Age at menarche by birth cohort: A pooled analysis of half a million women in Asia.

OBJECTIVES: To evaluate changes in the age at menarche in Asian populations. STUDY DESIGN: Retrospective cohort study. METHODS: We included 548,830 women from six countries in Asia. The data were sourced from 20 cohorts participating in the Asia Cohort Consortium (ACC) and two additional cohort studies: Japan Multi-institutional Collaborative Cohorts (J-MICC), and Japan Nurse Health Study (JNHS) with data on age at menarche. Joinpoint regression was used to evaluate changes in age at menarche by birth year and by country. RESULTS: The study includes data from cohorts in six Asian countries namely, China, Iran, Japan, Korea, Malaysia and Singapore. Birth cohorts ranged from 1873 to 1995. The mean age of menarche was 14.0 years with a standard deviation (SD) of 1.4 years, ranged from 12.6 to 15.5 years. Over 100 years age at menarche showed an overall decrease in all six countries. China showed a mixed pattern of decrease, increase, and subsequent decrease from 1926 to 1960. Iran and Malaysia experienced a sharp decline between about 1985 and 1990, with APC values of -4.48 and -1.24, respectively, while Japan, South Korea, and Singapore exhibited a nearly linear decline since the 1980s, notably with an APC of -3.41 in Singapore from 1993 to 1995. CONCLUSIONS: Overall, we observed a declining age at menarche, while the pace of the change differed by country. Additional long-term observation is needed to examine the contributing factors of differences in trend across Asian countries. The study could serve as a tool to strengthen global health campaigns.

Effect and cost-effectiveness of national gastric cancer screening in Japan: a microsimulation modeling study.

BACKGROUND: A national endoscopic screening program for gastric cancer was rolled out in Japan in 2015. We used a microsimulation model to estimate the cost-effectiveness of current screening guidelines and alternative screening strategies in Japan. METHODS: We developed a microsimulation model that simulated a virtual population corresponding to the Japanese population in risk factor profile and life expectancy. We evaluated 15 endoscopic screening scenarios with various starting ages, stopping ages, and screening intervals. The primary outcomes were quality-adjusted life-years (QALYs), costs, and incremental cost-effectiveness ratio. Cost-effective screening strategies were determined using a willingness-to-pay threshold of $50,000 per QALY gained. One-way sensitivity and probabilistic sensitivity analyses were done to explore model uncertainty. RESULTS: Using the threshold of $50,000 per QALY, a triennial screening program for individuals aged 50 to 75 years was the cost-effective strategy, with an incremental cost-effectiveness ratio of $45,665. Compared with no endoscopic screening, this strategy is predicted to prevent 63% of gastric cancer mortality and confer 27.2 QALYs gained per 1000 individuals over a lifetime period. Current screening guidelines were not on the cost-effectiveness efficient frontier. The results were robust on one-way sensitivity analyses and probabilistic sensitivity analysis. CONCLUSIONS: This modeling study suggests that the endoscopic screening program in Japan would be cost-effective when implemented between age 50 and 75 years, with the screening repeated every 3 years. These findings underscore the need for further evaluation of the current gastric cancer screening recommendations.

Cancer incidence attributable to tuberculosis in 2015: global, regional, and national estimates.

BACKGROUND: Tuberculosis is associated with increased risk of cancer. However, the impact of tuberculosis on global cancer burden is unknown. METHODS: We performed random-effects meta-analyses and meta-regressions of studies reporting the association between tuberculosis and cancer risks by searching PubMed, Web of Science, Embase, Cochrane library, and CINAHL from inception to 1 June 2019. Population attributable fractions (PAFs) of cancer incidence attributable to tuberculosis were calculated using relative risks from our meta-analyses and tuberculosis prevalence data from Global Health Data Exchange by age, sex, and country. The study has been registered with PROSPERO (CRD42016050691). RESULTS: Fourty nine studies with 52,480 cancer cases met pre-specified inclusion criteria. Tuberculosis was associated with head and neck cancer (RR 2.64[95% CI 2.00-3.48]), hepatobiliary cancer (2.43[1.82-3.25]), Hodgkin's lymphoma (2.19[1.62-2.97]), lung cancer (1.69[1.46-1.95]), gastrointestinal cancer (1.62[1.26-2.08]), non-Hodgkin's lymphoma (1.61[1.34-1.94]), pancreatic cancer (1.58[1.28-1.96]), leukaemia (1.55[1.25-1.93]), kidney and bladder cancer (1.54[1.21-1.97]), and ovarian cancer (1.43[1.04-1.97]). We estimated that 2.33%(1.14-3.81) or 381,035(187145-623,404) of global cancer incidences in 2015 were attributable to tuberculosis. The PAFs varied by Socio-demographic Index (SDI)-ranging from 1.28% (0.57-2.31%) in the high-SDI countries to 3.51% (1.84-5.42%) in the middle-SDI countries. Individually, China and India accounted for 47% of all tuberculosis-related cancer cases. CONCLUSIONS: Tuberculosis is associated with increased risk of cancer at ten sites. The burden of tuberculosis attributable cancer skewed towards lower resource countries. Research priorities are to better understand regional disparities and underlying mechanism linking tuberculosis and cancer development.

Association of hormone replacement therapy with mortality in colorectal cancer survivor: a systematic review and meta-analysis.

BACKGROUND: Hormone replacement therapy (HRT) use has shown to be associated with a reduced risk of colorectal cancer, however, its impact on survival among women with colorectal cancer remains uncertain. This meta-analysis aimed to systematically assess the survival benefit of HRT use in patients with colorectal cancer. METHODS: PRISMA guidelines for the reporting of meta-analyses were followed. We systematically searched PubMed, Embase, Cochrane library, Scopus, and PsycINFO from inception to 12 January 2019, with no language restrictions, for randomized controlled trials and cohort studies reporting the association between hormone replacement therapy and risk of colorectal cancer mortality or all-cause mortality in colorectal cancer survivors. We used the Newcastle-Ottawa Scale to assess the risk of bias of the included studies. We summarized the association as hazard ratio (HR; 95% CI) using random-effects meta-analysis. The study protocol was registered in PROSPERO (CRD42017071914). RESULTS: Of 1648 articles identified, five cohorts including 10,013 colorectal cancer survivors were included in this meta-analysis. Compared with women with no prior use of HRT, those reporting current use of HRT had lower risks of colorectal cancer-specific mortality (HR, 0.71 [95% CI, 0.62-0.80], I2 = 0%) and overall mortality (HR, 0.74 [95% CI, 0.67-0.81], I2 = 0%). Low between-study variance was also suggested by the narrow prediction interval for colorectal cancer-specific mortality (0.58-0.86) and overall mortality (0.63-0.87), which indicated that a future study will show survival benefits in women with current HRT use compared with those with no HRT exposure. Inverse associations with colorectal cancer-specific (HR, 1.02 [95% CI, 0.82-1.28], I2 = 0%) and overall mortality (HR, 1.07 [95% CI, 0.90-1.27], I2 = 0%) were not observed for former users of HRT. Sensitivity analyses revealed no differences in the risk estimates between two groups. CONCLUSIONS: The findings suggest that the current use of HRT is associated with lower risks of colorectal cancer-specific and overall mortality in patients with colorectal cancer. Further investigations to elucidate the underlying mechanism are warranted.

Door-to-antibiotic time and mortality in patients with sepsis: Systematic review and meta-analysis.

OBJECTIVES: To evaluate whether the timing of initial antibiotic administration in patients with sepsis in hospital affects mortality. METHODS: This systematic review and meta-analysis included studies from inception up to 19 May 2022. Interventional and observational studies including adult human patients with suspected or confirmed sepsis and reported time of antibiotic administration with mortality were included. Data were extracted by two independent reviewers. Summary estimates were calculated by using random-effects model. The primary outcome was mortality. RESULTS: We included 42 studies comprising 190,896 patients with sepsis. Pooled data showed that the OR for patient mortality who received antibiotics ≤1 hr was 0.83 (95 %CI: 0.67 to 1.04) when compared with patients who received antibiotics >1hr. Significant reductions in the risk of death in patients with earlier antibiotic administration were observed in patients ≤3 hrs versus >3 hrs (OR: 0.80, 95 %CI: 0.68 to 0.94) and ≤6 hrs vs 6 hrs (OR: 0.57, 95 %CI: 0.39 to 0.82). CONCLUSIONS: Our findings show an improvement in mortality in sepsis patients with early administration of antibiotics at <3 and <6 hrs. Thus, these results suggest that antibiotics should be administered within 3 hrs of sepsis recognition or ED arrival regardless of the presence or absence of shock.

Association of Menopausal Hormone Therapy with Risk of Pancreatic Cancer: A Systematic Review and Meta-analysis of Cohort Studies.

BACKGROUND: Although menopausal hormone therapy (MHT) is commonly prescribed, little is known about the association between MHT use and risk of pancreatic cancer. METHODS: We searched PubMed, Embase, and Cochrane Library, from inception until April 20, 2022. The risk of bias was assessed with the Newcastle-Ottawa Quality Assessment Scale. Pooled relative risks (RR) for pancreatic cancer risk were calculated using random-effects models. We computed prediction intervals (PI) and performed subgroup meta-analyses. Meta-regression was performed to investigate the sources of heterogeneity. RESULTS: This study included 2,712,313 women from 11 cohort studies. There was no association between MHT and pancreatic cancer risk (RR, 0.92; 95% confidence interval (CI), 0.83-1.02; I2, 64%; 95% PI, 0.68-1.25). Subgroup meta-analyses of four studies stratified by MHT formulations showed inverse associations with the risk of pancreatic cancer (women receiving estrogen-only MHT: RR, 0.77; 95% CI, 0.64-0.94; I2, 57%; estrogen plus progestin MHT: RR, 0.85; 95% CI, 0.75-0.96; I2, 0%). Subgroup analysis defined by recency and duration of treatment did not reveal evidence of associations between MHT and pancreatic cancer risk. CONCLUSIONS: This study found no association between the overall use of MHT and risk of pancreatic cancer. However, among four studies with data on MHT formulations, subgroup analysis showed a decreased risk of pancreatic cancer among users of estrogen-only and combined estrogen-progestin therapy. Owing to the inconsistent findings between our main and subgroup analyses, future studies stratified by MHT formulations are warranted. IMPACT: The findings of this study indicate that future investigation should focus on MHT formulations.

Association of hormone replacement therapy with risk of gastric cancer: a systematic review and meta-analysis.

Hormone replacement therapy (HRT) is widely used to relieve menopausal symptoms; however, it remains unclear whether the use of HRT was associated with gastric cancer. We conducted a systematic review and meta-analysis to synthesize available evidence. This study followed the PRISMA guideline to report meta-analysis. PubMed, Embase, and Cochrane library were searched from conception through 23 February 2022. Eligible studies reporting risk of gastric cancer after HRT were screened and accessed by two independent reviewers. Random-effects meta-analysis was used to calculate pooled risk estimate as relative risk (RR, 95% CI). Pre-established review protocol was registered in PROSPERO (CRD42021281260). Among the 1095 articles identified, we included 11 studies with 1,919,089 women in this meta-analysis. The combined risk estimate (RR, 0.72; 95% CI 0.64-0.81; I2 = 2%) indicated that the use of HRT was associated with a 28% reduction in risk of gastric cancer compared with those who had no HRT exposure. The narrow prediction interval (0.62-0.84) for gastric cancer risk suggested a low between-study variance. In subgroup analysis defined by HRT formulation, there were reduction in risks of gastric cancer after the use of estrogen-only therapy (Pooled RR, 0.63; 95% CI 0.51-0.77, I2 = 0%) and estrogen-progestin therapy (Pooled RR, 0.70; 95% CI 0.57-0.87; I2 = 0%), as compared with non-users. In this systematic review and meta-analysis, the use of HRT was associated with a reduced gastric cancer risk regardless of HRT formulation. Further investigations are warranted to confirm underlying mechanisms.

Comparison of Severity of Genitourinary Syndrome of Menopause Symptoms After Carbon Dioxide Laser vs Vaginal Estrogen Therapy: A Systematic Review and Meta-analysis.

Importance: Vaginal estrogen for genitourinary syndrome of menopause (GSM) should be used with caution in women with contraindications, highlighting the need for effective treatment alternatives. Objective: To compare the severity of GSM after vaginal laser vs estrogen therapy. Data Sources: The PubMed, Embase, and Cochrane Library databases were searched for articles published from database inception to April 8, 2022, with no language restrictions. Reference lists were also searched. Study Selection: Randomized clinical trials (RCTs) that compared the use of lasers with vaginal estrogen in adults were selected. Data Extraction and Synthesis: Two investigators independently extracted data from included studies. The Cochrane risk of bias tool for RCTs was used to assess risk of bias of each study. A random-effects model was used to pool mean differences (MDs) with 95% CIs. Main Outcomes and Measures: Primary outcomes were Vaginal Analog Scale (VAS; higher scores indicate severer symptoms), Vaginal Health Index (VHI; higher scores indicate better vaginal health), Vaginal Maturation Index (VMI; higher scores indicate higher estrogen effect on the vaginal epithelium), Female Sexual Function Index (FSFI; higher scores indicate better female sexual function), and Sexual Quotient-Female (SQ-F; higher scores indicate better female sexual function) questionnaire scores. Urinary symptoms were assessed as an additional outcome. Data analyses were performed from April 9 to 12, 2022. Results: A total of 6 RCTs with 270 women with GSM were included (135 were randomized to laser therapy and 135 to estrogen therapy; mean age ranged from 54.6 to 61.0 years). No significant differences were found between carbon dioxide laser and vaginal estrogen from baseline to the end of follow-up in overall VAS scores (MD, -0.16; 95% CI, -0.67 to 0.36; I2, 33.31%), VHI (MD, 0.20; 95% CI, -0.56 to 0.97; I2, 83.25%), VMI (MD, -0.56; 95% CI, -1.14 to 0.02; I2, 35.07%), FSFI (MD, -0.04; 95% CI, -0.45 to 0.36; I2, 41.60%), and SQ-F (P = .37 based on 1 study). Other questionnaire-based outcome measures demonstrated no difference between groups from baseline to the end of follow-up for changes in urinary symptoms. Conclusions and Relevance: This systematic review and meta-analysis of RCTs found that vaginal laser treatment is associated with similar improvement in genitourinary symptoms as vaginal estrogen therapy. Further research is needed to test whether vaginal laser therapy could be a potential treatment option for women with contraindications to vaginal estrogen.

Association of Marital Status With Total and Cause-Specific Mortality in Asia.

Importance: Marital status has been shown to be associated with mortality, but evidence in Asian populations is limited. Objective: To examine the association of marital status with total and cause-specific mortality. Design, Setting, and Participants: This cohort study included individual participant data from 16 prospective studies in the Asia Cohort Consortium conducted between 1963 and 2015. Asian participants with complete information on marital and vital status were included. Study-specific hazard ratios (HRs) and 95% CIs were estimated using Cox proportional hazards model and then pooled using a random-effects meta-analysis. The analysis began in February 2021 and ended in August 2021. Exposures: Marital status. Main Outcomes and Measures: All-cause and cause-specific mortality. Results: Of 623 140 participants (326 397 women [52.4%] and 296 743 men [47.6%]; mean [SD] age, 53.7 [10.2] years; mean [SD] follow-up time, 15.5 [6.1] years), 123 264 deaths were ascertained. Compared with married individuals, those who were unmarried had pooled HRs of 1.15 (95% CI, 1.07-1.24) for total mortality, 1.12 (95% CI, 1.03-1.22) for cerebrovascular disease mortality, 1.20 (95% CI, 1.09-1.31) for coronary heart disease mortality, 1.17 (95% CI, 1.07-1.28) for circulatory system diseases mortality, 1.06 (95% CI, 1.01-1.11) for cancer mortality, 1.14 (95% CI, 1.05-1.23) for respiratory diseases mortality, and 1.19 (95% CI, 1.05-1.34) for external causes of death. Positive associations with total mortality were also observed for those who were single (HR, 1.62; 95% CI, 1.41-1.86), separated (HR, 1.35; 95% CI, 1.13-1.61), divorced (HR, 1.38; 95% CI, 1.13-1.69), and widowed (HR, 1.09; 95% CI, 1.04-1.13). In subgroup analyses, the positive association persisted across baseline health conditions, and the risk of death was more pronounced among men or people younger than 65 years. Conclusions and Relevance: This large pooled cohort study of individual participant data provides strong evidence that being unmarried, as well as belonging to the unmarried subcategories, was positively associated with total and cause-specific mortality. Investment of targeted social support services might need to be considered in light of the mortality differences between married and unmarried individuals.

Sugary drink consumption and risk of kidney and bladder cancer in Japanese adults.

Globally, sugary drinks are widely consumed, however, few epidemiologic studies have investigated the association between sugary drink consumption and risk of kidney and bladder cancer. We examined the association of sugary drinks with risk of kidney and bladder cancer in 73,024 participants from the Japan Public Health Center-based Prospective Study who reported no history of cancer. Sugary drink consumption was assessed using a validated food frequency questionnaire at study baseline (1995-1999). Individuals were followed to December 31, 2013. Multivariable Cox proportional hazards regression models were used to calculate hazard ratios (HR) and 95% confidence intervals (CIs). During 1,069,815 person years of follow-up, 169 kidney cancer and 297 bladder cancer cases were documented. After adjusting for potential confounders, no greater risk of kidney and bladder cancer was observed. However, sugary drink consumption was positively associated with the risk of kidney cancer (HR for 100 ml/day increase in consumption was 1.11 [95% CI 1.01-1.22]) and bladder cancer (HR for 100 ml/d increase in consumption was 1.11 [95% CI 1.01-1.22]) among women after exclusion of cases diagnosed in the first three years of follow-up. In this large prospective cohort, consumption of sugary drinks was significantly associated with a small increase in hazard ratio for kidney and bladder cancer among women after exclusion of cases diagnosed within the first three years.

Sugary Drink Consumption and Subsequent Colorectal Cancer Risk: The Japan Public Health Center-Based Prospective Cohort Study.

BACKGROUND: Most studies examining the associations of sugary drink consumption on colorectal cancer risk have been conducted in Western populations. METHODS: This study consisted of 74,070 participants in the Japan Public Health Center-based Prospective Study who completed a food frequency questionnaire (1995-1999). The participants were followed until December 2013 to investigate the associations between sugary drink consumption and colorectal cancer risk using Cox proportional hazards regression models. RESULTS: Among the 74,070 participants, mean age was 56.5 years at baseline, with a mean body mass index (BMI) of 23.5 and a mean daily consumption of 286 mL/day for men and 145 mL/day for women. During a follow-up of 15 years, 1,648 colorectal cancer cases were identified. No overall greater risk of colorectal cancer was observed among men [multivariable HR = 0.84; 95% confidence of interval (CI), 0.70-1.02; ≥254 mL/day vs. nonconsumers] and women (HR = 1.20; 95% CI, 0.96-1.50, ≥134 mL/day vs. nonconsumers). Sugary drink consumption was associated with colon cancer among women (HR = 1.36; 95% CI, 1.03-1.78, ≥134 mL/day vs. nonconsumers). HRs for proximal colon cancer among women who consumed sugary drinks, as compared with nonconsumers, were 1.47 (95% CI, 1.03-2.10) for sugary drink consumption less than 134 mL/day, and 1.45 (95% CI, 1.01-2.09) for at least 134 mL/day. CONCLUSIONS: In this large prospective cohort of Japanese with a moderate sugary drink consumption level and low prevalence of obesity, we observed a 36% increased risk of colon cancer in women. IMPACT: Our findings highlight the importance of subsite- and sex-specific investigation.

Mass-like Dieulafoy's lesion associated with advanced gastric cancer at the antrum of stomach: a case report and literature review.

BACKGROUND: Dieulafoy's lesion, also known as a caliber-persistent artery, is a shallow, small, and rare lesion that occurs along the lesser curvature of proximal stomach. It is rare for a Dieulafoy's lesion to present as a mass-like lesion that coexists with gastric cancer. To our best knowledge, we report the first case and histopathological pictures of a mass-like Dieulafoy's lesion coexisting with advanced gastric cancer in the antrum of the stomach. CASE PRESENTATION: A 57-year-old female presented with a 6-month history of intermittent epigastric dull pain and dyspepsia. Subsequent upper gastrointestinal endoscopy revealed a friable mass that was located between the distal antrum and the pyloric ring. Biopsy revealed it to be an intestinal type adenocarcinoma. Subtotal gastrectomy was performed after neoadjuvant chemotherapy. Grossly, a large irregular plaque-like tumor lesion was noted at the anterior wall of the distal antrum and pylorus ring near the lesser curvature, measuring 5.6 × 4.8 × 1.0 cm. Histopathological examination of the resected stomach revealed that the plaque-like lesion largely consisted of numerous abnormally large-caliber and tortuous arteries in the submucosa. The increased fibrosis of the submucosa resulted in the formation of elevated plaque. The intestinal type adenocarcinoma was noted to be largely confined to the mucosa layer, with focal submucosal and muscular propria involvement. The patient was discharged one week after the subtotal gastrectomy, and she was alive and well 17 months after discharge, with no major complications. CONCLUSION: This is the first case of a mass-like Dieulafoy's lesion coexisting with advanced gastric cancer at the distal antrum area. This case highlights the possibility of life-threatening gastric bleeding after mucosal resection or biopsy that could be encountered by endoscopists.

Novel mutations in the PATCHED gene in basal cell nevus syndrome.

Basal cell nevus syndrome (BCNS) is an autosomal dominant disease characterized by the presence of multiple basal cell carcinomas, odontogenic keratocysts, palmoplantar pits, and calcification in the falx cerebri caused by mutational inactivation of the PTCH gene. To investigate the molecular basis of BCNS in Chinese, we did a mutational analysis of the PTCH gene by performing denaturing high-performance liquid chromatography in three BCNS families. In this study, three novel mutations, two 1-bp frameshift insertions, i.e., 1468insA and 2392insC, and one 8-bp deletion, i.e., IVS5 + 1delGTAAGTGT, affecting a donor splice site, were identified. All the mutations cause a shift of the open reading frames and lead to premature termination of PTCH protein translation. Our results showed that mutational inactivation of the PTCH gene causes BCNS in Chinese.