Barcelona clinic liver cancer-stage C hepatocellular carcinoma: A novel approach to subclassification and treatment.

Barcelona clinic liver cancer-stage C (BCLC-C) encompasses a broad spectrum of tumor burdens, liver function statuses, patient prognoses, and treatment strategies. Currently, sorafenib is the only recommended treatment for patients with BCLC-C and outcomes remain suboptimal. The aims of this study were to assess the heterogeneity of BCLC-C hepatocellular carcinoma (HCC) cases, propose a novel subclassification for these cases, and suggest optimal treatment strategies other than sorafenib.We retrospectively analyzed 196 consecutive BCLC-C HCC patients who were diagnosed and treated between January 2008 and December 2015.All 196 patients were classified according to the modified Union for International Cancer Control (Stage I, 0.0%; Stage II, 8.2%; Stage III, 64.3%; Stage IVA, 21.9%; and Stage IVB, 5.6%) and American Joint Committee on Cancer TNM staging systems (Stage I, 0.0%; Stage II, 16.3%; Stage IIIA, 27.6%; Stage IIIB, 49.5%; Stage IIIC, 1.5%; Stage IVA, 1.0%; and Stage IVB, 4.1%). First-line treatment modalities included surgical resection (8.7%), transarterial chemoembolization (49.5%), hepatic arterial infusion therapy (5.6%), sorafenib therapy (9.2%), radiotherapy (9.2%), and best supportive care (10.7%). In univariate analysis, Child-Pugh score, tumor size, distant metastasis, multinodular or infiltrative/diffuse type of HCC, main portal vein invasion, hepatic vein invasion, and bile duct invasion were significantly associated with survival (P < .001). Tumor size, distant metastasis, HCC type, and bile duct invasion remained significantly associated with 1-, 3-, and 5-year survival rates in multivariate Cox regression analyses. Using these 4 characteristics, a novel subclassification of BCLC-C was developed and applied to the patient cohort. The subclassification included 5 substages (stages C0-C4), as defined based on the number of characteristics that were present in each HCC case (0-4). The subclassification showed significant associations with survival, with median survival times of 3026 days, 605 days, 224 days, 126 days, and 82 days for patients with Stage C0, C1, C2, C3, and C4 disease, respectively (P < .001). Additionally, diverse survival rates were observed when different treatment modalities were selected for cases within each substage.The proposed BCLC-C subclassification of HCC patients is effective in providing better prognostic subclassifications and more appropriate treatment strategies.

Pretreatment antimicrobial susceptibility-guided vs. clarithromycin-based triple therapy for Helicobacter pylori eradication in a region with high rates of multiple drug resistance.

OBJECTIVES: Helicobacter pylori eradication rates with clarithromycin-based triple therapy are declining, and an alternative strategy is needed urgently. We sought to compare the efficacy of pretreatment antimicrobial susceptibility-guided vs. clarithromycin-based triple therapy for H. pylori eradication in a region with high rates of multiple drug resistance. METHODS: Consecutive H. pylori-infected patients with gastric epithelial neoplasms were randomized to receive antimicrobial susceptibility-guided therapy or clarithromycin-based triple therapy for 7 days. In patients in whom the infection was not eradicated, antibiotics were given according to an initial antimicrobial susceptibility test as a second-line therapy in both groups. Eradication rates, antibiotics resistance rates, and drug compliance owing to adverse effects were compared between the groups. RESULTS: In total, 114 patients were enrolled, and 112 completed the protocols. Drug compliance and side effects were similar between the groups. The intention-to-treat eradication rates were 94.7% (95% confidence interval (CI)=88.8-100%, 54/57) in the antimicrobial susceptibility-guided group and 71.9% (95% CI=60.2-83.5%, 41/57) in the clarithromycin-based triple therapy group after the initial treatment (P=0.002), whereas the per-protocol (PP) eradication rates were 96.4% (95% CI=91.5-100%, 54/56) in the antimicrobial susceptibility-guided group and 73.2% (95% CI=61.5-84.8%, 41/56) in the clarithromycin-based triple therapy group (P=0.001). In H. pylori with clarithromycin resistance, the eradication failure rate with first-line treatment was lower in the susceptibility-guided therapy group (0%, 0/12) compared with the clarithromycin-based triple therapy group (80.0%, 95% CI=59.7-100%, 12/15) by PP analysis (P<0.001). CONCLUSIONS: Pretreatment antimicrobial susceptibility-guided therapy is more effective than clarithromycin-based triple therapy for H. pylori eradication in a region with high rates of multiple drug resistance.

A comparative study of DA-9601 and misoprostol for prevention of NSAID-associated gastroduodenal injury in patients undergoing chronic NSAID treatment.

Misoprostol is reported to prevent non-steroidal anti-inflammatory drug (NSAID)-associated gastroduodenal complications. There is, however, limited information regarding the efficacy of DA-9601 in this context. We performed a comparative study on the relative efficacy of DA-9601 and misoprostol for prevention of NSAID-associated complications. In this multicenter, double-blinded, active-controlled, stratified randomized, parallel group, non-inferiority trial, 520 patients who were to be treated with an NSAID (aceclofenac, 100 mg, twice daily) over a 4-week period were randomly assigned to groups for coincidental treatment with DA-9601 (60 mg, thrice daily) (236 patients for full analysis) or misoprostol (200 µg, thrice daily) (242 patients for full analysis). [corrected]. The primary endpoint was the gastric protection rate, and secondary endpoints were the duodenal protection rate and ulcer incidence rate. Endpoints were assessed by endoscopy after the 4-week treatment period. Drug-related adverse effects, including gastrointestinal (GI) symptoms, were also compared. At week 4, the gastric protection rates with DA-9601 and misoprostol were 81.4 % (192/236) and 89.3 % (216/242), respectively. The difference between the groups was -14.2 %, indicating non-inferiority of DA-9601 to misoprostol. Adverse event rates were not different between the two groups; however, the total scores for GI symptoms before and after administration were significantly lower in the DA-9601 group than in the misoprostol group (-0.2 ± 2.8 vs 1.2 ± 3.2; p < 0.0001). DA-9601 is as effective as misoprostol in preventing NSAID-associated gastroduodenal complications, and has a superior adverse GI effect profile.

Clinical significance and risk factors of postembolization fever in patients with hepatocellular carcinoma.

AIM: To investigate tumor response and survival in patients with postembolization fever (PEF) and to determine the risk factors for PEF. METHODS: Four hundred forty-three hepatocellular carcinoma (HCC) patients who underwent the first session of transcatheter arterial chemoembolization (TACE) between January 2005 and December 2009 were analyzed retrospectively. PEF was defined as a body temperature greater than 38.0 °C that developed within 3 d of TACE without evidence of infection. The tumor progression-free interval was defined as the interval from the first TACE to the second TACE based on mRECIST criteria. Clinical staging was based on the American Joint Committee on Cancer tumor, node, metastases (TNM) classification of malignant tumors. All patients were admitted before their 1(st) TACE treatment, and blood samples were obtained from all patients before and after treatment. Clinicoradiological variables and host-related variables were compared between two groups: patients with PEF vs patients without PEF. Additionally, variables related to 20-mo mortality and tumor progression-free survival were analyzed. RESULTS: The study population comprised 370 (85.4%) men and 73 (14.6%) women with a mean age of 62.29 ± 10.35 years. A total of 1836 TACE sessions were conducted in 443 patients, and each patient received between 1 and 27 (mean: 4.14 ± 3.57) TACE sessions. The mean follow-up duration was 22.23 ± 19.6 mo (range: 0-81 mo). PEF developed in 117 patients (26.41%) at the time of the first TACE session. PEF was not associated with 20-mo survival (P = 0.524) or computed tomography (CT) response (P = 0.413) in a univariate analysis. A univariate analysis further indicated that diffuse-type HCC (P = 0.021), large tumor size (≥ 5 cm) (P = 0.046), lipiodol dose (≥ 7 mL, P = 0.001), poor blood glucose control (P = 0.034), alanine aminotransferase (ALT) value after TACE (P = 0.004) and C-reactive protein (CRP) value after TACE (P = 0.036) served as possible risk factors correlated with PEF. The ALT value after TACE (P = 0.021) and lipiodol dose over 7 mL (P = 0.011) were independent risk factors for PEF in the multivariate analysis. For the 20-mo survival, poor blood sugar control (P < 0.001), portal vein thrombosis (P = 0.001), favorable CT response after TACE (P < 0.001), initial aspartate aminotransferase (P = 0.02), initial CRP (P = 0.042), tumor size (P < 0.001), TNM stage (P < 0.001) and lipiodol dose (P < 0.001) were possible risk factors in the univariate analysis. Tumor size (P = 0.03), poor blood sugar control (P = 0.043), and portal vein thrombosis (P = 0.031) were significant predictors of survival in the multivariate analysis. Furthermore, the tumor progression-free interval was closely associated with CRP > 1 mg/dL (P = 0.003), tumor size > 5 cm (P < 0.001), tumor type (poorly defined) (P < 0.001), and lipiodol dose (> 7 mL, P < 0.001). CONCLUSION: PEF has no impact on survival at 20 mo or radiologic response. However, the ALT level after TACE and the lipiodol dose represent significant risk factors for PEF.

Prevention of NSAID-associated gastroduodenal injury in healthy volunteers-a randomized, double-blind, multicenter study comparing DA-9601 with misoprostol.

In addition to inhibiting cyclooxygenase and prostaglandin, nonsteroidal anti-inflammatory drugs (NSAIDs) may cause gastroduodenal injuries due to reactive oxygen species produced by recruited inflammatory cells. DA-9601 is a novel antioxidant with anti-inflammatory and cyto-protective effects. This study was conducted to compare the efficacy and safety of DA-9601 with misoprostol for preventing NSAID-associated gastroduodenal injury. In this randomized, double-blind, multicenter, noninferiority trial we compared the extents of protection of gastric and duodenal mucosae by endoscopy after 4 weeks of treatment with DA-9601 60 mg or misoprostol 200 µg three times daily, in subjects with normal baseline endoscopic findings who received an NSAID twice daily for 4 weeks. A total of 266 subjects were randomized to treatment. At week 4, the gastric protection rates with DA-9601 and misoprostol were 85.1% and 95.2%, respectively; the difference between the groups was -10.1% (var = 0.001), which was shown to indicate noninferiority of DA-9601 compared to misoprostol. Adverse events were lower in the DA-9601 group, 56.4% (95% CI, 48.0%-64.8%) than in the misoprostol group, 69.2% (95% CI, 61.3%-77.0%) (P = 0.031). DA-9601 is not inferior to misoprostol for preventing NSAID-associated gastroduodenal injury, and superior to it with respect to treatment-related side effects.

[Cerebral lipiodol embolism after transcatheter arterial chemoembolization of hepatocellular carcinoma].

Transcatheter arterial chemoembolization (TACE) is the mainstay of treatment for unresectable hepatocellular carcinoma (HCC). Although various complications of TACE have been reported, cerebral lipiodol embolism after TACE is rare. We report a 67-year-old man, who had patent foramen ovale and developed cerebral lipiodol embolism after TACE via the inferior phrenic artery. At 20 months after third TACE of 3 cm sized HCC in the left hepatic lobe, computed tomography (CT) revealed about 1.6 cm newly developed HCC in the anterior superior segment of right hepatic lobe. The angiogram revealed the HCC was supplied from the right inferior phrenic artery. Toward the end of TACE, there were accumulations of the iodized oil in the pulmonary vasculature. Immediately after TACE, he complained of weakness in right upper and lower limbs and sensory decrease in right limbs and right hemitrunk. Magnetic resonance imaging revealed a cerebral lipiodol embolism. Transesophageal echocardiography revealed no visible thrombi but contrast-echocardiography using hand agitated saline revealed an intracardiac right to left shunt consistent with patent foramen ovale. Motor weakness and sensory decrease were gradually improved, and all neurological symptoms disappeared over 4 weeks.

[A case of pneumatosis cystoides intestinalis in a cirrhosis patient].

Pneumatosis cystoides intestinalis (PCI) is a relatively rare condition in which gas is found as a linear or cystic form in the submucosa or subserosa of bowel wall. PCI is usually found incidentally on an imaging study. Treatment is usually conservative including oxygen and antibiotics therapy. So far, etiology and pathogenesis of PCI remain uncertain. PCI is associated with various medical conditions including various pulmonary diseases, connective tissue diseases, and endoscopic procedures. However, there are only few reports on lactulose causing PCI in patients with cirrhosis. Oral lactulose or enema is one of the main treatment modalities in hepatic encephalopathy. Here, we report a case of PCI which was found during the treatment with lactulose therapy in a patient with liver cirrhosis and hepatic encephalopathy.

Neostigmine for the treatment of acute hepatic encephalopathy with acute intestinal pseudo-obstruction in a cirrhotic patient.

We treated a 49-yr-old man with neostigmine, who had liver cirrhosis, acute hepatic encephalopathy, and acute intestinal pseudoobstruction. He was admitted in a state of hepatic confusion. On physical examination, the abdomen was distended; and bowel sound was absent. Plain abdomen film revealed multiple air-fluid levels and distention of bowel loops. Initially, we gave him lactulose enemas every 6 hr for one day without improvement in his mental state. Furthermore, he became to a state of coma. Therefore, we gave him 0.5 mg of neostigmine subcutaneously to improve his peristaltic movement, and 2 L of polyethylene glycol electrolyte solution through a nasogastric tube for 4 hr to reduce the production and absorption of gut-derived toxins of nitrogenous compounds. After these treatments, the venous ammonia level decreased to the normal range within 12 hr, and the coma disappeared after 2 days. We suggest that neostigmine may be one of the most effective treatments to initiate peristaltic movement and bowel cleansing in cirrhotic patients with acute hepatic encephalopathy and acute intestinal pseudoobstruction.