Emergency endoscopic variceal ligation following variceal rupture in patients with advanced hepatocellular carcinoma and portal vein tumor thrombosis: a retrospective study.

BACKGROUND: The outcomes of treatment of ruptured varices in patients with hepatocellular carcinoma (HCC) and portal vein tumor thrombus (PVTT) are unclear. We therefore evaluated the long- (rebleeding and death) and short-term (immediate death within 24 h of variceal bleeding diagnosis) outcomes of patients with PVTT who underwent emergency variceal band ligation. METHODS: Data on 62 patients with PVTT and endoscopically proven esophageal or gastric variceal bleeding from 2007 to 2012 were studied. In most cases, the varices were treated using endoscopic variceal band ligation (EVL). We assessed the patients' rebleeding-free and overall survival using the Kaplan-Meier method, and a Cox proportional hazard model was used to analyze effect of independent factors on rebleeding-free and overall survival times. RESULTS: Most patients had decompensated cirrhosis and were classified as Child-Pugh class B (56%) or C (36%). A total of 35 patients (56%) had PVTT in the main portal trunk. Among all patients, 58 (94%) and 4 (6%) had esophageal and gastric variceal bleeding, respectively. Bleeding was managed using EVL in all, but one patient (98%) who was treated with a Sengstaken-Blakemore tube. A total of 24 patients (39.3%) experienced rebleeding, and these patients had a median overall survival time of 36 days. A PVTT in the main portal trunk was predictive of rebleeding (hazard ratio 3.706, p = .0223), and α-fetoprotein-L3 levels <37.4% (hazard ratio 0.464, p = 0.015) and Child-Pugh class A/B (hazard ratio 0.398, p = 0.007) were associated with overall survival. We observed 95 bleeding events in 62 patients. EVL achieved hemostasis in 92 of the 95 bleeding events, whereas seven immediate deaths occurred due to variceal bleeding (7/92, 7.6%). All three bleeding events treated with modalities other than EVL resulted in immediate deaths. CONCLUSIONS: EVL is a safe and effective treatment of variceal ruptures in patients with HCC and PVTT. After successful hemostasis, alleviation of the underlying liver function impairment and tumor control are equally important for a good prognosis.

[Ultrasonography in Large-Vessel Arteritis].

Vasculitides are a group of diseases in which inflammation occurs in various vascular walls of the whole body, and ischemic symptoms are caused by stenoses and occlusions of blood vessels. Various parts of blood vessels of the whole body are affected, and the clinical manifestations are diverse. In the Chapel Hill Consensus Conference (CHCC) 2012, vasculitides are classified into seven categories. Takayasu arteritis and giant cell arteritis are included in large-vessel vasculitis. Large-vessel arteritis is defined as vasculitis affecting the aorta and its major branches more often than other vasculitides, but any sized artery may be affected. Ultrasonography has been progressing rapidly, so we can easily depict vessels of the surface of the body, in 0.1-mm units, and indicate the blood flow noninvasively. Ultrasonography has been used for the diagnosis of and estimation of the treatment for large-vessel vasculitis, and its importance has been increasing.

GWAS for systemic sclerosis identifies six novel susceptibility loci including one in the Fcγ receptor region.

Here we report the largest Asian genome-wide association study (GWAS) for systemic sclerosis performed to date, based on data from Japanese subjects and comprising of 1428 cases and 112,599 controls. The lead SNP is in the FCGR/FCRL region, which shows a penetrating association in the Asian population, while a complete linkage disequilibrium SNP, rs10917688, is found in a cis-regulatory element for IRF8. IRF8 is also a significant locus in European GWAS for systemic sclerosis, but rs10917688 only shows an association in the presence of the risk allele of IRF8 in the Japanese population. Further analysis shows that rs10917688 is marked with H3K4me1 in primary B cells. A meta-analysis with a European GWAS detects 30 additional significant loci. Polygenic risk scores constructed with the effect sizes of the meta-analysis suggest the potential portability of genetic associations beyond populations. Prioritizing the top 5% of SNPs of IRF8 binding sites in B cells improves the fitting of the polygenic risk scores, underscoring the roles of B cells and IRF8 in the development of systemic sclerosis. The results also suggest that systemic sclerosis shares a common genetic architecture across populations.

The incidence of all organ malignancies and overall survival of patient with sustained virological response of HCV-comparable to SMR (standardized mortality ratio) of Japan general population.

OBJECTIVE: This study prospectively observed the incidence of all malignancies and the prognosis of all patients in a population of patients who achieved Sustained Virological Response (SVR) with a 100% capture rate. DESIGN: A prospective study of 651 SVR cases was conducted from July 2013 to December 2021. The primary endpoint was the occurrence of all malignancies, and the secondary endpoint was overall survival. The cancer incidence during the follow-up period was calculated using the man-year method, and risk factors were analyzed. In addition, sex- and age-matched standardized mortality ratio (SMR) was used to compare the general population with the study population. RESULTS: The overall median follow-up was 5.44 years. 107 malignancies occurred in 99 patients during the follow-up. The incidence of all malignancies was 3.94/100 person-years. The cumulative incidence was 3.6% at 1 year, 11.1% at 3 years, and 17.9% at 5 years, and continued to increase almost linearly. The incidence of liver cancer and non-liver cancer was 1.94/100 patient-years vs. 1.81%/100 patient-years. The 1-year, 3-year, and 5-year survival rates were 99.3%, 96.5%, and 94.4%, respectively. This life expectancy was compared to the standardized mortality ratio of the Japanese population, which proved non-inferior. CONCLUSION: It was found that malignancies of other organs occur as frequently as hepatocellular carcinoma (HCC). Therefore, follow-up of patients who have achieved SVR should focus not only on HCC but also on malignant tumors of other organs, and lifelong follow could contribute prolonged life expectancy for the previously short-lived.

Hepatocellular carcinoma with extrahepatic metastasis: clinical features and prognostic factors.

BACKGROUND: Despite significant advances in the treatment of intrahepatic lesions, the prognosis for patients with hepatocellular carcinoma (HCC) who have extrahepatic metastasis remains poor. The objective of this study was to further elucidate the clinical course and prognostic determinants of patients with this disease. METHODS: In total, 342 patients who had HCC with extrahepatic metastasis were enrolled. The metastases were diagnosed at initial presentation with HCC in 28 patients and during follow-up in the remaining patients. The authors analyzed clinical features, prognoses, and treatments and established a scoring system to predict prognosis using a split-sample method with a testing set and a training set. RESULTS: The most frequent site of extrahepatic metastasis was the lung followed by lymph nodes, bone, and adrenal glands. These metastases were related directly to death in only 23 patients (7.6%). The median survival after diagnosis of extrahepatic metastasis was 8.1 months (range, 0.03-108.7 months). In univariate analysis of the training set (n = 171), performance status, Child-Pugh classification, the number and size of intrahepatic lesions, macroscopic vascular invasion, symptomatic extrahepatic metastases, α-fetoprotein levels, and complete responses to treatment were associated significantly with prognosis. On the basis of multivariate analysis, a scoring system was developed to predict prognosis that assessed uncontrollable intrahepatic lesions, extent of vascular invasion, and performance status. This scoring system was validated in the testing set (n = 171) and produced a concordance index of 0.73. CONCLUSIONS: The controllability of intrahepatic lesions and performance status were identified as important prognostic factors in patients with advanced HCC who had extrahepatic metastasis.

The efficacy and safety of lenvatinib for advanced hepatocellular carcinoma in a real-world setting.

BACKGROUND/PURPOSE: Lenvatinib (an inhibitor of vascular endothelial growth factor (GF) receptors 1-3, fibroblast GF receptors 1-4, platelet-derived GF receptor α, rearranged during transfection, and stem cell factor receptor) was non-inferior to sorafenib in a phase 3 (REFLECT) trial of advanced hepatocellular carcinoma. This study examined the efficacy and safety of lenvatinib in a real-world setting. METHODS: This was a retrospective, multicenter, observational study. Inclusion and exclusion criteria were based on the phase 3 trial, and participants were observed for at least 12 weeks. Therapeutic effect was determined using the modified Response Evaluation Criteria In Solid Tumors (m-RECIST) at the 8th week. Patients received oral lenvatinib 12 mg/day (body weight > 60 kg) or 8 mg/day (body weight < 60 kg). Dose interruptions followed by reductions for lenvatinib-related toxicities were permitted. Grades of adverse events (AEs) complied with the Common Terminology Criteria for Adverse Events version 4.0. RESULTS: All 16 patients included in this study had prior treatment history, and a median 3.9 years had passed since the first treatment. Fatigue, hypertension, and proteinuria were the most frequent AEs, and were higher than Grade 2. AEs could be controlled by appropriate dose reduction, interruption, and symptomatic treatment according to the protocol. In the m-RECIST evaluation at the 8th week, 0, 6, 8, and 1 patients had achieved complete response, partial response, stable disease, and progressive disease, respectively. The objective response rate was 40%. CONCLUSION: Lenvatinib treatment could be accomplished with safety and good response in a real-world setting.

Extrahepatic metastasis of hepatocellular carcinoma: incidence and risk factors.

BACKGROUND: Extrahepatic metastasis of hepatocellular carcinoma (HCC) is of growing importance as the survival of patients has been improved owing to advances in treatments to intrahepatic lesions. METHODS: To elucidate the incidence and risk factors of extrahepatic metastasis of HCC, we enrolled 1573 (1131 treatment-naïve and 442 previously treated on referral) patients with HCC without extrahepatic tumour spread treated at the authors' department between 1990 and 2003. Patients received medical treatment including percutaneous ablation and transcatheter arterial chemoembolization, and followed by dynamic computed tomography (CT) or magnetic resonance imaging (MRI) and tumour markers every 3-4 months. Extrahepatic metastasis was diagnosed by plain X-ray, CT, MRI and scintigraphy. Clinical parameters at the time of treatment to intrahepatic lesions were evaluated as a predictor of subsequent extrahepatic metastasis among the 1131 treatment-naïve patients by Cox's proportional hazard model. RESULTS: During the average observation period of 3.9 years, extrahepatic metastasis was diagnosed in 123 in the treatment-naïve and 53 in the patients treated previously. The incidence rate of extrahepatic metastasis, as detected during the lifetime after medical treatment of HCC, was approximately 13% at 5 years. Multivariate analysis with Cox proportional hazard model revealed that positivity for viral markers, lager tumour diameter, multiple tumour nodules, presence of vascular tumour invasion and elevated tumour markers were associated with the development of extrahepatic metastasis. CONCLUSION: The incidence of extrahepatic metastasis of HCC diagnosed during clinical course was not frequent. Advanced intrahepatic lesions, presence of vascular tumour invasion, elevated tumour markers and presence of viral hepatitis were risk factors for extrahepatic metastasis.

Age-related comparison of the profiles of patients with hepatocellular carcinoma.

BACKGROUND/AIMS: It is not known whether the putative etiologic factors and clinical and pathological features of hepatocellular carcinoma differ between young adults and older patients. Therefore this study aims to evaluate whether the clinicopathological features in young patients with HCC significantly differ from those of elderly patients. METHODOLOGY: A total of 1014 consecutive patients with HCC were divided into two groups based on age. Among them, 73 patients younger than 50 years of age comprised the first group and 941 patients 50 years and older made up the second. Clinical, laboratory, and pathological characteristics were compared between the two age groups. RESULTS: The male: female ratio and the incidence of positive hepatitis B surface antigen were significantly higher in young patients than in elderly patients. Tumor size, pathological grading of the tumor, and the severity of liver disease did not differ between the two groups. Especially in those patients demonstrating positive antibody to hepatitis C virus, alanine aminotransferase was higher in the younger, and platelet count was lower. Younger patients also had a higher ratio of alcohol consumption compared to elderly patients. CONCLUSIONS: There were age-related differences in the clinicopathological characteristics of HCC patients. Concerning hepatocarcinogenesis, male and HBsAg positive patients were at high risk in young. Of the HCV-related HCC patients, heavy drinking may accelerate the progression from chronic hepatitis to cirrhosis and HCC.

Analysis of factors influencing hepatocellular carcinoma detection: efficient use of computed tomography during arterial portography and during hepatic arteriography.

BACKGROUND: This study was performed to investigate the situations in which computed tomography (CT) combined with arterial portography and hepatic arteriography surpassed dynamic CT in the detection of hepatocellular carcinoma. METHODS: Computed tomography combined with arterial portography and hepatic arteriography was performed on 137 patients with chronic hepatitis (92 men and 45 women; mean age, 66.5 years) with hepatocellular carcinoma (HCC) as revealed or suspected by dynamic CT. We analyzed the clinical factors leading to the discovery of additional HCC lesions on CT combined with arterial portography and hepatic arteriography that were undetected by dynamic CT. RESULTS: Computed tomography combined with arterial portography and hepatic arteriography detected additional HCC lesions that had not been revealed by dynamic CT in 33 of 137 patients. Univariate analysis revealed that in the event of HCC recurrence (vs. primary), multiple HCC lesions detected by dynamic CT (vs. single) and decreased liver function (Child's classification B/C vs. A) significantly favored the additional detection of HCC lesions. Multivariate logistic regression indicated that recurrence was the strongest predicting factor for finding additional lesions on computed tomography combined with arterial portography and hepatic arteriography. CONCLUSIONS: Computed tomography combined with arterial portography and hepatic arteriography is capable of finding additional HCC lesions undetectable by dynamic CT, especially in advanced cases such as HCC recurrence, which may affect the choice of treatment.

Intraarterial 5-fluorouracil and interferon therapy is safe and effective for nonresectable biliary tract adenocarcinoma.

PURPOSE: The prognosis in advanced biliary carcinoma has remained poor. The purpose of this study was to investigate the efficacy of intraarterial 5-fluorouracil and interferon therapy against unresectable biliary carcinoma. METHODS: Patients with unresectable biliary carcinoma with performance status 0 or 1 were enrolled between January 2002 and September 2012. They received pegylated interferon-α 2a and intraarterial 5-FU every 4 weeks. The therapy was either terminated at the end of the first cycle for the patients with progressive disease or continued for at least three cycles. Patients' characteristics (physical, laboratory and radiographic) at the time of starting intraarterial 5-FU therapy were investigated. The relationship between the patients' characteristics and outcome, i.e., survival time and radiographic therapeutic evaluation of patients, was statistically analyzed. RESULTS: Tumor sites were the intrahepatic bile ducts in 23 patients and gallbladder in 2 patients. Previous treatment had been administered in ten patients. The overall response rate was 24% (6 partial responses in 25 patients). Stable disease was observed in 13 patients. The median overall survival was 358 days. Among the six partial responses, three patients received surgery, and one patient received radiofrequency ablation because clinical downstaging was obtained. The treatment was well tolerated. The survival analyses revealed that two factors (serum albumin ≥ 3.5 and hypovascular tumor) were significantly associated with overall survival. CONCLUSIONS: Combination therapy with 5-FU and interferon-α was safe and may improve the prognosis of advanced biliary carcinomas.

Congenital absence of portal vein with multiple hyperplastic nodular lesions in the liver.

Congenital absence of the portal vein is an extremely rare anomaly, in which enteric blood bypasses the liver and drains into the inferior vena cava. A 16-year-old girl was referred to our hospital presenting with liver tumor. Although she had suffered from galactosemia soon after birth, the galactosemia had improved spontaneously 1 year later. Between the ages of 8 and 12 years, chronic hepatitis with a mild elevation of aspartate transaminase (AST) and alanine transaminase (ALT) was observed, but liver tumor had not been detected on computed tomography (CT) in regular medical examinations. However, at age 16, liver tumors, 10 cm in diameter, were found. Abdominal angiography indicated complete absence of the portal vein, suggesting that enteric blood was bypassing the liver and draining into the inferior vena cava. In biopsy specimens obtained under ultrasonographic guidance, liver tumors were confirmed histologically as hyperplastic nodules. In addition to this case report, the clinical features of 25 reported cases of congenital absence of the portal vein are reviewed.

Systemic combination therapy of intravenous continuous 5-fluorouracil and subcutaneous pegylated interferon alfa-2a for advanced hepatocellular carcinoma.

BACKGROUND: In Japan, sorafenib is now the first-line therapy for individuals with advanced hepatocellular carcinoma (HCC), but no other treatment is available for such patients. The aim of this study was to assess the efficacy and safety of combination therapy with systemic continuous intravenous infusion of 5-fluorouracil (5-FU) and subcutaneous peginterferon alfa-2a, which was used before sorafenib was introduced to Japan. METHODS: Two hundred and twenty-three HCC patients, who were not amenable to curative surgery, percutaneous ablation, or transarterial chemoembolization (TACE), and for whom intraarterial chemotherapy was not indicated because of the presence of extrahepatic metastasis or stenosis of the common hepatic artery, received peginterferon alfa-2a (90 µg subcutaneously on days 1, 8, 15, and 22) and 5-FU (500 mg/day intravenously given continuously on days 1-5 and 8-12). We assessed their response to treatment and survival, and treatment safety. RESULTS: The response rate was 9.4 % (including six patients with complete response) and the disease-control rate was 32.7 %. The median time to progression was 2.0 months. The overall median survival time was 6.5 months (Child-Pugh class A: 9.2 months vs. Child-Pugh class B: 2.8 months). In a multivariate analysis, Eastern Cooperative Oncology Group (ECOG) performance status >0, Child-Pugh class B, and the presence of macroscopic vascular invasion were independent predictors of poor prognosis. The major grade 3-4 adverse events were leucopenia (13.9 %) and thrombocytopenia (5.8 %). No treatment-related deaths occurred. CONCLUSIONS: This combination therapy was well tolerated and showed promising efficacy. Further studies are needed to establish the usefulness of this treatment.

Changes in hepatic functional reserve after percutaneous tumor ablation for hepatocellular carcinoma: long-term follow up for 227 consecutive patients with a single lesion.

BACKGROUND/AIMS: Percutaneous tumor ablation (PTA), such as ethanol injection, is currently accepted as a potentially curative treatment for hepatocellular carcinoma (HCC). Percutaneous tumor ablation is presumed to be relatively non-invasive, but there are few studies on long-term follow-up of liver function after tumor ablation. METHODS: Changes in liver functions were monitored in 227 consecutive patients treated for a solitary HCC nodule by PTA between 1993 and 1997. The liver function evaluated based on Child-Turcotte classification prior to the initial treatment was Child A in 119 (52.4%) patients, B in 81(35.7%), and C in 27 (11.9%). The follow-up period was 46 +/- 21 months. RESULTS: The five-year survival rates of patients in Child A, B, and C group after treatment were respectively 76%, 45%, and 43%. Annual shift rate of Child A to Child B was 7%, and that of Child B to Child C was 14%. Tumor recurrence significantly affected aggravation of liver function in Child A (P = 0.002) but not in Child B patients (P = 0.55). Tumor size at initial treatment influenced changes of liver function in Child B group patients (P = 0.009). CONCLUSIONS: Preservation of liver function may be essential when treating HCC patients with impaired liver function.

Combination therapy of intraarterial 5-fluorouracil and systemic interferon-alpha for advanced hepatocellular carcinoma with portal venous invasion.

BACKGROUND: Hepatocellular carcinoma (HCC) with portal venous invasion (PVI) has a very poor prognosis, with a median survival of 3 months and virtually no survival at 1 year. The combination of intraarterial 5-fluorouracil (FU) and systemic interferon-alpha (IFNalpha) was recently reported to be effective against HCC with PVI, but these were small pilot studies. METHODS: One hundred and sixteen patients with HCC with PVI received IFNalpha (5,000,000 U intramuscularly on Days 1, 3, and 5 of each week of treatment) and 5-FU (500 mg into hepatic artery on Days 1-5 of the first and second week of each 4-week cycle). The therapy was either terminated at the end of the first cycle in cases with progressive disease, or continued for at least 3 cycles, when responses to treatment were evaluated by Eastern Cooperative Oncology Group criteria. The survival rate was compared with that of historical controls (n = 40). RESULTS: Nineteen (16%) patients showed complete response and another 42 (36%) showed partial response. Adverse events were limited to nausea and appetite loss. The survival rates at 12 and 24 months among overall patients were 34% and 18%, respectively, in contrast to 15% and 5% among the historical controls. Survival rates at 12 and 24 months were 81% and 59% among complete responders, respectively, and 43% and 18% among partial responders. CONCLUSION: The combination therapy with 5-FU and IFN was safe, and substantially improved the survival rate among the complete responders. These results provide a rationale for future randomized controlled trials.