Endoplasmic Reticulum Stress-induced Endothelial Dysfunction Promotes Neointima Formation after Arteriovenous Grafts in Mice on High-fat Diet.

OBJECTIVE: Endothelial dysfunction is one candidate for triggering neointima formation after arteriovenous grafts (AVGs), but the factors mediating this process are unclear. The purpose of this study was to investigate the role of endoplasmic reticulum stress (ERS)-induced endothelial dysfunction in neointima formation following AVGs in high-fat diet (HFD) mice. METHODS: CCAAT-enhancer-binding protein-homologous protein (CHOP) knockout (KO) mice were created. Mice were fed with HFD to produce HFD model. AVGs model were applied in the groups of WT ND, WT HFD, and CHOP KO HFD. Human umbilical vein endothelial cells (HUVECs) were cultured with oxidized low density lipoprotein (ox-LDL) (40 mg/L) for the indicated time lengths (0, 6, 12, 24 h). ERS inhibitor tauroursodeoxycholic acid (TUDCA) was used to block ERS. Immunohistochemical staining was used to observe the changes of ICAM1. Changes of ERS were detected by real-time RT-PCR. Protein expression levels and ERS activation were detected by Western blotting. Endothellial cell function was determined by endothelial permeability assay and transendothelial migration assay. RESULTS: HFD increased neointima formation in AVGs associated with endothelial dysfunction. At the same time, ERS was increased in endothelial cells (ECs) after AVGs in mice consuming the HFD. In vitro, ox-LDL was found to stimulate ERS, increase the permeability of the EC monolayer, and cause endothelial dysfunction. Blocking ERS with TUDCA or CHOP siRNA reversed the EC dysfunction caused by ox-LDL. In vivo, knockout of CHOP (CHOP KO) protected the function of ECs and decreased neointima formation after AVGs in HFD mice. CONCLUSION: Inhibiting ERS in ECs could improve the function of AVGs.

Evaluation of Adjunctive Ultrasonography for Breast Cancer Detection Among Women Aged 40-49 Years With Varying Breast Density Undergoing Screening Mammography: A Secondary Analysis of a Randomized Clinical Trial.

Importance: Mammography has limited accuracy in breast cancer screening. Ultrasonography, when used in conjunction with mammography screening, is helpful to detect early-stage and invasive cancers for asymptomatic women with dense and nondense breasts. Objective: To evaluate the performance of adjunctive ultrasonography with mammography for breast cancer screening, according to differences in breast density. Design, Setting, and Participants: This study is a secondary analysis of the Japan Strategic Anti-cancer Randomized Trial. Between July 2007 and March 2011, asymptomatic women aged 40 to 49 years were enrolled in Japan. The present study used data from cases enrolled from the screening center in Miyagi prefecture during 2007 to 2020. Participants were randomly assigned in a 1:1 ratio to undergo either mammography with ultrasonography (intervention group) or mammography alone (control group). Data analysis was performed from February to March 2020. Exposures: Ultrasonography adjunctive to mammography for breast cancer screening regardless of breast density. Main Outcomes and Measures: Sensitivity, specificity, recall rates, biopsy rates, and characteristics of screen-detected cancers and interval breast cancers were evaluated between study groups and for each modality according to breast density. Results: A total of 76 119 women were enrolled, and data for 19 213 women (mean [SD] age, 44.5 [2.8] years) from the Miyagi prefecture were analyzed; 9705 were randomized to the intervention group and 9508 were randomized to the control group. A total of 11 390 women (59.3%) had heterogeneously or extremely dense breasts. Among the overall group, 130 cancers were found. Sensitivity was significantly higher in the intervention group than the control group (93.2% [95% CI, 87.4%-99.0%] vs 66.7% [95% CI, 54.4%-78.9%]; P < .001). Similar trends were observed in women with dense breasts (sensitivity in intervention vs control groups, 93.2% [95% CI, 85.7%-100.0%] vs 70.6% [95% CI, 55.3%-85.9%]; P < .001) and nondense breasts (sensitivity in intervention vs control groups, 93.1% [95% CI, 83.9%-102.3%] vs 60.9% [95% CI, 40.9%-80.8%]; P < .001). The rate of interval cancers per 1000 screenings was lower in the intervention group compared with the control group (0.5 cancers [95% CI, 0.1-1.0 cancers] vs 2.0 cancers [95% CI, 1.1-2.9 cancers]; P = .004). Within the intervention group, the rate of invasive cancers detected by ultrasonography alone was significantly higher than that for mammography alone in both dense (82.4% [95% CI, 56.6%-96.2%] vs 41.7% [95% CI, 15.2%-72.3%]; P = .02) and nondense (85.7% [95% CI, 42.1%-99.6%] vs 25.0% [95% CI, 5.5%-57.2%]; P = .02) breasts. However, sensitivity of mammography or ultrasonography alone did not exceed 80% across all breast densities in the 2 groups. Compared with the control group, specificity was significantly lower in the intervention group (91.8% [95% CI, 91.2%-92.3%] vs 86.8% [95% CI, 86.2%-87.5%]; P < .001). Recall rates (13.8% [95% CI, 13.1%-14.5%] vs 8.6% [95% CI, 8.0%-9.1%]; P < .001) and biopsy rates (5.5% [95% CI, 5.1%-6.0%] vs 2.1% [95% CI, 1.8%-2.4%]; P < .001) were significantly higher in the intervention group than the control group. Conclusions and Relevance: In this secondary analysis of a randomized clinical trial, screening mammography alone demonstrated low sensitivity, whereas adjunctive ultrasonography was associated with increased sensitivity. These findings suggest that adjunctive ultrasonography has the potential to improve detection of early-stage and invasive cancers across both dense and nondense breasts. Supplemental ultrasonography should be considered as an appropriate imaging modality for breast cancer screening in asymptomatic women aged 40 to 49 years regardless of breast density. Trial Registration: NIPH Clinical Trial Identifier: UMIN000000757.

Sensitivity and specificity of mammography and adjunctive ultrasonography to screen for breast cancer in the Japan Strategic Anti-cancer Randomized Trial (J-START): a randomised controlled trial.

BACKGROUND: Mammography is the only proven method for breast cancer screening that reduces mortality, although it is inaccurate in young women or women with dense breasts. We investigated the efficacy of adjunctive ultrasonography. METHODS: Between July, 2007, and March, 2011, we enrolled asymptomatic women aged 40-49 years at 42 study sites in 23 prefectures into the Japan Strategic Anti-cancer Randomized Trial (J-START). Eligible women had no history of any cancer in the previous 5 years and were expected to live for more than 5 years. Randomisation was done centrally by the Japan Clinical Research Support Unit. Participants were randomly assigned in 1:1 ratio to undergo mammography and ultrasonography (intervention group) or mammography alone (control group) twice in 2 years. The primary outcome was sensitivity, specificity, cancer detection rate, and stage distribution at the first round of screening. Analysis was by intention to treat. This study is registered, number UMIN000000757. FINDINGS: Of 72,998 women enrolled, 36,859 were assigned to the intervention group and 36,139 to the control group. Sensitivity was significantly higher in the intervention group than in the control group (91·1%, 95% CI 87·2-95·0 vs 77·0%, 70·3-83·7; p=0·0004), whereas specificity was significantly lower (87·7%, 87·3-88·0 vs 91·4%, 91·1-91·7; p<0·0001). More cancers were detected in the intervention group than in the control group (184 [0·50%] vs 117 [0·32%], p=0·0003) and were more frequently stage 0 and I (144 [71·3%] vs 79 [52·0%], p=0·0194). 18 (0·05%) interval cancers were detected in the intervention group compared with 35 (0·10%) in the control group (p=0·034). INTERPRETATION: Adjunctive ultrasonography increases sensitivity and detection rate of early cancers. FUNDING: Ministry of Health, Labour and Welfare of Japan.

Participants' understanding of a randomized controlled trial (RCT) through informed consent procedures in the RCT for breast cancer screening, J-START.

BACKGROUND: It is often difficult to enrol healthy volunteers into a randomized controlled trial (RCT) as there are barriers to participants' proper understanding of a trial. This study aimed to evaluate degrees of understanding of the informed consent (IC) process among healthy volunteers who participated in an RCT. Additionally, factors associated with degree of understanding were investigated. METHODS: The J-START (the Japan STrategic Anti-cancer Randomized controlled Trial) is an RCT investigating the effectiveness of ultrasonography screening for breast cancer in women aged 40 to 49 years. To evaluate participants' understanding of the J-START, we administered questionnaires to 376 Japanese women on the day of enrolment at five study sites across Japan. The respondents were asked to complete the anonymous questionnaire within 2 weeks. We assessed objective understanding and perceived subjective understanding of IC using a Japanese version of the Quality of Informed Consent scale (QuIC). Then we analyzed the characteristics of women whose understanding was poor, and clarified the association between providing information and their understanding of the study protocol. RESULTS: The average QuIC scores were 78.2 and 82.2 (out of 100 each) for objective and subjective understanding, respectively. These are generally acceptable scores for participants' understanding of an RCT. However, there were four domains with low scores, indicating poor understanding: (1) experimental nature of the study, (2) potential risks or discomfort, (3) benefit to self, and (4) compensation. CONCLUSIONS: Healthy volunteers generally well understood the J-START. Nevertheless, there were some domains in need of improvement. In order to facilitate participants' understanding, it is necessary to provide training to reduce differences in information-providing procedures between medical centres and to endeavour to provide consistent information and conditions. TRIAL REGISTRATION: The J-START was registered with the University Hospital Medical Information Network Clinical Trial Registration (UMIN-CTR), Japan (registration number: UMIN000000757), on July 1, 2007.

Classification tree analysis to enhance targeting for follow-up exam of colorectal cancer screening.

BACKGROUND: Follow-up rate after a fecal occult blood test (FOBT) is low worldwide. In order to increase the follow-up rate, segmentation of the target population has been proposed as a promising strategy, because an intervention can then be tailored toward specific subgroups of the population rather than using one type of intervention for all groups. The aim of this study is to identify subgroups that share the same patterns of characteristics related to follow-up exams after FOBT. METHODS: The study sample consisted of 143 patients aged 50-69 years who were requested to undergo follow-up exams after FOBT. A classification tree analysis was performed, using the follow-up rate as a dependent variable and sociodemographic variables, psychological variables, past FOBT and follow-up exam, family history of colorectal cancer (CRC), and history of bowel disease as predictive variables. RESULTS: The follow-up rate in 143 participants was 74.1% (n = 106). A classification tree analysis identified four subgroups as follows; (1) subgroup with a high degree of fear of CRC, unemployed and with a history of bowel disease (n = 24, 100.0% follow-up rate), (2) subgroup with a high degree of fear of CRC, unemployed and with no history of bowel disease (n = 17, 82.4% follow-up rate), (3) subgroup with a high degree of fear of CRC and employed (n = 24, 66.7% follow-up rate), and (4) subgroup with a low degree of fear of CRC (n = 78, 66.7% follow-up rate). CONCLUSION: The identification of four subgroups with a diverse range of follow-up rates for CRC screening indicates the direction to take in future development of an effective tailored intervention strategy.

Factors associated with intentions to adhere to colorectal cancer screening follow-up exams.

BACKGROUND: To increase adherence rate to recommendations for follow-up after abnormal colorectal cancer (CRC) screening results, factors that inhibit and facilitate follow-up must be identified. The purpose of this study was to identify the factors associated with intention to adhere to CRC screening follow-up exams. METHODS: During a 4-week period in October 2003, this survey was conducted with 426 subjects participating in a community-based CRC screening program in Nagano, Japan. Study measures included intention to adhere to recommendation for clinical follow-up in the event of an abnormal fecal occult blood test (FOBT) result, perceived susceptibility and severity of CRC, perceived benefits and barriers related to undergoing follow-up examination, social support, knowledge of CRC risk factors, health status, previous CRC screening, personality and social demographic characteristics. Univariate and multivariate logistic regression analyses on intention to adhere to recommendations for follow-up were performed. RESULTS: Among the 288 individuals analyzed, approximately 74.7% indicated that they would definitely adhere to recommendations for follow-up. After controlling for age, gender, marital status, education, economic status, trait anxiety, bowel symptoms, family history of CRC, and previous screening FOBT, analyses revealed that lower levels of perceived barriers, higher levers of perceived benefits and knowledge of CRC risk factors were significantly associated with high intention respectively. CONCLUSION: The results of this study suggest that future interventions should focus on reducing modifiable barriers by clarifying misperceptions about follow-up, promoting the acceptance of complete diagnostic evaluations, addressing psychological distress, and making follow-up testing more convenient and accessible. Moreover, educating the public regarding the risk factors of CRC and increasing understanding of the benefits of follow-up is also important.