Prevalence of hazardous drinking and suspected alcohol dependence in Japanese primary care settings.

OBJECTIVE: We aimed to assess the prevalence of hazardous drinking and potential alcohol dependence among Japanese primary care patients, and their readiness to change and awareness of others' concerns. METHODS: From July to August 2023, we conducted a multi-site cross-sectional study as a screening survey for participants in a cluster randomized controlled trial. The trial included outpatients aged 20-74 from primary care clinics. Using the Alcohol Use Disorders Identification Test (AUDIT) alongside a self-administered questionnaire, we evaluated the prevalence of hazardous drinking and suspected alcohol dependence, patients' readiness to change, and their awareness of others' concerns. RESULTS: Among the 1388 participants from 18 clinics, 22% (95% confidence interval (CI): 20% to 24%) were identified as engaging in hazardous drinking or suspected of being alcohol dependent. As the AUDIT scores increased, so did their readiness to change. However, only 22% (95%CI: 16% to 28%) of those with scores ranging from 8 to 14 reported that others, including physicians, had expressed concerns about their drinking during the past year. For those with scores of 15 or higher, the figure was 74%. CONCLUSIONS: This study underscores the need for universal or high-risk alcohol screening and brief intervention in Japanese primary care settings. Trial registry UMIN-CTR (https://www.umin.ac.jp/ctr/) (UMIN000051388).

Royal Jelly Increases Hematopoietic Stem Cells in Peripheral Blood: A Double-Blind, Placebo-Controlled, Randomized Trial in Healthy Subjects.

Objectives: Royal jelly (RJ), produced by honeybees, influences stem cell functions, such as pluripotency maintenance of mouse embryonic stem cells and prevention of aging-related muscle stem cell functional deterioration. Thus, we hypothesized that RJ administration has various health-promoting effects based on stem cells. However, its effects are unknown in humans. In this study, we have attempted for the first time to clarify whether the administration of RJ in humans affects stem cells. Materials and Methods: This randomized, double-blind, placebo-controlled study was performed on healthy subjects (n = 90) who received protease-treated RJ at a dose of 1200 mg/day or placebo daily for four weeks. Also, the participants with a low number of hematopoietic stem cells (HSCs) in peripheral blood were preferentially selected. HSC counts, endothelial progenitor cell (EPC) counts, blood cell counts in peripheral blood, cytokines in serum, and physical conditions were evaluated. Results and Conclusion. Eligible data from 86 subjects (placebo: 42, RJ: 44) who completed the study were analyzed. There were no significant differences between the two groups regarding the changes in peripheral HSC count (p=0.103), while diastolic blood pressure showed a significant improvement in the RJ group compared to that in the placebo group (p=0.032). The subgroup analysis excluded 14 subjects who complained of cold symptoms at baseline or within five days of the four-week study. The changes in the HSC populations were significantly higher in the RJ group than those in the placebo group (p=0.042). No adverse effects were observed in any of the groups. These results suggest that RJ administration affected the peripheral HSC count and may influence stem cell functions. Further research is needed to reveal the various health-promoting benefits of RJ based on stem cells.

Mixed HCV Infection of Genotype 1B and Other Genotypes Influences Non-response during Daclatasvir + Asunaprevir Combination Therapy.

Daclatasvir (DCV) + asunaprevir (ASV) combination therapy has become available for patients with hepatitis C virus (HCV) serogroup 1 infection. We studied the efficacy of this therapy by focusing on the factors associated with sustained virological responses (SVR) including resistance-associated variants (RAVs) and mixed infection of different HCV genotypes. We enrolled 951 HCV serogroup 1-positive patients who received this combination therapy at our hospital or affiliated hospitals. The presence of RAVs in non-structural (NS) regions 3 and 5A was analyzed by direct sequencing. HCV genotypes were determined by PCR with genotype-specific primers targeting HCV core and NS5B regions. SVR was achieved in 91.1% of patients. Female sex, age > 70 years, and RAVs were significantly associated with non-SVR (p<0.01 for all). Propensity score-matching results among the patients without RAVs regarding sex, age, and fibrosis revealed that mixed HCV infection determined by HCV NS5B genotyping showed significantly lower SVR rates than 1B-mono infection (p=0.02). Female sex and RAVs were significant factors associated with treatment failure of this combination therapy for patients with HCV serogroup 1 infection. Mixed HCV infection other than 1B-mono infection would be useful for predicting treatment failure.

An Exploratory Study on the Anti-inflammatory Effects of Fucoidan in Relation to Quality of Life in Advanced Cancer Patients.

BACKGROUND: Conventional anticancer therapies still cause difficulties with selective eradication and accompanying side effects that reduce patients' quality of life (QOL). Fucoidan is extracted from seaweeds and has already exhibited broad bioactivities, including anticancer and anti-inflammatory properties, in basic studies. It is expected to enhance therapeutic efficacy and minimize side effects in cancer patients; however, despite its potential benefits, there are very few clinical trials using fucoidans. Therefore, we performed an exploratory clinical study for advanced cancer patients to examine the efficacy of fucoidans, especially focusing on inflammation in relation to QOL scores. METHODS: We conducted a prospective, open-label clinical study for advanced cancer patients using fucoidans via oral administration; 20 advanced cancer patients with metastases were recruited and were given 400 mL/d fucoidan (10 mg/mL) for at least 4 weeks. Inflammatory biomarkers, including high-sensitivity C-reactive protein and various cytokines, and QOL scores were monitored before treatment, after 2 weeks, and after 4 weeks of fucoidan ingestion. RESULTS: The main proinflammatory cytokines, including interleukin-1ß (IL-1ß), IL-6, and tumor necrosis factor-α (TNF-α) were significantly reduced after 2 weeks of fucoidan ingestion. QOL scores, including fatigue, stayed almost stable without significant changes during the study period. The univariate and multivariate analyses revealed that the responsiveness of IL-1ß was a significant independent prognostic factor. CONCLUSION: This is the first study providing evidence of the anti-inflammatory effects of fucoidans for advanced cancer patients. In future studies, larger blinded, controlled trials are required to establish the efficacy of fucoidan as supportive care for cancer patients, especially those undergoing chemotherapy.

Diffuse Intestinal Ganglioneuromatosis Showing Multiple Large Bowel Ulcers in a Patient with Neurofibromatosis Type 1.

A 67-year-old Japanese man with neurofibromatosis type 1 underwent right hemicolectomy owing to abscess formation around the cecum. A pathological analysis revealed diffuse intestinal ganglioneuromatosis in the cecum and colon. Colonoscopy performed eight months after hemicolectomy revealed multiple ulcers throughout the colon and rectum. The colorectal ulcers failed to respond to conservative treatment and ultimately required surgical resection. Diffuse ganglioneuromatosis was observed again in the resected specimen. This report illustrates a rare manifestation of diffuse intestinal ganglioneuromatosis in a patient with neurofibromatosis type 1.

Efficacy and cost-effectiveness of consensus interferon monotherapy with high-dose induction for hepatitis C patients with genotype 2.

OBJECTIVE: Several treatment strategies for patients with chronic hepatitis C have been compared mainly in terms of their efficacy, and it has been found that pegylated interferon (IFN) plus ribavirin has become the standard therapy, but aged patients may not tolerate ribavirin and the cost-effectiveness of treatment should also be further considered. We conducted a study to evaluate the efficacy, safety, and cost-effectiveness of consensus IFN monotherapy with high-dose induction for patients with chronic hepatitis C in clinical practice. MATERIAL AND METHODS: We consecutively enrolled 104 patients with chronic hepatitis C. Patients were scheduled to receive 12 or 18 µg of consensus IFN daily for 2 weeks, then three times a week for 22 weeks. Efficacy, safety, and cost-effectiveness were assessed. A Markov model was developed to investigate cost-effectiveness in patients with chronic hepatitis C treated by different IFN-based treatment strategies. RESULTS: Of the 104 study patients, a sustained virological response (SVR) was achieved in 66 (63%). Logistic regression analysis revealed that genotype 2, lower hepatitis C virus RNA levels, and patient age were independently associated with SVR. The response rate was significantly higher in patients with genotype 2 (51/66, 77%) versus genotype 1 (15/38, 40%). Cost-effectiveness analysis in patients with genotype 2 revealed that high-dose induction with consensus IFN monotherapy was as highly cost-effective as pegylated IFN plus ribavirin. CONCLUSION: Consensus IFN monotherapy with high-dose induction shows high efficacy and cost-effectiveness in chronic hepatitis C patients with genotype 2 infection. Thus, it may be a reliable alternative in aged patients and for those excluded from standard combination therapy.

Addition of transcatheter arterial chemoembolization decreased local recurrence but had no survival benefit to percutaneous ethanol injection therapy for patients with small hepatocellular carcinoma: A multicenter randomized control study.

To assess the efficacy of the additional treatment of transcatheter arterial chemoembolization (TACE) to percutaneous ethanol injection (PEI) therapy for relatively small hepatocellular carcinomas (HCCs), a multicenter randomized control study (RCT) was performed. We conducted an RCT and follow-up study during the enrollment period from 1997 to 1999. Newly diagnosed patients with one to three HCC tumors measuring from 2 to 4 cm (4 cm maximum) in diameter were enrolled. A total of 30 patients initially underwent a combination TACE-PEI or PEI-alone therapies at eight randomly assigned Japanese hospitals. However, 3 patients withdrew. Of the 27 remaining patients, 13 were treated with the combination TACE-PEI therapy and 14 with PEI therapy alone. The patients were observed over several months [median (interquartile range) 33.2 (24.6) months]. There were no significant differences in the background of the patients between the two groups. Among the patients treated with TACE-PEI, the development of a local residual tumor was of significantly lower occurence, compared to the group receiving PEI alone (7.6 and 42.9%, respectively; P=0.024). However, the mean cancer-free time (absence of local or multiple nodule recurrence) or patient survival time was not significantly different between the two groups [PEI alone vs. TACE-PEI: cancer-free time 16.7 (95% CI 7.3-26.0) vs. 22.9 months (95% CI 12.4-33.4); survival time 57.2 (95% CI 37.2-77.2) vs. 42.4 months (95% CI 29.2-55.6)]. Although the combination of TACE and PEI had significant effects on the local tumor control, no efficacy of the addition of TACE to PEI was noted in the prognosis among patients with relatively small HCC tumors.

Two cases of development of entecavir resistance during entecavir treatment for nucleoside-naive chronic hepatitis B.

BACKGROUND: Entecavir (ETV) is a potent nucleoside analogue against hepatitis B virus (HBV), and emergence of drug resistance is rare in nucleoside-naive patients because development of ETV resistance (ETVr) requires at least three amino acid substitutions in HBV reverse transcriptase. We observed two cases of genotypic ETVr with viral rebound and biochemical breakthrough during ETV treatment of nucleoside-naive patients with chronic hepatitis B (CHB). RESULTS: Case 1: A 44-year-old HBeAg-positive man received ETV 0.1 mg/day for 52 weeks and 0.5 mg/day for 96 weeks consecutively. HBV DNA was 10.0 log(10) copies/ml at baseline, declined to a nadir of 3.1 at week 100, and rebounded to 4.5 at week 124 and 6.7 at week 148. Alanine aminotransferase (ALT) level increased to 112 IU/l at week 148. Switching to a lamivudine (LVD)/adefovir-dipivoxil combination was effective in decreasing HBV DNA. Case 2: A 47-year-old HBeAg-positive man received ETV 0.5 mg/day for 188 weeks. HBV DNA was 8.2 log(10) copies/ml at baseline, declined to a nadir of 2.9 at week 124, and then rebounded to 4.7 at week 148 and 6.4 at week 160. ALT level increased to 72 IU/l at week 172. The ETVr-related substitution (S202G), along with LVD-resistance-related substitutions (L180M and M204V), was detected by sequence analysis at week 124 in both case 1 and case 2. CONCLUSIONS: ETVr emerged in two Japanese nucleoside-naive CHB patients after prolonged therapy and incomplete suppression and in one patient after <0.5 mg of dosing. ETV patients with detectable HBV DNA or breakthrough after extended therapy should be evaluated for compliance to therapy and potential emergence of resistance.

A prospective and comparative cohort study on efficacy and drug resistance during long-term lamivudine treatment for various stages of chronic hepatitis B and cirrhosis.

BACKGROUND AND AIMS: A prospective, non-randomized cohort study on long-term lamivudine treatment, comparing efficacy, drug resistance, and prognosis for various stages of chronic hepatitis B virus (HBV)-related liver disease was performed to elucidate the significance and indication of lamivudine for individual patients at each stage of disease. METHODS: A total of 158 cases consisting of 87 chronic hepatitis, 28 compensated cirrhosis, and 43 decompensated cirrhosis, with serum HBV-DNA > 5 log(10) copies/mL and with elevated alanine aminotransferase (ALT) over twice the upper normal limit or complications of hepatic insufficiency, were administered 100 mg of lamivudine daily and monitored for HBV markers, biochemistry, and prognosis. RESULTS: Lamivudine reduced HBV-DNA and ALT equally in all groups. Serum albumin, prothrombin time (%), and platelet count increased in all groups. The increased margin of albumin was the highest in the decompensated cirrhosis and higher in the compensated cirrhosis than the chronic hepatitis groups. Cumulative incidence of virologic breakthrough was 16%, 42%, 49%, and 53% at 12, 24, 36, and 48 months, respectively, and the strongest predictive factor for lamivudine resistance was persistent HBV-DNA at 3 months. Ascites, encephalopathy, and jaundice improved in the majority of patients with decompensated cirrhosis. On the other hand, hepatic failure developed or deteriorated in 10 patients after virologic breakthrough, and nine of them had decompensated cirrhosis. CONCLUSIONS: Lamivudine was effective in reducing HBV-DNA and improving hepatic reserve at all stages and was most beneficial and significant for decompensated cirrhosis. Meanwhile, close monitoring of viral load and immediate rescue treatment for lamivudine resistance is necessary to prevent hepatic failure in decompensated cirrhosis.

Limitation of combination therapy of interferon and ribavirin for older patients with chronic hepatitis C.

In contrast to the United States, Japanese patients with chronic hepatitis C currently treated with interferon are generally 10 to 15 years older. Older patients, however, tend to experience more frequent adverse events. This study was conducted to clarify the effect of patient age on the efficacy and safety of combination therapy. We consecutively enrolled 208 patients with naïve chronic hepatitis C. Patients were classified into three groups according to age: younger than 50 years of age (n = 52); 50 to 59 years old (n = 83); and 60 years of age or older (n = 73). Interferon alpha-2b therapy was administered daily for 2 weeks, followed by 3 times per week for 22 weeks, while ribavirin was administered daily. Of the 208 study patients, discontinuation of therapy or dose reduction was required in 116 (56%) and was more frequent in older patient groups: 38%, 48%, and 77% for the < 50, 50-59, and > or = 60-year-old patient groups, respectively (P < .001). Multivariate analysis showed patient age to be independently associated with adherence to therapy. A sustained virological response was achieved in 77 (37%) patients, with genotype, viral load, and adherence to therapy associated with this achievement. A tendency toward a lower sustained virological response rate was seen in the older patients. In conclusion, patient age is an important factor contributing to the safety of combination therapy. Thus, treatment schedule should be modified, or other therapeutic modalities should be considered for older patients with chronic hepatitis C.

Risk factors for hepatocellular carcinoma in Hepatitis C patients with sustained virologic response to interferon therapy.

BACKGROUND: Although a variety of papers demonstrated inhibited hepatocarcinogenesis with interferon (IFN) therapy for chronic hepatitis C, a small number of hepatocellular carcinomas (HCCs) were still observed even in sustained virologic responders. AIMS: To clarify factors affecting the development of HCC, we analyzed the frequency of HCC in sustained virologic responders over a long-term observation period. METHODS: Seven hundred and ninety-two out of the 2623 IFN-treated hepatitis C patients who had undergone liver biopsy showed sustained virologic response. Screening for development of HCC was performed periodically during an average follow-up of 5.1 years. Fibrosis of the pretreatment liver biopsy sample was graded. Risk factors for HCC were analyzed by using Cox proportional hazards regression. RESULTS: Of 792 patients, 23 developed HCC. Univariate analysis showed that stage of hepatic fibrosis, age, and alcohol consumption were significantly associated with a risk of HCC (P<0.001). There was a significant difference in the cumulative incidence between patients stratified according to these variables (P<0.001). CONCLUSIONS: Pretreatment hepatic fibrosis score, age, and alcohol consumption may affect development of HCC even in sustained virologic responders. Thus, patients with these factors should be carefully followed even after eradication of the virus.

Arachidonic acid in mononuclear cells and its clinical significance in HCV cirrhotic patients.

OBJECTIVES: An abnormal fatty acid pattern in patients with advanced liver cirrhosis (LC) has been reported in plasma phospholipids and some other tissues. To elucidate the significance of arachidonic acid deficiency on the clinical pathophysiology of LC and hepatocellular carcinoma (HCC), we analyzed the fatty acid compositions of mononuclear cell phospholipids, plasma alpha-tocopherol, and thiobarbituric acid-reactive substances and serum tumor necrosis factor-alpha (TNF-alpha) in cirrhotic patients infected with the hepatitis C virus with and without HCC. METHODS: Twelve cirrhotic patients without HCC (LC patients) and 11 with HCC (HCC patients) were enrolled. Fatty acids were analyzed with gas chromatography. alpha-Tocopherol and TNF-alpha were analyzed by high-performance liquid chromatography and enzyme-linked immunosorbent assay, respectively. Statistical analysis was performed by using the unpaired t test with Welch's correction and Spearman's rank-correlation analysis. RESULTS: Significantly low levels of linoleic, dihomo-gamma-linolenic, arachidonic, and eicosapentaenoic acids from mononuclear cell phospholipids were observed in LC and HCC patients compared with control subjects. Plasma alpha-tocopherol was lower and thiobarbituric acid-reactive substances were higher in HCC patients than in controls. Arachidonic acid molar percentage in mononuclear cell phospholipids correlated significantly with lymphocyte count (r = 0.460, P < 0.05) in the cirrhotic patients and with lymphocyte (r = 0.680, P < 0.01) and platelet (r = 0.763, P < 0.01) counts in all subjects. CONCLUSIONS: These results suggested that arachidonic acid in mononuclear cells may have an important role in the pathophysiology of hepatitis C virus associated with cirrhosis and that nutritional management preventing arachidonic acid deficiency may have some beneficial effects on the progression of LC.