Clinical outcomes of coronavirus disease in patients with breast cancer treated with granulocyte colony-stimulating factor following chemotherapy: Triangulation of evidence using population-based cohort and Mendelian randomization analyses.

Recombinant human granulocyte colony-stimulating factor (G-CSF) administration in patients with cancer and coronavirus disease (COVID-19) remains controversial. Concerns exist that it may worsen COVID-19 outcomes by triggering an inflammatory cytokine storm, despite its common use for managing chemotherapy-induced neutropenia (CIN) or febrile neutropenia post-chemotherapy. Here, we determined whether prophylactic or therapeutic G-CSF administration following chemotherapy exacerbates COVID-19 progression to severe/critical conditions in breast cancer patients with COVID-19. Between December 2022 and February 2023, all 503 enrolled breast cancer patients had concurrent COVID-19 and received G-CSF post-chemotherapy, with most being vaccinated pre-chemotherapy. We prospectively observed COVID-19-related adverse outcomes, conducted association analyses, and subsequently performed Mendelian randomization (MR) analyses to validate the causal effect of genetically predicted G-CSF or its associated granulocyte traits on COVID-19 adverse outcomes. Only 0.99% (5/503) of breast cancer patients experienced COVID-19-related hospitalization following prophylactic or therapeutic G-CSF administration after chemotherapy. No mortality or progression to severe/critical COVID-19 occurred after G-CSF administration. Notably, no significant associations were observed between the application, dosage, or response to G-CSF and COVID-19-related hospitalization (all p >.05). Similarly, the MR analyses showed no evidence of causality of genetically predicted G-CSF or related granulocyte traits on COVID-19-related hospitalization or COVID-19 severity (all p >.05). There is insufficient evidence to substantiate the notion that the prophylactic or therapeutic administration of G-CSF after chemotherapy for managing CIN in patients with breast cancer and COVID-19 would worsen COVID-19 outcomes, leading to severe or critical conditions, or even death, especially considering the context of COVID-19 vaccination.

Inequality in benefit distribution of reducing the outpatient cost-sharing: evidence from the outpatient pooling scheme in China.

Objective: The implementation of the outpatient pooling scheme in China has substantially elevated the compensation levels for outpatient expenses. This study aims to assess whether socioeconomically disadvantaged enrollees benefit proportionally compared to their non-disadvantaged counterparts. Method: A cohort comprising 14,581 Urban and Rural Resident Basic Medical Insurance (URRBMI) enrollees and 830 Urban Employee Basic Medical Insurance (UEBMI) enrollees was derived from the China Health and Retirement Longitudinal Study 2018. Outpatient pooling scheme benefits were evaluated based on two metrics: the probability of obtaining benefits and the magnitude of benefits (reimbursement amounts and ratios). Two-part models were employed to adjust outpatient benefits for healthcare needs. Inequality in benefit distribution was assessed using the concentration curve and concentration index (CI). Results: Following adjustments for healthcare needs, the CI for the probability of receiving outpatient benefits for URRBMI and UEBMI enrollees were - 0.0760 and - 0.0514, respectively, indicating an evident pro-poor pattern under the outpatient pooling scheme. However, the CIs of reimbursement amounts (0.0708) and ratio (0.0761) for URRBMI recipients were positive, signifying a discernible pro-rich inequality in the degree of benefits. Conversely, socioeconomically disadvantaged UEBMI enrollees received higher reimbursement amounts and ratios. Conclusion: Despite a higher likelihood of socioeconomically disadvantaged groups receiving outpatient benefits, a pro-rich inequality persists in the degree of benefits under the outpatient pooling scheme in China. Comprehensive strategies, including expanding outpatient financial benefits, adopting distinct reimbursement standards, and enhancing the accessibility of outpatient care, need to be implemented to achieve equity in benefits distribution.

Whole-tumor histogram models based on quantitative maps from synthetic MRI for predicting axillary lymph node status in invasive ductal breast cancer.

PURPOSE: To investigate the potential of using histogram analysis of synthetic MRI (SyMRI) images before and after contrast enhancement to predict axillary lymph node (ALN) status in patients with invasive ductal carcinoma (IDC). METHODS: From January 2022 to October 2022, a total of 212 patients with IDC underwent breast MRI examination including SyMRI. Standard T2 weight images, DCE-MRI and quantitative maps of SyMRI were obtained. 13 features of the entire tumor were extracted from these quantitative maps, standard T2 weight images and DCE-MRI. Statistical analyses, including Student's t-test, Mann-Whiney U test, logistic regression, and receiver operating characteristic (ROC) curves, were used to evaluate the data. The mean values of SyMRI quantitative parameters derived from the conventional 2D region of interest (ROI) were also evaluated. RESULTS: The combined model based on T1-Gd quantitative map (energy, minimum, and variance) and clinical features (age and multifocality) achieved the best diagnostic performance in the prediction of ALN between N0 (with non-metastatic ALN) and N+ group (metastatic ALN ≥ 1) with the AUC of 0.879. Among individual quantitative maps and standard sequence-derived models, the synthetic T1-Gd model showed the best performance for the prediction of ALN between N0 and N+ groups (AUC = 0.823). Synthetic T2_entropy and PD-Gd_energy were useful for distinguishing N1 group (metastatic ALN ≥ 1 and ≤ 3) from the N2-3 group (metastatic ALN > 3) with an AUC of 0.722. CONCLUSIONS: Whole-tumor histogram features derived from quantitative parameters of SyMRI can serve as a complementary noninvasive method for preoperatively predicting ALN metastases.

Comparative efficacy and safety of extended adjuvant endocrine therapy for hormone receptor-positive early breast cancer: a Bayesian network meta-analysis.

PURPOSE: Optimal extended adjuvant endocrine therapy (ET) duration and strategy for hormone receptor-positive (HR +) early breast cancer remain unclear. In this network meta-analysis (NMA), the efficacy and safety of all available extended adjuvant ETs were compared and ranked. METHODS: PubMed, Embase, and Cochrane Library and abstracts presented at ASCO, SABCS, and ESMO were searched on March 5, 2022. Fourteen randomized controlled trials (RCTs) comprising eight extended adjuvant ETs for HR + breast cancer and 38,070 patients were analyzed. Main outcomes were disease-free survival (DFS), overall survival (OS), grade ≥ 3 adverse events (AEs), and contralateral breast cancer (CBC). Direct and indirect comparisons were integrated via Bayesian NMA. Hierarchical cluster analysis was performed to jointly rank efficacy and safety outcomes. RESULTS: Compared with that of 5 year ET, extended 10 year aromatase inhibitor (AI) treatment provided the greatest DFS benefit (HR = 0.45, 95%CrI 0.23-0.83), whereas no strategy differed significantly in terms of the other main outcomes. Extended 10 year AI treatment was the preferred strategy for DFS improvement and CBC prevention (surface under the cumulative ranking curve: 93.51% and 91.29% probability, respectively). All strategies had comparable safeties (grade ≥ 3 AEs). Compared with that of 5 year ET, 10 year extended AI significantly increased arthralgia (OR = 1.65, 95%CrI 1.02-2.93) and osteoporosis (OR = 3.33, 95%CrI 1.19-9.68). CONCLUSION: Extended 10 year AI therapy may be optimal for HR + early breast cancer given its relatively high efficacy and safety.

Prognostic Value of Immunohistochemistry-based Subtyping Before and After Neoadjuvant Chemotherapy in Patients with Triple-negative Breast Cancer.

To assess the predictive and prognostic value of a subtyping method based on immunohistochemistry in patients with triple-negative breast cancer (TNBC) treated with neoadjuvant chemotherapy (NAC). This study included patients with TNBC treated with anthracycline- and taxane-based NAC and curative surgery. Immunohistochemical (IHC) subtyping was performed using core needle biopsy specimens before NAC (pre-NAC) and residual tumors after NAC (post-NAC). Logistic regression was performed to identify predictive biomarkers of pathological complete response (pCR). Invasive disease-free survival (iDFS), distant disease-free survival (DDFS), and overall survival (OS) were assessed using the log-rank test and Cox proportional hazards regression. A total of 230 patients were followed up for a median of 59 months. Clinical lymph node status and the pre-NAC subtype were independent predictors of pCR (P=0.006 and 0.005, respectively). The pre-NAC subtype was an independent prognostic factor for long-term survival (iDFS: P < 0.001, DDFS: P=0.010, and OS: P=0.044). Among patients with residual disease (RD) after NAC, approximately 45% of tumors changed their IHC subtype. Furthermore, the post-NAC subtype, but not the pre-NAC subtype, was strongly associated with the survival of patients with RD (iDFS: P < 0.001, DDFS: P=0.005, and OS: P=0.006). The IHC subtype predicted response to NAC and long-term survival in patients with early TNBC. In patients with RD, almost 45% of the tumors changed subtype after NAC. The IHC subtype should be considered when planning additional therapies pre- and post-NAC.

Mediating and Moderating Effects of Internet Use on Urban-Rural Disparities in Health Among Older Adults: Nationally Representative Cross-Sectional Survey in China.

BACKGROUND: The urban-rural disparities in health outcomes in China are remarkable. The internet has shown the potential to reduce the likelihood of contracting a disease by increasing disease knowledge. However, little is known about the effects of internet use in alleviating health inequities between urban and rural areas. OBJECTIVE: This study aimed to examine the mediation and moderation of health disparities between urban and rural older adults through internet use. METHODS: A total of 8223 respondents were selected from the China Health and Retirement Longitudinal Study 2018 data set. Basic activities of daily living, a brief Community Screening Instrument for Dementia, and the Centre for Epidemiologic Studies Depression Scale were used to measure functional disability, cognitive function, and depressive symptoms, respectively. Logistic regressions testing "internet use×urban-rural status" interactions for moderation and Karlson-Holm-Breen decomposition for mediation were performed. RESULTS: Internet use moderated the urban-rural disparities in cognitive function (odds ratio 7.327, 95% CI 3.011-17.832) and depressive symptoms (odds ratio 1.070, 95% CI 1.037-1.787), but the moderating effects were significant only for those using the internet daily. Karlson-Holm-Breen results showed the suppression effects of using the internet daily (ß=.012, 95% CI .002-.021) on the association between urban-rural status and cognitive function. The urban-rural inequality in depressive symptoms was partially attributed to the disparity in internet use (ß=-.027, 95% CI -.043 to -.009). CONCLUSIONS: The urban-rural inequalities in mental health are partially attributable to disparities in the prevalence of internet use between the 2 groups. However, using the internet is more beneficial for the psychological health of rural users, thereby alleviating the urban-rural disparities in health. Providing convenient channels for rural older adults to use the internet, improving the ability of rural users to effectively use the internet, and promoting internet popularity in rural areas are effective approaches to reducing urban-rural health inequalities.

Bisphenol A substitutes and childhood obesity at 7 years: a cross-sectional study in Shandong, China.

Bisphenol A (BPA) substitutes, such as bisphenol S (BPS) and bisphenol AF (BPAF), are increasingly used due to restrictions on BPA usage, a known endocrine disrupting chemical and putative obesogen. However, little is known about the obesogenic effects of exposure to BPA substitutes in children. A total of 426 children aged 7 years old originally recruited from Laizhou Wan Birth Cohort in Shandong, China, during 2010-2013 participated in the 2019-2020 survey. Urinary BPA and its substitutes including BPS, BPAF, bisphenol B (BPB), bisphenol AP (BPAP), bisphenol Z (BPZ), and bisphenol P (BPP) were determined. Anthropometric measures including height, weight, waist circumference, and body fat percentage were assessed, and overweight/obesity was defined as BMI z-score ≥ 85th percentile. Linear and logistic regressions were used on continuous and binary obesity measures, respectively, and weighted quantile sum (WQS) regression was further used to estimate the mixture effects of exposure to diverse bisphenols, and sex-stratified analysis was performed. BPA substitutes were widely detected (> 75%) in children's urine samples. A positive association with obesity measures was consistently observed for urinary BPS and BPAF, i.e., BMI z-score, waist circumference, and overweight/obesity. Further analysis from the WQS regression model demonstrated a positive association between bisphenol mixtures and all measures of obesity, with BPAF contributing the greatest weighing to the observed associations. Sex difference might exist as the positive associations were only significant in boys. No significant association was found between obesity and BPA or other BPA substitutes. Our study adds to mounting evidence that BPA substitutes BPS and BPAF are linked to obesity in children, especially in boys. Further longitudinal studies with larger sample size with continued biomonitoring these chemicals and their obesogenic effects are necessary.

Impact of body mass index in therapeutic response for HER2 positive breast cancer treated with neoadjuvant targeted therapy: a multi-center study and meta-analysis.

While overweight/obesity has become a major public health issue worldwide, any association between body mass index (BMI) and therapeutic response in neoadjuvant targeted therapy treated HER2 positive breast cancer patients remain unclear. The information from a total of four-hundred and ninety-one neoadjuvant targeted therapy treated HER2 positive breast cancer patients from four institutions were retrospectively collected. Univariate and multivariate logistic analysis was developed to determine the association between BMI and therapeutic response. A meta-analysis of published literature was then conducted to confirm the effect of overweight/obesity on pCR for patients treated with neoadjuvant targeted therapy. Restricted cubic spline (RCS) adjusted for confounding factors demonstrated a decrease pCR with increasing BMI (OR = 0.937, P = 0.045). Patients were then categorized into under/normal weight (n = 299) and overweight/obesity (n = 192). Overweight/obese patients were independently associated with a poor therapeutic response. In the subgroup analysis, a significant negative impact of overweight/obesity on pCR can be observed both in single-targeted (OR = 0.556; P = 0.02) and dual-targeted (OR = 0.392; P = 0.021) populations. Six eligible studies involving 984 neoadjuvant targeted therapy treated HER2 positive breast cancer patients were included in the meta-analysis. The meta-analysis also demonstrated that overweight/obesity was significantly associated with a poor response to neoadjuvant anti-HER2 therapy (OR = 0.68; P = 0.007). Our result show that overweight and obese HER2 positive breast cancer patients are less likely to achieve pCR after neoadjuvant targeted therapy.

High leukocyte mitochondrial DNA copy number contributes to poor prognosis in breast cancer patients.

BACKGROUND: Compelling evidence has indicated a significant association between leukocyte mitochondrial DNA copy number (mtDNAcn) and prognosis of several malignancies in a cancer-specific manner. However, whether leukocyte mtDNAcn can predict the clinical outcome of breast cancer (BC) patients has not been well investigated. METHODS: The mtDNA copy number of peripheral blood leukocytes from 661 BC patients was measured using a Multiplex AccuCopy™Kit based on a multiplex fluorescence competitive PCR principle. Kaplan-Meier curves and Cox proportional hazards regression model were applied to investigate the association of mtDNAcn with invasive disease-free survival (iDFS), distant disease-free survival (DDFS), breast cancer special survival (BCSS), and overall survival (OS) of patients. The possible mtDNAcn-environment interactions were also evaluated by the Cox proportional hazard regression models. RESULTS: BC patients with higher leukocyte mtDNA-CN exhibited a significantly worse iDFS than those with lower leukocyte mtDNAcn (5-year iDFS: fully-adjusted model: HR = 1.433[95%CI 1.038-1.978], P = 0.028). Interaction analyses showed that mtDNAcn was significantly associated with hormone receptor status (adjusted p for interaction: 5-year BCSS: 0.028, 5-year OS: 0.022), so further analysis was mainly in the HR subgroup. Multivariate Cox regression analysis demonstrated that mtDNAcn was an independent prognostic factor for both BCSS and OS in HR-positive patients (HR+: 5-year BCSS: adjusted HR (aHR) = 2.340[95% CI 1.163-4.708], P = 0.017 and 5-year OS: aHR = 2.446 [95% CI 1.218-4.913], P = 0.011). CONCLUSIONS: For the first time, our study demonstrated that leukocyte mtDNA copy number might influence the outcome of early-stage breast cancer patients depending on intrinsic tumor subtypes in Chinese women.

Impacts of Outpatient Payment Reforms on Volume and Expenditures in Public Hospitals: Evidence from a Quasi-Experimental Analysis in Zhejiang, China.

Purpose: China developed an innovative episode-based payment scheme for outpatient care, namely "Ambulatory Patient Groups (APGs) + capitation" payment, to constrain inflation in outpatient expenditures. This study aimed to assess the effects of this payment method on volume and expenditures in Chinese public hospitals. Methods: A quasi-experimental study was conducted with 7 municipal and 12 county hospitals from Jinhua as the intervention group and 15 municipal and 24 county hospitals from three neighbouring cities as the control group. The payment reform was introduced to municipal and county hospitals in the intervention group in January 2020 and January 2021, respectively. Monthly data on volumes and outpatient expenditures were collected from each hospital from January 2019 to December 2021. Controlled interrupted time-series analyses were performed to determine the effects of the funding reforms. Results: Outpatient visits in municipal hospitals decreased by 1417.54 (p=0.048) per month on average compared with control ones after the reform was implemented, whilst that in county hospitals increased by 1058.04 (p=0.041) per month on average. The trend of drug expenditures (ß 7=-1.41, p=0.019) in municipal hospitals dropped, which was accompanied by an immediate reduction in consumable expenditures (ß 6 =-6.89, p=0.044). The funding reform also led to the significant declines in drug (ß 6=-10.96, p=0.009) and consumable (ß 6=-4.78, p=0.041) expenditures in county hospitals. Municipal hospitals experienced the drop in the trend of total outpatient expenditures (ß 7=-3.99, p=0.018) over the same period. Conclusion: The strength of the "AGPs + capitation" payment for outpatient care lies in its ability to control the excessive growth of medical expenses through correcting inappropriate incentives. However, minimising potential cost-shifting and risk-shifting to uninsured service items should be given attention.

Sexual assault and associated factors among middle school students in one city of Sichuan Province / 中国学校卫生

Objective@#To understand the current situation and influencing factors of sexual assault among middle school students, and to provide a basis for promoting healthy psychosocial environment for children and adolescents.@*Methods@#A questionnaire survey was conducted among 1 471 middle school students in one city of Sichuan Province from April to May 2020 using multi stage stratified cluster sampling.@*Results@#The proportion of middle school students who have been raped, indecent assault and sexual assault was 1.6%, 3.7% and 9.4%, respectively. About 23.8% of them had suffered two or more types of sexual assault; 75.1 % to 82.1% of sexual assault occurred between the ages of 9 and 15. Between 36.3% and 62.3% of sexual assault subjects were acquaintances of the same generation. Pornography exposure was the same risk factor for the three types of sexual assault (rape: OR= 9.93, 95%CI =3.09-27.57; sexual obscenity: OR=7.83, 95%CI =3.95-15.53; sexual harassment: OR=5.22, 95%CI= 3.52- 7.73, P <0.01). Low gender identity was the same risk factor for both suffering sexual obscenity and sexual harassment (sexual obscenity: OR=2.37, 95%CI =1.31-4.29; sexual harassment: OR=1.73, 95%CI=1.16-2.58, P <0.01). The long term absence of mothers was a risk factor for suffering sexual rape among middle school students ( OR=3.10, 95%CI =1.31-7.30), as well as father s sex education was a risk factor for suffering sexual obscenity among middle school students ( OR=2.52, 95%CI = 1.26 - 5.03 )( P <0.01).@*Conclusion@#Pornography exposure is the same risk factor for all types of sexual assault among middle school students. Low gender identity is the same risk factor for indecent assault and sexual harassment. Sexual education capabilities of families and schools should be improved, and attention should be paid to the gender identity and sexual mental health of middle school students.

Clinical application of artificial neural network (ANN) modeling to predict BRCA1/2 germline deleterious variants in Chinese bilateral primary breast cancer patients.

BACKGROUND: Bilateral breast cancer (BBC), as well as ovarian cancer, are significantly associated with germline deleterious variants in BRCA1/2, while BRCA1/2 germline deleterious variants carriers can exquisitely benefit from poly (ADP-ribose) polymerase (PARP) inhibitors. However, formal genetic testing could not be carried out for all patients due to extensive use of healthcare resources, which in turn results in high medical costs. To date, existing BRCA1/2 deleterious variants prediction models have been developed in women of European or other descent who are quite genetically different from Asian population. Therefore, there is an urgent clinical need for tools to predict the frequency of BRCA1/2 deleterious variants in Asian BBC patients balancing the increased demand for and cost of cancer genetics services. METHODS: The entire coding region of BRCA1/2 was screened for the presence of germline deleterious variants by the next generation sequencing in 123 Chinese BBC patients. Chi-square test, univariate and multivariate logistic regression were used to assess the relationship between BRCA1/2 germline deleterious variants and clinicopathological characteristics. The R software was utilized to develop artificial neural network (ANN) and nomogram modeling for BRCA1/2 germline deleterious variants prediction. RESULTS: Among 123 BBC patients, we identified a total of 20 deleterious variants in BRCA1 (8; 6.5%) and BRCA2 (12; 9.8%). c.5485del in BRCA1 is novel frameshift deleterious variant. Deleterious variants carriers were younger at first diagnosis (P = 0.0003), with longer interval between two tumors (P = 0.015), at least one medullary carcinoma (P = 0.001), and more likely to be hormone receptor negative (P = 0.006) and HER2 negative (P = 0.001). Area under the receiver operating characteristic curve was 0.903 in ANN and 0.828 in nomogram modeling individually (P = 0.02). CONCLUSION: This study shows the spectrum of the BRCA1/2 germline deleterious variants in Chinese BBC patients and indicates that the ANN can accurately predict BRCA deleterious variants than conventional statistical linear approach, which confirms the BRCA1/2 deleterious variants carriers at the lowest costs without adding any additional examinations.

Thrombospondin 2 is a Functional Predictive and Prognostic Biomarker for Triple-Negative Breast Cancer Patients With Neoadjuvant Chemotherapy.

Background: Triple-negative breast cancer (TNBC) is characterized by a more aggressive biological behavior and unfavorable outcome. Circulating and histological expression of THBS2 has been demonstrated to be a novel diagnostic and prognostic biomarker in patients with various types of tumors. However, few studies have evaluated the predictive and prognostic value of THBS2 in TNBC specifically. Methods: In total, 185 triple-negative breast cancer patients (TNBC) with preoperative neoadjuvant chemotherapy were enrolled in this study. Serum THBS2 (sTHBS2) level was measured both prior to the start of NAC and at surgery by enzyme-linked immunosorbent assay (ELISA). Histological THBS2 (hTHBS2) expression in patients with residual tumors was evaluated by immunohistochemistry (IHC) staining method. Correlations between variables and treatment response were studied. Kaplan-Meier plots and Cox proportional hazard regression model were applied for survival analysis. Functional activities of THBS2 in TNBC cells were determined by CCK-8 assay, colony formation, wound healing, and transwell assay. Results: Of the 185 patients, 48 (25.9%) achieved pathological complete response (pCR) after completion of NAC. Elevated pCR rates were observed in patients with a lower level of sTHBS2 at surgery and higher level of sTHBS2 change (OR = 0.88, 95%CI: 0.79-0.98, p = 0.020 and OR = 1.12, 95%CI: 1.02-1.23, p = 0.015, respectively). In survival analysis, hTHBS2 expression in residual tumor was of independent prognostic value for both disease-free survival (HR = 2.21, 95%CI = 1.24-3.94, p = 0.007) and overall survival (HR = 2.07, 95%CI = 1.09-3.92, p = 0.026). For functional studies, THBS2 was indicated to inhibit proliferation, migration, and invasion abilities of TNBC cells in vitro. Conclusion: Our findings confirmed the value of serum THBS2 level to predict pCR for TNBC patients and the prognostic performance of histological THBS2 expression in non-pCR responders after NAC. THBS2 might serve as a promising functional biomarker for patients with triple-negative breast cancer.

[Effectiveness of Different Testing Strategies Applied for Cervical Cancer Screening in Shuangliu District, Chengdu City].

Objective: To evaluate the clinical value of different combination strategies of high-risk HPV (hr-HPV) testing and Thinprep cytology test (TCT), a cervical cytology test, for cervical cancer screening, especially for high or higher-grade squamous intraepithelial lesion (HSIL+) in Shuangliu District, Chengdu City. Methods: The study is a population-based randomized clinical trial. Women aged 35 to 65 years meeting the inclusion criteria were enrolled for the study. At the baseline screening conducted in the first year, the participants were randomly assigned to either cytology test or hr-HPV testing at a ratio of 1∶2. If the paticipants had positive results for the baseline hr-HPV test, they would then undergo either cytology test or colposcopy by random assignment. After 24 months, all participants were called back, and combined screening of cytology test and hr-HPV test were performed. Women who had negative results at baseline screening and who entered and completed the third-year follow-up were selected as the subjects of the study. Based on the aforementioned testing findings, the related data were extracted and four different screening protocols were simulated: 1) combined TCT and hr-HPV screening, with referral for colposcopy when there was positive results for either one of the two; 2) combined TCT and hr-HPV screening, with referral for colposcopy when both tests had positive results at the same time; 3) TCT was done for preliminary screening and those who were found to be positive would then undergo hr-HPV test for triage purpose, with subsequent referral made for colposcopy if the hr-HPV results were positive; 4) hr-HPV was done for preliminary screening and those who were found to be positive would then undergo TCT, with subsequent referral made for colposcopy if TCT results were positive. With the detection of HSIL+ on histological examination as the endpoint event, the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and area under curve ( AUC) of different combination screening models were calculated. Results: A total of 3102 women were screened, and 2967 women were included in the statistical analysis in this study. Among the 2967 women, 979 were randomized to cytology and 1988 to hr-HPV genotyping. For prescreening, the positive rate of the cytology group was 5.6% (55/979), with of HSIL+ positive rate being 0.2% (2/979), while the positive rate of the hr-HPV group was 7.5% (149/1988), with HSIL+ positive rate being 0.9% (18/1988). After 24 months, 2456 women were called back and were given cervical cytology test and hr-HPV test at the same time. Among them, the positive rate of the cytology group was 3.2% (78/2456), while the positive rate of hr-HPV group was 8.7% (215/2456). The overall positive rate of HSIL+ was 0.69%(17/2456). Women with a negative baseline hr-HPV had a lower incidence of HSIL+ lesions in the long term. The strategy of cervical cytology screening combined with hr-HPV test for triage purpose is the best method, with a sensitivity of 88.9%, a specificity of 58.3%, a PPV of 44.4%, a NPV of 93.3%, and an AUC of 0.736, P=0.039 (95% CI: 0.555-0.917). Conclusion: This randomized clinical trial from Shuangliu District, Chengdu City shows that the sensitivity of hr-HPV testing is better than that of cytology test, and the prevalence of HSIL+ in women with negative baseline hr-HPV results is lower than that of women with negative baseline cytology results. The screening program of TCT for prescreening plus subsequent hr-HPV test for triage purpose shows better value for the detection of HSIL+.

Improved false-negative rates using a novel patient selection flowchart in initially biopsy-proven node-positive breast cancer undergoing blue-dye alone guided sentinel lymph node biopsy after neoadjuvant chemotherapy.

PURPOSE: Current trials support the application of sentinel lymph node biopsy (SLNB) in node-positive breast cancer treated with neoadjuvant chemotherapy (NAC) with a lower false-negative rate (FNR) if dual-tracer (radioisotope and blue-dye) is used. However, radioisotopes are not available in many areas of the world. In this study, we evaluated the feasibility and accuracy of SLNB mapped with methylene-blue-dye alone. METHODS: This study enrolled 132 patients with biopsy-proven node-positive breast cancer with a clip placed in the positive node who then received NAC. After chemotherapy and before operation, all patients underwent axillary ultrasound (AUS) assessment and were classified as either negative (AUS-) or positive (AUS +) according to the axillary status. All patients underwent both SLNB and axillary lymph node dissection (ALND). SLNB was mapped with methylene-blue-dye alone. FNRs were evaluated on factors potentially affecting false-negative SLN finding. RESULTS: Using methylene-blue-dye alone, the FNR of SLNB was 9.9%. Post-NAC AUS assessment (p = 0.009) and the number of SLNs retrieved (p = 0.029) showed association with FNRs in multivariate analysis. In AUS- group, FNR was as low as 2.5%. In AUS + group, retrieving ≥ 4 SLNs including the clipped node improved FNR from 17.1% to 4.8%. A flowchart was designed with the combination of post-NAC AUS assessment, retrieved SLN number, and the retrieved of clipped node further improve overall FNR to 3.3%. CONCLUSION: In biopsy-proven node-positive breast cancer treated with NAC, using a flowchart to optimize patient selection reduces the FNR of single-tracer (methylene-blue-dye) guided SLNB.

Associations between repeated measurements of childhood triclosan exposure and physical growth at 7 years.

BACKGROUND: Epidemiological studies suggested that triclosan (TCS) exposure was ubiquitous among children and could affect their physical growth. However, most studies relied on TCS exposure at single time point, and the impacts of multiple time points TCS exposure were unclear. OBJECTIVES: To estimate the associations between repeated TCS measurements in childhood (at ages 1, 2, 5, and 7 years) and physical growth at 7 years. METHODS: This study included 206 children from Laizhou Wan Birth Cohort (LWBC), China. Urinary TCS concentrations were detected at age of 1, 2, 5, and 7 years, and physical growth including height, weight, waist circumference, and fat percentage was measured at 7 years. Multiple informant models were applied to examine the relationships of repeated TCS measurements in childhood with physical growth, and stratified analysis by gender was performed. RESULTS: The detection rates of TCS at age of 1, 2, 5, and 7 years were above 60%, with median declining from 0.89 to 0.33 µg/g creatinine. We found TCS at 5 years was positively associated with waist-to-height ratio, and TCS at 7 years was positively associated with physical growth, including weight z-score, BMI z-score, waist circumference, waist-to-height ratio, and fat percentage. Moreover, the above associations for weight z-score, BMI z-score, and fat percentage significantly varied by the period of exposure (pint ˂ 0.05). After stratified by gender, positive associations were only found among boys. CONCLUSIONS: In our study, TCS levels decreased as children's age increased. TCS exposures at age of 5 and 7 years were positively associated with physical growth at 7 years, and these associations were only significant in boys. Given the relatively small sample size, our findings should be interpreted with caution until confirmed by further investigation.

Associations between Adverse Childhood Experiences and Obesity in a Developing Country: A Cross-Sectional Study among Middle-Aged and Older Chinese Adults.

BACKGROUND: The association between adverse childhood experiences (ACEs) and obesity in developing countries has been underexplored and inconsistent. METHODS: This cross-sectional study used data of 10,054 adults aged ≥ 45 years from the China Health and Retirement Longitudinal Study. Information on 12 ACE indicators was collected via questionnaires. General obesity was defined as a body mass index (BMI) of ≥28 kg/m². Central obesity was defined as a waist circumference of ≥90 cm for males and ≥85 cm for females. Logistic and linear regression analyses were conducted to evaluate the association of ACEs with general obesity, central obesity, BMI, and waist circumference where appropriate. RESULTS: Compared to the non-exposed group, the experience of ≥3 ACEs was significantly associated with decreased risks of general obesity (OR = 0.83, 95% CI: 0.69, 0.999), central obesity (OR = 0.88, 95% 0.77, 0.997), and smaller BMI (ß = -0.27, 95% CI: -0.50, -0.04) and waist circumference (ß = -0.89, 95% CI: -1.52, -0.26). Compared to the high socioeconomic status (SES) group, such associations were more evident in those with a low SES, except for central obesity. CONCLUSION: ACEs were shown to be inversely associated with later-life obesity in China, especially in socioeconomically disadvantaged populations. The context-specific impacts reflect divergent roles of socioeconomic position in the obesity epidemic between developed and developing countries. Further investigations are needed to confirm whether physical activity could shift the direction of this association.

YTHDF3 facilitates triple-negative breast cancer progression and metastasis by stabilizing ZEB1 mRNA in an m6A-dependent manner.

Background: The YTH domain family protein 3 (YTHDF3) is an important N6-methyladenosine (m6A) reader which is involved in multiple cancers. However, the biological role and mechanisms of action for YTHDF3 in triple-negative breast cancer (TNBC) remains to be elucidated. Methods: The expression of YTHDF3 in TNBC tissues was evaluated using The Cancer Genome Atlas (TCGA) database, BC-GenExMiner, and immunohistochemistry (IHC) staining. Cell migration, invasion, and epithelial-mesenchymal transition (EMT) were validated by wound healing assays, transwell assays, and Western blot (WB) analyses. The association between YTHDF3 and zinc finger E-box-binding homeobox 1 (ZEB1) was confirmed by Pearson correlation analysis. RNA-binding protein immunoprecipitation (RIP) assays and mRNA actinomycin stability analyses were applied to confirm whether YTHDF3 could interact with ZEB1in an m6A-dependent manner. Results: The expression of YTHDF3 was correlated with poorer disease-free survival (DFS) and overall survival (OS) in TNBC patients. Functional experiments indicated that YTHDF3 positively regulated cell migration, invasion, and EMT in TNBC cells. Moreover, ZEB1 was identified as a key downstream target for YTHDF3 and YTHDF3 could enhance ZEB1 mRNA stability in an m6A-dependent manner. Inhibition of YTHDF3 reduced migration, invasion, and EMT, all of which were reversed by rescue experiments overexpressing ZEB1. Conclusions: The findings herein confirmed that the YTHDF3/ZEB1 axis plays an important role in the progression and metastasis of TNBC. YTHDF3 is a promising prognosis biomarker and potential therapeutic target for patients with TNBC.

Integrative proteomic and phosphoproteomic profiling of invasive micropapillary breast carcinoma.

Invasive micropapillary carcinoma (IMPC) is a rare subtype of breast cancer with an aggressive phenotype and a poor prognosis. The mechanism of tumorigenesis of IMPC in breast remains unknown. Integrative analysis of the proteome and phosphoproteome may shed light on the mechanism of IMPC carcinogenesis. In our study, primary IMPC and paired normal breast tissue were collected from six patients and subjected to label free LC-MS/MS for quantitative proteomic and phosphoproteomic analysis. Kinase-substrate enrichment analysis (KSEA) was conducted to identify hyperactivated/inhibited kinases. Proteomic and phosphoproteomic data was combined to investigate cancer specific activated pathways. A total of 1331 differentially expressed proteins were identified. The proteomic analysis revealed a dysregulation of protein homeostasis in IMPC. Phosphoproteomic profiling identified 856 differentially phosphorylated phosphosites in 655 proteins. KSEA found that cyclin dependent kinases (CDKs) and the p90 ribosomal S6 kinases (RSKs) were highly activated, while protein kinase A (PKA) and protein kinase C (PKC) families were significantly inhibited in IMPC. Finally, cancer-specific activation of mTORC1/S6K2 signaling was also discerned in our integrative analysis. Overall, this study provides a comprehensive landscape of the proteome and phosphoproteome of IMPC, which will contribute to a further understanding of IMPC tumorigenesis and treatment. SIGNIFICANCE: This is the first study to provide the integrative proteomic and phosphoproteomic landscape of IMPC. Our study demonstrated that protein homeostasis dysregulation is one of the most prominent characteristics in IMPC. We also identifying several kinases which might have the potential to be novel targets in clinical practice. Cancer-specific activation of mTORC1/S6K2 signaling was discerned by integrative proteomic and phosphoproteomic analysis. The present study might contribute to a further understanding of IMPC tumorigenesis and treatment.

Association of Adjuvant Hormone Therapy Timing With Overall Survival Among Patients With Hormone Receptor-Positive Human Epidermal Growth Factor Receptor-2-Negative Early Breast Cancer Without Chemotherapy.

Importance: Studies have shown that delayed initiation of surgery and adjuvant chemotherapy is associated with lower rates of breast cancer survival. However, it remains unclear whether delayed initiation of adjuvant hormone therapy (AHT) is associated with survival. Objective: To assess the association of time to adjuvant hormone therapy (TTH) with breast cancer survival and evaluate the factors associated with AHT. Design, Setting, and Participants: This cohort study examined data from the National Cancer Database from 2004 through 2014 to assess the association of TTH (stratified as ≤150 and >150 days) with cancer survival. All patients included were diagnosed with stage I to stage III hormone receptor-positive, human epidermal growth factor receptor-2 (ERBB2; formerly HER2)-negative invasive breast cancer and underwent AHT without chemotherapy. Data were analyzed from April 2019 to May 2020. Exposures: AHT was administered at different time points following surgical procedures for breast cancer treatment. Main Outcomes and Measures: An inverse probability of treatment weighting (IPTW) model was constructed to evaluate overall survival by adjusting for treatment facility, patient demographics, tumor characteristics, and treatment; multivariable logistic regression was conducted to assess factors associated with delayed treatment. Results: A total of 144 103 patients (median [IQR] follow-up, 36.6 months [25.5-49.2 months]; mean [SD] age, 63.7 [11.6] years) were identified, which included 142 916 (99.2%) women, 11 574 (8.0%) Black patients, and 126 013 (87.4%) White patients. Of these, 134 873 patients (93.6%) had a TTH of 150 days or less and 9230 patients (6.4%) had a TTH longer than 150 days. The IPTW-based Cox model demonstrated that patients with delayed AHT (ie, a TTH past 150 days) were associated with decreased survival (hazard ratio [HR], 1.31; 95% CI, 1.26-1.35; P < .001) compared with those receiving the timely treatment (TTH ≤150 days). Several sensitivity analyses (including IPTW with stabilized weight [HR, 1.31; 95% CI, 1.19-1.45; P < .001], propensity score matching [HR, 1.41; 1.13-1.76; P = .002], and propensity score regression adjustment [HR, 1.29; 95% CI, 1.16-1.43; P < .001]) and exploratory subgroup analyses yielded similar trends. Factors associated with delayed AHT included Black racial identity (OR, 1.66; 95% CI, 1.55-1.77), nonprivate insurance (eg, no insurance: OR, 1.46; 95% CI, 1.26-1.70), living in large metropolitan or metropolitan areas (reference vs urban, less urban, or rural: OR, 0.82; 95% CI, 0.76-0.87), treatment in a community hospital (reference vs academic or research: OR, 0.91; 95% CI, 0.84-0.98), Charlson-Deyo Comorbidity Index score 2 or higher (OR, 1.17; 95% CI, 1.04-1.32), poor grade differentiation (OR, 1.42; 95% CI, 1.32-1.53), II and III pathological stage (stage III: OR, 3.13; 95% CI, 2.76-3.54), estrogen receptor-positive (ER+)/progesterone receptor-negative (PR-) or ER-/PR+ (OR, 1.22; 95% CI, 1.13-1.31), receiving breast conservation surgery (reference vs mastectomy: OR, 0.87; 95% CI, 0.79-0.94), and radiotherapy (reference vs no radiotherapy: OR, 0.56; 95% CI, 0.52-0.61). Conclusions and Relevance: The delay of the initiation of AHT past 150 days was associated with diminished survival in hormone receptor-positive, ERBB2-negative patients with breast cancer who did not receive chemotherapy. Efforts should be made to address factors associated with delayed treatment to improve survival.