Nonalcoholic steatohepatitis in hepatocarcinoma: new insights about its prognostic role in patients treated with lenvatinib.

BACKGROUND: Hepatocellular carcinoma (HCC) treatment remains a big challenge in the field of oncology. The liver disease (viral or not viral) underlying HCC turned out to be crucial in determining the biologic behavior of the tumor, including its response to treatment. The aim of this analysis was to investigate the role of the etiology of the underlying liver disease in survival outcomes. PATIENTS AND METHODS: We conducted a multicenter retrospective study on a large cohort of patients treated with lenvatinib as first-line therapy for advanced HCC from both Eastern and Western institutions. Univariate and multivariate analyses were performed. RESULTS: Among the 1232 lenvatinib-treated HCC patients, 453 (36.8%) were hepatitis C virus positive, 268 hepatitis B virus positive (21.8%), 236 nonalcoholic steatohepatitis (NASH) correlate (19.2%) and 275 had other etiologies (22.3%). The median progression-free survival (mPFS) was 6.2 months [95% confidence interval (CI) 5.9-6.7 months] and the median overall survival (mOS) was 15.8 months (95% CI 14.9-17.2 months). In the univariate analysis for OS NASH-HCC was associated with longer mOS [22.2 versus 15.1 months; hazard ratio (HR) 0.69; 95% CI 0.56-0.85; P = 0.0006]. In the univariate analysis for PFS NASH-HCC was associated with longer mPFS (7.5 versus 6.5 months; HR 0.84; 95% CI 0.71-0.99; P = 0.0436). The multivariate analysis confirmed NASH-HCC (HR 0.64; 95% CI 0.48-0.86; P = 0.0028) as an independent prognostic factor for OS, along with albumin-bilirubin (ALBI) grade, extrahepatic spread, neutrophil-to-lymphocyte ratio, portal vein thrombosis, Eastern Cooperative Oncology Group (ECOG) performance status and alpha-fetoprotein. An interaction test was performed between sorafenib and lenvatinib cohorts and the results highlighted the positive predictive role of NASH in favor of the lenvatinib arm (P = 0.0047). CONCLUSION: NASH has been identified as an independent prognostic factor in a large cohort of patients with advanced HCC treated with lenvatinib, thereby suggesting the role of the etiology in the selection of patients for tyrosine kinase treatment. If validated, this result could provide new insights useful to improve the management of these patients.

Automated detection of outbreaks of antimicrobial-resistant bacteria in Japan.

BACKGROUND: Hospital outbreaks of antimicrobial-resistant (AMR) bacteria should be detected and controlled as early as possible. AIM: To develop a framework for automatic detection of AMR outbreaks in hospitals. METHODS: Japan Nosocomial Infections Surveillance (JANIS) is one of the largest national AMR surveillance systems in the world. For this study, all bacterial data in the JANIS database were extracted between 2011 and 2016. WHONET, a free software for the management of microbiology data, and SaTScan, a free cluster detection tool embedded in WHONET, were used to analyse 2015-2016 data of eligible hospitals. Manual evaluation and validation of 10 representative hospitals around Japan were then performed using 2011-2016 data. FINDINGS: Data from 1031 hospitals were studied; mid-sized (200-499 beds) hospitals accounted for 60%, followed by large hospitals (≥500 beds; 24%) and small hospitals (<200 beds; 16%). More clusters were detected in large hospitals. Most of the clusters included five or fewer patients. From the in-depth analysis of 10 hospitals, ∼80% of the detected clusters were unrecognized by infection control staff because the bacterial species involved were not included in the priority pathogen list for routine surveillance. In two hospitals, clusters of more susceptible isolates were detected before outbreaks of more resistant pathogens. CONCLUSION: WHONET-SaTScan can automatically detect clusters of epidemiologically related patients based on isolate resistance profiles beyond lists of high-priority AMR pathogens. If clusters of more susceptible isolates can be detected, it may allow early intervention in infection control practices before outbreaks of more resistant pathogens occur.

Comprehensive molecular exploration identified promoter DNA methylation of the CRBP1 gene as a determinant of radiation sensitivity in rectal cancer.

BACKGROUND: Neoadjuvant chemoradiotherapy (NCRT) for advanced rectal cancer (RC) is a well-evidenced therapy; however, some RC patients have no therapeutic response. Patient selection for NCRT so that non-responsive patients are excluded has been subjective. To date, no molecular markers indicating radiation sensitivity have been reported. METHODS: We irradiated six colorectal cancer (CRC) cell lines and identified HCT116 cells as radiation-sensitive and HCT15 and DLD-1 cells as radiation resistant. Using a microarray, we selected candidate radiation sensitivity marker genes by choosing genes whose expression was consistent with a radiation-resistant or sensitive cell phenotype. RESULTS: Among candidate genes, cellular retinol binding protein 1 (CRBP1) was of particular interest because it was not only induced in HCT116 cells by tentative 10 Gy radiation treatments, but also its expression was increased in HCT116-derived radiation-resistant cells vs parental cells. Forced expression of CRBP1 decreased the viability of both HCT15 and DLD-1 cells in response to radiation therapy. We also confirmed that CRBP1 was epigenetically silenced by hypermethylation of its promoter DNA, and that the quantitative methylation value of CRBP1 significantly correlated with histological response in RC patients with NCRT (P=0.031). CONCLUSIONS: Our study identified CRBP1 as a radiation-sensitive predictor in RC.

Genotypes and infection sites in an outbreak of multidrug-resistant Pseudomonas aeruginosa.

An outbreak of multidrug-resistant (MDR) Pseudomonas aeruginosa occurred in an acute care hospital in Japan, which lasted for more than three years. During January 2006 to June 2009, 59 hospitalised patients with MDR P. aeruginosa were mainly detected by urine culture in the first half, whereas isolation from respiratory tract samples became dominant in the latter half of the outbreak. Non-duplicate MDR P. aeruginosa isolates were available from 51 patients and all isolates were positive for bla(VIM-2). Pulsed-field gel electrophoresis (PFGE) analysis categorised the isolates into three major clusters; types A, B and C with eight, 19 and 21 isolates, respectively. The outbreak started with patients harbouring PFGE type A strains, followed by type B, and type C strains. Multivariate analysis demonstrated that patients with PFGE type C strains were more likely to be detected by respiratory tract samples (odds ratio: 11.87; 95% confidence interval: 1.21-116.86). Improved aseptic urethral catheter care controlled PFGE type A and type B strains and improvement in respiratory care procedures finally contained the transmission of PFGE type C strains.

Long-term effect of xylitol gum use on mutans streptococci in adults.

Many studies have shown the effects of chewing xylitol gum on mutans streptococci (MS) over short- and long-term periods in children; however, few studies have addressed long-term periods in adults. The objective of this investigation was to examine for 6 months the effects of chewing xylitol gum on MS in saliva and plaque in 127 adults (mean age 28.0 years). The participants were assigned to three groups according to gum type, in part taking preference for flavor into account and in part at random: xylitol (XYL), maltitol (MAL) and control (CR); 33, 34 and 27 subjects in each group, respectively, completed the trial. Daily gum use of the XYL and MAL groups was 7.9 and 7.1 g, respectively. MS levels, which declined significantly in saliva (p < 0.05) and plaque (p < 0.001) in the XYL group after 6 months, exhibited a significant increase in plaque in the MAL group (p < 0.001). Differences in relative changes of MS levels in plaque during the experimental period were significant between the XYL group and the CR (p < 0.05) and MAL groups (p < 0.001). Differences in relative change of amount of plaque during the experimental period were not statistically significant between the groups. The present study demonstrated that chewing xylitol gum for 6 months continued to inhibit the growth of mutans streptococci in adults.

Association of lip pigmentation with smoking and gingival melanin pigmentation.

OBJECTIVE: We investigated the association of lip pigmentation with smoking and melanin pigmentation in the gingiva. DESIGN: Case-control study. SETTING: Health check-up in an institute. SUBJECTS AND METHODS: Photos of 213 males employed in an institution were assessed in terms of pigmentation in lip and gingiva. MAIN OUTCOME MEASURES: Prevalence and scores of lip and gingival pigmentation and smoking status. RESULTS: Among subjects displaying lip and gingival pigmentation, 73% and 87% respectively, were current smokers, whereas 33% and 27% of individuals lacking pigmentation were current smokers respectively. Odds ratios of current smoking relative to lip and gingival pigmentation were 5.6 (95% confidence interval: 2.8-11.1) and 17.0 (8.1-36.0) respectively. Daily consumption, duration of smoking and lifetime exposure exhibited significant correlation with scores of lip and gingival pigmentation (P<0.0001). Odds ratios increased in lip and gingival pigmentation upon exposure. In current smokers, scores of lip and gingival pigmentation demonstrated meaningful correlation (P<0.0001); moreover, 95% of participants with lip pigmentation were positive for gingival pigmentation. CONCLUSION: These results indicated the presence of a striking association between smoking and pigmentation in the lip and gingiva, which was stronger with respect to gingival pigmentation. Health professionals could educate smokers, utilizing visible symptoms in the lip and gingiva.

Estrogen receptor levels and lipid peroxidation in hepatocellular carcinoma with hepatitis C virus infection.

AIMS/BACKGROUND: Our preliminary studies showed that estradiol suppresses hepatic carcinogenesis and fibrogenesis in animal models. Hepatic estrogen receptors (ERs) medicate estradiol action in the liver. This study was performed to assess possible implications of menopause and hepatic ER levels for the development of cirrhosis with hepatocellular carcinoma (HCC). METHODS: One thousand, one hundred and ninety-nine consecutive HCC patients with hepatitis C virus (HCV)-related cirrhosis were divided into two groups, based on a menopausal age of 49 years. Liver tissues were obtained during surgical resection of HCC and metastatic liver tumor. RESULTS: The proportion of females among the HCC subjects < or =49 years of age was significantly lower (15.0%) than was the proportion of females among subjects >49 years of age (29.8%). Univariate analysis showed that HCV-related cirrhotic patients who developed HCC were more likely to have low hepatic levels of ER and copper-zinc superoxide dismutase (CuZn-SOD) protein and a high hepatic level of a lipid peroxidation product, malondialdehyde (MDA). Logistic regression identified age greater than 49 years (odds ratio [OR]: 7.9, 95% confidence interval [CI]: 2.8-21.3), male sex (OR: 3.5, 95% CI: 1.3-10.2), a decreased ER level (OR: 16.8, 95% CI: 7.3-34.6), and an increased MDA (OR: 8.3, 95% CI: 2.8-24.0) as the variables independently associated with the development of HCC in HCV-infected patients with cirrhosis. ER level was significantly correlated with CuZn-SOD level (r=0.583) and was inversely proportional to MDA level (r=-0.553). The study also showed that ER levels in the cirrhotic livers from premenopausal females were significantly higher than in male cirrhotic livers. CONCLUSIONS: These findings suggest that increased lipid peroxidation and impaired SOD function in the liver may be associated with decreased hepatic ER levels in HCV-infected patients with cirrhosis and HCC, and that HCV-related cirrhotic women before menopause might have the ability to protect against developing HCC via hepatic ER.

Quantitative analysis of red color sign in the endoscopic evaluation of esophageal varices.

BACKGROUND AND STUDY AIMS: Bleeding due to esophageal variceal rupture is associated with an extremely high mortality rate. Variceal bleeding is frequent in patients who have a red color sign on endoscopy. However, the red color sign is subjectively evaluated on the basis of color tone and the shape of the varices. To allow standardization and facilitate consensus, an objective method of assessing the red color sign is needed. In this study, a system was established for quantifying the red color sign during endoscopic evaluation. PATIENTS AND METHODS: Between July 1995 and February 1997, 55 untreated patients with portal hypertension and esophageal varices identified on upper gastrointestinal endoscopy were enrolled in the study. Images obtained about 5 cm oral to the esophagogastric junction during endoscopy were stored on magnetic optical disks using an endoscopic image processor. The still images were transmitted to a computer and analyzed using computer software. The RGB components (R, red; G, green; B, blue) were measured at points showing flare consistent with the red color sign. The endoscopic assessment was based on the Japanese Research Society for Portal Hypertension's general rules for recording endoscopic findings in esophagogastric varices. RESULTS: The ratio of the red color area to the variceal area increased with increasing red color grade. There were significant positive correlations between the R and G, and G and B components. This suggests that comparing the R components alone would allow assessment of the color differences in the red color area and in the varices. The R value was significantly higher in the red color area (115 +/- 20) than in the varices (57 +/- 19). An R value of 90 was found at the boundary between the two parts (P < 0.001). CONCLUSIONS: The red color area can be automatically calculated and quantified using the analysis program. Improvements in data storage methods may allow real-time evaluation during endoscopy in the future.

Estrogen therapy in a male patient with chronic hepatitis C and irradiation-induced testicular dysfunction.

We report an 18-year-old male patient who developed chronic hepatitis C after blood transfusion and had testicular dysfunction after irradiation for a testicular relapse of childhood acute lymphocytic leukemia after cessation of maintenance therapy, and the initiation of testosterone replacement therapy at puberty. Concomitant administration of estradiol resulted in a reduction in serum alanine aminotransferase and ferritin levels and hepatic iron concentration and staining after 2 years of estrogen therapy, although interferon therapy was withdrawn because of adverse effects. This observation suggests that endogenous estradiol may play a beneficial role in male patients with chronic hepatitis C.

The prevalence of dental caries and fluorosis in Japanese communities with up to 1.4 ppm of naturally occurring fluoride.

OBJECTIVES: The purpose of this study was to determine the relationship between the concentration of fluoride in drinking water and the prevalence of dental caries and fluorosis in seven Japanese communities with different concentrations of fluoride occurring naturally in the drinking water. METHODS: A total of 1,060 10- to 12-year-old lifetime residents were examined to determine the prevalence of dental caries and fluorosis in communities with trace amounts to 1.4 ppm fluoride in the drinking water in 1987. Systemic fluorides (drops or tablets) have never been available in Japan and the market share of fluoride-containing toothpaste was 12 percent at the time of the study. RESULTS: The prevalence of dental caries was inversely related and the prevalence of fluorosis was directly related to the concentration of fluoride in the drinking water. The mean DMFS in the communities with 0.8 to 1.4 ppm fluoride was 53.9 percent to 62.4 percent lower than that in communities with negligible amounts of fluoride. Multivariate analysis showed that water fluoride level was the strongest factor influencing DMFS scores. The prevalence of fluorosis ranged from 1.7 percent to 15.4 percent, and the increase in fluorosis with increasing fluoride exposure was limited entirely to the milder forms. CONCLUSIONS: The findings of this study conducted in 1987 in Japan parallel those reported by Dean et al. in the early 1940s.

The utility and limitations of an ultrasonic miniprobe in the staging of gastric cancer.

To determine the utility and limitations of an ultrasonic miniprobe (UMP) in the staging of gastric cancer, we evaluated 46 patients who underwent endoscopic ultrasonography (EUS) using an UMP and who were histologically determined to have gastric cancers. In every case, UMP findings were compared with histopathological findings after treatment. The total accuracy of UMP relative to the depth of tumor invasion was 71.7% (33/46 cases). Accuracy with respect to T1-m tumor diagnosis was 75.7% (22/29 cases), and for T1-sm, 76.9% (10/13 cases), but accuracy for T2 tumor diagnosis was low, due to ultrasound attenuation. When the analysis was carried out based on the size of tumor, the accuracy for UMP was 50.0% (9/18 cases) for all tumors over 20 mm and 85.7% (24/28 cases) for all tumors smaller than 20 mm. We conclude that UMP is suitable for investigation of tumor extension when the lesion is superficial and/or small gastric cancers which do not cause ultrasonic attenuation, but not when the tumor is large or located in certain sites, although conventional EUS is useful in some of these cases.

[Subsegmental transcatheter hepatic arterial embolization under balloon occlusion of the corresponding hepatic vein with SMANCS].

Recently, subsegmental transcatheter hepatic arterial embolization under balloon occlusion of the corresponding hepatic vein has been performed to treat hepatic infarction in subregion hepatocellular carcinoma (HCC). Here, we report subsegmental transcatheter hepatic arterial embolization under balloon occlusion of the corresponding hepatic vein with styrene maleic acid neocarzinostatin lipiodol (SMANCS) (SMANCS-TAE under balloon occlusion of the corresponding hepatic vein). This study included 9 patients with HCC who underwent SMANCS-TAE under balloon occlusion of the corresponding hepatic vein. In all patients, the therapeutic effects (TE) were evaluated according to the criteria of direct response to liver cancer treatment on abdominal computed tomography (CT) 3 weeks after surgery. In 7 patients who could be followed for more than one year, there was no postoperative relapse at the site of treatment. Furthermore, this procedure facilitated the detection of accumulation of SMANCS not only in the tumor but also in the subregion of the tumor in patients with HCC involving immature arterial tumor neoplastic vessels. In patients with large HCC complicated by severe heart failure showing a poor general condition, this procedure allowed treatment to be completed without complication. SMANCS-TAE under balloon occlusion of the corresponding hepatic vein, which can also embolize the portal vein by applying targeting chemotherapy with SMANCS, may cause necrosis not only in the tumor but also in noncancerous liver tissues. This procedure may be an indication for a larger number of cases than standard TAE, facilitating more complete local treatment.

Treatment and posttreatment effects of fluoride mouthrinsing after 17 years.

OBJECTIVES: This study assessed the treatment and posttreatment effects of a school-based, fluoride mouthrinse regimen. METHODS: Children in a nonfluoridated community in Japan participated in a daily rinse program using a 0.05 percent NaF solution in nursery and primary schools, and a weekly rinse with 0.2 percent NaF in junior high school. Students were examined at least annually for dental caries and dental treatment was provided in a public dental clinic through the ninth grade. Incipient carious lesions with no cavitation were not restored. RESULTS: The percent of children in grades one through nine (6-14 years of age) with caries-free permanent teeth increased from 13.4 percent in 1974 to 73.0 percent in 1991, while the mean DMFT decreased by 86 percent during this period. For 12-year-olds, mean DMFT scores declined to about one tooth per child after 1982. For adults 20 years of age, there was a 64 percent difference in DMFS between the treatment group who started the rinse regimen at 4 years of age and continued for 11 years, and the controls who lived in different districts and did not participate in a fluoride rinse regimen. CONCLUSIONS: Children who began rinsing at 4 or 5 years of age benefited the most from the program. The program was inexpensive, simple to implement and well accepted by families and teachers. The conservative treatment policy in the public clinic likely contributed to the benefits derived by participants.

The status of fluoride mouthrinse programmes in Japan: a national survey.

The purpose of this investigation was to determine the current status of fluoride mouthrinse programmes throughout Japan. Data collection and analysis took place in 1992. The focus of this study was on schools that were participating in the rinse programme at the time of the survey. Questionnaires were sent by mail to 49 dentist-members of the Association for the Promotion of Fluoride Use in Japan. These members gathered information from the schools and, when necessary, also from local government offices. Starting with a single prefecture in 1970, the rinse programme increased to 32 out of 47 prefectures by 1992. The total number of schools using fluoride mouthrinse was 1,183 (nursery schools and kindergartens 48 per cent, primary schools 46 per cent, and secondary schools 6 per cent). In nursery schools and kindergartens, 60 per cent of the participating schools adopted the daily method using 0.05 per cent NaF solution. In primary and secondary schools, 78 per cent adopted the weekly method using 0.2 per cent NaF solution. The costs for the rinse regimen were paid for by public funds of the prefectural and municipal governments in 71 per cent of the schools. Fifty-four per cent of the schools which first initiated the rinse programmes in their districts identified dentists and dental associations as the most influential in programme acceptance and implementation. Although the number of fluoride rinse programmes is increasing, it is still modest. These results suggest that cooperation between dental organisations, dental schools and prefectural governments can play very important roles in implementing school based rinse programmes.