High Ki-67 expression is significantly associated with poor prognosis of ovarian cancer patients: evidence from a meta-analysis.

OBJECTIVE: The prognostic significance of Ki-67 expression in patients with ovarian cancer was controversial in various studies. Therefore, we carried out a meta-analysis to determine the prognostic significance of Ki-67 in ovarian cancer patients. METHODS: We searched PubMed, Cochrane Library, EMBASE, Web of Knowledge, China National Knowledge Infrastructure database and WanFang digital database for eligible studies from January 1, 1990 to June 1, 2017. The pooled hazard ratios and 95% confidence intervals were calculated to assess the prognostic significance of Ki-67 expression for overall survival in ovarian cancer patients. RESULTS: Finally, 38 eligible studies and 5004 ovarian cancer patients were included in the current study. The pooled hazard ratio was 1.35 (95% confidence interval 1.24-1.46, P = 0.001) for overall survival in ovarian cancer patients. The funnel plot bias was obviously asymmetrical and Egger's test also detected significant publication bias (P = 0.001). The Contour-enhanced funnel plot with trim-and-fill method supplemented 11 dummy studies to balance the funnel plot and nine new supplementary studies were in area with statistical significance. Sensitivity analysis and cumulative meta-analysis further demonstrated that the association between high Ki-67 expression and poor overall survival of ovarian cancer patients was stable and reliable. CONCLUSIONS: High Ki-67 expression is significantly related to poor overall survival and may serve as a prognostic biomarker for ovarian cancer patients.

Secondary cancer after a childhood cancer diagnosis: viewpoints considering primary cancer.

BACKGROUNDS: Multidisciplinary therapy has increased the risk of subsequent late effects, but detailed analyses on secondary cancers in childhood cancer survivors (CCSs) are limited in Asian countries. METHODS: This was a retrospective cohort study comprising 10,069 CCSs who were diagnosed between 1980 and 2009 across 15 Japanese hospitals. We conducted secondary analyses to estimate the incidence of secondary cancer according to each primary malignancy and to elucidate the association between primary and secondary cancers. We also explored the risk factors for the development of secondary cancer in each independent primary malignancy. RESULTS: The cumulative incidence of secondary cancer at 20 years varied among primary cancers: hematological malignancy, 3.1% (95% CI 2.2-4.3); retinoblastoma, 6.6% (95% CI 1.5-16.8); pediatric solid tumor, 2.5% (95% CI 1.3-4.2); brain tumors, 5.2% (95% CI 1.7-11.8) bone/soft tissue sarcoma, 5.2% (95% CI 2.3-10.1); and others, 3.3% (95% CI 1.6-6.0) (p = 0.015). The cumulative incidence of secondary cancers is highest in those with osteosarcoma (13.1%) followed by those with hepatoblastoma (8.4%) and retinoblastoma (6.6%). Close association between the primary and secondary cancer diagnoses was found. The risk factors for secondary cancer development depended on the primary cancer, but autologous/allogeneic stem cell transplantation was a relatively common risk factor. CONCLUSION: The cumulative incidence of secondary cancer varied among primary cancers. The primary cancer was closely associated with the secondary cancer but stem cell transplantation was a common risk factor for secondary cancers among CCSs.

Secondary cancers after a childhood cancer diagnosis: a nationwide hospital-based retrospective cohort study in Japan.

BACKGROUND: The epidemiology of secondary cancers in childhood cancer survivors has been unknown in Asian countries. Our aim is to assess the incidence and risk factors for secondary cancers through a nationwide survey in Japan. METHODS: A retrospective cohort study comprising 10,069 children who were diagnosed with cancer between 1980 and 2009 was conducted in 15 Japanese hospitals. The cumulative incidence rate was calculated using death as the competing risk and compared by the Gray method. The standardized incidence ratio (SIR) was defined as the ratio of the number of observed cancers divided by the number of expected cancers. The risk factors were analyzed using Cox regression analysis. RESULTS: One hundred and twenty-eight patients (1.3 %) developed secondary cancers within a median follow-up of 8.4 years. The cumulative incidence rate was 1.1 % (95 % confidence interval [CI] 0.9-1.4) at 10 years and 2.6 % (95 % CI 2.1-3.3) at 20 years after primary cancer diagnosis. Sensitivity analysis, limited to 5-year survivors (n = 5,387), confirmed these low incidence rates. The SIR of secondary cancers was 12.1 (95 % CI 10.1-14.4). In the Cox analysis, the hazard ratios for secondary cancers were 3.81 (95 % CI 1.53-9.47) for retinoblastoma, 2.78 (95 % CI 1.44-5.38) for bone/soft tissue sarcomas, and 1.81 (95 % CI 1.16-2.83) for allogeneic stem cell transplantation. CONCLUSIONS: The cumulative incidence of secondary cancers in children in Japan was not high; however, the SIR was relatively high. Retinoblastoma or sarcoma in addition to allogeneic stem cell transplantation were significant risk factors for secondary cancers.

The expression of beclin-1, an autophagic gene, in hepatocellular carcinoma associated with clinical pathological and prognostic significance.

BACKGROUND: A role for autophagy, a conserved cellular response to stress, has recently been demonstrated in human cancers. Aberrant expression of Beclin-1, an important autophagic gene, has been reported in various human cancers. In the present study, we investigated the significance and relationship between Beclin-1 expression and cell proliferation, apoptosis, microvessel density (MVD) and clinical pathological changes or prognosis in human hepatocellular carcinoma (HCC). METHODS: A total of 103 primary HCC patients were involved in the study. Expression of Beclin-1, PCNA, NET-1, Bcl-2, Bax, Survivin in cancer cells and CD34 in stromal microvessels were evaluated immunohistochemically in tissue microarrays comprising 103 cases of HCC and 57 matched adjacent nontumor liver tissues. Correlations between clinicopathological characteristics and survival of HCC patients were explored. RESULTS: The positive rate of Beclin-1 was significantly lower in HCC tissues than adjacent tissues (72.8 vs. 89.5%, χ2 = 6.085, P = 0.015). In HCC, Beclin-1 expression was negatively correlated with cirrhosis background (r = -0.216, P = 0.029), Edmondson grade (r = -0.249, P = 0.011), vascular invasion (r = -0.246, P = 0.012), PCNA (r = -0.242, P = 0.014), NET-1 (r = -0.245, P = 0.013), anti-apoptosis protein Bcl-2 (r = -0.245, P = 0.013) and MVD (r = -0.292, P = 0.003), and positively correlated with pro-apoptosis protein Bax (r = 0.242, P = 0.014).Significant differences in the 5-year survival rates were seen among patients with Beclin-1 strong positive (++) (59.1%, 13/22), moderate positive (+) (28.3%, 15/53) and weak negative expression (-) (14.6%, 7/28) (P = 0.043). Significant differences were detected between Beclin-1 (++) and either Beclin-1 (+) (P = 0.036) or Beclin-1 (-) groups (P = 0.008), but no significant difference between Beclin-1 (+) and Beclin-1 (-) groups (P = 0.281) was observed.Survival rates were positively related to high Beclin-1 co-expressed with low PCNA, NET-1, or Bcl-2, lower MVD, and high Bax. Univariate and multivariate Cox regression analysis revealed that Beclin-1 expression was an independent indicator for overall survival in HCC patients (P < 0.05). CONCLUSIONS: The pathogenesis and progression of HCC are associated with reduced autophagy. The expression of Beclin-1 and Bax in HCC tissues may provide a synergistic effect towards inhibiting HCC proliferation, infiltration, metastasis and angiogenesis. Beclin-1 expression may be a valuable prognostic marker of HCC.

Body mass index for children aged 6-18 years in Beijing, China.

BACKGROUND: Obesity constitutes one of the most important worldwide public health concerns. AIM: To develop BMI percentile curves by age, sex and urban-rural regions for Beijing children and compare the results with Chinese national data and international references. SUBJECTS AND METHODS: Boys (4078) and girls (4077), aged 6-18 years, were recruited from 1 September to 30 November 2005 in Beijing, China. BMI percentile curves were constructed using the LMS method. RESULTS: BMI curves differed between boys and girls. BMI curves for urban children were higher than rural children at the upper percentile. Beijing BMI curves were higher than the Chinese national level. Beijing boys had a higher BMI in medium (6.5-14 years) and upper percentiles and a lower BMI in lower percentiles than WHO and developed references, whereas Beijing girls were lower in medium and lower percentiles, but higher compared to a WHO reference before age 15.5 years in upper percentiles. CONCLUSIONS: Beijing children are fatter than the Chinese national level. Beijing urban children are fatter than rural Beijing children. The polarization of BMI values for Beijing boys suggests these children face a dual-burden of nutrition. Effective policies and interventions to control obesity and underweight in Chinese children are necessary.

The Association between Prenatal Exposure to Per- and Polyfluoroalkyl Substances and Respiratory Tract Infections in Preschool Children: A Wuhan Cohort Study.

This study investigates the association between prenatal exposure to per- and polyfluoroalkyl substances (PFASs) and the incidence and frequency of respiratory tract infections (RTIs) in preschool children. We selected 527 mother-infant pairs from Wuhan Healthy Baby Cohort (WHBC), China. Ten PFASs were measured in umbilical cord serum, and we collected data on common RTIs in preschool children aged 4 years through a questionnaire. Associations of single PFASs with the incidence and frequency of RTIs were analyzed via Logistic regression and Poisson regression, while the collective effect was assessed by weighted quantile sum (WQS) regression. Furthermore, stratified and interaction analyses were performed to evaluate if there were sex-specific associations. We found a positive correlation between perfluorododecanoic acid (PFDoDA) and the incidence of tonsillitis, with several PFASs also showing positive associations with its frequency. Moreover, perfluorotridecanoic acid (PFTrDA) showed a positive link with the frequency of common cold. The results of WQS regression revealed that after adjusting for other covariates, PFASs mixture showed a positive association with the incidence of tonsillitis, the frequency of common cold, and episodes. In particular, perfluoroundecanoic acid (PFUnDA), PFDoDA, PFTrDA, perfluorodecanoic acid (PFDA) and 8:2 chlorinated polyfluorinated ether sulfonic acid (8:2 Cl-PFESA) had the most significant impact on this combined effect. The results suggest that both single and mixed exposures to PFASs may cause RTIs in preschool children. However, there was no statistically significant interaction between different PFASs and sex.

Impaction of factors associated with oxidative stress on the pathogenesis of gestational hypertension and preeclampsia: A Chinese patients based study.

ABSTRACT: We aimed to investigate the effect of Kelch-like ECH-associated protein 1/NF-E2 p45-related factor 2 (Keap1/Nrf2) pathway on the biological function of trophoblast cells in oxidative stress model at the cellular level, and analyzed the expression level and clinical significance of Keap1/Nrf2 pathway and related antioxidant factors in placental tissues of Preeclampsia (PE) patients at clinical level. In present study, we found that under hypoxia/reoxygenation conditions, the activity of oxidative stress-related enzymes (CAT, GSH-Px, SOD) in HTR8/SVneo cells was significantly lower than that before treatment (P < .01). The activities of CAT, GSH-Px and SOD in HTR8/SVneo cells in SiRNA+H/R group decreased significantly (P < .01), indicating the important defense effect of Keap1/Nrf2 signaling pathway in oxidative stress. As a control group of Nrf2 SiRNA+H/R group, Si-NC+H/R group had CAT, GSH-Px and SOD activities decreasing, which was similar to that in H/R group. Moreover, the activities of oxidative stress-related active enzymes in patients with PE were further confirmed by detecting and comparing the activities of CAT, GSH-Px and SOD in placental tissues. The results showed that the activity of SOD (P < .001), GSH-Px (P < .01) and CAT (P < .01) in placental tissues of patients with PE were significant different from those of normal placental tissues. The expression level of Keap1 in placenta of patients with PE was slightly lower than that of normal placenta. While the expression of Nrf2 in placenta of patients with PE was significantly higher than that of normal placenta. HO-1 expression in placenta of patients with PE was significantly higher than that of normal placenta. These results implicate the importance of Keap-1/Nrf2 pathway in PE.

[Current Situation of Cannabis Use in Japan: Based on Data from the Nationwide General Population Survey on Drug Use in Japan 2017].

This study aimed to review the current state and trends in cannabis use in Japan, using data from several national epidemiological surveys. The number of cannabis users in the general population was estimated approximately 1.3 million people. Cannabis use increased between 2015 and 2017. In 2017, the lifetime prevalence of cannabis use was greater than that of inhalants, and cannabis had become the most abused drug in Japan. The increase in cannabis users is thought influenced by increased access to illegal cultivation and positive thinking about cannabis use among many people, especially younger individuals.

A Joinpoint regression analysis of long-term trends in cancer mortality in Japan (1958-2004).

Cancer is one of the major targets of disease control programs in Japan. A Joinpoint regression model was used to analyze the long-term trends of mortality related to overall cancer and the 15 most common cancers based on published data from the National Vital Statistics of Japan between 1958 and 2004. Since 1996, a decline has been seen in overall cancer for both sexes in Japan. Most of the common sites, including cancers of the stomach, colon, liver, gallbladder and lung and leukemia in both sexes, cancer of esophagus in men and rectal and ovarian cancers in women showed a decreasing trend, and cancers of the rectum, pancreas, prostate and urinary bladder and malignant lymphoma in men and cancers of the esophagus and uterus in women leveled off during the most recent period. However, an increasing trend was confirmed for cancers of the pancreas, breast and urinary bladder and malignant lymphoma in women. An effective cancer control program including prevention, early detection and treatment should be implemented to further reduce the cancer mortality, particularly for cancer sites that show higher mortality rates or increasing trends.

Dual-specificity phosphatase 5 suppresses ovarian cancer progression by inhibiting IL-33 signaling.

Ovarian cancer (OC) is the leading cause of death from gynecological malignancy. Dual-specificity phosphatases (DUSPs) are proteins that are reported involved in carcinogenesis, but their roles in OC have not be extensively studied. Here, we found that DUSP5 is markedly down-regulated in OC tissues. We reanalyzed DUSP5 expression in OC using published microarray data from the Gene Expression Omnibus (GEO) database and found that patients with low DUSP5 expression have significantly shorter overall survival than those with high expression (P < 0.001). Down-regulation of DUSP5 in OC tissues was immunohistochemically confirmed in tissue microarrays containing 15 normal ovary tissue samples and 60 OC specimens. Functional studies suggest that DUSP5 silence facilitates cell proliferation, migration, and invasion of OC cells in vitro. DUSP5 over-expression inhibits cell proliferation but has no effect on OC cell migration or invasion. Mechanistically, silencing DUSP5 transcriptionally activates interleukin 33 (IL-33) expression and secretion. Blockage of IL-33 with a neutralizing anti-IL33 antibody attenuates the effect of DUSP5 silencing to promote cell proliferation, migration, and invasion. Moreover, recombinant IL-33 protein treatment dramatically promotes OC cell proliferation, migration, and invasion with DUSP5 over-expression. Our study provides proof of principle that DUSP5 down-regulation promotes proliferation, migration, and invasion of OC cells via activation of IL-33 signaling.

Hypertensive disorders of pregnancy: a strong risk factor for subsequent hypertension 5 years after delivery.

Hypertensive disorders of pregnancy are known to be a risk factor for future cardiovascular diseases. In contrast, there is a paucity of data on the not so distant future prognosis of hypertensive disorders of pregnancy. In the present study, we evaluated the incidence of the diseases causing cardiovascular problems (hypertension, diabetes mellitus, dyslipidemia and metabolic syndrome) 5 years after delivery in Japanese women with hypertensive disorders of pregnancy. We performed a double-cohort study and compared medical conditions between women with and without a history of hypertensive disorders of pregnancy. A total of 1513 women who participated in the cohort study were invited to undergo a medical checkup 5 years after the index delivery, of whom 829 responded. After excluding pregnant and lactating women at the time of examination, 25 women with hypertensive disorders of pregnancy and 746 control subjects were analyzed. The incidence of hypertension was significantly higher among women with hypertensive disorders of pregnancy than women who were normotensive during pregnancy (24.0 vs. 2.5%, P<0.001). They were also at an increased risk of subsequent hypertension 5 years after the index delivery, after adjusting for confounding factors such as age, body mass index, family history of hypertension and salt intake (odds ratio 7.1, 95% CI, 2.0-25.6, P<0.003). These is no significant difference in the incidence of diabetes mellitus, dyslipidemia and metabolic syndrome. In conclusion, hypertensive disorders of pregnancy are strong risk factors for subsequent hypertension only 5 years after delivery.

Overview of epidemiology of bile duct and gallbladder cancer focusing on the JACC Study.

BACKGROUND: This review discusses the epidemiologic features of bile duct and gallbladder cancer in Japan, mainly focusing on results of Japan Collaborative Cohort Study (JACC Study) for Evaluation of Cancer Risk Sponsored by the Ministry of Education, Science, Sports and Culture of Japan (Monbusho) in comparison with results of other studies. METHODS: The theses and papers derived from JACC Study on bile duct and gallbladder cancer were all collected for this review. Hirayama's cohort study, which is a representative epidemiologic study, and a large scale case-control study on bile duct and gallbladder cancer in Japan by Kato et al. were also taken into consideration. Small scale cross-sectional studies or ecological studies and the studies conducted outside Japan were collected by the literature reference services on the web net such as Pub Med or Japan Centra Revuo Medicina (Igaku- Chuo- Zasshi) limited to the published after 1980 and use key words bile duct cancer, gallbladder cancer and epidemiology. RESULTS: In the JACC Study, high intake of fried food was regarded as a factor that significantly elevated the risk of the diseases (hazard ratio [HR]=2.58, 95% confidence interval [CI]: 1.08-6.16 in males; HR=2.98, 95% CI: 1.28-6.86 in females). The JACC Study indicated that a high intake of boiled beans had a significant preventive relation to the diseases in females (relative risk [RR]=0.50, 95% CI: 0.26-0.98). High consumption of fish also had a significant preventive relationship to bile duct cancer in males (RR=0.53, 95% CI: 0.26-0.98) and gallbladder cancer in females (RR=0.43, 95% CI: 0.24- 0.79). A history of blood transfusion also had a significant relationship (HR=2.27, 95% CI: 1.29-3.98) as which elevated the risk. The JACC Study determined bowel movement as a risk factor. The group with bowel movements less than once per six days had a significantly elevated hazard ratio (HR=5.21, 95% CI: 1.25-21.68). CONCLUSION: As to recent epidemiologic features of bile duct and gallbladder cancer revealed by the JACC Study, its outline became obvious in comparison with the results of other studies. Evidence for the contribution of the JACC Study is strong because it provides some important findings on the epidemiology of bile duct and gallbladder cancer.

Overview of the epidemiology of pancreatic cancer focusing on the JACC Study.

BACKGROUND: The objective of this article was to overview the epidemiology of pancreatic cancer. We summarize the results of the Japan Collaborative Cohort Study (JACC Study) and some previous studies. METHODS: References were mainly in a Medline search through Pub Med database. In addition, 3 papers about the JACC Study were quoted. RESULTS: In the JACC Study, the standardized mortality ratio of pancreatic cancer was 0.97 in females and 0.84 in males. Diabetes mellitus (DM) has increased the risk for pancreatic cancer in many studies. In the JACC Study, DM had a risk for pancreatic cancer in males (hazard ratio=2.12). Cigarette smoking has been associated with pancreatic cancer in many studies. In the JACC Study, the hazard ratio for current smokers was 1.6 in males, and 1.7 in females. The ratio was 3.3 who smoked 40+ cigarettes/day in males. In the JACC Study, alcohol intake was not associated with pancreatic cancer. These results are consistent with the other studies. Coffee consumption has not been associated with pancreatic cancer in many studies. In the JACC Study, the hazard ratio significantly increased to 3.19 among men who consumed 4+ cups of coffee per day. The relationships between diet /nutrition and pancreatic cancer are not clear in many studies. CONCLUSION: The relation between smoking and pancreatic cancer is most consistently described. A further analysis of the relationships between family history, hormonal factors in females, dietary and nutritional factors, obesity, physical activity and pancreatic cancer is necessary.

A cohort study on cerebrovascular disease in middle-aged and elderly population in rural areas in Jiangxi Province, China.

To clarify the risk factors of CVD deaths in rural areas in Jiangxi Province, China, a cohort study was carried out from September 1, 1994 through December 31, 2000 involving 50,252 participants aged 40 years or older in 4 counties. Among the 3,429 deaths, 671 cases (398 males and 273 females) died of CVD. In addition, excluding 183 cases with a previous history of CVD, 632 CVD deaths out of 50,069 subjects were analyzed using Cox proportional hazard models. The multivariate hazard ratio (HR) for CVD mortality significantly increased in parallel with age, blood pressure and degree of liking for salty foods (p for trend < 0.01). The multivariate HR for CVD mortality of ex-drinkers was 1.55 (95% CI: 1.04, 2.31) compared with non-drinkers. The multivariate HR for CVD mortality of subjects who ate meat once or twice per month was 0.75 (95% CI: 0.62, 0.91) compared with those who never ate meat or seldom. There was no significant relationship between smoking and CVD mortality. Our results indicated that the main risk factors for CVD mortality were advancing age, high-normal blood pressure and hypertension. The risk in these areas was lower in subjects who disliked salty foods and those who ate meat once or twice per month.

Relationship between a high mortality rate and extreme heat during the summer of 1999 in Hokkaido Prefecture, Japan.

In order to describe the relationship between mortality rate and extreme heat during the summer of 1999 in Hokkaido, we calculated the monthly age-adjusted death rates, average monthly mean temperature and average monthly high temperature for the years 1995 to 1999 in Hokkaido. The materials were derived from Statistics and Information Department, Minister's Secretariat, Ministry of Health, Labour and Welfare of Japan, Statistical Bureau Management and Coordination Agency Government of Japan and the Japan Meteorological Agency. Trends in the monthly age-adjusted death rates and temperature changes in the same period were analyzed. The highest average monthly high temperature for August and September (28.8 degrees C and 23.8 degrees C, respectively) occurred in 1999; the similar trend was observed in the highest average monthly mean temperature. In August 1999, there were 14 days with highest temperatures of 30 degrees C and over. The age-adjusted rate in August 1999 was significantly higher compared with those for the years 1995 to 1998 (p<0.01). We concluded that an unusually hot spell in 1999 was followed by a high mortality rate in Hokkaido.