Branched-chain amino acids prevent hepatocarcinogenesis and prolong survival of patients with cirrhosis.

BACKGROUND & AIMS: Although a low plasma level of branched-chain amino acids (BCAAs) is a marker of cirrhosis, it is not clear whether BCAA supplements affect disease progression. We performed a multicenter study to evaluate the effects of BCAA supplementation on hepatocarcinogenesis and survival in patients with cirrhosis. METHODS: We enrolled 299 patients from 14 medical institutions in Japan in a prospective, multicenter study in 2009; 267 patients were followed through 2011. Patients were given BCAA supplements (5.5-12.0 g/day) for more than 2 years (n = 85) or no BCAAs (controls, n = 182). The primary end points were onset of hepatocellular carcinoma (HCC) and death. Factors associated with these events were analyzed by competing risk analysis. RESULTS: During the study period, 41 of 182 controls and 11 of 85 patients given BCAAs developed HCC. On the basis of the Cox and the Fine and Gray models of regression analyses, level of α-fetoprotein, ratio of BCAA:tyrosine, and BCAA supplementation were associated with development of HCC (relative risk for BCAAs, 0.45; 95% confidence interval, 0.24-0.88; P = .019). Sixteen controls and 2 patients given BCAAs died. Factors significantly associated with death were Child-Pugh score, blood level of urea nitrogen, platelet count, male sex, and BCAA supplementation (relative risk of death for BCAAs, 0.009; 95% confidence interval, 0.0002-0.365; P = .015) in both regression models. CONCLUSIONS: On the basis of a prospective study, amino acid imbalance is a significant risk factor for the onset of HCC in patients with cirrhosis. BCAA supplementation reduces the risk for HCC and prolongs survival of patients with cirrhosis.

Successful treatment of a patient with Budd-Chiari syndrome with main hepatic vein obstruction with percutaneous transluminal angioplasty and stent placement.

A woman in her 40s presented at our department with abdominal fullness. Abdominal computed tomography showed hepatomegaly and ascites, and gastrointestinal endoscopy showed esophageal varices. A diagnosis of Budd-Chiari syndrome (BCS) was confirmed by percutaneous hepatic venography, which detected obstruction of the main hepatic vein. It was treated using percutaneous transluminal angioplasty and metallic stent placement. Rupture of the esophageal varices occurred 5 months later because of the occlusion of the stent lumen; however, she was successfully retreated with further stent placement.

Hepatocellular carcinoma in Child-Pugh C cirrhosis: prognostic factors and survival benefit of nontransplant treatments.

A retrospective multicenter study was conducted to clarify the survival benefit of nontransplant treatments for patients with hepatocellular carcinoma (HCC) associated with Child-Pugh C cirrhosis. Data on 436 patients, including 203 treated patients with HCC, were collected from 20 institutions in Japan. Cox's proportional hazards model corrected for bias by propensity score analysis clearly showed the following as significant independent prognostic factors, including all four nontransplant treatments examined: transarterial chemoembolization, hepatic arterial infusion chemotherapy, percutaneous ethanol injection therapy, radiofrequency ablation, hepatitis B virus, number of tumors, log α-fetoprotein, encephalopathy, ascites and prothrombin time. The cumulative survival rate was significantly higher in the treated group than in the untreated group. The present findings suggest that prognosis can be improved by nontransplant treatments in patients with low Child-Pugh scores. Since this study was retrospective, the possibility of selection bias cannot be ruled out. Therefore, verification by a prospective controlled study is warranted.

Phosphorylated Smad2 and Smad3 signaling: Shifting between tumor suppression and fibro-carcinogenesis in chronic hepatitis C.

AIM: Insight into hepatic fibrogenesis and carcinogenesis (fibro-carcinogenesis) caused by hepatitis C virus (HCV) infection has come from recent analyses of transforming growth factor (TGF)-ß signaling. TGF-ß type I receptor and pro-inflammatory cytokine-activated kinases differentially phosphorylate Smad2 and Smad3 to create C-terminally (C), linker (L) or dually (L/C) phosphorylated (p) isoforms. This study aimed to elucidate how HCV infection affected hepatic fibro-carcinogenesis, particularly via phospho-Smad signaling. METHODS: We first studied phospho-Smad2/3 positivity of 100 patients in different stages of HCV-related chronic liver disease. To examine changes in phospho-Smad2/3 after HCV clearance, we analyzed 32 paired liver biopsy samples obtained before and after sustained virological response (SVR), dividing patients into two groups: 20 patients not developing hepatocellular carcinoma (HCC) after attaining SVR (non-HCC group), and 12 patients who developed HCC despite SVR (HCC group). RESULTS: Hepatocytic tumor-suppressive pSmad3C signaling shifted to carcinogenic pSmad3L and fibrogenic pSmad2L/C signaling as liver diseases progressed. In the non-HCC group, 13 patients (65%) displayed fibrotic regression and inflammation reduction after SVR. Interestingly, SVR restored cytostatic pSmad3C signaling in hepatocytes, while eliminating prior carcinogenic pSmad3L and fibrogenic pSmad2L/C signaling. In the HCC group, seven patients (58%) displayed unchanged or even progressed fibrosis despite smoothened inflammatory activity, reflecting persistently high numbers of hepatocytes with pSmad3L- and pSmad2L/C-signaling and low pSmad3C-signaling. CONCLUSION: HCV clearance limits fibrosis and reduces HCC incidence by switching inflammation-dependent phospho-Smad signaling from fibro-carcinogenesis to tumor suppression. However, progression to HCC would occur in severely fibrotic livers if an inflammation-independent fibro-carcinogenic process has already begun before HCV clearance.

Narrowing the Patient-Physician Gap Based on Self-Reporting and Monthly Hepatologist Feedback for Patients With Alcohol-Related Liver Disease: Interventional Pilot Study Using a Journaling Smartphone App.

BACKGROUND: Screening and intervention for alcohol use disorders (AUDs) are recommended to improve the prognosis of patients with alcohol-related liver disease (ALD). Most patients' smartphone app diaries record drinking behavior for self-monitoring. A smartphone app can be expected to also be helpful for physicians because it can provide rich patient information to hepatologists, leading to suitable feedback. We conducted this prospective pilot study to assess the use of a smartphone app as a journaling tool and as a self-report-based feedback source for patients with ALD. OBJECTIVE: The aims of this study were assessment of whether journaling (self-report) and self-report-based feedback can help patients maintain abstinence and improve liver function data. METHODS: This pilot study used a newly developed smartphone journaling app for patients, with input data that physicians can review. After patients with ALD were screened for harmful alcohol use, some were invited to use the smartphone journaling app for 8 weeks. Their self-reported alcohol intake, symptoms, and laboratory data were recorded at entry, week 4, and week 8. Biomarkers for alcohol use included gamma glutamyl transferase (GGT), percentage of carbohydrate-deficient transferrin to transferrin (%CDT), and GGT-CDT (GGT-CDT= 0.8 × ln[GGT] + 1.3 × ln[%CDT]). At each visit, their recorded data were reviewed by a hepatologist to evaluate changes in alcohol consumption and laboratory data. The relation between those outcomes and app usage was also investigated. RESULTS: Of 14 patients agreeing to participate, 10 completed an 8-week follow-up, with diary input rates between 44% and 100% of the expected days. Of the 14 patients, 2 withdrew from clinical follow-up, and 2 additional patients never used the smartphone journaling app. Using the physician's view, a treating hepatologist gave feedback via comments to patients at each visit. Mean self-reported alcohol consumption dropped from baseline (100, SD 70 g) to week 4 (13, SD 25 g; P=.002) and remained lower at week 8 (13, SD 23 g; P=.007). During the study, 5 patients reported complete abstinence. No significant changes were found in mean GGT and mean %CDT alone, but the mean GGT-CDT combination dropped significantly from entry (5.2, SD 1.2) to the week 4 visit (4.8, SD 1.1; P=.02) and at week 8 (4.8, SD 1.0; P=.01). During the study period, decreases in mean total bilirubin (3.0, SD 2.4 mg/dL to 2.4, SD 1.9 mg/dL; P=.01) and increases in mean serum albumin (3.0, SD 0.9 g/dL to 3.3, SD 0.8 g/dL; P=.009) were recorded. CONCLUSIONS: These pilot study findings revealed that a short-term intervention with a smartphone journaling app used by both patients and treatment-administering hepatologists was associated with reduced drinking and improved liver function. TRIAL REGISTRATION: UMIN CTR UMIN000045285; http://tinyurl.com/yvvk38tj.

Effect of vitamin K2 on the recurrence of hepatocellular carcinoma.

UNLABELLED: Hepatocellular carcinoma (HCC) is characterized by frequent recurrence, even after curative treatment. Vitamin K2, which has been reported to reduce HCC development, may be effective in preventing HCC recurrence. Patients who underwent curative ablation or resection of HCC were randomly assigned to receive placebo, 45 mg/day, or 90 mg/day vitamin K2 in double-blind fashion. HCC recurrence was surveyed every 12 weeks with dynamic computed tomography/magnetic resonance imaging, with HCC-specific tumor markers monitored every 4 weeks. The primary aim was to confirm the superiority of active drug to placebo concerning disease-free survival (DFS), and the secondary aim was to evaluate dose-response relationship. Disease occurrence and death from any cause were treated as events. Hazard ratios (HRs) for disease occurrence and death were calculated using a Cox proportional hazards model. Enrollment was commenced in March 2004. DFS was assessed in 548 patients, including 181 in the placebo group, 182 in the 45-mg/day group, and 185 in the 90-mg/day group. Disease occurrence or death was diagnosed in 58, 52, and 76 patients in the respective groups. The second interim analysis indicated that vitamin K2 did not prevent disease occurrence or death, with an HR of 1.150 (95% confidence interval: 0.843-1.570, one-sided; P=0.811) between the placebo and combined active-drug groups, and the study was discontinued in March 2007. CONCLUSION: Efficacy of vitamin K2 in suppressing HCC recurrence was not confirmed in this double-blind, randomized, placebo-controlled study.

A randomized phase II trial of intra-arterial chemotherapy using SM-11355 (Miriplatin) for hepatocellular carcinoma.

BACKGROUND: SM-11355 is a platinum complex developed to treat hepatocellular carcinoma (HCC) via administration into the hepatic artery as a sustained-release suspension in iodized oil. We conducted a multicenter phase II trial in patients with HCC to evaluate the efficacy and safety of SM-11355, using a Zinostatin stimalamer suspension in iodized oil as a reference. METHODS: Patients with unresectable HCC were randomized 2:1 to receive administration of the SM-11355 or Zinostatin stimalamer suspension into the hepatic artery. A second injection was given 4-12 weeks later. Efficacy was evaluated by CT 3 months after treatment and categorized as therapeutic effect (TE) V to I, where TE V was defined as disappearance or 100% necrosis of all treated tumors. RESULTS: A total of 122 patients were evaluated for efficacy and toxicity (SM-11355, n = 83; Zinostatin stimalamer, n = 39). Baseline characteristics were similar in the two groups. The TE V rates were 26.5% (22/83) and 17.9% (7/39) in the SM-11355 and Zinostatin stimalamer groups, respectively. In the SM-11355 group,the most frequent drug-related adverse events (AEs) of ≥ grade 3 were elevated AST, elevated ALT, thrombocytopenia, and hyperbilirubinemia. The AEs with the largest difference between the two groups (SM-11355 vs. Zinostatin stimalamer) were hepatic vascular injury (0 vs. 48.4%) and eosinophilia (84.3 vs. 41.0%). The 2-year and 3-year survival rates were 75.9% vs. 70.3% and 58.4% vs. 48.7%, respectively. CONCLUSIONS: The results suggest that SM-11355 in iodized oil has similar efficacy to Zinostatin stimalamer and that repeated dosing of SM-11355 is possible without hepatic vascular injury in cases of relapse.

A prospective randomized controlled trial of preoperative whole-liver chemolipiodolization for hepatocellular carcinoma.

BACKGROUND: We previously reported that preoperative chemolipiodolization of the whole liver is effective for reducing the incidence of postoperative recurrence and prolonging survival in patients with resectable hepatocellular carcinoma (HCC). The present randomized controlled trial was performed to evaluate the influence of preoperative transcatheter arterial chemoembolization (TACE) on survival after the resection of HCC. METHODS: Operative results and long-term outcome were prospectively compared among 42 patients who received only selective TACE targeting the tumor (selective group), 39 patients who received TACE targeting the tumor plus chemolipiodolization of the whole liver (whole-liver group), and 43 patients without preoperative TACE or chemolipiodolization (control group). RESULTS: There were no serious side effects of TACE or chemolipiodolization and the operative outcomes did not differ among the three groups. Even though preoperative TACE induced complete tumor necrosis, there were no significant differences in the pattern of intrahepatic recurrence or the time until recurrence among the three groups. There were also no significant differences in disease-free survival or overall survival among the three groups, even among patients with larger tumor size. CONCLUSION: These results indicate that preoperative selective TACE and whole-liver chemolipiodolization plus TACE do not reduce the incidence of postoperative recurrence or prolong survival in patients with resectable HCC.

Gel Immersion Endoscopic Mucosal Resection (EMR) for Superficial Nonampullary Duodenal Epithelial Tumors May Reduce Procedure Time Compared with Underwater EMR (with Video).

Materials and Methods: This was a retrospective cohort study conducted in two municipal hospitals. We identified 24 patients with SNADETs of 3-18 mm in diameter who underwent UEMR or GIEMR. One lesion was excluded from the analysis because it was found to be in the stomach after surgery. The primary outcome was procedure time. Results: GIEMR significantly reduced the procedure time compared with UEMR (5 min vs. 10 min, P = 0.016). There was no significant difference between the UEMR and GIEMR groups for en bloc resection rate (93% vs. 100%, P = 1.0) and R0 resection rate (57% vs. 80%, P = 0.39). No serious complications were observed in either group. Conclusions: GIEMR of SNADET has the potential to reduce procedure time compared with UEMR and may be particularly effective in areas where immersion in water is difficult.

Viral Infection in Esophageal, Gastric, and Colorectal Cancer.

The human gastrointestinal tract, which constitutes the digestive system, contains a large number of virus particles that maintain organizational homeostasis and health. Conversely, viral pathogens have also attracted attention for their involvement in the pathogenesis of certain cancers, including gastrointestinal cancers. To aid prevention and treatment of these cancers, the relevance of gastrointestinal viral factors as potential risk factors needs to be carefully investigated. This review summarizes and discusses the available literature on the relationship between the development of esophageal, gastric, and colorectal cancers and their corresponding viruses. This review reveals that research on the association between colorectal cancer and viruses, in particular, is still in its infancy compared to the association between HPV and esophageal cancer and between EBV and gastric cancer.

Expression of pituitary tumor-transforming gene 1 (PTTG1)/securin in hepatitis B virus (HBV)-associated liver diseases: evidence for an HBV X protein-mediated inhibition of PTTG1 ubiquitination and degradation.

Chronic infection with hepatitis B virus (HBV) is strongly associated with hepatocellular carcinoma (HCC), and the viral HBx protein plays a crucial role in the pathogenesis of liver tumors. Because the protooncogene pituitary tumor-transforming gene 1 (PTTG1) is overexpressed in HCC, we investigated the regulation of this protein by HBx. We analyzed PTTG1 expression levels in liver biopsies from patients chronically infected with HBV, presenting different disease stages, and from HBx transgenic mice. PTTG1 was undetectable in biopsies from chronic hepatitis B patients or from normal mouse livers. In contrast, hyperplastic livers from transgenic mice and biopsies from patients with cirrhosis, presented PTTG1 expression which was found mainly in HBx-expressing hepatocytes. PTTG1 staining was further increased in HCC specimens. Experiments in vitro revealed that HBx induced a marked accumulation of PTTG1 protein without affecting its messenger RNA levels. HBx expression promoted the inhibition of PTTG1 ubiquitination, which in turn impaired its degradation by the proteasome. Glutathione S-transferase pull-down and co-immunoprecipitation experiments demonstrated that the interaction between PTTG1 and the Skp1-Cul1-F-box ubiquitin ligase complex (SCF) was partially disrupted, possibly through a mechanism involving protein-protein interactions of HBx with PTTG1 and/or SCF. Furthermore, confocal analysis revealed that HBx colocalized with PTTG1 and Cul1. We propose that HBx promotes an abnormal accumulation of PTTG1, which may provide new insights into the molecular mechanisms of HBV-related pathogenesis of progressive liver disease leading to HCC development.

Efficacy of microwave ablation versus radiofrequency ablation for hepatocellular carcinoma: a propensity score analysis.

PURPOSE: To evaluate the efficacy and safety of radiofrequency ablation (RFA) and new-generation microwave ablation (MWA) for the treatment of hepatocellular carcinoma (HCC). METHODS: The propensity score matching method was applied to patients with HCC treated with MWA (93 patients) or RFA (156 patients) at a single institution from January 2014 to April 2020. The local tumor progression (LTP), intrahepatic distant recurrence (IDR), and recurrence-free survival (RFS) of the two matched therapies were analyzed using the Kaplan-Meier method. Cox proportional hazard models were used to identify risk factors for LTP and RFS. The therapeutic effects and complications of the two treatments were also compared. RESULTS: The LTP, IDR, and RFS of MWA and RFA were equivalent (LTP: hazard ratio [HR] = 0.87; 95% confidence interval [95% CI] 0.36- 2.07; P = 0.746, IDR: HR = 1.03; 95% CI 0.61-1.73; P = 0.890, RFS: HR = 1.15; 95% CI 0.69-1.91; P = 0.566). Para-vessel lesions was the only risk factor for LTP, whereas age, previous treatment, Albumin-Bilirubin score, and tumor diameter were risk factors for RFS. On the other hand, the ablation time per nodule (6.79 ± 2.73 and 9.21 ± 4.90 min; P = 0.008) and number of sessions per nodule required to achieve technical success (1.16 ± 0.39 and 1.34 ± 0.57; P = 0.009) were significantly lower in MWA than in RFA. The major complication rate of MWA and RFA was also equivalent. CONCLUSION: MWA and RFA have similar therapeutic effects and safety, although MWA has advantages over RFA regarding efficacy, including shorter ablation time and fewer sessions required.

Phospho-Smad3 signaling is predictive biomarker for hepatocellular carcinoma risk assessment in primary biliary cholangitis patients.

INTRODUCTION: Patients with primary biliary cholangitis (PBC) are at increased risk for development of hepatocellular carcinoma (HCC), particularly in the presence of comorbidities such as excessive alcohol consumption. Although liver fibrosis is an important risk factor for HCC development, earlier predictors of future HCC development in livers with little fibrosis are needed but not well defined. The transforming growth factor (TGF)-ß/Smad signaling pathway participates importantly in hepatic carcinogenesis. Phosphorylated forms (phospho-isoforms) in Smad-related pathways can transmit opposing signals: cytostatic C-terminally-phosphorylated Smad3 (pSmad3C) and carcinogenic linker-phosphorylated Smad3 (pSmad3L) signals. METHODS AND RESULTS: To assess the balance between Smad signals as a biomarker of risk, we immunohistochemically compared Smad domain-specific Smad3 phosphorylation patterns among 52 PBC patients with various stages of fibrosis and 25 non-PBC patients with chronic hepatitis C virus infection. HCC developed in 7 of 11 PBC patients showing high pSmad3L immunoreactivity, but in only 2 of 41 PBC patients with low pSmad3L. In contrast, 9 of 20 PBC patients with minimal Smad3C phosphorylation developed HCC, while HCC did not occur during follow-up in 32 patients who retained hepatic tumor-suppressive pSmad3C. Further, PBC patients whose liver specimens showed high pSmad3L positivity were relatively likely to develop HCC even when little fibrosis was evident. CONCLUSION: In this study, Smad phospho-isoform status showed promise as a biomarker predicting likelihood of HCC occurrence in PBC. Eventually, therapies to shift favorably Smad phospho-isoforms might decrease likelihood of PBC-related HCC.