Impact of COVID-19 Restrictions on Stage of Breast Cancer at Presentation and Time to Treatment at an Urban Safety-Net Hospital.

BACKGROUND: COVID-19 disrupted health systems across the country. Pre-pandemic, patients accessing our urban safety-net hospital presented with three-fold higher rates of late-stage breast cancer than other Commission-on-Cancer sites. We sought to determine the effect of the COVID-19 pandemic on stage of breast cancer presentation and time to first treatment at our urban safety-net hospital. METHODS: An Institutional Review Board-approved cohort study of newly diagnosed breast cancer patients was conducted at our safety-net hospital comparing a COVID cohort (March 2020-February 2021, n = 82) with a pre-COVID cohort (March 2018-February 2019, n = 90). Demographic information, stage at presentation, and time to first treatment-subdivided into time from symptom to diagnosis and diagnosis to treatment-were collected and analyzed for effect of COVID pandemic. RESULTS: Cohorts were similar in age, race, and payor. More patients had late-stage disease during COVID (32%) than pre-COVID (19%, p = 0.05). There was a significantly longer time to first treatment during COVID (p = 0.0001) explained by a significantly longer time from symptom to diagnosis (p = 0.0001), with no difference in time from diagnosis to treatment. CONCLUSION: It was significantly more likely for patients to present to our safety-net hospital with late-stage breast cancer during COVID than pre-COVID. There was longer time to first treatment during COVID, driven by the increased time from symptom to diagnosis. Patients may have perceived that care was inaccessible during the pandemic or had competing priorities, driving delays. Efforts should be made to minimize disruption to safety-net hospitals during future shut-downs as these are among the most vulnerable patients.

Text-Based Intervention Increases Mammography Uptake at an Urban Safety-Net Hospital.

BACKGROUND: The low mammography rates at the authors' safety-net hospital (SNH) are associated with higher rates of late-stage disease. Previously, they showed that a phone call-based intervention with reminder and scheduling components significantly increased mammography uptake by 12% in their population, but implementation was resource-heavy. This study analyzed whether a text-based intervention with reminder and scheduling components could increase mammography uptake at 3 months compared with usual care. METHODS: This randomized controlled study analyzed 1277 women ages 50 to 65 years who were overdue for a mammogram but had established care at a primary-care clinic within an urban SNH. The patients received intervention 1 (a text reminder with specific scheduling options), intervention 2 (a text reminder with open-ended scheduling options), or usual care (control). Differences in the percentage of mammography uptake at 3 months were compared between the intervention and control groups using a two-tailed chi-square test. RESULTS: The patients receiving a text-based reminder and scheduling opportunity were significantly more likely to receive mammograms within 3 months than those in the usual-care control group (10.2% vs 6.2%; χ2 = 5.6279; p = 0.03). In the intervention group, 10.3% of the participants scheduled an appointment for a mammogram via text, and 63% of these participants received a mammogram. Finally, mammography compliance did not differ by the type of scheduling offered (specific vs general) or by primary care clinic. CONCLUSIONS: Leveraging technology for reminders and scheduling via two-way text messaging is effective in increasing mammography uptake in an urban safety-net setting and may be used as part of a multi-tiered intervention to increase breast cancer screening in a safety-net setting.

Impact of Phone-Call and Access-Enhancing Intervention on Mammography Uptake among Primary Care Patients at an Urban Safety-Net Hospital: A Randomized Controlled Study.

BACKGROUND: Our urban safety-net hospital (SNH) has very low screening mammogram rates within its primary care clinics. Despite Commission on Cancer (CoC) accreditation, we see ~ 3 × more late-stage breast cancer diagnoses than other CoC sites across the country, and recently showed this to be strongly associated with lack of screening (Ahmadiyeh et al. in J Health Care Poor Underserved, in press, 2020). Here we study whether a two-step intervention (phone calls and assistance scheduling mammograms) increases uptake over usual care. PATIENTS AND METHODS: Randomized controlled study of 890 women aged 50-65 years who were due for biennial screening mammograms and who were established within one of five primary care clinics at an urban SNH. Each patient in the intervention group was called with overdue status (up to three times, voicemail left if needed) and offered assistance scheduling mammogram appointment. Mammography uptake at 3 and 6 months was analyzed. RESULTS: Intervention significantly increased uptake compared with usual care at both timepoints (18% versus 6% at 3 months; χ2 = 27.597, p < 0.0001; 23% versus 12% at 6 months; χ2 = 18.0, p < 0.0001), with scheduling component driving effectiveness. Of those who were successfully contacted, uptake was significantly greater among those who scheduled appointments versus those who did not (47% versus 9%, χ2 = 95, p < 0.0001), and uptake was no different between contacted but not scheduled patients and usual care controls. CONCLUSIONS: Phone call with access-enhancing intervention (facilitating mammogram appointments) increased screening mammogram uptake among primary care patients in an urban safety-net setting and may be applicable to other urban SNHs around the country.

Large painful lactating adenomas effectively treated during pregnancy with bromocriptine.

Lactating adenomas are painful, benign breast lesions, typically presenting during pregnancy and treated with surgery. Here we present a case of a 25-year-old pregnant woman who developed multiple, bilateral lactating adenomas and was successfully treated during her third trimester with bromocriptine alone. Bromocriptine, a dopamine agonist, may be used in pregnancy to effectively treat lactating adenomas in lieu of surgery.

Papilloma on core biopsy: excision vs. observation.

BACKGROUND: Intraductal papillomas (IPs) are commonly seen breast lesions with variable clinical presentation. For a palpable lesion and/or evidence of cellular atypia and/or pathologic nipple discharge, excision is warranted to rule out adjacent carcinoma, while for asymptomatic IPs lacking atypia current data for excision vs. observation are controversial. We reviewed outcomes of IPs diagnosed at our institution. METHODS: With IRB approval, we reviewed consecutive patients with IPs seen on core biopsy (CBx) between 2005 and 2013. All patients had an excision, with subspecialty breast pathology review of CBx and excisions. The rate of upgrade to cancer on excision was recorded. Differences between atypia and no-atypia groups were determined by two-tailed t test and Fisher's exact test. RESULTS: We identified 97 patients (age range 31-83 years) with IPs on CBx. Among 52 atypical IPs, DCIS was seen in 11 (upgrade 21 %). In 45 IPs without atypia, 3 cancers were seen (upgrade 6. %): 2 had palpable lesions and were found to have DCIS, and 1 invasive cancer was found in a non-palpable mammographically detected BIRADS 4C lesion, whose Cbx result was discordant. If the 2 palpable lesions are excluded, the upgrade rate for IPs without atypia is 2.2 %. CONCLUSIONS: This series shows a low upgrade rate for IP without atypia seen on CBx in the absence of a palpable mass and radiographic/pathologic discordance, suggesting that a surgical biopsy may not be necessary. Further prospective studies to better estimate the upgrade rate for IPs without atypia may be helpful.

8q24 prostate, breast, and colon cancer risk loci show tissue-specific long-range interaction with MYC.

The 8q24 gene desert contains risk loci for multiple epithelial cancers, including colon, breast, and prostate. Recent evidence suggests these risk loci contain enhancers. In this study, data are presented showing that each risk locus bears epigenetic marks consistent with enhancer elements and forms a long-range chromatin loop with the MYC proto-oncogene located several hundred kilobases telomeric and that these interactions are tissue-specific. We therefore propose that the 8q24 risk loci operate through a common mechanism-as tissue-specific enhancers of MYC.

Factors Associated with Late-Stage Breast Cancer Diagnosis in an Urban Safety-net Hospital.

BACKGROUND: Late diagnosis of breast cancer is associated with lower survival. This study determines the factors associated with late-stage breast cancer diagnosis in an urban safety-net hospital (SNH) with excess late-stage disease. STUDY DESIGN: Single-institution retrospective study of all early-stage vs. late-stage breast cancer cases diagnosed or treated at the primary SNH in the Kansas City, Missouri area between January 2011-July 2018. Multiple logistic regression was performed to determine the variables that contributed most to late stage at diagnosis. RESULTS: The most significant factor associated with late-stage diagnosis was lack of screening mammogram within two years of diagnosis (p<.0001, OR 7.5, CI = 3.6, 15.3). Patients referred from within the SNH compared with those presenting from community health centers were significantly less likely to present with late-stage disease (p=.04, OR 0.50, CI = 0.25, 0.98). CONCLUSIONS: Screening mammography ought to be actively promoted in SNH settings with excess late-stage diagnosis.

Identification of genetic loci involved in diabetes using a rat model of depression.

While diabetic patients often present with comorbid depression, the underlying mechanisms linking diabetes and depression are unknown. The Wistar Kyoto (WKY) rat is a well-known animal model of depression and stress hyperreactivity. In addition, the WKY rat is glucose intolerant and likely harbors diabetes susceptibility alleles. We conducted a quantitative trait loci (QTL) analysis in the segregating F(2) population of a WKY x Fischer 344 (F344) intercross. We previously published QTL analyses for depressive behavior and hypothalamic-pituitary-adrenal (HPA) activity in this cross. In this study we report results from the QTL analysis for multiple metabolic phenotypes, including fasting glucose, post-restraint stress glucose, postprandial glucose and insulin, and body weight. We identified multiple QTLs for each trait and many of the QTLs overlap with those previously identified using inbred models of type 2 diabetes (T2D). Significant correlations were found between metabolic traits and HPA axis measures, as well as forced swim test behavior. Several metabolic loci overlap with loci previously identified for HPA activity and forced swim behavior in this F(2) intercross, suggesting that the genetic mechanisms underlying these traits may be similar. These results indicate that WKY rats harbor diabetes susceptibility alleles and suggest that this strain may be useful for dissecting the underlying genetic mechanisms linking diabetes, HPA activity, and depression.

Management of intraductal papillomas of the breast: an analysis of 129 cases and their outcome.

INTRODUCTION: The management of intraductal papillomas of the breast has been controversial; some advocate surgical excision of all lesions despite benign pathologic features, whereas others excise only those specimens with atypia. METHODS: We conducted a retrospective review of 129 core-biopsy-proven papillomas of the breast with atypia (n = 43) and without atypia (n = 86) and determined the rate of missed carcinoma in surgically excised specimen in each group. RESULTS: Carcinoma was found in 22.5% of the surgically excised specimens in the atypia group (9/40) and in 3% of the surgically excised specimens in the no atypia group (1/29). CONCLUSIONS: Our findings confirm the practice that papillomas with atypical features should be excised, and suggest that in patients with adequate follow-up, benign papillomas may be managed conservatively.

Context and strain-dependent behavioral response to stress.

BACKGROUND: This study posed the question whether strain differences in stress-reactivity lead to differential behavioral responses in two different tests of anxiety. Strain differences in anxiety-measures are known, but strain differences in the behavioral responses to acute prior stress are not well characterized. METHODS: We studied male Fisher 344 (F344) and Wistar Kyoto (WKY) rats basally and immediately after one hour restraint stress. To distinguish between the effects of novelty and prior stress, we also investigated behavior after repeated exposure to the test chamber. Two behavioral tests were explored; the elevated plus maze (EPM) and the open field (OFT), both of which are thought to measure activity, exploration and anxiety-like behaviors. Additionally, rearing, a voluntary behavior, and grooming, a relatively automatic, stress-responsive stereotyped behavior were measured in both tests. RESULTS: Prior exposure to the test environment increased anxiety-related measures regardless of prior stress, reflecting context-dependent learning process in both tests and strains. Activity decreased in response to repeated testing in both tests and both strains, but prior stress decreased activity only in the OFT which was reversed by repeated testing. Prior stress decreased anxiety-related measures in the EPM, only in F344s, while in the OFT, stress led to increased freezing mainly in WKYs. CONCLUSION: Data suggest that differences in stressfulness of these tests predict the behavior of the two strains of animals according to their stress-reactivity and coping style, but that repeated testing can overcome some of these differences.

Genetic analysis of the stress-responsive adrenocortical axis.

The underlying genetic components contributing to individual variability in functions of the stress-responsive hypothalamic-pituitary-adrenal (HPA) axis are poorly understood. To determine genetic loci mediating three aspects of the adrenocortical function, we conducted a quantitative trait locus (QTL) analysis in the segregating F2 generation of a Wistar Kyoto (WKY) x Fischer 344 (F344) cross, two inbred rat strains that differ in several HPA axis measures. The following three components of adrenocortical function are known to be regulated by different mechanisms that are mediated via suprahypothalamic, hypothalamic, pituitary, and intra-adrenal influences: basal plasma corticosterone (Cort) levels, plasma Cort response to a 10-min restraint stress, and adrenal weight. Genome scans identified a complex genetic architecture for the basal Cort phenotype, including sex and maternal lineage effects. Pairwise interactions were also identified for this trait. We identified three significant and two suggestive QTLs for stress Cort, along with two pairs of interacting loci for this trait. Four highly significant and two suggestive loci were identified for adrenal weight, with no interacting loci. In contrast to basal Cort, no sex- or lineage-dependent QTL were identified for stress Cort or adrenal weight, despite the large sex differences in these phenotypes. We identified three nucleotide alterations in an obvious candidate gene mapped to the most significant QTL for stress Cort, Cort-binding globulin (CBG), one of which is known to alter CBG binding. This analysis confirms that three separate traits regulated by the HPA axis are controlled by multiple, but mainly nonoverlapping, QTLs.

Test- and behavior-specific genetic factors affect WKY hypoactivity in tests of emotionality.

Inbred Wistar-Kyoto rats consistently display hypoactivity in tests of emotional behavior. We used them to test the hypothesis that the genetic factors underlying the behavioral decision-making process will vary in different environmental contexts. The contexts used were the open-field test (OFT), a novel environment with no explicit threats present, and the defensive-burying test (DB), a habituated environment into which a threat has been introduced. Rearing, a voluntary behavior was measured in both tests, and our study was the first to look for genetic loci affecting grooming, a relatively automatic, stress-responsive stereotyped behavior. Quantitative trait locus analysis was performed on a population of 486 F2 animals bred from reciprocal inter-crosses. The genetic architectures of DB and OFT rearing, and of DB and OFT grooming, were compared. There were no common loci affecting grooming behavior in both tests. These different contexts produced the stereotyped behavior via different pathways, and genetic factors seem to influence the decision-making pathways and not the expression of the behavior. Three loci were found that affected rearing behavior in both tests. However, in both contexts, other loci had greater effects on the behavior. Our results imply that environmental context's effects on decision-making vary depending on the category of behavior.

Quantitative trait loci associated with elevated thyroid-stimulating hormone in the Wistar-Kyoto rat.

Thyroid hormones are essential for the regulation of developmental and physiological processes. The genetic factors underlying naturally occurring variability in mammalian thyroid function are, however, only partially understood. Genetic control of thyroid function can be studied with animal models such as the inbred Wistar-Kyoto (WKY) rat strain. Previous studies established that WKY rats have elevated TSH, slightly elevated total T3, and normal total T4 levels compared with Wistar controls. The present study confirmed a persistent 24-h elevation of TSH in WKY rats compared with the Fisher 344 (F344) rat, another inbred strain. Acute T3 challenge (25 microg/100 g body weight ip) suppressed serum TSH and T4 levels in both strains. Quantitative trait locus analysis of elevated TSH in a reciprocally bred WKY x F344 F2 population identified one highly significant locus on chromosome 6 (LOD=11.7, TSH-1) and one suggestive locus on chromosome 5 (LOD=2.3, TSH-2). The confidence interval of TSH-1 contains the TSH receptor and type 2 deiodinase genes, and TSH-2 contains the type 1 deiodinase gene. The WKY alleles of each gene contain sequence alterations, but additional studies are indicated to identify the specific gene or genes responsible for altered regulation of the thyroid axis. These findings suggest that one or more genetic alterations within the TSH-1 locus significantly contribute to the altered thyroid function tests of the WKY rat.

Maternal behavior modulates X-linked inheritance of behavioral coping in the defensive burying test.

BACKGROUND: Complex behavioral traits such as coping strategies in response to stress are usually formed by genetic and environmental influences. METHODS: By exploiting the phenotypic and genotypic differences between the Wistar Kyoto (WKY) and Fischer 344 (F344) inbred rat strains, we recently identified three X chromosome-linked quantitative trait loci contributing to differences in coping strategies in the defensive burying (DB) paradigm. In this article we study the influence of postnatal maternal environment in these behaviors by characterizing the maternal behavior of these strains and the effect of cross-fostering on DB behavior of male offspring from reciprocal crossing (F1). RESULTS: Maternal behavior of WKY rats can be quantitatively characterized by less contact and more periods of neglect of their F1 pups. In contrast, F344 mothers engaged in more active behaviors such as licking/grooming and arched-back nursing. Cross-fostering male F1 pups at birth did not influence the latency to bury measure in DB; however, duration of burying and prod approaches were influenced by both genotype and maternal environment in an additive manner. CONCLUSIONS: These results demonstrate that different measures of behavioral coping in the DB paradigm are influenced by maternal environment to differing degrees and in addition by genetic factors.

Genome-wide association study of breast cancer in Latinas identifies novel protective variants on 6q25.

The genetic contributions to breast cancer development among Latinas are not well understood. Here we carry out a genome-wide association study of breast cancer in Latinas and identify a genome-wide significant risk variant, located 5' of the Estrogen Receptor 1 gene (ESR1; 6q25 region). The minor allele for this variant is strongly protective (rs140068132: odds ratio (OR) 0.60, 95% confidence interval (CI) 0.53-0.67, P=9 × 10(-18)), originates from Indigenous Americans and is uncorrelated with previously reported risk variants at 6q25. The association is stronger for oestrogen receptor-negative disease (OR 0.34, 95% CI 0.21-0.54) than oestrogen receptor-positive disease (OR 0.63, 95% CI 0.49-0.80; P heterogeneity=0.01) and is also associated with mammographic breast density, a strong risk factor for breast cancer (P=0.001). rs140068132 is located within several transcription factor-binding sites and electrophoretic mobility shift assays with MCF-7 nuclear protein demonstrate differential binding of the G/A alleles at this locus. These results highlight the importance of conducting research in diverse populations.