Long-term Mammography Screening Trends and Predictors of Return to Screening after the COVID-19 Pandemic: Results from a Statewide Registry.

Purpose To evaluate long-term trends in mammography screening rates and identify sociodemographic and breast cancer risk characteristics associated with return to screening after the COVID-19 pandemic. Materials and Methods In this retrospective study, statewide screening mammography data of 222 384 female individuals aged 40 years or older (mean age, 58.8 years ± 11.7 [SD]) from the Vermont Breast Cancer Surveillance System were evaluated to generate descriptive statistics and Joinpoint models to characterize screening patterns during 2000-2022. Log-binomial regression models estimated associations of sociodemographic and risk characteristics with post-COVID-19 pandemic return to screening. Results The proportion of female individuals in Vermont aged 50-74 years with a screening mammogram obtained in the previous 2 years declined from a prepandemic level of 61.3% (95% CI: 61.1%, 61.6%) in 2019 to 56.0% (95% CI: 55.7%, 56.3%) in 2021 before rebounding to 60.7% (95% CI: 60.4%, 61.0%) in 2022. Screening adherence in 2022 remained substantially lower than that observed during the 2007-2010 apex of screening adherence (66.1%-67.0%). Joinpoint models estimated an annual percent change of -1.1% (95% CI: -1.5%, -0.8%) during 2010-2022. Among the cohort of 95 644 individuals screened during January 2018-March 2020, the probability of returning to screening during 2020-2022 varied by age (eg, risk ratio [RR] = 0.94 [95% CI: 0.93, 0.95] for age 40-44 vs age 60-64 years), race and ethnicity (RR = 0.84 [95% CI: 0.78, 0.90] for Black vs White individuals), education (RR = 0.84 [95% CI: 0.81, 0.86] for less than high school degree vs college degree), and by 5-year breast cancer risk (RR = 1.06 [95% CI: 1.04, 1.08] for very high vs average risk). Conclusion Despite a rebound to near prepandemic levels, Vermont mammography screening rates have steadily declined since 2010, with certain sociodemographic groups less likely to return to screening after the pandemic. Keywords: Mammography, Breast, Health Policy and Practice, Neoplasms-Primary, Epidemiology, Screening Supplemental material is available for this article. © RSNA, 2024.

Prospectively assessed summer mood status in major depression, recurrent with seasonal pattern: Evidence for SAD's construct validity.

OBJECTIVE: Seasonal patterns are often undetectable in population-based depression studies, calling into question the existence of winter seasonal affective disorder (SAD). If SAD has construct validity, individuals with SAD should show spontaneous depression remission in the summer. Data are sparse on prospectively assessed summer mood status in confirmed SAD patients. METHOD: We conducted prospective summer followup of community adults who, the winter before, were diagnosed with Major Depression, Recurrent with Seasonal Pattern on the Structured Clinical Interview for DSM-IV Axis I Disorders, developed a current SAD episode on the Structured Interview Guide for the Hamilton Rating Scale for Depression-Seasonal Affective Disorder Version (SIGH-SAD), and enrolled in a clinical trial comparing group cognitive-behavioral therapy for SAD and light therapy. In July/August after treatment, 143/153 (93.5 %) participants provided data on the SIGH-SAD, the Beck Depression Inventory-Second Edition, and the Longitudinal Interval Followup Evaluation (LIFE). RESULTS: Summer mean depression scores were in the normal range, with the substantial majority in remission across different measures. On the LIFE, 113/143 (79.0 %) experienced complete summer remission, 19/143 (13.3 %) experienced partial summer remission, and 11/143 (7.7 %) had major depression in the summer. Depression scores were significantly lower at summer than post-treatment in both treatments, indicating incomplete treatment response. LIMITATIONS: This was a single-site study with a relatively homogeneous sample. CONCLUSIONS: Supporting construct validity for SAD, the substantial majority experienced complete summer remission, with a minority in partial remission and a very small minority in episode. Both treatments left residual symptoms at treatment endpoint compared to summer.

Risk Factors for Concomitant Meniscal Injury With Sport-Related Anterior Cruciate Ligament Injury.

Background: Previous studies of concomitant meniscal injury in athletes with anterior cruciate ligament (ACL) injury have examined age, sex, body mass index (BMI), injury mechanism, and time from injury to surgery as potential risk factors. Purpose: To identify additional risk factors for concomitant meniscal injury, including preinjury joint laxity and lower extremity alignment, in athletes with sport-related ACL injury. Study Design: Cross-sectional study; Level of evidence, 3. Methods: This study included 180 participants aged 13 to 26 years who underwent ACL reconstruction (ACLR) after a first-time ACL injury sustained during participation in sport. Contralateral lower extremity alignment and joint laxity were used as surrogate measures for the injured knee before trauma. Concomitant meniscal tear patterns were identified at the time of ACLR. Sex-specific analyses were conducted. Results: Concomitant meniscal injury was observed in 60.6% of the subjects. The prevalence of concomitant injury was higher in male than female participants (69.9% vs 54.2%; P = .035) due to a higher prevalence of lateral meniscal injuries (56.2% vs 38.3%; P = .018). Among male patients, there was a significant difference in the prevalence of concomitant lateral meniscal tear according to sport participation (≥9 vs <9 h/week: 67.4% vs 35.7%; P = .032). Among male patients, the likelihood of concomitant injury to both the lateral and medial menisci increased by 28.8% for each 1-mm decrease in navicular drop. Among female patients, the likelihood of concomitant injury to the lateral meniscus increased by 15% per degree increase in genu recurvatum and 14% per degree decrease in standing quadriceps angle, with similar effects on the likelihood of concurrent injury to both the lateral and medial menisci. Conclusion: Measures of lower extremity alignment and genu recurvatum previously identified as risk factors for ACL injury were also associated with concomitant meniscal injury in female patients while other risk factors, including BMI and joint laxity, were not. Increased time spent participating in sport and navicular drop were associated with concomitant meniscal injury in male patients.

Identification of molecularly unique tumor-associated mesenchymal stromal cells in breast cancer patients.

The tumor microenvironment is a complex mixture of cell types that bi-directionally interact and influence tumor initiation, progression, recurrence, and patient survival. Mesenchymal stromal cells (MSCs) of the tumor microenvironment engage in crosstalk with cancer cells to mediate epigenetic control of gene expression. We identified CD90+ MSCs residing in the tumor microenvironment of patients with invasive breast cancer that exhibit a unique gene expression signature. Single-cell transcriptional analysis of these MSCs in tumor-associated stroma identified a distinct subpopulation characterized by increased expression of genes functionally related to extracellular matrix signaling. Blocking the TGFß pathway reveals that these cells directly contribute to cancer cell proliferation. Our findings provide novel insight into communication between breast cancer cells and MSCs that are consistent with an epithelial to mesenchymal transition and acquisition of competency for compromised control of proliferation, mobility, motility, and phenotype.

Intrinsic Risk Factors for First-Time Noncontact ACL Injury: A Prospective Study of College and High School Athletes.

BACKGROUND: A comprehensive understanding of the intrinsic risk factors for anterior cruciate ligament (ACL) disruption is important for identifying individuals at increased risk for suffering this trauma and developing interventions to mitigate risk. HYPOTHESIS: A variety of risk factors predispose athletes to first-time, noncontact ACL injury and some of these differ between male and female athletes. STUDY DESIGN: Prospective cohort study with nested case-control sampling. LEVEL OF EVIDENCE: Level 2. METHODS: Sport teams at 28 high schools and 8 colleges were monitored prospectively over 4 years, and 109 of 130 athletes who suffered their first noncontact ACL injury participated in the study. At the time of injury, matched control subjects were randomly selected from among the case's teammates and a total of 227 athletes participated. Demographic characteristics, joint laxity, lower extremity alignment, strength, and personality characteristics were measured. The association of each risk factor with injury risk was assessed by conditional logistic regression. RESULTS: The risk factors that were associated with ACL injury in both male and female athletes included having a parent with prior ACL injury and increases of the following variables: body weight, anterior displacement of the tibia relative to the femur, genu recurvatum, and generalized joint laxity. Risk factors that are unique to female athletes included increased body mass index, increased trunk flexion strength, and prior non-ACL knee injury. The risk factors specific to male athletes were decreased standing quadriceps angle, decreased hip adduction strength, and chronic disease. CONCLUSION: A diverse set of risk factors predispose both male and female athletes to ACL injury, whereas others appear to be sex-specific. CLINICAL RELEVANCE: Different approaches for assessing risk and preventing ACL injury are needed for male and female athletes. In addition, personalized prevention strategies may be needed to target the specific characteristics that place an individual at increased risk of suffering this trauma.

Trends and costs of stereotactic body radiation therapy in metastatic non-small cell lung cancer.

Background: The purpose of this study is to describe stereotactic body radiation therapy (SBRT) use, outcomes, hospitalizations and costs compared to patients receiving chemotherapy among patients with metastatic non-small cell lung cancer (NSCLC). Methods: Using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database, we identified patients aged ≥66 with metastatic NSCLC treated with SBRT as first-line treatment between 2004 and 2014. Multivariable logistic regression identified covariates associated with SBRT. Overall survival (OS) between SBRT and chemotherapy was compared using the Kaplan-Meier estimator and Cox proportional hazards regression. To compare hospitalizations and associated costs, we matched patients treated with SBRT to those with comparable prognostic factors receiving chemotherapy. Results: We identified 215 patients with metastatic NSCLC who received SBRT and 12,486 patients who received chemotherapy as first-line treatment. SBRT use increased from 0.5% to 3% and was associated with older age, female sex, poor disability status, and lower T- and N-stage. OS increased with SBRT, female sex, higher income and decreased with higher Charlson Comorbidity Score ≥2, poor disability status, higher T-stage and higher N-stage. Among a matched sample, SBRT patients underwent fewer hospitalizations vs. chemotherapy patients (73% vs. 81%, P=0.02). Among those hospitalized, SBRT patients incurred higher hospitalization costs ($33,063 vs. $23,865, P<0.001) but costs per month of survival were similar. Conclusions: SBRT is increasing among Medicare patients with metastatic NSCLC. Our findings suggest that SBRT may play a role in management of select metastatic NSCLC patients in addition to standard-of-care chemotherapy.

Elucidating treatment targets and mediators within a confirmatory efficacy trial: study protocol for a randomized controlled trial of cognitive-behavioral therapy vs. light therapy for winter depression.

BACKGROUND: This study is a confirmatory efficacy trial of two treatments for winter seasonal affective disorder (SAD): SAD-tailored group cognitive-behavioral therapy (CBT-SAD) and light therapy (LT). In our previous efficacy trial, post-treatment outcomes for CBT-SAD and LT were very similar, but CBT-SAD was associated with fewer depression recurrences two winters later than LT (27.3% in CBT-SAD vs. 45.6% in LT). CBT-SAD engaged and altered a specific mechanism of action, seasonal beliefs, which mediated CBT-SAD's acute antidepressant effects and CBT-SAD's enduring benefit over LT. Seasonal beliefs are theoretically distinct from LT's assumed target and mechanism: correction of circadian phase. This study applies the experimental therapeutics approach to determine how each treatment works when it is effective and to identify the best candidates for each. Biomarkers of LT's target and effect include circadian phase angle difference and the post-illumination pupil response. Biomarkers of CBT-SAD's target and effect include decreased pupillary and sustained frontal gamma-band EEG responses to seasonal words, which are hypothesized as biomarkers of seasonal beliefs, reflecting less engagement with seasonal stimuli following CBT-SAD. In addition to determining change mechanisms, this study tests the efficacy of a "switch" decision rule upon recurrence to inform clinical decision-making in practice. METHODS: Adults with SAD (target N = 160) will be randomzied to 6-weeks of CBT-SAD or LT in winter 1; followed in winter 2; and, if a depression recurrence occurs, offered cross-over into the alternate treatment (i.e., switch from LT➔CBT-SAD or CBT-SAD➔LT). All subjects will be followed in winter 3. Biomarker assessments occur at pre-, mid-, and post-treatment in winter 1, at winter 2 follow-up (and again at mid-/post-treatment for those crossed-over), and at winter 3 follow-up. Primary efficacy analyses will test superiority of CBT-SAD over LT on depression recurrence status (the primary outcome). Mediation analyses will use parallel process latent growth curve modeling. DISCUSSION: Consistent with the National Institute of Mental Health's priorities for demonstrating target engagement at the level of Research Domain Criteria-relevant biomarkers, this work aims to confirm the targets and mechanisms of LT and CBT-SAD to maximize the impact of future dissemination efforts. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03691792 . Registered on October 2, 2018.

A Novel Fluoroscopic Method for Assessing Rotational Malalignment of the Tibia.

OBJECTIVE: To evaluate the accuracy and reliability of a novel fluoroscopic technique for assessing tibial rotation and compare it with a previously described fluoroscopic method. METHODS: A multiplanar circular ring external fixator was secured to the tibial diaphysis of 5 cadaveric lower extremity specimens. Using deformity correction software, the frame and tibia were programed to randomly rotate 5, 10, 15, 20, 25, and 30 degrees of internal and external rotation. After each rotation, 2 blinded, independent observers measured the degree of tibial rotation using 2 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 interobserver reliability were calculated. RESULTS: Both intermalleolar and mortise methods had a mean absolute rotational difference from the true torsion of 3 degrees (standard error 1; range, 0-10 degrees intermalleolar vs. 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 with 93.8% (122/130) using the mortise method. Both the intermalleolar and the mortise methods had excellent interobserver reliability (intraclass correlation coefficient 0.99 and 0.96, respectively). CONCLUSION: Measuring tibial rotation fluoroscopically using the intermalleolar method is both accurate and reliable. Compared with the previously described mortise method, it has similar accuracy and provides a value that approximates the true tibial rotation. Also, it can be used reliably and effectively intraoperatively to identify tibial malrotation and assist in intraoperative rotational corrections.

Articular cartilage thickness changes differ between males and females 4 years following anterior cruciate ligament reconstruction.

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 4-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 posttraumatic 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.

Compliance and Fidelity With an Injury Prevention Exercise Program in High School Athletics.

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.

Mammary collagen architecture and its association with mammographic density and lesion severity among women undergoing image-guided breast biopsy.

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 < 0.001) and with local percent mammographic density volume at both the biopsy target (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 < 0.05). 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.

Association of Geometric Characteristics of Knee Anatomy (Alpha Angle and Intercondylar Notch Type) With Noncontact ACL Injury.

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.

Predictive validity of the Seasonal Beliefs Questionnaire for discriminating between seasonal and nonseasonal major depressive disorder.

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).

Downregulation of epithelial DUOX1 in chronic obstructive pulmonary disease.

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 downregulated in the airways of patients with COPD. 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 downregulation in correlation with extracellular matrix remodeling was observed in a genetic model of COPD, transgenic SPC-TNF-α 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.

Collagen Organization in Relation to Ductal Carcinoma In Situ Pathology and Outcomes.

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.

Polygenic risk score for the prediction of breast cancer is related to lesser terminal duct lobular unit involution of the breast.

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.

Prospective evaluation of drug-drug interactions in ambulatory cancer patients initiated on prophylactic anticoagulation.

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.

Relationship of Serum Progesterone and Progesterone Metabolites with Mammographic Breast Density and Terminal Ductal Lobular Unit Involution among Women Undergoing Diagnostic Breast Biopsy.

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.

Microarray and RNA in situ hybridization assay for recurrence risk markers of breast carcinoma and ductal carcinoma in situ: Evidence supporting the use of diverse pathways panels.

Breast tumor stratification by recurrence-risk is critical for deciding patient treatment. Here an approach combining cancer pathways microarray data complemented by RNA in situ hybridization (ISH) was investigated as a means for recurrence marker discovery and visualization in pathology specimens. LncRNA and mRNA expressions in breast carcinomas with low (n = 8) vs intermediate/high (n = 10) recurrence-scores as estimated by 21-gene assay and pathology review were compared by microarray assay. Tissue microarrays were prepared from breast carcinomas (n = 20) and ductal carcinoma in situ (DCIS) specimens (n = 84 patients) with known outcomes. Thirteen RNA ISH assays were performed: lncRNAs (BBC3-1, FER3, RAD21-AS1, ZEB1-2) and mRNAs (GLO1, GLTSCR2, TGFB1, TLR2) (implicated by the microarray data); MKI67; a pooled panel of recurrence-associated proliferation markers (BIRC5, Cyclin B1, MKI67, MYBL2, STK15); a pooled panel of non-proliferation recurrence-associated markers (CEACAM5, HTF9C, NDRG1, TP53, SLC7A5); and lncRNAs H19 and HOTAIR. Seven lncRNAs and 10 mRNAs showed significantly (P < .05) altered upregulation or downregulation by microarray assay: carcinoma RNA ISH staining did not mirror these patterns. HOTAIR staining was associated with a higher breast cancer recurrence score (P = .0152); qualitatively, H19 was massively expressed in a metaplastic triple negative breast carcinoma. Among the DCIS cohort, significant associations with multiple outcome variables were noted for TGFB1 and the non-proliferation panel (P-value range: .0001 to .047); proliferation panel staining showed an association with increasing DCIS grade (P = .0269) but not with outcomes. The findings support recurrence-risk estimation by the use of multi-marker panels that are representative of diverse cellular pathways rather than over-reliance on proliferation targets. H19, HOTAIR, and TGFB1 RNA ISH show potential for selective diagnostics.