Clinical relevance of increased serum preneoplastic antigen in hepatitis C-related hepatocellular carcinoma.

BACKGROUND: The prognosis of hepatocellular carcinoma (HCC) patients remains poor despite advances in treatment modalities and diagnosis. It is important to identify useful markers for the early detection of HCC in patients. Preneoplastic antigen (PNA), originally reported in a rat carcinogenesis model, is increased in the tissues and serum of HCC patients. AIM: To determine the diagnostic value of PNA for discriminating HCC and to characterize PNA-positive HCC. METHODS: Patients with hepatitis C virus (HCV)-related hepatic disorders were prospectively enrolled in this study, which included patients with hepatitis, with cirrhosis, and with HCC. A novel enzyme-linked immunosorbent assay was developed to measure serum PNA concentrations in patients. RESULTS: Serum PNA concentrations were measured in 89 controls and 141 patients with HCV infections (50 hepatitis, 44 cirrhosis, and 47 HCC). Compared with control and non-HCC patients, PNA was increased in HCC. On receiver operating characteristic curve analysis, the sensitivity of PNA was similar to the HCC markers des-γ-carboxy-prothrombin (DCP) and α-fetoprotein (AFP), but the specificity of PNA was lower. There was no correlation between PNA and AFP and a significant but weak correlation between PNA and DCP in HCC patients. Importantly, the correlations with biochemical markers were completely different for PNA, AFP, and DCP; glutamyl transpeptidase was highly correlated with PNA, but not with AFP or DCP, and was significantly higher in PNA-high patients than in PNA-low patients with HCV-related HCC. CONCLUSION: PNA may have the potential to diagnose a novel type of HCC in which glutamyl transpeptidase is positively expressed but AFP or DCP is weakly or negatively expressed.

Early Predictors of Objective Response in Patients with Hepatocellular Carcinoma Undergoing Lenvatinib Treatment.

There are limited reports regarding early predictors of objective response (OR) in patients with hepatocellular carcinoma (HCC) treated with lenvatinib. This retrospective study including 70 patients aimed to investigate the efficacy of hepatic biochemical markers. Changes in tumor marker (alpha-fetoprotein (AFP)/des-gamma-carboxy prothrombin (DCP)) levels and albumin-bilirubin (ALBI) score between the baseline value and that estimated one month after treatment were evaluated. We identified several predictors of OR, including changes in tumor marker levels. The OR rate calculated using modified Response Evaluation Criteria in Solid Tumor (mRECIST) was 41.4%. Response was defined as a reduction in AFP and DCP levels of ≥40% from baseline. OR was significantly associated with AFP response, but not with DCP. Predictors of OR were evaluated in two groups (high-AFP group: baseline AFP ≥ 10 ng/mL; low-AFP group: remaining patients). A multivariate analysis identified AFP response (odds ratio, 51.389; p = 0.001) and ALBI score (odds ratio, 6.866; p = 0.039) as independent predictors of OR in the high-AFP and low-AFP groups, respectively. Changes in the ALBI score indicated deterioration in both responders and non-responders, with a significant difference in non-responders (p = 0.003). AFP response, baseline ALBI score, and change in the ALBI score were early predictors of OR in patients with HCC undergoing lenvatinib treatment.

Efficacy and safety of a 14-day administration of tolvaptan in the treatment of patients with ascites in hepatic oedema.

OBJECTIVE: To investigate the efficacy and safety of 14 days' orally administered tolvaptan as adjunctive treatment for hepatic oedema in Japanese liver cirrhosis patients with insufficient response to conventional diuretics, with the option to increase dose in those who did not respond initially. METHODS: This multicentre, single-arm, phase 3 study allocated patients with liver cirrhosis and persistent ascites to 7-day treatment with 7.5 mg/day tolvaptan followed by an additional 7 days' treatment. Responders at day 7 (achieving ≥ 1 kg body-weight reduction) continued on 7.5 mg/day tolvaptan; nonresponders (<1 kg body-weight reduction) received 15 mg/day tolvaptan. Conventional diuretic treatment continued throughout. The primary endpoint was change in body weight from baseline, as a marker of ascites volume. RESULTS: A total of 51 patients received 7.5 mg/day tolvaptan for 7 days, which caused a significant reduction in mean body weight (55% response rate). During the second 7-day treatment period, 30 patients received 7.5 mg/day tolvaptan and 13 patients received tolvaptan 15 mg/day: response rates were 43% and 23%, respectively. Two serious adverse events were observed. Serum sodium was within normal range. CONCLUSIONS: Tolvaptan therapy for 14 days (with possible dose increase as necessary), in combination with conventional diuretics, effectively reduced body weight in patients with hepatic oedema.

Giant cavernous hepatic hemangioma shrunk by use of sorafenib.

Here we report a case of a 76-year-old man with a giant cavernous hepatic hemangioma of more than 20 cm in diameter. Since the hepatic hemangioma was actually growing and might possibly rupture and he complained of abdominal symptoms, we decided to perform interventional therapy. First we performed transcatheter arterial embolization (TAE) of the hepatic arteries. However, since this was not sufficiently effective, we added sorafenib (600 mg/day). As a result, the tumor shrank with symptomatic improvement. Subsequently, an adverse event occurred, and we suspended the sorafenib therapy. Then, the tumor began to grow, and we resumed administering sorafenib at 400 mg/day. The tumor shrank again, and we continued the sorafenib therapy thereafter. The tumor shrinkage, although possibly induced by the effect of TAE, is considered primarily due to the effect of treatment with sorafenib, because (1) TAE did not sufficiently reduce the blood supply to the inside of the tumor; (2) other tumors shrank in the area not targeted by TAE; and (3) the tumor grew during suspension of sorafenib therapy and shrank again after resuming the treatment.

Clinical effectiveness of bipolar radiofrequency ablation for small liver cancers.

BACKGROUND: Radiofrequency ablation (RFA) is minimally invasive and can achieve a high rate of cure of liver cancer. This study was conducted to evaluate the efficacy and safety of a bipolar RFA device (CelonPOWER System) in the treatment of Japanese liver cancer patients. METHODS: The study was a multicenter, single-group, open-label trial. The indications for RFA were based on the Japanese guidelines for the management of liver cancer. The subjects had a Child-Pugh classification of A or B, and the target tumors were defined as nodular, numbering up to 3 lesions, each of which was 3 cm or less in diameter, or solitary lesions up to 4 cm in diameter. To test for the non-inferiority of the CelonPOWER System, this system was compared with the Cool-tip RF System, which has already been approved in Japan, in terms of the complete necrosis rate (CNR). RESULTS: The CNR obtained with the CelonPOWER System was 97.8 % (88/90 patients). The CNR obtained with the Cool-tip RF System was 86.2 % (50/58 patients), confirming the non-inferiority of the CelonPOWER System (p < 0.001, Fisher's exact test based on binomial distribution). Throughout the treatment and follow-up periods, there were no adverse events regarding safety that were uniquely related to the CelonPOWER System and there were no cases of device failure. CONCLUSIONS: The CelonPOWER System was confirmed to be an effective and safe RFA device. It could become extensively used as a safe next-generation RFA device, reducing the physical burden on patients.

[A case of anorectal malignant melanoma appearing 1 year after endoscopic mucosal resection of a rectal adenocarcinoma].

We present a case of a 61-year-old woman who underwent endoscopic mucosal resection (EMR) for early-stage colorectal cancer. However, because the condition of the horizontal margin of the resected tumor was unknown, she further underwent local transanal excision. Lower gastrointestinal endoscopy performed 1 year later showed protruding lesions both on the scar tissue and in the vicinity. Biopsy revealed malignant melanoma. She then underwent laparoscopic abdominoperineal resection and colostomy. This was an extremely rare case of adenocarcinoma complicated by malignant melanoma after resection.

The Effects of Percutaneous Endoscopic Gastrostomy on Quality of Life in Patients With Dementia.

BACKGROUND: To examine the effects of percutaneous endoscopic gastrostomy (PEG) on quality of life (QOL) in patients with dementia. METHODS: We retrospectively included 53 Japanese community and tertiary hospitals to investigate the relationship between the newly developed PEG and consecutive dementia patients with swallowing difficulty between Jan 1st 2006 and Dec 31st 2008. We set improvements in 1) the level of independent living, 2) pneumonia, 3) peroral intake as outcome measures of QOL and explored the factors associated with these improvements. RESULTS: Till October 31st 2010, 1,353 patients with Alzheimer's dementia (33.1%), vascular dementia (61.7%), dementia with Lewy body disease (2.0%), Pick disease (0.6%) and others were followed-up for a median of 847 days (mean 805 ± 542 days). A total of 509 deaths were observed (mortality 59%) in full-followed patients. After multivariate adjustments, improvement in the level of independent living was observed in milder dementia, or those who can live independently with someone, compared with advanced dementia, characterized by those who need care by someone: Odds Ratio (OR), 3.90, 95% confidence interval (95%CI), 1.59 - 9.39, P = 0.003. Similarly, improvement of peroral intake was noticed in milder dementia: OR, 2.69, 95%CI, 1.17 - 6.17, P = 0.02. Such significant associations were not observed in improvement of pneumonia. CONCLUSIONS: These results suggest that improvement of QOL after PEG insertion may be expected more in milder dementia than in advanced dementia.

Efficient detection of hepatocellular carcinoma by a hybrid blood test of epigenetic and classical protein markers.

BACKGROUND: There are few blood tests for an efficient detection of hepatocellular carcinoma (HCC) associated with hepatitis C virus (HCV) infection. METHODS: The abilities of quantitative analyses of 7 genes hypermethylation in serum DNA, α-fetoprotein (AFP) and prothrombin-induced vitamin K absence II (PIVKA-II), and various combinations to detect HCC were evaluated in a training cohort of 164 HCV-infected patients (108 HCCs; 56 non-HCCs). An optimal hybrid detector, built using data for 2 methylated genes (SPINT2 and SRD5A2), AFP, and PIVKA-II, achieved the most satisfactory ability to detect HCC in the training cohort. We evaluated the ability of the optimal hybrid detector to detect HCC in an independent validation cohort of 258 consecutive HCV-infected patients (112 HCCs; 146 non-HCCs) who were newly enrolled in 4 distinct institutes. RESULTS: In the validation cohort of 258 patients, accuracy, sensitivity, and specificity of the hybrid detector for detection of HCC were 81.4%, 73.2%, and 87.7%, respectively. Notably, even when detecting HCC ≤ 2 cm in diameter, the hybrid detector maintained markedly high abilities (84.6% accuracy, 72.2% sensitivity, 87.7% specificity). Youden's index (sensitivity+specificity - 1) for HCC ≤ 2cm was 0.60, vastly much superior to the 0.39 for AFP at a cut-off value of 20 ng/ml and the 0.28 for PIVKA-II at a cut-off value of 40 mAU/ml. CONCLUSIONS: These results show that the optimal hybrid blood detector can detect HCV-related HCC more accurately.

Survival of geriatric patients after percutaneous endoscopic gastrostomy in Japan.

AIM: To examine the long term survival of geriatric patients treated with percutaneous endoscopic gastrostomy (PEG) in Japan. METHODS: We retrospectively included 46 Japanese community and tertiary hospitals to investigate 931 consecutive geriatric patients (≥ 65 years old) with swallowing difficulty and newly performed PEG between Jan 1st 2005 and Dec 31st 2008. We set death as an outcome and explored the associations among patient's characteristics at PEG using log-rank tests and Cox proportional hazard models. RESULTS: Nine hundred and thirty one patients were followed up for a median of 468 d. A total of 502 deaths were observed (mortality 53%). However, 99%, 95%, 88%, 75% and 66% of 931 patients survived more than 7, 30, 60 d, a half year and one year, respectively. In addition, 50% and 25% of the patients survived 753 and 1647 d, respectively. Eight deaths were considered as PEG-related, and were associated with lower serum albumin levels (P = 0.002). On the other hand, among 28 surviving patients (6.5%), PEG was removed. In a multivariate hazard model, older age [hazard ratio (HR), 1.02; 95% confidence interval (CI), 1.00-1.03; P = 0.009], higher C-reactive protein (HR, 1.04; 95% CI: 1.01-1.07; P = 0.005), and higher blood urea nitrogen (HR, 1.01; 95% CI: 1.00-1.02; P = 0.003) were significant poor prognostic factors, whereas higher albumin (HR, 0.67; 95% CI: 0.52-0.85; P = 0.001), female gender (HR, 0.60; 95% CI: 0.48-0.75; P < 0.001) and no previous history of ischemic heart disease (HR, 0.69; 95% CI: 0.54-0.88, P = 0.003) were markedly better prognostic factors. CONCLUSION: These results suggest that more than half of geriatric patients with PEG may survive longer than 2 years. The analysis elucidated prognostic factors.

[A case report of internal hernia through an abnormal defect in the broad ligament of the uterus].

We report a rare case of internal hernia through an abnormal defect in the broad ligament of the uterus. A 49-year-old woman, without any previous surgery, was admitted because of vomiting and lower abdominal pain. Three days after admission a small amount of small intestinal gas was pointed out on her plain abdominal X-ray film. An enema examination by ileus tube revealed a pooling of gastrografin on the left side of the pelvic cavity, showing an obstruction of the ileum. Therefore, an emergency operation was performed, whereupon we found an abnormal defect in the left broad ligament of the uterus. This case describes an internal hernia through an abnormal defect in a female ileus patient without a history of surgery.

[Oral rehydration therapy with OS-1 for advanced and recurrent gastrointestinal cancer patients].

The aim of this study was to introduce an oral rehydration therapy with OS-1 for advanced and recurrent gastrointestinal cancer patients to reduce a hospital stay as well as having a good QOL. We targeted 10 advanced cancer patients. In this study, We recommended the OS-1 drinking amount to be 500 mL to 1, 000 mL whenever the following symptoms were observed:(1) the patient's meal consumption was decreased in half, (2) the volume of urine was decreased, and (3) the frequency of urine was decreased. Nine out of 10 patients were able to drink OS-1 in the range of 500 mL to 1, 000 mL. Most of the patients were taking the chemotherapy along with OS-1 therapy. We confirmed two distinct cases: The patients with OS- 1 short-term drinker at the time of appetite fall because of chemotherapy. Another case was the patients with OS-1 longterm drinkers due to the end of life stage which decreased in meal frequency. ORT with OS-1 may contribute to improve QOL of the terminal patient with chemotherapy.

The sky blue method as a screening test to detect misplacement of percutaneous endoscopic gastrostomy tube at exchange.

BACKGROUND: During tube exchange for percutaneous endoscopic gastrostomy (PEG), a misplaced tube can cause peritonitis and death. Thus, endoscopic or radiologic observation is required at tube exchange to make sure the tube is placed correctly. However, these procedures cost extensive time and money to perform in all patients at the time of tube exchange. Therefore, we developed the "sky blue method" as a screening test to detect misplacement of the PEG tube during tube exchange. METHODS: First, sky blue solution consisting of indigocarmine diluted with saline was injected into the gastric space via the old PEG tube just before the tube exchange. Next, the tube was exchanged using a standard method. Then, we checked whether the sky blue solution could be collected through the new tube or not. Finally, we confirmed correct placement of the tube by endoscopic or radiologic observation for all patients. RESULTS: A total of 961 patients were enrolled. Each tube exchange took 1 to 3 minutes, and there were no adverse effects. Four patients experienced a misplaced tube, all of which were detectable with the sky blue method. Diagnostic parameters of the sky blue method were as follows: sensitivity, 94% (95%CI: 92-95%); specificity, 100% (95%CI: 40-100%); positive predictive value, 100% (95%CI: 100-100%); negative predictive value, 6% (95%CI: 2-16%). CONCLUSION: These results suggest that the number of endoscopic or radiologic observations to confirm correct replacement of the PEG tube may be reduced to one fifteenth using the sky blue method.

Effect of a late evening snack on outpatients with liver cirrhosis.

AIMS: We have reported that one-week administration of a late evening snack (LES) improved not only malnutrition but also glucose intolerance in hospitalized patients with liver cirrhosis. Thus, we investigated whether long-term LES administration to outpatients for 3 months could reproduce the results obtained from hospitalized patients, especially improved glucose intolerance. If this treatment aggravated glucose intolerance, we tried to find any marker predicting this aggravation before the treatment. METHODS: Outpatients were prescribed one pack of oral supplementation of a branched-chain amino acid (BCAA)-enriched nutrient, Aminoleban EN (210 kCal) as a LES without dietician supervision. Both before LES administration and after 3 months, glucose tolerance and liver function were examined using a 75 g oral glucose tolerance test (OGTT), biochemical parameters in blood and the relationship between glucose tolerance (area under the curve (AUC)) and the following serum markers. RESULTS: Branched-chain amino acid/tyrosine ratio (BTR), the number of red blood cells (RBC), and hematocrit (Ht) significantly increased, with significant reduction of blood NH(3) level in patients with a blood glucose level less than 200 mg/dL 2 h after 75 g OGTT. However, the increase of AUC was seen after 3 months of LES administration in patients who had blood glucose higher than 200 mg/dL 2 h after 75 g OGTT. AUC weakly correlated positively with serum 7S collagen and negatively with choline esterase (ChE) and albumin (Alb). CONCLUSION: 75 g OGTT is a useful marker to predict the worst outcome and avoid the adverse effect of LES treatment in liver cirrhosis patients if performed without adequate nutrient conduct by a dietician.

Alpha-tocopherol [corrected] and ascorbic acid attenuates the ribavirin [corrected] induced decrease of eicosapentaenoic acid in erythrocyte membrane in chronic hepatitis C patients.

BACKGROUND: Oxidative damage of the erythrocyte membrane plays an important role in ribavirin-induced anemia. The purpose of the present paper was to assess whether supplementation of alpha-tocopherol and ascorbic acid (vitamins) causes changes in the erythrocyte membrane fatty acid composition during interferon and ribavirin combination therapy for chronic hepatitis C patients. METHODS: Fatty acid compositions in erythrocyte membrane phospholipids were determined by gas chromatography at 0, 2, 4, 8 weeks, and at the end of combination therapy (26 weeks) for interferon with ribavirin in 32 patients with chronic hepatitis C who were randomized to receive vitamins or not (controls). RESULTS: Good compliance with orally administered vitamins and ribavirin were confirmed by their concentrations in erythrocytes or plasma. The hemoglobin level was negatively correlated with the ribavirin concentration at 8 weeks (r = 0.59, P = 0.01) after initiation of therapy in controls, but not in the vitamin group. Among the 26 kinds of fatty acids analyzed, only eicosapentaenoic acid (EPA) significantly decreased at 8 weeks after initiation of therapy (P = 0.03) and at the end of therapy (P = 0.004) in controls. Vitamins did not inhibit ribavirin-induced anemia, but attenuated the decrease of EPA in erythrocytes. The EPA level was negatively correlated with the drop in hemoglobin levels at 8 weeks after initiation of therapy in controls (r = 0.58, P = 0.015), but not in the vitamin group. CONCLUSIONS: Supplementation of alpha-tocopherol and ascorbic acid attenuates the ribavirin-induced decrease of EPA in erythrocyte membrane phospholipids in chronic hepatitis C patients.

Molecular epidemiologic analysis of hepatitis C virus infection in injecting drug users with acute hepatitis C in Japan.

BACKGROUND AND AIM: The aim of this study was to examine whether particular hepatitis C virus (HCV) subtypes are spreading among injecting drug users (IDUs) in Yamaguchi prefecture, on the south-western tip of the island of Honshu in Japan, as found in European countries. METHODS: We prospectively enrolled acute hepatitis C patients from January 2001 to March 2003. E2 gene sequences of HCV isolates from IDUs with acute hepatitis C were phylogenetically compared to those from 30 chronic hepatitis C patients with the same HCV subtypes who had or did not have a history of intravenous drug use. RESULTS: Nine of 11 patients (82%) with acute hepatitis C were IDUs. The HCV subtypes were 2a in four and 2b in five, which contrasted with the high prevalence of subtype 1b in patients with chronic liver diseases in Japan. IDUs with acute hepatitis C (22.0 +/- 2.4 years old) were significantly younger than those with chronic hepatitis C (49.5 +/- 9.5 years old) for subtype 2a (P = 0.0005), but not for subtype 2b (25.6 +/- 5.4 vs 28.1 +/- 2.4 years old). Some HCV isolates of subtype 2b from IDUs with acute hepatitis C were phylogenetically related to those from IDUs with chronic hepatitis C. By contrast, there was no phylogenetic segregation of HCV in IDUs with subtype 2a. HCV isolates from non-IDUs were genetically divergent from each other and those from IDUs, irrespective of the HCV subtype. CONCLUSION: Hepatitis C virus of the non-1b subtype, particularly subtype 2b, seemed to be transmitted between IDUs very recently in Yamaguchi prefecture, Japan.

Cytokine-dependent anti-viral role of CD4-positive T cells in therapeutic vaccination against chronic hepatitis B viral infection.

There are several lines of evidence suggesting that specific vaccine therapy with a standard hepatitis B virus (HBV) vaccination reduces HBV replication. The aim of this study was to investigate the anti-viral mechanism of vaccine therapy in chronic hepatitis B patients. Nineteen patients were assigned to receive either vaccine therapy (n = 13) or no treatment as a control (n = 6). Vaccinated patients were analyzed for T cell proliferative responses specific for envelope antigen and cytokine production by antigen-specific T cells. ELISPOT and cytotoxicity assays also were carried out for limited blood samples. Serum HBV DNA levels decreased significantly at 3 months after completion of therapy and thereafter as compared to the baseline ones, and were significantly lower in vaccinated patients than in controls at 12 and 18 months after completion of therapy. Vaccination induced antigen-specific CD4+ T cell proliferative responses in four patients (30.8%). The production of high levels of interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) by antigen-specific T cells was found in six patients (46.0%) who showed significantly lower HBV DNA levels in serum at 6 (P = 0.04) and 18 months (P = 0.005) after completion of therapy than those without high levels of cytokine production. Vaccination did not induce antigen-specific CD8+ T cells or cytotoxic T cells. These results suggest that envelope-specific CD4+ T cells may control directly HBV replication by producing anti-viral cytokines rather than providing help for cytotoxic T cells in therapeutic vaccination against chronic HBV infection.