first-line treatment for HCC. PATIENTS AND METHODS: Advanced HCC patients who had no prior systemic therapy were randomly assigned (ratio, 1:1) to receive sorafenib 400 mg twice daily orally (n = 578) or brivanib 800 mg once daily orally (n = 577). Primary end point was overall survival (OS). Secondary end points included time to progression (TTP), objective response rate (ORR), disease control rate (DCR) based on modified Response Evaluation Criteria in Solid Tumors (mRECIST), and safety. RESULTS: The primary end point of OS noninferiority for brivanib versus sorafenib in the per-protocol population (n = 1,150) was not met (hazard ratio [HR], 1.06; 95.8% CI, 0.93 to 1.22), based on the prespecified margin (upper CI limit for HR ≤ 1.08). Median OS was 9.9 months for sorafenib and 9.5 months for brivanib. TTP, ORR, and DCR were similar between the study arms. Most frequent grade 3/4 adverse events for sorafenib and brivanib were hyponatremia (9% and 23%, respectively), AST elevation (17% and 14%), fatigue (7% and 15%), hand-foot-skin reaction (15% and 2%), and hypertension (5% and 13%). Discontinuation as a result of adverse events was 33% for sorafenib and 43% for brivanib; rates for dose reduction were 50% and 49%, respectively. CONCLUSION: Our study did not meet its primary end point of OS noninferiority for brivanib versus sorafenib. However, both agents had similar antitumor activity, based on secondary efficacy end points. Brivanib had an acceptable safety profile, but was less well-tolerated than sorafenib.

Randomized comparison of two non-bismuth-containing second-line rescue therapies for Helicobacter pylori.

BACKGROUND: Classical second-line anti-Helicobacter pylori includes proton-pump inhibitor, tetracycline, metronidazole, and bismuth salts, but alternative therapies are required owing to the restricted availability of the latter. Levofloxacin-containing triple therapy is recommended but is expensive. Besides, quinolone resistance in an endemic tuberculosis infection area like Taiwan is concerned. The low in vitro antibiotic resistance to amoxicillin and tetracycline in Taiwanese H. pylori strains implies that in vivo esomeprazole/amoxicillin/tetracycline (EAT) second-line rescue therapy may be effective. This study compared the efficacy of esomeprazole/amoxicillin/levofloxacin (EAL) and EAT second-line eradication therapies and determines the clinical factors influencing the efficacy of salvage regimens. MATERIALS AND METHODS: One hundred and twenty-eight patients who failed H. pylori eradication using the standard triple therapy for 7 days are randomly assigned to either EAL group (esomeprazole 40 mg twice daily, amoxicillin 1 g twice daily, and levofloxacin 500 mg once daily) for 7 days or EAT group (esomeprazole 40 mg twice daily, amoxicillin 1 g twice daily, tetracycline 500 mg four times daily) for 14 days. Follow-up endoscopy or urea breath test was performed 8 weeks later to assess treatment response. RESULTS: The eradication rates of EAL and EAT groups were 78.1 versus 75.0%, p = .676 (in intention-to-treat analysis) and 80.3 versus 80%, p = .0964 (per-protocol analysis). Both groups exhibited similar drug compliance (95.3 vs 96.9%, p = .952) but more adverse events in the EAT group (6.3 vs 12.5%, p = .225). CONCLUSIONS: Despite low in vitro drug resistances to amoxicillin and tetracycline, the efficacy of 14-day EAT regimens attained an unacceptable report card of 75% eradication rates in intention-to-treat analysis and was not even superior to the 7-day EAL regimen. Drug-drug interaction between combined antibiotics should be considered other than in vivo drug resistances.

Effect of ginger on gastric motility and symptoms of functional dyspepsia.

AIM: To evaluate the effects of ginger on gastric motility and emptying, abdominal symptoms, and hormones that influence motility in dyspepsia. METHODS: Eleven patients with functional dyspepsia were studied twice in a randomized double-blind manner. After an 8-h fast, the patients ingested three capsules that contained ginger (total 1.2 g) or placebo, followed after 1 h by 500 mL low-nutrient soup. Antral area, fundus area and diameter, and the frequency of antral contractions were measured using ultrasound at frequent intervals, and the gastric half-emptying time was calculated from the change in antral area. Gastrointestinal sensations and appetite were scored using visual analog questionnaires, and blood was taken for measurement of plasma glucagon-like peptide-1 (GLP-1), motilin and ghrelin concentrations, at intervals throughout the study. RESULTS: Gastric emptying was more rapid after ginger than placebo [median (range) half-emptying time 12.3 (8.5-17.0) min after ginger, 16.1 (8.3-22.6) min after placebo, P≤0.05]. There was a trend for more antral contractions (P=0.06), but fundus dimensions and gastrointestinal symptoms did not differ, nor did serum concentrations of GLP-1, motilin and ghrelin. CONCLUSION: Ginger stimulated gastric emptying and antral contractions in patients with functional dyspepsia, but had no impact on gastrointestinal symptoms or gut peptides.

One-week versus two-week H2-receptor antagonist in combination with amoxicillin and tinidazole for eradication of Helicobacter pylori infection.

BACKGROUND/AIMS: Eradication regimens combining two antibiotics with a proton pump inhibitor have been studied intensively in Helicobacter pylori (H. pylori) infection; however, only a few reports have focused on the role of H2-receptor antagonists (H2-RAs) in eradication therapy. The mechanism involved in the synergy between antibiotics and H2RAs are still elusive. So we compared the efficacy of two regimens: a 1-week or 2-week course of high-dose H2-RA-based triple therapy in patients with H. pylori infection, and assessed the impact of primary resistance for metronidazole on the treatment outcome. METHODOLOGY: One hundred and twenty patients with peptic ulcers and nonulcer dyspepsia were randomly assigned to a one-week course of famotidine 40mg b.i.d., amoxicillin lg b.i.d. and tinidazole 500 mg b.i.d. (FAT1 group; n = 60) or a 2-week course of famotidine 40 mg b.i.d., amoxicillin lg b.i.d. and tinidazole 500 mg b.i.d. (FAT2 group; n = 60). Upper endoscopy was performed prior to treatment and at least 4 weeks after completion of treatment and discontinuation of the antisecretory therapy. H. pylori status was assessed by biopsy urease test, histology and culture. RESULTS: In the intention-to-treat analysis, eradication of H. pylori was achieved in 38 of 60 patients (63.3%; 95% CI: 51-76%) in the FAT1 group, compared to 48 of 60 patients (80%; 95% CI: 70-92%) in the FAT2 group (NS). In the per protocol analysis, eradication therapy was achieved in 38 of 54 patients (70.4%; 95% CI: 58-82%) in the FAT1 group and 48 of 53 patients (90.6%; 95% CI: 83-98%) in the FAT2 group (p < 0.05). The overall eradication rates for strains susceptible and resistant to metronidazole were 79.7% (95% CI: 71-89%) vs. 60% (95% CI: 44-74%) in the intention-to-treat analysis (p = 0.016) and 84% (95% CI: 76-92%) vs. 71.9% (95% CI: 56-88%) in the per protocol analysis (p = 0.12). Seven patients in the FAT1 group and six patients in the FAT2 group available for follow-up reported adverse events (11.7% and 10% respectively) without necessity of discontinuation of the study medications. Serious adverse events were not observed. CONCLUSIONS: A 2-week course of high-dose H2-RA-based triple therapy is well tolerated and sufficiently effective in eradicating H. pylori infection. Presence of metronidazole resistance has a negative impact on the treatment efficacy.