Biochemical characterisation and production kinetics of high molecular-weight (HMW) putative antibacterial proteins of insect pathogenic Brevibacillus laterosporus isolates.

BACKGROUND: Bacterial genomes often encode structures similar to phage capsids (encapsulins) and phage tails which can be induced spontaneously or using genotoxic compounds such as mitomycin C. These high molecular-weight (HMW) putative antibacterial proteins (ABPs) are used against the competitive strains under natural environment. Previously, it was unknown whether these HMW putative ABPs originating from the insect pathogenic Gram-positive, spore-forming bacterium Brevibacillus laterosporus (Bl) isolates (1821L, 1951) are spontaneously induced during the growth and pose a detrimental effect on their own survival. Furthermore, no prior work has been undertaken to determine their biochemical characteristics. RESULTS: Using a soft agar overlay method with polyethylene glycol precipitation, a narrow spectrum of bioactivity was found from the precipitated lysate of Bl 1951. Electron micrographs of mitomycin C- induced filtrates showed structures similar to phage capsids and contractile tails. Bioactivity assays of cell free supernatants (CFS) extracted during the growth of Bl 1821L and Bl 1951 suggested spontaneous induction of these HMW putative ABPs with an autocidal activity. Sodium dodecyl sulphate-polyacrylamide gel electrophoresis of spontaneously induced putative ABPs showed appearance of ~ 30 kDa and ~ 48 kDa bands of varying intensity across all the time intervals during the bacterial growth except in the initial hours. Statistically, spontaneously induced HMW putative ABPs of Bl 1951 exhibited a significant decrease in the number of viable cells of its producer strain after 18 h of growth in liquid. In addition, a significant change in pH and prominent bioactivity of the CFS of this particular time period was noted. Biochemically, the filtered supernatant derived from either Bl 1821L or Bl 1951 maintained bioactivity over a wide range of pH and temperature. CONCLUSION: This study reports the spontaneous induction of HMW putative ABPs (bacteriocins) of Bl 1821L and Bl 1951 isolates during the course of growth with potential autocidal activity which is critically important during production as a potential biopesticide. A narrow spectrum of putative antibacterial activity of Bl 1951 precipitate was found. The stability of HMW putative ABPs of Bl 1821L and Bl 1951 over a wide range of pH and temperature can be useful in expanding the potential of this useful bacterium beyond the insecticidal value.

Analysis of Breast Cancer Mortality in the US-1975 to 2019.

Importance: Breast cancer mortality in the US declined between 1975 and 2019. The association of changes in metastatic breast cancer treatment with improved breast cancer mortality is unclear. Objective: To simulate the relative associations of breast cancer screening, treatment of stage I to III breast cancer, and treatment of metastatic breast cancer with improved breast cancer mortality. Design, Setting, and Participants: Using aggregated observational and clinical trial data on the dissemination and effects of screening and treatment, 4 Cancer Intervention and Surveillance Modeling Network (CISNET) models simulated US breast cancer mortality rates. Death due to breast cancer, overall and by estrogen receptor and ERBB2 (formerly HER2) status, among women aged 30 to 79 years in the US from 1975 to 2019 was simulated. Exposures: Screening mammography, treatment of stage I to III breast cancer, and treatment of metastatic breast cancer. Main Outcomes and Measures: Model-estimated age-adjusted breast cancer mortality rate associated with screening, stage I to III treatment, and metastatic treatment relative to the absence of these exposures was assessed, as was model-estimated median survival after breast cancer metastatic recurrence. Results: The breast cancer mortality rate in the US (age adjusted) was 48/100 000 women in 1975 and 27/100 000 women in 2019. In 2019, the combination of screening, stage I to III treatment, and metastatic treatment was associated with a 58% reduction (model range, 55%-61%) in breast cancer mortality. Of this reduction, 29% (model range, 19%-33%) was associated with treatment of metastatic breast cancer, 47% (model range, 35%-60%) with treatment of stage I to III breast cancer, and 25% (model range, 21%-33%) with mammography screening. Based on simulations, the greatest change in survival after metastatic recurrence occurred between 2000 and 2019, from 1.9 years (model range, 1.0-2.7 years) to 3.2 years (model range, 2.0-4.9 years). Median survival for estrogen receptor (ER)-positive/ERBB2-positive breast cancer improved by 2.5 years (model range, 2.0-3.4 years), whereas median survival for ER-/ERBB2- breast cancer improved by 0.5 years (model range, 0.3-0.8 years). Conclusions and Relevance: According to 4 simulation models, breast cancer screening and treatment in 2019 were associated with a 58% reduction in US breast cancer mortality compared with interventions in 1975. Simulations suggested that treatment for stage I to III breast cancer was associated with approximately 47% of the mortality reduction, whereas treatment for metastatic breast cancer was associated with 29% of the reduction and screening with 25% of the reduction.

Collaborative Modeling to Compare Different Breast Cancer Screening Strategies: A Decision Analysis for the US Preventive Services Task Force.

Importance: The effects of breast cancer incidence changes and advances in screening and treatment on outcomes of different screening strategies are not well known. Objective: To estimate outcomes of various mammography screening strategies. Design, Setting, and Population: Comparison of outcomes using 6 Cancer Intervention and Surveillance Modeling Network (CISNET) models and national data on breast cancer incidence, mammography performance, treatment effects, and other-cause mortality in US women without previous cancer diagnoses. Exposures: Thirty-six screening strategies with varying start ages (40, 45, 50 years) and stop ages (74, 79 years) with digital mammography or digital breast tomosynthesis (DBT) annually, biennially, or a combination of intervals. Strategies were evaluated for all women and for Black women, assuming 100% screening adherence and "real-world" treatment. Main Outcomes and Measures: Estimated lifetime benefits (breast cancer deaths averted, percent reduction in breast cancer mortality, life-years gained), harms (false-positive recalls, benign biopsies, overdiagnosis), and number of mammograms per 1000 women. Results: Biennial screening with DBT starting at age 40, 45, or 50 years until age 74 years averted a median of 8.2, 7.5, or 6.7 breast cancer deaths per 1000 women screened, respectively, vs no screening. Biennial DBT screening at age 40 to 74 years (vs no screening) was associated with a 30.0% breast cancer mortality reduction, 1376 false-positive recalls, and 14 overdiagnosed cases per 1000 women screened. Digital mammography screening benefits were similar to those for DBT but had more false-positive recalls. Annual screening increased benefits but resulted in more false-positive recalls and overdiagnosed cases. Benefit-to-harm ratios of continuing screening until age 79 years were similar or superior to stopping at age 74. In all strategies, women with higher-than-average breast cancer risk, higher breast density, and lower comorbidity level experienced greater screening benefits than other groups. Annual screening of Black women from age 40 to 49 years with biennial screening thereafter reduced breast cancer mortality disparities while maintaining similar benefit-to-harm trade-offs as for all women. Conclusions: This modeling analysis suggests that biennial mammography screening starting at age 40 years reduces breast cancer mortality and increases life-years gained per mammogram. More intensive screening for women with greater risk of breast cancer diagnosis or death can maintain similar benefit-to-harm trade-offs and reduce mortality disparities.

Unveiling a Microexon Switch: Novel Regulation of the Activities of Sugar Assimilation and Plant-Cell-Wall-Degrading Xylanases and Cellulases by Xlr2 in Trichoderma virens.

Functional microexons have not previously been described in filamentous fungi. Here, we describe a novel mechanism of transcriptional regulation in Trichoderma requiring the inclusion of a microexon from the Xlr2 gene. In low-glucose environments, a long mRNA including the microexon encodes a protein with a GAL4-like DNA-binding domain (Xlr2-α), whereas in high-glucose environments, a short mRNA that is produced encodes a protein lacking this DNA-binding domain (Xlr2-ß). Interestingly, the protein isoforms differ in their impact on cellulase and xylanase activity. Deleting the Xlr2 gene reduced both xylanase and cellulase activity and growth on different carbon sources, such as carboxymethylcellulose, xylan, glucose, and arabinose. The overexpression of either Xlr2-α or Xlr2-ß in T. virens showed that the short isoform (Xlr2-ß) caused higher xylanase activity than the wild types or the long isoform (Xlr2-α). Conversely, cellulase activity did not increase when overexpressing Xlr2-ß but was increased with the overexpression of Xlr2-α. This is the first report of a novel transcriptional regulation mechanism of plant-cell-wall-degrading enzyme activity in T. virens. This involves the differential expression of a microexon from a gene encoding a transcriptional regulator.

Linocin M18 protein from the insect pathogenic bacterium Brevibacillus laterosporus isolates.

Brevibacillus laterosporus (Bl) is a Gram-positive and spore-forming bacterium. Insect pathogenic strains have been characterised in New Zealand, and two isolates, Bl 1821L and Bl 1951, are under development for use in biopesticides. However, growth in culture is sometimes disrupted, affecting mass production. Based on previous work, it was hypothesised that Tectiviridae phages might be implicated. While investigating the cause of the disrupted growth, electron micrographs of crude lysates showed structural components of putative phages including capsid and tail-like structures. Sucrose density gradient purification yielded a putative self-killing protein of ~30 kDa. N-terminal sequencing of the ~30 kDa protein identified matches to a predicted 25 kDa hypothetical and a 31.4 kDa putative encapsulating protein homologs, with the genes encoding each protein adjacent in the genomes. BLASTp analysis of the homologs of 31.4 kDa amino acid sequences shared 98.6% amino acid identity to the Linocin M18 bacteriocin family protein of Brevibacterium sp. JNUCC-42. Bioinformatic tools including AMPA and CellPPD defined that the bactericidal potential originated from a putative encapsulating protein. Antagonistic activity of the ~30 kDa encapsulating protein of Bl 1821L and Bl 1951during growth in broth exhibited bacterial autolytic activity. LIVE/DEAD staining of Bl 1821L cells after treatment with the ~30 kDa encapsulating protein of Bl 1821L substantiated the findings by showing 58.8% cells with the compromised cell membranes as compared to 37.5% cells in the control. Furthermore, antibacterial activity of the identified proteins of Bl 1821L was validated through gene expression in a Gram-positive bacterium Bacillus subtilis WB800N. KEY POINTS: • Gene encoding the 31.4 kDa antibacterial Linocin M18 protein was identified • It defined the autocidal activity of Linocin M18 (encapsulating) protein • Identified the possible killing mechanism of the encapsulins.

Mortality risk and physical activity across the lifespan in endometrial cancer survivors.

PURPOSE: Physical activity (pre- and post-diagnosis) has been studied in prevention and survivorship contexts for endometrial cancer. However, the association of physical activity (PA) across the lifespan on mortality risk among endometrial cancer survivors is understudied. The study's objective was to identify the association of lifetime PA on mortality risk in endometrial cancer survivors. METHODS: Seven hundred forty-five endometrial cancer survivors drawn from a population-based cancer registry (diagnosed between 1991 and 1994) reported the frequency (sessions/week) of moderate- and vigorous intensity physical activity (MVPA) at age 12, age 20, and 5 years pre-interview (post-diagnosis). Cox proportional hazards were used to estimate hazard ratios (HR) and 95% confidence intervals for the association between PA, all-cause, and cardiovascular disease mortality as assessed in 2016. MVPA was modeled using natural cubic splines. RESULTS: Diagnosis age, body mass index, and smoking (pack-years) were each positively associated with increased all-cause mortality risk. Those who did one session of MVPA 5 years pre-interview had a lower mortality risk (HR 0.61; 95% CI 0.41-0.92) compared to those with no MVPA. Those reporting one session of MVPA was similarly observed at age 12 (HR 0.95; 95% CI 0.86-1.06) and at age 20 (HR 0.87; 95% CI 0.65-1.16). CONCLUSION: Those who participated in PA, compared to those who did not, in the 5 years before diagnosis had a lower mortality risk. While PA was not independently protective against mortality risk at ages 12 or 20, PA is still important for endometrial cancer survivors for other non-mortality outcomes.

Insights into Metabolic Changes Caused by the Trichoderma virens-Maize Root Interaction.

The interactions of crops with root-colonizing endophytic microorganisms are highly relevant to agriculture, because endophytes can modify plant resistance to pests and increase crop yields. We investigated the interactions between the host plant Zea mays and the endophytic fungus Trichoderma virens at 5 days postinoculation grown in a hydroponic system. Wild-type T. virens and two knockout mutants, with deletion of the genes tv2og1 or vir4 involved in specialized metabolism, were analyzed. Root colonization by the fungal mutants was lower than that by the wild type. All fungal genotypes suppressed root biomass. Metabolic fingerprinting of roots, mycelia, and fungal culture supernatants was performed using ultrahigh performance liquid chromatography coupled to diode array detection and quadrupole time-of-flight tandem mass spectrometry. The metabolic composition of T. virens-colonized roots differed profoundly from that of noncolonized roots, with the effects depending on the fungal genotype. In particular, the concentrations of several metabolites derived from the shikimate pathway, including an amino acid and several flavonoids, were modulated. The expression levels of some genes coding for enzymes involved in these pathways were affected if roots were colonized by the ∆vir4 genotype of T. virens. Furthermore, mycelia and fungal culture supernatants of the different T. virens genotypes showed distinct metabolomes. Our study highlights the fact that colonization by endophytic T. virens leads to far-reaching metabolic changes, partly related to two fungal genes. Both metabolites produced by the fungus and plant metabolites modulated by the interaction probably contribute to these metabolic patterns. The metabolic changes in plant tissues may be interlinked with systemic endophyte effects often observed in later plant developmental stages.[Formula: see text] Copyright © 2021 The Author(s). This is an open access article distributed under the CC BY 4.0 International license.

Does margin width impact breast cancer recurrence rates in women with breast conserving surgery for ductal carcinoma in situ?

PURPOSE: Controversy remains regarding the optimal margin width for patients with ductal carcinoma in situ (DCIS) who undergo breast conserving surgery (BCS). METHODS: Women with a primary DCIS diagnosis were enrolled in a statewide population-based cohort from 1997 to 2006. Patients were surveyed every two years with follow-up data available through 2016. Surgical pathology reports were collected for 559 participants following breast conserving surgery. Multivariable Cox proportional hazard models evaluated relationships between locoregional recurrence (LRR) and margin width in the presence or absence of adjuvant radiation therapy while controlling for age, menopausal status and duration of endocrine therapy use. RESULTS: The majority of women in this study were over 50yo (74%), 34% had high grade disease, and 77% underwent radiation. The overall LRR rate was 12%. A LRR occurred in 46 women who had radiation (11%) and 23 women who did not undergo radiation (19%). Univariate analysis identified smaller margin width, younger age, premenopausal status, no radiotherapy, and shorter endocrine therapy use associated with LRR. Multivariable models demonstrated that close margins (< 2 mm) were associated with an increased risk of recurrence when compared to margins ≥ 2 mm in width whether women received radiation (HR 1.98 CI 0.87-4.54) or not (HR 1.32 CI 0.27-6.49), but confidence intervals were wide. CONCLUSIONS: In this study, patients with DCIS and close margins were less likely to experience recurrence after routine re-excision to margins greater than 2 mm.

A population-based study of causes of death after endometrial cancer according to major risk factors.

OBJECTIVE: To identify the most common causes of death and potentially modifiable risk factors in endometrial cancer patients. METHODS: 745 women diagnosed with incident endometrial cancer were enrolled in a population-based study from 1991 to 1994. Participants completed structured interviews about 1 year after diagnosis. Study files were linked with the National Death Index to identify dates and causes of death through 2016. Proportional hazards regression was used to estimate hazard rate ratios for cause of death adjusting for age and stage of disease. Hazard ratios were also examined according to comorbidities. RESULTS: Of the 745 women, 450 were deceased after a median of 19.9 years. The two most common causes of death were cardiovascular disease (N = 145, 32%) and any cancer (N = 135, 30%), with only 10% of women dying from endometrial cancer (N = 46). Obesity, diabetes and smoking increased risk of all-cause mortality (HRR 1.77, 95%CI 1.36-2.31; HRR 1.74, 95%CI 1.34-2.27; HRR 1.59, 95%CI 1.16-2.17). Diabetes also increased risk of cardiovascular disease-specific mortality (HRR 1.98, 95%CI 1.38-3.08), but not endometrial cancer mortality (HRR 0.55, 95%CI 0.21-1.48). Neither obesity nor smoking was associated with increased risk of cardiovascular disease-specific mortality (HRR 1.46, 95%CI 0.92-2.32; HRR 1.21, 95%CI 0.67-2.18) nor endometrial-cancer specific mortality (HRR 1.81, 95%CI 0.83-3.93; HRR 0.61, 95%CI 0.17-2.15). CONCLUSIONS: Endometrial cancer patients were 3 times more likely to die of cardiovascular disease than endometrial cancer. Obesity, smoking and diabetes increase the risk of death in these patients and are potentially modifiable. Clinical trials should be developed that incorporate counseling regarding these risk factors into survivorship care to determine impact on mortality.

Clinical Benefits, Harms, and Cost-Effectiveness of Breast Cancer Screening for Survivors of Childhood Cancer Treated With Chest Radiation : A Comparative Modeling Study.

BACKGROUND: Surveillance with annual mammography and breast magnetic resonance imaging (MRI) is recommended for female survivors of childhood cancer treated with chest radiation, yet benefits, harms, and costs are uncertain. OBJECTIVE: To compare the benefits, harms, and cost-effectiveness of breast cancer screening strategies in childhood cancer survivors. DESIGN: Collaborative simulation modeling using 2 Cancer Intervention and Surveillance Modeling Network breast cancer models. DATA SOURCES: Childhood Cancer Survivor Study and published data. TARGET POPULATION: Women aged 20 years with a history of chest radiotherapy. TIME HORIZON: Lifetime. PERSPECTIVE: Payer. INTERVENTION: Annual MRI with or without mammography, starting at age 25, 30, or 35 years. OUTCOME MEASURES: Breast cancer deaths averted, false-positive screening results, benign biopsy results, and incremental cost-effectiveness ratios (ICERs). RESULTS OF BASE-CASE ANALYSIS: Lifetime breast cancer mortality risk without screening was 10% to 11% across models. Compared with no screening, starting at age 25 years, annual mammography with MRI averted the most deaths (56% to 71%) and annual MRI (without mammography) averted 56% to 62%. Both strategies had the most screening tests, false-positive screening results, and benign biopsy results. For an ICER threshold of less than $100 000 per quality-adjusted life-year gained, screening beginning at age 30 years was preferred. RESULTS OF SENSITIVITY ANALYSIS: Assuming lower screening performance, the benefit of adding mammography to MRI increased in both models, although the conclusions about preferred starting age remained unchanged. LIMITATION: Elevated breast cancer risk was based on survivors diagnosed with childhood cancer between 1970 and 1986. CONCLUSION: Early initiation (at ages 25 to 30 years) of annual breast cancer screening with MRI, with or without mammography, might reduce breast cancer mortality by half or more in survivors of childhood cancer. PRIMARY FUNDING SOURCE: American Cancer Society and National Institutes of Health.

Evaluation of Long-Term Satisfaction with Breast Surgery in Patients Treated for Ductal Carcinoma In Situ: A Population-Based Longitudinal Cohort Study.

BACKGROUND: Breast-conserving surgery (BCS) and mastectomy have equivalent survival for ductal carcinoma in situ (DCIS), allowing patients to participate in selecting a personalized surgical option; however, this decision-making role can increase patient anxiety. Data evaluating patient satisfaction with their decision to undergo BCS versus mastectomy for the treatment of DCIS are limited. METHODS: Women with DCIS were enrolled in a population-based, state-wide cohort from 1997 to 2006. Participants were surveyed about their satisfaction with their surgical and reconstruction decisions. Quality-of-life (QoL) evaluations were performed with biennial follow-up surveys though 2016. Multivariable logistic regression modeling examined the relationship between type of surgery and reconstruction with patient satisfaction. RESULTS: Overall, 1537 women were surveyed, on average, 2.9 years following DCIS diagnosis. Over 90% reported satisfaction with their treatment decision regardless of surgery type. Women who underwent mastectomy with reconstruction were more likely to report lower levels of satisfaction than women who underwent BCS (odds ratio [OR] 2.98, 95% confidence interval [CI] 1.18-7.51, p < 0.01). However, over 80% of women who underwent mastectomies reported satisfaction with their reconstruction decision. Women without reconstruction had the highest levels of satisfaction, while women with implants were more likely to be dissatisfied (implant + autologous: OR 2.77, 95% CI 1.24-6.24; implant alone: OR 4.02, 95% CI 1.947-8.34, p ≤ 0.01). QoL scores were not associated with differences in surgical or reconstruction satisfaction at 5, 10, and 15 years following DCIS diagnosis. CONCLUSIONS: Women undergoing surgery for DCIS express satisfaction with their treatment decisions. Following mastectomy, most women are satisfied with their reconstruction decision, including women who did not undergo reconstruction.

Age-based versus Risk-based Mammography Screening in Women 40-49 Years Old: A Cross-sectional Study.

Background Risk-based screening in women 40-49 years old has not been evaluated in routine screening mammography practice. Purpose To use a cross-sectional study design to compare the trade-offs of risk-based and age-based screening for women 45 years of age or older to determine short-term outcomes. Materials and Methods A retrospective cross-sectional study was performed by using a database of 20 539 prospectively interpreted consecutive digital screening mammograms in 10 280 average-risk women aged 40-49 years who were screened at an academic medical center between January 1, 2006, and December 31, 2013. Two hypothetical screening scenarios were compared: an age-based (≥45 years) scenario versus a risk-based (a 5-year risk of breast cancer greater than that of an average 50-year-old) scenario. Risk factors for risk-based screening included family history, race, age, prior breast biopsy, and breast density. Outcomes included breast cancers detected at mammography, false-positive mammograms, and benign biopsy findings. Short-term outcomes were compared by using the χ2 test. Results The screening population included 71 148 screening mammograms in 24 928 women with a mean age of 55.5 years ± 8.9 (standard deviation) (age range, 40-74 years). In women 40-49 years old, usual care included 50 screening-detected cancers, 1787 false-positive mammograms, and 384 benign biopsy results. The age-based (≥45 years) screening strategy revealed more cancers than did the risk-based strategy (34 [68%] vs 13 [26%] of 50; P < .001), while prompting more false-positive mammograms (899 [50.3%] vs 216 [12.1%] of 1787; P < .001) and benign biopsy results (175 [45.6%] vs 49 [12.8%] of 384; P < .001). The risk-based strategy demonstrated low levels of eligibility (few screenings) in the 40-44-year age group. Differences in outcomes in the 45-49-year age group explained the overall hypothetical screening strategy differences. Conclusion Risk-based screening for women 40-49 years old includes few women in the 40-44-year age range. Significant trade-offs in the 45-49-year age group explain the overall difference between hypothetical screening scenarios, both of which reduce the benefits as well as the harms of mammography for women 40-49 years old. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Joe and Hayward in this issue.

Variation in coordination of care reported by breast cancer patients according to health literacy.

BACKGROUND: Health literacy is the ability to perform basic reading and numerical tasks to function in the healthcare environment. The purpose of this study is to describe how health literacy is related to perceived coordination of care reported by breast cancer patients. METHODS: Data were retrieved from the Patient-Centered Outcomes Research Institute-sponsored "Share Thoughts on Breast Cancer" Study including demographic factors, perceived care coordination and responsiveness of care, and self-reported health literacy obtained from a mailed survey completed by 62% of eligible breast cancer survivors (N = 1221). Multivariable analysis of variance was used to characterize the association between presence of a single healthcare professional that coordinated care ("care coordinator") and perceived care coordination, stratified by health literacy level. RESULTS: Health literacy was classified as low in 24% of patients, medium in 34%, and high in 42%. Women with high health literacy scores were more likely to report non-Hispanic white race/ethnicity, private insurance, higher education and income, and fewer comorbidities (all p < 0.001). The presence of a care coordinator was associated with 17.1% higher perceived care coordination scores among women with low health literacy when compared to those without a care coordinator, whereas a coordinator modestly improved perceived care coordination among breast cancer survivors with medium (6.9%) and high (6.2%) health literacy. CONCLUSION: The use of a single designated care coordinator may have a strong influence on care coordination in patients with lower levels of health literacy.

Obesity and mortality after locoregional breast cancer diagnosis.

PURPOSE: Higher mortality after a breast cancer diagnosis has been observed among women who are obese. We investigated the relationships between body mass index (BMI) and all-cause or breast cancer-specific mortality after a diagnosis of locoregional breast cancer. METHODS: Women diagnosed in 2004 with AJCC Stage I, II, or III breast cancer (n = 5394) were identified from a population-based National Program of Cancer Registries (NPCR) patterns of care study (POC-BP) drawing from registries in seven U.S. states. Differences in overall and breast cancer-specific mortality were investigated using Cox proportional hazards regression models adjusting for demographic and clinical covariates, including age- and stage-based subgroup analyses. RESULTS: In women 70 or older, higher BMI was associated with lower overall mortality (HR for a 5 kg/m2 difference in BMI = 0.85, 95% CI 0.75-0.95). There was no significant association between BMI and overall mortality for women under 70. BMI was not associated with breast cancer death in the full sample, but among women with Stage I disease; those in the highest BMI category had significantly higher breast cancer mortality (HR for BMI ≥ 35 kg/m2 vs. 18.5-24.9 kg/m2 = 4.74, 95% CI 1.78-12.59). CONCLUSIONS: Contrary to our hypothesis, greater BMI was not associated with higher overall mortality. Among older women, BMI was inversely related to overall mortality, with a null association among younger women. Higher BMI was associated with breast cancer mortality among women with Stage I disease, but not among women with more advanced disease.

Comparative effectiveness of incorporating a hypothetical DCIS prognostic marker into breast cancer screening.

PURPOSE: Due to limitations in the ability to identify non-progressive disease, ductal carcinoma in situ (DCIS) is usually managed similarly to localized invasive breast cancer. We used simulation modeling to evaluate the potential impact of a hypothetical test that identifies non-progressive DCIS. METHODS: A discrete-event model simulated a cohort of U.S. women undergoing digital screening mammography. All women diagnosed with DCIS underwent the hypothetical DCIS prognostic test. Women with test results indicating progressive DCIS received standard breast cancer treatment and a decrement to quality of life corresponding to the treatment. If the DCIS test indicated non-progressive DCIS, no treatment was received and women continued routine annual surveillance mammography. A range of test performance characteristics and prevalence of non-progressive disease were simulated. Analysis compared discounted quality-adjusted life years (QALYs) and costs for test scenarios to base-case scenarios without the test. RESULTS: Compared to the base case, a perfect prognostic test resulted in a 40% decrease in treatment costs, from $13,321 to $8005 USD per DCIS case. A perfect test produced 0.04 additional QALYs (16 days) for women diagnosed with DCIS, added to the base case of 5.88 QALYs per DCIS case. The results were sensitive to the performance characteristics of the prognostic test, the proportion of DCIS cases that were non-progressive in the model, and the frequency of mammography screening in the population. CONCLUSION: A prognostic test that identifies non-progressive DCIS would substantially reduce treatment costs but result in only modest improvements in quality of life when averaged over all DCIS cases.

Urinary Magnesium and Other Elements in Relation to Mammographic Breast Density, a Measure of Breast Cancer Risk.

PURPOSE: Heavy metals and other elements may act as breast carcinogens due to estrogenic activity. We investigated associations between urine concentrations of a panel of elements and breast density. METHODS: Mammographic density categories were abstracted from radiology reports of 725 women aged 40-65 yr in the Avon Army of Women. A panel of 27 elements was quantified in urine using high resolution magnetic sector inductively coupled plasma mass spectrometry. We applied LASSO (least absolute shrinkage and selection operator) logistic regression to the 27 elements and calculated odds ratios (OR) and 95% confidence intervals (CI) for dense vs. nondense breasts, adjusting for potential confounders. RESULTS: Of the 27 elements, only magnesium (Mg) was selected into the optimal regression model. The odds ratio for dense breasts associated with doubling the Mg concentration was 1.24 (95% CI 1.03-1.49). Doubling the calcium-to-magnesium ratio was inversely associated with dense breasts (OR 0.83, 95% CI 0.70-0.98). CONCLUSIONS: Our cross-sectional study found that higher levels of urinary magnesium were associated with greater breast density. Prospective studies are needed to confirm whether magnesium as evaluated in urine is prospectively associated with breast density and, more importantly, breast cancer.

The association between post-diagnosis health behaviors and long-term quality of life in survivors of ductal carcinoma in situ: a population-based longitudinal cohort study.

PURPOSE: Women diagnosed with ductal carcinoma in situ (DCIS) often experience adverse changes in health-related behaviors following diagnosis. The impact of health behaviors on long-term quality of life (QoL) in DCIS survivors has not been investigated. METHODS: We examined the association of post-diagnosis body mass index (BMI), physical activity, alcohol, and smoking with QoL among 1448 DCIS survivors aged 20-74 enrolled in the population-based Wisconsin in situ Cohort from 1997 to 2006. Health behaviors and QoL were self-reported during biennial post-diagnosis interviews. Physical and mental QoL were measured using the validated SF-36 questionnaire. Generalized linear regression was used to determine the association between behaviors and QoL with adjustment for confounders. Lagged behavior variables were used to predict QoL during follow-up and avoid reverse causation. RESULTS: Women reported 3,536 QoL observations over an average 7.9 years of follow-up. Women maintaining a healthy BMI had on average a significantly higher summary measure score of physical QoL than obese women (normal versus obese: ß = 3.02; 2.18, 3.85). Physical QoL scores were also elevated among those who were physically active (5 + h/week vs. none: ß = 1.96; 0.72, 3.20), those consuming at least seven drinks/week of alcohol (vs. none; ß = 1.40; 0.39, 2.41), and nonsmokers (vs. current smokers: ß = 1.80; 0.89, 2.71). Summary measures of mental QoL were significantly higher among women who were moderately physically active (up to 2 h/week vs. none: ß = 1.11; 0.30, 1.92) and nonsmokers (vs. current smokers: ß = 1.49;0.45, 2.53). CONCLUSIONS: Our results demonstrate that maintaining healthy behaviors following DCIS treatment is associated with modest improvements in long-term QoL. These results inform interventions aimed at promoting healthy behaviors and optimizing QoL in DCIS survivors.

Tailoring Breast Cancer Screening Intervals by Breast Density and Risk for Women Aged 50 Years or Older: Collaborative Modeling of Screening Outcomes.

Background: Biennial screening is generally recommended for average-risk women aged 50 to 74 years, but tailored screening may provide greater benefits. Objective: To estimate outcomes for various screening intervals after age 50 years based on breast density and risk for breast cancer. Design: Collaborative simulation modeling using national incidence, breast density, and screening performance data. Setting: United States. Patients: Women aged 50 years or older with various combinations of breast density and relative risk (RR) of 1.0, 1.3, 2.0, or 4.0. Intervention: Annual, biennial, or triennial digital mammography screening from ages 50 to 74 years (vs. no screening) and ages 65 to 74 years (vs. biennial digital mammography from ages 50 to 64 years). Measurements: Lifetime breast cancer deaths, life expectancy and quality-adjusted life-years (QALYs), false-positive mammograms, benign biopsy results, overdiagnosis, cost-effectiveness, and ratio of false-positive results to breast cancer deaths averted. Results: Screening benefits and overdiagnosis increase with breast density and RR. False-positive mammograms and benign results on biopsy decrease with increasing risk. Among women with fatty breasts or scattered fibroglandular density and an RR of 1.0 or 1.3, breast cancer deaths averted were similar for triennial versus biennial screening for both age groups (50 to 74 years, median of 3.4 to 5.1 vs. 4.1 to 6.5 deaths averted; 65 to 74 years, median of 1.5 to 2.1 vs. 1.8 to 2.6 deaths averted). Breast cancer deaths averted increased with annual versus biennial screening for women aged 50 to 74 years at all levels of breast density and an RR of 4.0, and those aged 65 to 74 years with heterogeneously or extremely dense breasts and an RR of 4.0. However, harms were almost 2-fold higher. Triennial screening for the average-risk subgroup and annual screening for the highest-risk subgroup cost less than $100 000 per QALY gained. Limitation: Models did not consider women younger than 50 years, those with an RR less than 1, or other imaging methods. Conclusion: Average-risk women with low breast density undergoing triennial screening and higher-risk women with high breast density receiving annual screening will maintain a similar or better balance of benefits and harms than average-risk women receiving biennial screening. Primary Funding Source: National Cancer Institute.

Emerging trends in surgical and adjuvant radiation therapies among women diagnosed with ductal carcinoma in situ.

BACKGROUND: The use of surgery and radiation therapy in treating ductal carcinoma in situ (DCIS) is directed by treatment guidelines and evidence from research. This study investigated recent patterns in DCIS treatment by demographic factors. METHODS: Data for women diagnosed with DCIS between 1998 and 2011 (n = 416,232) in the National Cancer Data Base were assessed for trends in treatment patterns by age group, calendar year, ancestral/ethnic group, and geographic region. The likelihood of receiving specific treatment modalities was analyzed with multivariable logistic regression. RESULTS: DCIS cases were most frequently treated with breast-conserving surgery (BCS) and adjuvant radiation (45.6%). After an initial rise, the use of adjuvant radiation after BCS plateaued at approximately 70% after 2007, with increasing utilization of mastectomy beyond 2005. In addition, there was an increasing trend in postmastectomy reconstruction over time, and women of African ancestry (odds ratio [OR], 0.69; 95% confidence interval [CI], 0.66-0.72) and Hispanic women (OR, 0.83; 95% CI, 0.78-0.89) were less likely to undergo reconstruction in comparison with women of European ancestry. A similar trend was observed in contralateral risk-reducing mastectomy utilization, with women of European ancestry having a more rapid rise in the utilization of contralateral risk-reducing mastectomy in comparison with all other ancestral/ethnic groups. CONCLUSIONS: Recent trends demonstrate a plateau in radiation therapy administration after BCS along with increasing utilization of mastectomy, reconstruction, and contralateral risk-reducing mastectomy. There are substantial differences in treatment utilization according to ancestry/ethnicity and geographical region. Further studies examining patient-physician decision making surrounding DCIS treatment are warranted. Cancer 2016. © 2016 American Cancer Society. Cancer 2016;122:2810-2818. © 2016 American Cancer Society.