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Relationship of Terminal Duct Lobular Unit Involution of the Breast with Area and Volume Mammographic Densities

Legends for supplementary figures and tables.

Supplementary Table 1

Supplementary Table 2B

Supplementary Figure 1. Average Percent Dense Area by Age Supplementary Figure 2. Average Percent Dense Volume by Age.

Supplementary Figure 2

Supplementary Table 1. Spearman partial rank-order correlations for TDLU measures among pre- and postmenopausal women Supplementary Table 2. Spearman partial rank-order correlations between global and peri-lesional volumetric mammographic density measures among pre- and postmenopausal women with benign breast disease Supplementary Tables 3 to 5: Association between TDLU and mammographic density measures (percent, absolute and nondense) among postmenopausal women with benign breast disease

Delayed terminal duct lobular unit (TDLU) involution is associated with elevated mammographic breast density (MD). Both are independent breast cancer risk factors among women with benign breast disease (BBD). Prior digital analyses of normal breast tissues revealed that epithelial nuclear density (END) and TDLU involution are inversely correlated. Accordingly, we examined associations of END, TDLU involution, and MD in BBD clinical biopsies. This study included digitized images of 262 representative image-guided hematoxylin and eosin–stained biopsies from 224 women diagnosed with BBD, enrolled within the cross-sectional BREAST-Stamp project that were visually assessed for TDLU involution (TDLU count/100 mm2, median TDLU span and median acini count per TDLU). A digital algorithm estimated nuclei count per unit epithelial area, or END. Single X-ray absorptiometry of prebiopsy ipsilateral craniocaudal digital mammograms measured global and localized MD surrounding the biopsy region. Adjusted ordinal logistic regression models assessed relationships between tertiles of TDLU and END measures. Analysis of covariance examined mean differences in MD across END tertiles. TDLU measures were positively associated with increasing END tertiles [TDLU count/100 mm2, ORT3vsT1: 3.42, 95% confidence interval (CI), 1.87–6.28; acini count/TDLUT3vsT1, OR: 2.40, 95% CI, 1.39–4.15]. END was significantly associated with localized, but not, global MD. Relationships were most apparent among patients with nonproliferative BBD. These findings suggest that quantitative END reflects different but complementary information to the histologic information captured by visual TDLU and radiologic MD measures and merits continued evaluation in assessing cellularity of breast parenchyma to understand the etiology of BBD.

Supplementary Table 3

Supplementary Figure 1

Background: Mammographic density (MD), the area of non–fatty-appearing tissue divided by total breast area, is a strong breast cancer risk factor. Most MD analyses have used visual categorizations or computer-assisted quantification, which ignore breast thickness. We explored MD volume and area, using a volumetric approach previously validated as predictive of breast cancer risk, in relation to risk factors among women undergoing breast biopsy.Methods: Among 413 primarily white women, ages 40 to 65 years, undergoing diagnostic breast biopsies between 2007 and 2010 at an academic facility in Vermont, MD volume (cm3) was quantified in craniocaudal views of the breast contralateral to the biopsy target using a density phantom, whereas MD area (cm2) was measured on the same digital mammograms using thresholding software. Risk factor associations with continuous MD measurements were evaluated using linear regression.Results: Percent MD volume and area were correlated (r = 0.81) and strongly and inversely associated with age, body mass index (BMI), and menopause. Both measures were inversely associated with smoking and positively associated with breast biopsy history. Absolute MD measures were correlated (r = 0.46) and inversely related to age and menopause. Whereas absolute dense area was inversely associated with BMI, absolute dense volume was positively associated.Conclusions: Volume and area MD measures exhibit some overlap in risk factor associations, but divergence as well, particularly for BMI.Impact: Findings suggest that volume and area density measures differ in subsets of women; notably, among obese women, absolute density was higher with volumetric methods, suggesting that breast cancer risk assessments may vary for these techniques. Cancer Epidemiol Biomarkers Prev; 23(11); 2338–48. ©2014 AACR.

Supplementary Figure 1. Spearman's rank correlation coefficients (rs) for volume and area density measures, stratified by age.

Supplementary Table 1. Age- and BMI-adjusted linear regression results for the association between participant characteristics and standardized volume and area mammographic density measures. Supplementary Table 2. Spearman's rank correlation coefficients for volume and area density measures, unadjusted and adjusted for age and body mass index.

Supplementary Table 4 from Mutagenicity and Potential Carcinogenicity of Thiopurine Treatment in Patients with Inflammatory Bowel Disease

Supplementary Table 1 from Mutagenicity and Potential Carcinogenicity of Thiopurine Treatment in Patients with Inflammatory Bowel Disease

Supplementary Figure 1 from Mutagenicity and Potential Carcinogenicity of Thiopurine Treatment in Patients with Inflammatory Bowel Disease

Supplementary Table 2 from Mutagenicity and Potential Carcinogenicity of Thiopurine Treatment in Patients with Inflammatory Bowel Disease

The development of risk-directed treatment protocols over the last 25 years has resulted in an increase in the survival rates of children treated for cancer. As a consequence, there is a growing population of pediatric cancer survivors in which the long-term genotoxic effects of chemotherapy is unknown. We previously reported that children treated for acute lymphocytic leukemia have significantly elevated somatic mutant frequencies at the hypoxanthine-guanine phosphoribosyltransferase (HPRT) gene in their peripheral T cells. To understand the molecular etiology of the increase in mutant frequencies following chemotherapy, we investigated the HPRT mutation spectra and the extent of clonal proliferation in 562 HPRT T cell mutant isolates of 87 blood samples from 47 subjects at diagnosis, during chemotherapy, and postchemotherapy. We observed a significant increase in the proportion of CpG transitions following treatment (13.6-23.3%) compared with healthy controls (4.0%) and a significant decrease in V(D)J-mediated deletions following treatment (0-6.8%) compared with healthy controls (17.0%). There was also a significant change in the class type percentage of V(D)J-mediated HPRT deletions following treatment. In addition, there was a >5-fold increase in T cell receptor gene usage–defined mean clonal proliferation from diagnosis compared with the completion of chemotherapeutic intervention. These data indicate that unique genetic alterations and extensive clonal proliferation are occurring in children following treatment for acute lymphocytic leukemia that may influence long-term risks for multifactorial diseases, including secondary cancers. (Cancer Res 2006; 66(17): 8455-61)

Supplementary Table 1 from Analysis of Genetic Alterations and Clonal Proliferation in Children Treated for Acute Lymphocytic Leukemia

Supplementary Table 3 from Mutagenicity and Potential Carcinogenicity of Thiopurine Treatment in Patients with Inflammatory Bowel Disease

The thiopurines azathioprine and 6-mercaptopurine (6-MP) are effective immune modulators and cytotoxic agents extensively used in the treatment of autoimmune diseases, graft rejection, and cancer. There is compelling epidemiologic evidence that thiopurine treatment increases the risk for a variety of tumors by mechanisms that are unclear. We investigated the in vivo mutagenicity of long-term thiopurine treatment by determining the frequency and spectra of somatic mutation events at the hypoxanthine phosphoribosyltransferase (HPRT) locus in peripheral T lymphocytes as well as the prevalence of mutant clonal proliferation in a cross-sectional analysis of data from 119 children and adults with inflammatory bowel disease (IBD). ANOVA and regression were performed to assess relationships among the frequency and spectra of HPRT mutations with disease, duration of illness, duration of treatment, and total therapeutic dose of azathioprine and 6-MP. We observed a significant increase in the frequency of somatic mutations in 56 subjects treated with thiopurines for IBD compared with 63 subjects not treated with thiopurines. This increase was related to both total dose (P < 0.001) and duration of treatment (P < 0.001). Comparative mutation spectra analysis of 1,020 mutant isolates revealed a significant increase in the proportion of all transitions (P < 0.001), particularly G:C to A:T transitions (P < 0.001). Combined analyses of two signatures for mutant clonality, HPRT mutation, and T-cell receptor β CDR3 region unique gene sequence also showed a significant thiopurine-dependent increase in mutant cell clonal proliferation (P < 0.001). These findings provide in vivo evidence for mutation induction as a potential carcinogenic mechanism associated with chronic thiopurine intervention. [Cancer Res 2009;69(17):7004–23]

Supplementary Figure Legend from Mutagenicity and Potential Carcinogenicity of Thiopurine Treatment in Patients with Inflammatory Bowel Disease

OBJECTIVE To evaluate the accuracy and reliability of a novel fluoroscopic technique for assessing tibial rotation and compare it to a previously described fluoroscopic method. METHODS A multiplanar circular ring external fixator was secured to the tibial diaphysis of five cadaveric lower extremity specimens. Using deformity correction software, the frame and tibia were programmed to randomly rotate 5, 10, 15, 20, 25, and 30 degrees of internal and external rotation. Following each rotation, two blinded, independent observers measured the degree of tibial rotation using two different fluoroscopic methods: the previously described "mortise" method and the novel "intermalleolar" method. A total of 65 measurements were made by each observer. Accuracy and inter-observer reliability were calculated. RESULTS Both intermalleolar and mortise methods had a mean absolute rotational difference from the true torsion of 3 degrees (SE 1, range 0-10 degrees intermalleolar versus 0-18 degrees mortise). We found that 98.5% (128/130) of measurements using the intermalleolar method were less than 10 degrees from the true rotation, compared to 93.8% (122/130) using the mortise method. Both the intermalleolar and mortise methods had excellent inter-observer reliability (ICC 0.99 and 0.96, respectively). CONCLUSION Measuring tibial rotation fluoroscopically using the intermalleolar method is both accurate and reliable. Compared to the previously described mortise method, it has similar accuracy and provides a value that approximates the true tibial rotation. Also, it can be employed reliably and effectively intraoperatively to identify tibial malrotation and assist in intraoperative rotational corrections.

Background Elevated mammographic breast density is a strong breast cancer risk factor with poorly understood etiology. Increased deposition of collagen, one of the main fibrous proteins present in breast stroma, has been associated with increased mammographic density. Collagen fiber architecture has been linked to poor outcomes in breast cancer. However, relationships of quantitative collagen fiber features assessed in diagnostic biopsies with mammographic density and lesion severity are not well-established. Methods Clinically indicated breast biopsies from 65 in situ or invasive breast cancer cases and 73 frequency matched-controls with a benign biopsy result were used to measure collagen fiber features (length, straightness, width, alignment, orientation and density (fibers/µm2)) using second harmonic generation microscopy in up to three regions of interest (ROIs) per biopsy: normal, benign breast disease, and cancer. Local and global mammographic density volumes were quantified in the ipsilateral breast in pre-biopsy full-field digital mammograms. Associations of fibrillar collagen features with mammographic density and severity of biopsy diagnosis were evaluated using generalized estimating equation models with an independent correlation structure to account for multiple ROIs within each biopsy section. Results Collagen fiber density was positively associated with the proportion of stroma on the biopsy slide (p p = 0.035) and within a 2 mm perilesional ring (p = 0.02), but not with global mammographic density measures. As severity of the breast biopsy diagnosis increased at the ROI level, collagen fibers tended to be less dense, shorter, straighter, thinner, and more aligned with one another (p Conclusions Collagen fiber density was positively associated with local, but not global, mammographic density, suggesting that collagen microarchitecture may not translate into macroscopic mammographic features. However, collagen fiber features may be markers of cancer risk and/or progression among women referred for biopsy based on abnormal breast imaging.

Anterior cruciate ligament injury and reconstruction (ACLR) affects articular cartilage thickness profiles about the tibial, femoral, and patellar surfaces; however, it's unclear whether the magnitudes of change in cartilage thickness, as well as the locations and areas over which these changes occur, differ between males and females. This is important to consider as differences exist between the sexes with regard to knee biomechanics, patellofemoral pain, and anatomic alignment, which influence risk of an index and repeated injury. Subjects underwent ACLR with a bone-patella tendon-bone autograft. At four-year follow-up, they had asymptomatic knees; however, significant ACL injured-to-contralateral normal knee differences in articular cartilage thickness values were observed. Both thickening and thinning of cartilage occurred about the tibiofemoral and patellofemoral joints, relative to matched control subjects with normal knees. Further, the location of the areas and magnitudes of thickening and thinning were different between females and males. Thickening (swelling) of articular cartilage is an early finding associated with the onset of post-traumatic osteoarthritis (PTOA). Therefore, the increases in cartilage thickness that were observed in this cohort may represent early signs of the onset of PTOA that occur prior to the patient developing symptoms and radiographic evidence of this disease. The different locations of areas that underwent a change in cartilage thicknesses between males and females suggest that each sex responds differently to knee ligament trauma, reconstruction, rehabilitation and return to activity, and indicates that sex specific analysis should be utilized in studies of PTOA. This article is protected by copyright. All rights reserved.

Background: There is widespread interest in discriminating indolent from aggressive ductal carcinoma in situ (DCIS). We sought to evaluate collagen organization in the DCIS tumor microenvironment in relation to pathologic characteristics and patient outcomes. Methods: We retrieved fixed tissue specimens for 90 DCIS cases within the population-based Vermont DCIS Cohort. We imaged collagen fibers within 75 μm of the tumor/stromal boundary on hematoxylin and eosin–stained slides using multiphoton microscopy with second-harmonic generation. Automated software quantified collagen fiber length, width, straightness, density, alignment, and angle to the tumor/stroma boundary. Factor analysis identified linear combinations of collagen fiber features representing composite attributes of collagen organization. Results: Multiple collagen features were associated with DCIS grade, necrosis pattern, or periductal fibrosis (P < 0.05). After adjusting for treatments and nuclear grade, risk of recurrence (defined as any second breast cancer diagnosis) was lower among cases with greater collagen fiber width [hazard ratio (HR), 0.57 per one standard deviation increase; 95% confidence interval (CI), 0.39–0.84] and fiber density (HR, 0.60; 95% CI, 0.42–0.85), whereas risk was elevated among DCIS cases with higher fiber straightness (HR, 1.47; 95% CI, 1.05–2.06) and distance to the nearest two fibers (HR, 1.47; 95% CI, 1.06–2.02). Fiber length, alignment, and fiber angle were not associated with recurrence (P > 0.05). Five composite factors were identified, accounting for 72.4% of the total variability among fibers; three were inversely associated with recurrence (HRs ranging from 0.60 to 0.67; P ≤ 0.01). Conclusions: Multiple aspects of collagen organization around DCIS lesions are associated with recurrence risk. Impact: Collagen organization should be considered in the development of prognostic DCIS biomarker signatures.

Delayed terminal duct lobular unit (TDLU) involution is associated with elevated mammographic breast density (MD). Both are independent breast cancer risk factors among women with benign breast disease (BBD). Prior digital analyses of normal breast tissues revealed that epithelial nuclear density (END) and TDLU involution are inversely correlated. Accordingly, we examined associations of END, TDLU involution, and MD in BBD clinical biopsies. This study included digitized images of 262 representative image-guided hematoxylin and eosin–stained biopsies from 224 women diagnosed with BBD, enrolled within the cross-sectional BREAST-Stamp project that were visually assessed for TDLU involution (TDLU count/100 mm2, median TDLU span and median acini count per TDLU). A digital algorithm estimated nuclei count per unit epithelial area, or END. Single X-ray absorptiometry of prebiopsy ipsilateral craniocaudal digital mammograms measured global and localized MD surrounding the biopsy region. Adjusted ordinal logistic regression models assessed relationships between tertiles of TDLU and END measures. Analysis of covariance examined mean differences in MD across END tertiles. TDLU measures were positively associated with increasing END tertiles [TDLU count/100 mm2, ORT3vsT1: 3.42, 95% confidence interval (CI), 1.87–6.28; acini count/TDLUT3vsT1, OR: 2.40, 95% CI, 1.39–4.15]. END was significantly associated with localized, but not, global MD. Relationships were most apparent among patients with nonproliferative BBD. These findings suggest that quantitative END reflects different but complementary information to the histologic information captured by visual TDLU and radiologic MD measures and merits continued evaluation in assessing cellularity of breast parenchyma to understand the etiology of BBD.

PURPOSE/OBJECTIVE(S) Stereotactic Body Radiation Therapy (SBRT) has emerged as a therapeutic option in patients with oligometastatic non-small cell lung cancer (NSCLC). Currently, the patterns of care of SBRT in elderly metastatic NSCLC patients are not known. Similarly, the impact that SBRT has on the overall frequency and costs of hospitalizations are not known. The purpose of this project is to describe early SBRT use, outcomes, hospitalizations and their costs, as compared to matched patients receiving chemotherapy among patients with metastatic NSCLC. MATERIALS/METHODS Using the SEER-Medicare database, we identified 215 patients with metastatic NSCLC who received SBRT as first line treatment and 12,486 patients who received chemotherapy between 2004 and 2014. We limited our sample to patients ≥66 years to have a full year of Medicare claims to determine pre-existing co-morbidities and disability score prior to their diagnosis. We excluded patients who had brain metastases, cancer-directed surgery, or survived less than 30 days from diagnosis. Multivariable logistic regression was used to identify covariates associated with SBRT use. Overall survival between SBRT and chemotherapy was compared using Cox proportional hazards regression and the Kaplan-Meier estimator. In order to compare hospitalizations and associated costs, we matched patients treated with SBRT to those receiving chemotherapy with comparable prognostic factors. All statistical tests were two-sided. RESULTS Median age was 74. SBRT use as first line treatment increased from 0.5% to 3% over the study period. SBRT use was independently associated with older age (OR 1.09, P < 0.001), female sex (OR 1.54, P = 0.002), poor disability status (OR 2.09, P < 0.001), and lower T- and N-stage (P < 0.001). Survival increased with SBRT use (HR 0.72, P < 0.001), female sex (HR 0.80, P < 0.001) higher income (≥$80,000, HR 0.85, P < 0.001) and decreased with higher Charlson Comorbidity Score (≥2, HR 1.09, P < 0.001), poor disability status (HR 1.22, P < 0.001), higher T-stage (HR 1.31, P < 0.001) and higher N-stage (N3, HR 1.21, P < 0.001). Among a sample matched on age, sex, Charlson comorbidity score, disability status, T-stage and N-stage, patients treated with first line SBRT underwent fewer hospitalizations compared to chemotherapy patients (73% vs. 81%, P < 0.01) however, SBRT patients incurred higher total hospitalization costs (mean $33,039 vs. $23,709, P < 0.001). The most common admitting diagnoses were shortness of breath and pneumonia. CONCLUSION In a sample of elderly Medicare patients, the use of SBRT among patients with metastatic lung cancer is increasing. Despite these patients having worse prognostic factors (e.g., older age, poor disability status), receipt of SBRT was associated with improved survival compared to chemotherapy. SBRT was associated with overall fewer hospitalizations but increased hospitalization costs, possibly reflecting more complex management of treatment-related complications.

Background: Use of injury prevention programs (IPPs) by high school athletes has increased but their success in reducing injury depends on program compliance and fidelity of exercise performance. Hypothesis: Compliance with the 11+ IPP and exercise performance fidelity by high school athletic teams depend on sex, sport, and level of play. Study Design: Secondary analyses of data from a randomized controlled trial (RCT). Level of Evidence: Level 2. Methods: The 11+ IPP was implemented by 100 male and female high school athletic teams (American football, soccer, basketball, and lacrosse). Team compliance and fidelity with the program were evaluated by direct observation of warm-up routines and a weekly online survey completed by coaches. Differences in compliance and fidelity due to sport, sex, and level of play were assessed by analysis of variance. Results: Coaches reported that their teams performed the full IPP an average of 1.45 times per week, and 28% of observed warm-ups included all exercises in the IPP. Compliance differed by sport but not by level of play or the athletes’ sex. At the end of the season, cueing was observed 19% of the time and differed by sport. Good technique was observed 66% of the time and varied by level of play. Conclusion: Team compliance with the IPP varied by sport and was below the recommended number of sessions per week needed to reduce injury. Removal of implementation barriers and improved support from coaches are needed at all levels of play for IPPs to be effective. Clinical Relevance: Clinical and sports practitioners intending to implement an IPP at the high school level should anticipate and address barriers that affect program compliance and fidelity of exercise performance. Frequent follow-up and instruction may be necessary for successful adoption of the IPP.

Background: The femoral intercondylar notch type and the alpha angle (the angle between the femoral notch roof and the long axis of the femur) are easily measured in clinical settings; however, their associations with anterior cruciate ligament (ACL) injury remain unclear. Hypothesis/Purpose: The purpose was to determine if the alpha angle and the femoral notch type are associated with noncontact ACL injury univariately and in combination with previously identified knee geometric risk factors. We hypothesized that the alpha angle and the femoral notch type are associated with noncontact ACL injury and that the association differs between men and women. Study Design: Case control study; Level of evidence, 3. Methods: The alpha angle and the femoral notch type were measured via 3T magnetic resonance imaging (MRI) acquired from 61 women and 25 men with a first-time noncontact ACL injury. Each injured patient was matched with a control participant based on age, sex, and participation on the same sports team. A conditional logistic regression was used to assess univariate associations with ACL injury as well as multivariate associations using MRI-based risk factors of knee geometry identified in previous analyses: femoral intercondylar notch width at the anterior outlet, femoral intercondylar notch anteromedial ridge thickness, volume of the ACL, tibial plateau lateral compartment subchondral bone slope, lateral compartment middle articular cartilage slope, lateral compartment meniscus-cartilage height, lateral compartment meniscus-bone angle, and medial tibial spine volume. Results: For female athletes, the alpha angle (odds ratio, [OR], 1.82 per 1-degree increase; P = .001), the tibial lateral compartment articular cartilage slope (OR, 1.25 per 1-degree increase in the posterior-inferior directed slope; P = .022), and the femoral notch anteromedial ridge thickness (OR, 3.36 per 1-mm increase; P = .027) were independently associated with ACL disruption. For men, no other variables entered the models after the alpha angle was inputted as the first step (OR, 2.19 per 1-degree increase; P = .010). Conclusion: For women, ACL injury was most strongly associated with increased alpha angle, increased tibial plateau slope, and increased femoral notch ridge thickness. For men, increased alpha angle was the most significant factor associated with ACL injury. The mechanism of injury might be associated with a combination of impingement of the ACL against the bone and increased ligament loading.

Background: Lower extremity injuries are common in high school sports and are costly, and some have poor outcomes. The FIFA 11+ injury prevention program has been shown to decrease injuries in elite athletes by up to 72%. Hypothesis: High schools in which coaches implement the FIFA 11+ injury prevention program in their athletic programs will have a decreased incidence of lower extremity injuries compared with schools using their usual prepractice warm-up. Study Design: Randomized controlled trial; Level of evidence, 1. Methods: Fourteen high schools that employed an athletic trainer were randomly assigned to either the FIFA 11+ group or control group (usual warm-up routine). Exposure to sports and injuries were recorded and used to determine the incidence rates of lower extremity injuries per athlete-exposure (AE). The FIFA 11+ program was implemented by coaches and complicance with the program recorded. Results: There were 196 lower extremity injuries among 1825 athletes in the FIFA 11+ group and 172 injuries among 1786 athletes in the control group (1.59 and 1.47 injuries per 1000 AEs, respectively; P = .771). The distribution of the types of injury in the 2 groups did not differ, but the body locations where the injuries occurred differed somewhat ( P = .051). The FIFA 11+ group had larger proportions of thigh and foot injuries, while the control group had higher proportions of knee and ankle injuries. Group differences in injury rates varied with sport ( P = .041 for interaction), but there were no significant differences in injury rates between the FIFA 11+ and control groups by sport, level of play, and sex. In the FIFA 11+ group, 62% of the coaches reported that their teams completed the full FIFA 11+ program at least once a week, and 32% reported that they completed it at least twice a week. Conclusion: This study did not demonstrate a reduction in lower extremity injuries in schools randomized to use the FIFA 11+ program compared with schools using their usual prepractice warm-up program. Coach-reported compliance with performing the FIFA 11+ program at least twice a week was low.

Aging is associated with enhanced oxidative stress and increased susceptibility to numerous diseases. This relationship is particularly striking with respect to the incidence of fibrotic lung disease. To identify potential mechanisms underlying the association between aging and susceptibility to fibrotic lung disease we analyzed transcriptome data from 342 disease-free human lung samples as a function of donor age. Our analysis reveals that aging in lung is accompanied by modest yet progressive changes in genes modulating redox homeostasis, the TGF-beta 1 signaling axis, and the extracellular matrix (ECM), pointing to an aging lung functional network (ALFN). Further, the transcriptional changes we document are tissue-specific, with age-dependent gene expression patterns differing across organ systems. Our findings suggest that the age-associated increased incidence of fibrotic pulmonary disease occurs in the context of tissue-specific, age-dependent transcriptional changes. Understanding the relationship between age-associated gene expression and susceptibility to fibrotic pulmonary disease may allow for more accurate risk stratification and effective therapeutic interventions within this challenging clinical space.

Background Mammographic density (MD) is a strong breast cancer risk factor that reflects fibroglandular and adipose tissue composition, but its biologic underpinnings are poorly understood. Insulin-like growth factor binding proteins (IGFBPs) are markers that may be associated with MD given their hypothesized role in breast carcinogenesis. IGFBPs sequester IGF-I, limiting its bioavailability. Prior studies have found positive associations between circulating IGF-I and the IGF-I:IGFBP-3 ratio and breast cancer risk. We evaluated the associations of IGF-I, IGFBP-3, and six other IGFBPs with MD. Methods Serum IGF measures were quantified in 296 women, ages 40–65, undergoing diagnostic image-guided breast biopsy. Volumetric density measures (MD-V) were assessed in pre-biopsy digital mammograms using single X-ray absorptiometry. Area density measures (MD-A) were estimated by computer-assisted thresholding software. Age, body mass index (BMI), and BMI2-adjusted linear regression models were used to examine associations of serum IGF measures with MD. Effect modification by BMI was also assessed. Results IGF-I and IGFBP-3 were not strongly associated with MD after BMI adjustment. In multivariable analyses among premenopausal women, IGFBP-2 was positively associated with both percent MD-V (β = 1.49, p value = 0.02) and MD-A (β = 1.55, p value = 0.05). Among postmenopausal women, positive relationships between IGFBP-2 and percent MD-V (β = 2.04, p = 0.003) were observed; the positive associations between IGFBP-2 and percent MD-V were stronger among lean women (BMI

OBJECTIVES: This study aimed to characterize the relationship between radiographic silicosis and exposure to respirable quartz and determine how exposure affects disease progression. METHODS: Surveillance chest radiographs from a cohort of 1902 workers were examined to identify 67 cases of radiographic silicosis and 167 matched controls. Exposures were estimated by linking work histories to a job exposure matrix (JEM) based on samples collected by the participating companies and historical estimates. Conditional logistic regression was used to examine exposure‒response relationships. Sequential radiographs from silicosis cases were used to assess associations between exposure and disease progression. RESULTS: Risk of silicosis increased with cumulative exposure [odds ratio (OR) 1.43 per 1 mg/m^3 years, 95% confidence interval (CI) 1.23–1.66], average exposure concentration (OR 1.30 per 0.10 mg/m^3, 95% CI 1.11–1.51) and net exposure duration (OR 1.10 per year, 95% CI 1.05–1.16). Multivariate analyses indicated that the risk associated with cumulative exposure varied depending on exposure duration and concentration. Analysis of the time worked at differing exposure levels indicated that exposures ≤0.05 mg/m^3 were not significantly associated with silicosis risk after adjustment for years worked at higher concentrations. Disease progression was related to subsequent exposure concentration, with a yearly increase in small opacity profusion of 0.052 subcategory per each 0.10 mg/m^3 increase in concentration. CONCLUSIONS: Workers with longer exposure at lower concentrations were at higher risk for silicosis than those with the same cumulative exposure who worked for a shorter time at higher concentrations. The rate of silicosis progression was related to subsequent exposure concentration.

The Seasonal Beliefs Questionnaire (SBQ) is a 26-item self-report measure of a winter seasonal affective disorder (SAD)-specific cognitive vulnerability consisting of maladaptive thoughts about the seasons, light availability, and weather conditions. In a known groups comparison, currently depressed adults with SAD had significantly higher SBQ scores than currently depressed adults with nonseasonal major depressive disorder (MDD) and healthy controls, and the MDD group had significantly higher SBQ scores than controls. Using that database, this study explored the predictive validity of using an SBQ cutoff score to differentiate SAD from MDD. Receiver operator characteristic curve analyses used SBQ total score to predict SAD versus MDD, SAD versus control, and MDD versus control status. The SBQ subscale combined score, derived from multivariable logistic regression with SBQ subscales, was examined as an alternative predictor. SBQ total score with a cutpoint of 132 had good predictive ability for distinguishing SAD from MDD (C-statistic = .792, sensitivity = .798, specificity = .794). The SBQ subscale combination score slightly improved predictive ability for the SAD/MDD distinction (C-statistic = .813), with better sensitivity (.930) but worse specificity (.571). In contrast, the score on a generic measure of depressogenic cognitive vulnerability, the Dysfunctional Attitudes Scale, was poor for differentiating SAD from MDD. SBQ total score was excellent in discriminating SAD cases from controls with a cutpoint of 121 (C-statistic = .962, sensitivity = .939, specificity .873), but had poor sensitivity for discriminating MDD cases from controls. Results support using the SBQ to screen for probable SAD in practice settings. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Chronic obstructive pulmonary disease (COPD) is a chronic respiratory disease characterized by small airway remodeling and alveolar emphysema due to environmental stresses such as cigarette smoking (CS). Oxidative stress is commonly implicated in COPD pathology, but recent findings suggest that one oxidant-producing NADPH oxidase homolog, dual oxidase 1 (DUOX1), is down regulated in the airways of patients with COPE). We evaluated lung tissue sections from patients with COPD for small airway epithelial DUOX1 protein expression, in association with measures of lung function and small airway and alveolar remodeling. We also addressed the impact of DUOX1 for lung tissue remodeling in mouse models of COPD. Small airway DUOX1 levels were decreased in advanced COPD and correlated with loss of lung function and markers of emphysema and remodeling. Similarly, DUOX1 down regulation in correlation with extracellular matrix remodeling was observed in a genetic model of COPD, transgenic SPC-TNF-alpha mice. Finally, development of subepithelial airway fibrosis in mice due to exposure to the CS-component acrolein, or alveolar emphysema induced by administration of elastase, were in both cases exacerbated in Duox1-deficient mice. Collectively, our studies highlight that downregulation of DUOX1 may be a contributing feature of COPD pathogenesis, likely related to impaired DUOX1-mediated innate injury responses involved in epithelial homeostasis.

Using data from a clinical trial comparing cognitive-behavioral therapy (CBT-SAD) and light therapy (LT) for winter seasonal affective disorder (SAD; n = 177), we explored critical decision points, or treatment weeks, that predict likelihood of nonremission at post-treatment and depression recurrence following treatment. In receiver operator characteristic (ROC) curve analyses, we used weekly Structured Clinical Interview for the Hamilton Rating Scale for Depression-SAD Version (SIGH-SAD) scores during treatment to predict nonremission at post-treatment (Week 6) and recurrence one winter later (Winter 1), two winters later (Winter 2), and any recurrence. Although several C-statistics of ≥ 0.70 were found, only Week 4 SIGH-SAD scores in CBT-SAD for nonremission had enough predictive ability to inform clinical decision-making (C-statistic = 0.80; sensitivity = 0.91; specificity = 0.68). Week 4 of CBT-SAD may be a critical time point to identify likely nonremitters who need tailoring of intervention, based on SIGH-SAD cutpoint score ≥ 13. This study illustrates how clinical trial data can inform detecting optimal decision points in treatment for identifying patients unlikely to remit, a critical first step to developing adaptive treatment strategies using decision rules to operationalize when and for whom treatment should change to maximize clinical benefit.

Terminal duct lobular units (TDLUs) are the predominant anatomical structures where breast cancers originate. Having lesser degrees of age-related TDLU involution, measured as higher TDLUs counts or more epithelial TDLU substructures (acini), is related to increased breast cancer risk among women with benign breast disease (BBD). We evaluated whether a recently developed polygenic risk score (PRS) based on 313-common variants for breast cancer prediction is related to TDLU involution in the background, normal breast tissue, as this could provide mechanistic clues on the genetic predisposition to breast cancer. Among 1398 women without breast cancer, higher values of the PRS were significantly associated with higher TDLU counts (P = 0.004), but not with acini counts (P = 0.808), in histologically normal tissue samples from donors and diagnostic BBD biopsies. Mediation analysis indicated that TDLU counts may explain a modest proportion (≤10%) of the association of the 313-variant PRS with breast cancer risk. These findings suggest that TDLU involution might be an intermediate step in the association between common genetic variation and breast cancer risk.

Introduction Drug options for VTE prophylaxis are increasing for ambulatory cancer patients and data regarding anticoagulant-drug interactions and their relationship to VTE and bleeding are needed to improve care. Methods Over one year, 108 cancer patients with high VTE risk were prospectively identified. Potential anticoagulant-drug interactions were ascertained by chart review and graded on need for intervention. Providers selected anticoagulant prophylaxis based on potential drug interactions and patient-provider discussion. A cross-sectional analysis was performed thereafter to evaluate VTE and bleeding endpoints within one year of anticoagulant initiation. Results The average number of potential drug interactions per patient was higher for warfarin than others (3.04 vs. 1.28 (apixaban), 1.02 (rivaroxaban), and 0.98 (LMWH)). The severity of the interactions based on grade was, for apixaban: 1.6% grade X, 50.8% grade D, and 47.5% grade C; for rivaroxaban: 2.1% grade X, 64.9% grade D, 33.0% grade C; for LMWH, 0% grade X, 66.7% grade D, 33.3% grade C; and for warfarin, 0% grade X, 29.4% grade D, 70.6% grade C. At the end of the investigational period, 11 bleeds and 7 VTEs were reported. Drug combinations significantly associated with an increased bleeding risk were crizotinib with apixaban or rivaroxaban and PPIs with warfarin. The use of sulfamethoxazole-trimethoprim with warfarin was associated with an increased VTE risk. Conclusions DOACs had fewer DDIs than warfarin, although interaction severity differed between anticoagulants. Some anticoagulant-drug interactions were associated with bleeding or VTE. Although not powered for analysis, DDI severity did not affect bleeding rates and inversely correlated with VTE risk.

The association of progesterone/progesterone metabolites with elevated mammographic breast density (MBD) and delayed age-related terminal duct lobular unit (TDLU) involution, strong breast cancer risk factors, has received limited attention. Using a reliable liquid chromatography-tandem mass-spectrometry assay, we quantified serum progesterone/progesterone metabolites and explored cross-sectional relationships with MBD and TDLU involution among women, ages 40–65, undergoing diagnostic breast biopsy. Quantitative MBD measures were estimated in pre-biopsy digital mammograms. TDLU involution was quantified in diagnostic biopsies. Adjusted partial correlations and trends across MBD/TDLU categories were calculated. Pregnenolone was positively associated with percent MBD-area (MBD-A, rho: 0.30; p-trend = 0.01) among premenopausal luteal phase women. Progesterone tended to be positively associated with percent MBD-A among luteal phase (rho: 0.26; p-trend = 0.07) and postmenopausal (rho: 0.17; p-trend = 0.04) women. Consistent with experimental data, implicating an elevated 5α-pregnanes/3α-dihydroprogesterone (5αP/3αHP) metabolite ratio in breast cancer, higher 5αP/3αHP was associated with elevated percent MBD-A among luteal phase (rho: 0.29; p-trend = 0.08), but not postmenopausal women. This exploratory analysis provided some evidence that endogenous progesterone and progesterone metabolites might be correlated with MBD, a strong breast cancer risk factor, in both pre- and postmenopausal women undergoing breast biopsy. Additional studies are needed to understand the role of progesterone/progesterone metabolites in breast tissue composition and breast cancer risk.

The breast stromal microenvironment is a pivotal factor in breast cancer development, growth and metastases. Although pathologists often detect morphologic changes in stroma by light microscopy, visual classification of such changes is subjective and non-quantitative, limiting its diagnostic utility. To gain insights into stromal changes associated with breast cancer, we applied automated machine learning techniques to digital images of 2387 hematoxylin and eosin stained tissue sections of benign and malignant image-guided breast biopsies performed to investigate mammographic abnormalities among 882 patients, ages 40–65 years, that were enrolled in the Breast Radiology Evaluation and Study of Tissues (BREAST) Stamp Project. Using deep convolutional neural networks, we trained an algorithm to discriminate between stroma surrounding invasive cancer and stroma from benign biopsies. In test sets (928 whole-slide images from 330 patients), this algorithm could distinguish biopsies diagnosed as invasive cancer from benign biopsies solely based on the stromal characteristics (area under the receiver operator characteristics curve = 0.962). Furthermore, without being trained specifically using ductal carcinoma in situ as an outcome, the algorithm detected tumor-associated stroma in greater amounts and at larger distances from grade 3 versus grade 1 ductal carcinoma in situ. Collectively, these results suggest that algorithms based on deep convolutional neural networks that evaluate only stroma may prove useful to classify breast biopsies and aid in understanding and evaluating the biology of breast lesions.

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. 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. 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. 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.

Background: Contralateral anterior cruciate ligament (CACL) injury after recovery from a first-time ACL rupture occurs at a high rate in young females; however, little is known about the risk factors associated with bilateral ACL trauma. Hypothesis: The geometric characteristics of the contralateral knee at the time of the initial ACL injury are associated with risk of suffering a CACL injury in these female athletes. Study Design: Case-control study; Level of evidence, 3. Methods: Sixty-two female athletes who suffered their first noncontact ACL injury while participating in sports at the high school or college level were identified, and geometry of the femoral notch, ACL, tibial spines, tibial subchondral bone, articular cartilage surfaces, and menisci of the contralateral, uninjured, knee was characterized in 3 dimensions. We were unable to contact 7 subjects and followed the remaining 55 until either a CACL injury or an ACL graft injury occurred or, if they were not injured, until the date of last contact (mean, 34 months after their first ACL injury). Cox regression was used to identify risk factors for CACL injury. Results: Ten (18.2%) females suffered a CACL injury. Decreases of 1 SD in femoral intercondylar notch width (measured at its outlet and anterior attachment of the ACL) were associated with increases in the risk of suffering a CACL injury (hazard ratio = 1.88 and 2.05, respectively). Likewise, 1 SD decreases in medial-lateral width of the lateral tibial spine, height of the medial tibial spine, and thickness of the articular cartilage located at the posterior region of the medial tibial compartment were associated with 3.59-, 1.75-, and 2.15-fold increases in the risk of CACL injury, respectively. Conclusion: After ACL injury, subsequent injury to the CACL is influenced by geometry of the structures that surround the ACL (the femoral notch and tibial spines). This information can be used to identify individuals at increased risk for CACL trauma, who might benefit from targeted risk-reduction interventions.

Background: Static and dynamic exercises are performed before activity to decrease injury risk and increase performance. Although evidence supports using dynamic over static stretching and performing Fédération Internationale de Football Association (FIFA) 11+ as a dynamic prepractice routine, we do not know the frequency at which these exercises are utilized in high school populations. Hypothesis: We hypothesize that there is a wide variety of preparticipation exercises performed by high school athletes, and that few high school teams perform FIFA 11+ as an injury prevention program in its entirety. Study Design: Observational study. Level of Evidence: Level 4. Methods: High school prepractice routines were observed for 185 teams (football, soccer, basketball, and lacrosse) over 1 season. The percentages of team warm-up routines that included components of FIFA 11+ were calculated, and the chi-square test was used to compare sex, sport, and level of competition. Results: Of a total 644 warm-up observations, 450 (69.9%) included only non–FIFA 11+ exercises, 56 (8.7%) included at least 1 FIFA 11+ exercise, and 38 (5.9%) included only jogging; 69 (10.6%) consisted only of sport-specific activities. The type of warm-up differed significantly between males and females ( P = 0.002), sports ( P < 0.001), and level of competition ( P < 0.001). Static stretching and athletes stretching on their own were observed in 14% and 15% of all observations. No team performed the FIFA 11+ injury prevention routine in its entirety. Conclusion: The type of warm-up differed by sex, sport, and level of competition. Static stretching was performed more frequently than anticipated, and an entire FIFA 11+ warm-up was never performed. Clinical Relevance: We need to identify the exercises that decrease injury and increase performance and better inform the athletic population about the risks and benefits of static and dynamic warm-up programs.