SFRP1 decreases WNT-Mediated M2 macrophage marker expression in breast tissue.

The Wnt family of secreted proteins are involved in mammary gland development and tumorigenesis. It has recently been shown that Wnt ligands promote M2 macrophage polarization and so we sought to determine the effects of a Wnt signaling antagonist, Secreted Frizzled Related Protein 1 (SFRP1), on M2 marker expression. We measured a murine M2 marker (Arg1) in mice with a targeted deletion of Sfrp1 during different stages of mammary gland development including puberty, pregnancy, and lactation, as well as in response to obesity. Next, to determine whether Wnt signaling/antagonism affects human M2 markers (CD209 and CCL18), we treated a human patient derived explant (PDE) breast tissue sample with exogenous Wnt3a in the presence and absence of rSFRP1. Finally, we expanded our PDE study to 13 patients and performed bulk RNAseq analysis following the treatment described above. We found that in loss of Sfrp1 in the murine mammary gland increased Arg1 expression. Moreover, we showed that Wnt3a increases CD209 and CCL18 mRNA and protein expression in breast PDEs and that their expression is decreased in response to rSFRP1. Our RNAseq analysis unveiled novel genes that were affected by Wnt3a treatment and subsequently reversed when rSFRP1 was added. Validation of these data exhibited that chemokines involved in promoting macrophage polarization and cancer metastasis, including CCL11 and CCL26, were stimulated by Wnt3a signaling and their expression was abrogated by treatment with rSFRP1. Our data suggest that SFRP1 may be an important mediator that tempers Wnt signaling in the tumor microenvironment.

Increased risk of upstage when combinations of breast lesions of uncertain malignant potential are found on core needle biopsy: The need for surgical excision.

BACKGROUND: Management of breast lesions of uncertain malignant potential diagnosed at core needle biopsy (CNB) is controversial due to variable upstage rate (UR) with surgical excision (SE). METHODS: We performed an IRB-approved retrospective analysis of adult women who underwent CNB demonstrating atypical ductal hyperplasia (ADH), flat epithelial atypia, radial scar, or intraductal papilloma then SE between 2010 and 2022. We evaluated CNB pathology for combination diagnoses (CD), defined as multiple primary lesions or primary with lobular neoplasia (LN), and surgical pathology for upstage. RESULTS: 719 patients were included. UR was 12.2% (88/719). CD experienced higher UR than pure (17.7% (45/254) vs. 9.2% (43/465), p â€‹= â€‹0.001). ADH/LN had the highest UR of all CD (34.6% (9/26), p â€‹= â€‹0.001). Increased size (15.6 vs. 10.5 â€‹mm, p â€‹< â€‹0.001), distance from nipple (79 vs. 66 â€‹mm, p â€‹< â€‹0.001), and personal history of breast cancer (p â€‹= â€‹0.04) were associated with UR. CONCLUSIONS: CD was associated with increased UR. ADH/LN had the highest UR.

The Influence of Screening Mammography Cessation and Resumption on Breast Cancer Presentation and Treatment: A Multi-Hospital Health System Experience During the Early COVID-19 Pandemic.

Objective: To assess the impact of the coronavirus disease-2019 (COVID-19) pandemic screening restrictions on the diagnosis and treatment of breast cancer in a single health system. Materials and Methods: We performed a retrospective, cohort investigation of breast cancer patients at a multi-institution health system from March 1, 2019 to December 31, 2020 with two time periods related to the pandemic: "Early phase" (March 18 - June 7) reflecting the time of the screening mammography moratorium and "Late phase" (June 8 - December 31) to reflect the time once screening mammography resumed. 2020 was compared to 2019 to exclude potential differences from temporal or seasonal changes. Variables included demographics, COVID related-deferral, cancer specific data, method of detection, type of treatment recommended and received. Results: Fewer patients presented with a breast cancer diagnosis during Early phase 2020 when compared to any other time period. Numbers increased significantly in Late phase 2020; total numbers of patients seen in 2020 approached but did not completely reach that of 2019. When compared to other time periods, patients who presented during the moratorium on screening were younger, more likely to be black, had a higher Body Mass Index, and were more likely to have a human epidermal growth factor receptor 2 positive tumor. There was a slight increase in size of presenting tumor and node positivity, although no differences in breast or axillary surgical management were identified. Conclusion: Despite an increase in tumor size and positive nodal status seen during the screening moratorium, surgical treatment was not negatively impacted.

The effect of delay of excisional biopsy on upstage rate for atypical ductal hyperplasia, flat epithelial atypia, intraductal papilloma, and radial scar.

PURPOSE: When Core Needle Biopsy (CNB) demonstrates Atypical Ductal Hyperplasia (ADH), Flat Epithelial Atypia (FEA), Intraductal Papilloma (IDP), or Radial Scar/Complex Sclerosing Lesion (RS), excisional biopsy (EB) is often performed to rule out underlying malignancy with upstage rates (UR) ranging between 1 and 20%. The COVID-19 pandemic led to delayed EB for many patients. We sought to evaluate whether this delay was associated with higher UR. METHODS: We performed a retrospective analysis of women who underwent CNB and then EB for ADH, FEA, IDP, or RS between 2017 and 2021 using an IRB-approved repository. UR was evaluated by days between CNB and EB. RESULTS: 473 patients met inclusion. 55 were upstaged to cancer (11.6%). 178 patients had pure ADH on CNB and 37 were upstaged (20.8%). 50 patients had pure FEA and 3 were upstaged (6%). 132 had pure IDP and 7 were upstaged (5.3%). 98 had pure RS and 1 was upstaged (1%). 7/15 (46.7%) had a combination of diagnoses or diagnosis with palpable mass and were upstaged. Days between CNB and EB were < 60 for 275 patients (58.1%), 60-90 for 108 (22.8%), 91-120 for 43 (9.1%), and > 120 for 47 (9.9%). There was no significant difference in UR (10.9% for < 60, 14.8% for 60-90, 7% for 90-120, and 12.8% for > 120, p = 0.54). UR for ADH was clinically increased after 60 days (27.8 vs. 17.5%), but this did not reach statistical significance (p = 0.1). CONCLUSION: Surgical delay was not associated with an increased UR.

Interindividual variation contributes to differential PCB 126 induced gene expression in primary breast epithelial cells and tissues.

PCB 126 is a pervasive, dioxin-like chemical pollutant which can activate the aryl hydrocarbon receptor (AhR). Despite being banned from the market, PCB 126 can be detected in breast milk to this day. The extent to which interindividual variation impacts the adverse responses to this chemical in the breast tissue remains unclear. This study aimed to investigate the impact of 3 nM PCB 126 on gene expression in a panel of genetically diverse benign human breast epithelial cell (HBEC) cultures and patient derived breast tissues. Six patient derived HBEC cultures were treated with 3 nM PCB 126. RNAseq was used to interrogate the impact of exposure on differential gene expression. Gene expression changes from the top critical pathways were confirmed via qRT-PCR in a larger panel of benign patient derived HBEC cultures, as well as in patient-derived breast tissue explant cultures. RNAseq analysis of HBEC cultures revealed a signature of 144 genes significantly altered by 3 nM PCB 126 treatment. Confirmation of 8 targets using a panel of 12 HBEC cultures and commercially available breast cell lines demonstrated that while the induction of canonical downstream target gene, CYP1A1, was consistent across our primary HBECs, other genes including AREG, S100A8, IL1A, IL1B, MMP7, and CCL28 exhibited significant variability across individuals. The dependence on the activity of the aryl hydrocarbon receptor was confirmed using inhibitors. PCB 126 can induce significant and consistent changes in gene expression associated with xenobiotic metabolism in benign breast epithelial cells. Although the induction of most genes was reliant on the AhR, significant variability was noted between genes and individuals. These data suggest that there is a bifurcation of the pathway following AhR activation that contributes to the variation in interindividual responses.

Breast-Specific Sensuality and Appearance Satisfaction: Comparison of Breast-Conserving Surgery and Nipple-Sparing Mastectomy.

BACKGROUND: We demonstrated previously that lumpectomy (L) patients reported higher appearance satisfaction, appreciation of a pleasurable breast caress, and persistence of the breast during intimacy than mastectomy with reconstruction, which we used to describe breast-specific sensuality. Our current objective was to compare breast-specific sensuality between L and nipple-sparing mastectomy (NSM). DESIGN: An anonymous, cross-sectional survey was distributed to breast cancer survivors between 2014 and 2016. Eligible patients underwent operation between 2000 and 2014, were adults older than 18 years, English-speaking, and at least one year into the post-operative period. Demographic characteristics, treatment details, Female Sexual Function Index metrics, and investigator-generated questions about appearance satisfaction and breast-specific sensuality were collected. RESULTS: Of the 600 women who participated, 585 surveys were eligible. Surgical modality was reported as L by 406 (69.4%), mastectomy alone by 50 (8.5%), and mastectomy with reconstruction by 129 (22.1%). Nipple-preservation data were available for 47 of 129 mastectomy with reconstruction patients (36.4%), with 21 NSM and 26 non-nipple-sparing mastectomy patients. Favorable postoperative appearance satisfaction was reported by 76.2% of L and 71.4% of NSM (p = 0.039). Lumpectomy patients reported feeling more comfortable being seen undressed than NSM patients (82.4% vs 71.4%; p = 0.0003). The chest remained a part of intimacy for 65.4% of L patients vs 42.9% of NSM patients (p = 0.0009). A pleasurable breast caress was reported more frequently by L patients than NSM patients (66.2% vs 20%; p ≤ 0.0001). The breast caress was unpleasant for 40% of NSM patients, nearly 4-fold higher than L patients (11.3%; p < 0.0001). CONCLUSIONS: NSM patients were significantly less satisfied with appearance, less comfortable being seen undressed, had decreased persistence of breast intimacy, and experienced a less pleasurable breast caress than L patients. Counseling patients about these findings will empower informed decision making, optimize expectations, and can enhance postoperative satisfaction.

Sexual Dysfunction in Survivorship; the Impact of Menopause and Endocrine Therapy.

BACKGROUND: Sexual dysfunction is common for breast cancer survivors. Premenopausal women with breast cancer are increasingly offered ovarian suppression and aromatase inhibitor (AI) therapy. We evaluated the association of menopausal status and treatment modalities on sexual dysfunction. METHODS: We conducted a cross-sectional anonymous Female Sexual Function Index (FSFI) survey of breast cancer survivors between 2000 and 2016. Analysis utilized Kruskal-Wallis test for FSFI scores, Chi square, or Fisher's exact test for categorical data, and regression analysis for associations. RESULTS: Of 585 respondents, 278 (47.5%) had complete FSFI scores. Of these, 24 (8.6%) were premenopausal and 80 (28.8%) were pre/perimenopausal at survey completion. Median FSFI scores for premenopausal (31.2, interquartile range [IQR] 26.8-33.6) and pre/perimenopausal (29.2, IQR 25.9-32.2) were similar, whereas postmenopausal women (25.9, IQR 21.0-30.3) were significantly lower (p = 0.0007 and p = 0.0002, respectively). Premenopausal women were less likely to meet criteria for sexual dysfunction (FSFI score ≤ 26.55) than postmenopausal women (21 versus 55%, p < 0.0001, univariate analysis [odds ratio (OR) 0.32, 95% confidence interval (CI) 0.18-0.56]). Adjusting for treatment modality did not impact the significance (OR 0.43, 95% [CI] 0.23-0.80) but revealed that AIs independently are associated with sexual dysfunction (OR 2.41, 95% CI 1.32-4.40). The interaction between menopausal status and AIs was not significant (p = 0.24). CONCLUSIONS: Our study demonstrates that menopausal status is associated with sexual dysfunction in breast cancer patients and sexual dysfunction in premenopausal women is not impacted by treatment modality outside of aromatase inhibitor therapy. As more premenopausal patients are treated with ovarian suppression, these data may guide clinicians in counseling patients regarding sexual dysfunction expectations.

Cocaine-induced splenic rupture.

Splenic rupture is a rare but serious complication from cocaine abuse. Given the ubiquitous prevalence of abuse and the potential for death from intraperitoneal bleeding, the prompt diagnosis and treatment of cocaine-induced disease including splenic rupture is essential. The management for splenic rupture from traumatic and atraumatic etiology has shifted from emergent laparotomy and splenectomy to non-operative approach with transcatheter splenic artery embolization. We report a 39-year-old male with a significant substance abuse history who presented with atraumatic splenic rupture. He was managed nonoperatively with adjunctive transcatheter splenic artery embolization. His post-procedure course was complicated by an intra-abdominal abscess requiring drainage via interventional radiology guided pigtail catheter placement and intravenous antibiotics. This case report is intended to raise awareness of the potentiating effects of cocaine use in this patient population and highlight questions raised during this patient's management.