Breast Glandular and Ductal Volume Changes during the Menstrual Cycle: A Study in 48 Breasts Using Ultralow-Frequency Transmitted Ultrasound Tomography/Volography.

The aim of this study was to show for the first time that low-frequency 3D-transmitted ultrasound tomography (3D UT, volography) can differentiate breast tissue types using tissue properties, accurately measure glandular and ductal volumes in vivo, and measure variation over time. Data were collected for 400 QT breast scans on 24 women (ages 18-71), including four (4) postmenopausal subjects, 6-10 times over 2+ months of observation. The date of onset of menopause was noted, and the cases were further subdivided into three (3) classes: pre-, post-, and peri-menopausal. The ducts and glands were segmented using breast speed of sound, attenuation, and reflectivity images and followed over several menstrual cycles. The coefficient of variation (CoV) for glandular tissue in premenopausal women was significantly larger than for postmenopausal women, whereas this is not true for the ductal CoV. The glandular standard deviation (SD) is significantly larger in premenopausal women vs. postmenopausal women, whereas this is not true for ductal tissue. We conclude that ducts do not appreciably change over the menstrual cycle in either pre- or post-menopausal subjects, whereas glands change significantly over the cycle in pre-menopausal women, and 3D UT can differentiate ducts from glands in vivo.

Toward AI-supported US Triage of Women with Palpable Breast Lumps in a Low-Resource Setting.

Background Most low- and middle-income countries lack access to organized breast cancer screening, and women with lumps may wait months for diagnostic assessment. Purpose To demonstrate that artificial intelligence (AI) software applied to breast US images obtained with low-cost portable equipment and by minimally trained observers could accurately classify palpable breast masses for triage in a low-resource setting. Materials and Methods This prospective multicenter study evaluated participants with at least one palpable mass who were enrolled in a hospital in Jalisco, Mexico, from December 2017 through May 2021. Orthogonal US images were obtained first with portable US with and without calipers of any findings at the site of lump and adjacent tissue. Then women were imaged with standard-of-care (SOC) US with Breast Imaging Reporting and Data System assessments by a radiologist. After exclusions, 758 masses in 300 women were analyzable by AI, with outputs of benign, probably benign, suspicious, and malignant. Sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) were determined. Results The mean patient age ± SD was 50.0 years ± 12.5 (range, 18-92 years) and mean largest lesion diameter was 13 mm ± 8 (range, 2-54 mm). Of 758 masses, 360 (47.5%) were palpable and 56 (7.4%) malignant, including six ductal carcinoma in situ. AI correctly identified 47 or 48 of 49 women (96%-98%) with cancer with either portable US or SOC US images, with AUCs of 0.91 and 0.95, respectively. One circumscribed invasive ductal carcinoma was classified as probably benign with SOC US, ipsilateral to a spiculated invasive ductal carcinoma. Of 251 women with benign masses, 168 (67%) imaged with SOC US were classified as benign or probably benign by AI, as were 96 of 251 masses (38%, P < .001) with portable US. AI performance with images obtained by a radiologist was significantly better than with images obtained by a minimally trained observer. Conclusion AI applied to portable US images of breast masses can accurately identify malignancies. Moderate specificity, which could triage 38%-67% of women with benign masses without tertiary referral, should further improve with AI and observer training with portable US. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Slanetz in this issue.

The Health of Women (HOW) Study®: a web-based survey of breast cancer risk factors, diagnosis, and treatment.

PURPOSE: Although improvements in breast cancer detection and treatment have significantly increased survival, important questions related to breast cancer risk, prognosis, and survivorship remain. This brief report describes the Health of Women (HOW) Study® methodology and characterizes the participants who completed the My Health Overview and My Breast Cancer modules. METHODS: The HOW Study® was a collection of cross-sectional, web-based modules designed to survey a large number of participants with and without breast cancer. RESULTS: A total of 42,540 participants completed the My Health Overview module, of whom 13,285 (31.2%) reported a history of breast cancer. The majority of participants were white (94.3%), female (99.5%), married (74.1%), college educated (73.2%), post-menopausal (91.1%), parous (68.8%), and reported breastfeeding their children (56.0%). A total of 11,670 participants reported a history of breast cancer in the My Breast Cancer module. The majority of survivors reported on their primary breast cancer and were diagnosed over the age of 40 years (83.5%), had either Stage I or Stage II breast cancer (63.1%), and were treated with surgery (98.8%), radiation (64.8%), and/or chemotherapy (62.3%). CONCLUSIONS: The HOW Study® provides an innovative framework for collecting large amounts of epidemiological data in an efficient and minimally invasive way. Data are publicly available to researchers upon request. IMPLICATIONS FOR CANCER SURVIVORS: The HOW Study® can be leveraged to answer important questions about survivorship, and researchers are encouraged to utilize this new data source.

The association of infectious mononucleosis and invasive breast cancer in The Health of Women (HOW) Study®.

BACKGROUND: The link between Epstein-Barr Virus (EBV) and breast cancer (BC) etiology remains unclear. We utilized the Health of Women (HOW) Study® to understand the association between infectious mononucleosis (IM), a surrogate for EBV infection, and invasive BC. METHODS: The HOW Study® was a web-based survey of BC risk factors with > 40, 000 participants; 183 had IM at < 10 years old, 3, 654 had IM between 10 and 22 years old, 764 had IM at > 22 years old, and 17, 026 never developed IM. Of these 21, 627 women, 2093 had Stages I-III BC and 14, 143 were cancer-free. Binary logistic regression ascertained the association between IM and invasive BC risk by controlling for confounders. RESULTS: A history of IM was associated with a lower likelihood of developing invasive BC compared to women who did not develop IM (adjusted OR = 0.83, 95% CI 0.72-0.94). That finding was driven by women who had IM between 10 and 22 years old (adjusted OR = 0.83, 95% CI 0.72-0.97) albeit no linear association between age at developing IM and breast cancer (p-trend > 0.05). Women who had IM between 10 and 22 years old were less likely to develop estrogen receptor positive (ER+ ; adjusted OR = 0.84, 95% CI 0.71-0.99) or hormone receptor positive (HR+ ; adjusted OR = 0.86, 95% CI 0.73-1.01) BC. There was no association between IM and ER- or HR- BC. CONCLUSION: In the HOW Study®, women diagnosed with IM between the ages of 10 and 22 had a lower risk of developing invasive BC compared to women who never developed IM.

Breast intraductal nanoformulations for treating ductal carcinoma in situ II: Dose de-escalation using a slow releasing/slow bioconverting prodrug strategy.

Ductal carcinoma in situ (DCIS) represents approximately 20-25% of newly diagnosed breast cancers. DCIS is treated by surgery and possibly radiotherapy. Chemotherapy is only used as adjuvant or neoadjuvant therapy but not as primary therapy. The present study investigated the intraductal administration of Ciclopirox (CPX) formulated in nanosuspensions (NSs) or nanoparticles (NPs) to treat DCIS locally in a Fischer 344 rat model orthotopically implanted with 13762 Mat B III cells. Slow converting esterase responsive CPX prodrugs (CPDs) were successfully synthesized at high purity (> 95%) by directly acetylating the hydroxyl group or by appending a self-immolative linker between CPX and a phenolic ester. Direct esterification CPDs were not sufficiently stable so self-immolative CPDs were formulated in NSs and NPs. Prodrug release was evaluated from poly(lactic-co-glycolic acid) NPs, and CPD4 demonstrated the slowest release rate with the rank order of CPD2 (R = methyl) > CPD3 (R = t-butyl) > CPD4 (R = phenyl). Intraductally administered CPX NS, CPD4 NS, and an innovative mixture of CDP4 NS and NPs (at 1 mg CPX equivalent/duct) demonstrated significant (p < 0.05) in vivo anti-tumor efficacy compared with immediate release (IR) CPX NS and non-treated controls. CPX mammary persistence at 6 h and 48 h after CPD4 NS or NP administration was also greater than after the immediate release CPX NS. A strong correlation between CPX mammary persistence and efficacy is demonstrated. In conclusion, nanoformulations utilizing a slow releasing/slow bioconverting CPX prodrug delivery strategy resulted in significant dose de-escalation (~ five fold) while maintaining anti-tumor efficacy.

Predicting positive outcomes and successful completion in an online parenting program for parents of children with disruptive behavior: An integrated data analysis.

Online delivery of parenting support is steadily increasing, yet the factors that influence program engagement and efficacy are still understudied. This study used an integrated data analysis approach to identify family and program-related factors that influence outcomes. We combined individual data from seven published efficacy trials of the web-based version of the Triple P-Positive Parenting Program. Data were analyzed for 985 families with children aged between 2 and 12 years (M = 4.87; SD = 2.14) using a Latent Change Score approach. At post-intervention, sociodemographic factors were not predictive of changes in child behavior problems, while parents of boys and those with higher education showed greater improvements in dysfunctional parenting. Parents who were initially more confident in their parenting showed more overall gains while parents with more initial adjustment difficulties showed less improvement. Only the effect of baseline child behavior problems on changes in dysfunctional parenting was moderated by treatment condition. At follow-up, program variant and completion were the primary outcome predictors, with completion found to be related to initial parenting confidence, internet usage and program variant. The implications of these findings for reaching and retaining parents in online programs across all phases of the engagement process are discussed.

Clinical practice to address tamoxifen nonadherence.

The primary and secondary benefits of tamoxifen as adjuvant therapy in women with hormone-receptor-positive breast cancer are substantial: a 1% decrease in the risk of death each year for 10 years with each additional year of treatment during the first 5 years. Considerable data, however, indicate that these benefits are lost to many patients because of treatment nonadherence. Nonadherence is examined within the framework of the Common-Sense Model of Self-Regulation to describe patients' models of disease and treatment that organize their thinking and behavior, and the crucial role of the practitioner in addressing and altering these models. Common patient education and social communications about patients' hormone-receptor-positive breast cancer and tamoxifen treatment promote an acute disease paradigm in which cancer occurs within specific locations and is either present or absent. We recommend that clinicians communicate the concepts of hormone-receptor-positive breast cancer as follows: i. a non-dichotomous systemic disorder entailing a treatment goal of homeostasis and disease quiescence and ii. a disorder undetectable by currently available tests in subclinical states. Equally important, the clinician can provide a comprehensive picture of the well-documented secondary effects of tamoxifen, noting in particular the beneficial effects. Specific action plans, grounded in individual patient understanding, can be developed and reinforced, in an ongoing process that validates and integrates patient values and goals as they change over time.

Importance of quality-of-life priorities and preferences surrounding treatment decision making in patients with cancer and oncology clinicians.

BACKGROUND: Shared decision-making (SDM) occurs when a patient partners with their oncologist to integrate personal preferences and values into treatment decisions. A key component of SDM is the elicitation of patient preferences and values, yet little is known about how and when these are elicited, communicated, prioritized, and documented within clinical encounters. METHODS: This cross-sectional study evaluated nationwide data collected by CancerCare to better understand current patterns of SDM between patients and their oncology clinicians. Patient surveys included questions about the importance of quality-of-life preferences and discussions regarding quality-of-life priorities with their clinicians. Clinician surveys included questions about the discussion of quality-of-life priorities and preferences with patients, the effect of quality-of-life priorities on treatment recommendations, and quality-of-life priority documentation in practice. RESULTS: Patient survey completers (n = 320; 33% response rate) were predominantly women (95%), had a diagnosis of breast cancer (59%), or were receiving active cancer treatment (59%). Clinician survey completers (n = 112; 5% response rate) predominately identified as hematologists or oncologists (66%). Although 67% of clinicians reported knowing their patients' personal quality-of-life priorities and preferences before finalizing treatment plans, only 37% of patients reported that these discussions occurred before treatment initiation. Most patients (95%) considered out-of-pocket expenses important during treatment planning, yet only 59% reported discussing out-of-pocket expenses with their clinician before finalizing treatment plans. A majority of clinicians (52%) considered clinic questionnaires as feasible to document quality-of-life priorities and preferences. CONCLUSIONS: Patients and clinicians reported that preferences related to quality-of-life should be considered in treatment decision making, yet barriers to SDM, preference elicitation, and documentation remain.

Breast intraductal nanoformulations for treating ductal carcinoma in situ I: Exploring metal-ion complexation to slow ciclopirox release, enhance mammary persistence and efficacy.

INTRODUCTION: Ductal Carcinoma In Situ (DCIS) represents a significant fraction (~20-25%) of all newly diagnosed breast cancer cases and, if left untreated, a significant fraction of patients will progress to invasive disease. Surgery is the only treatment option. Ciclopirox (CPX), an FDA-approved antifungal drug, has exhibited promising antitumor activity by down-regulating the expression of vital antiapoptotic cellular proteins and inhibiting the genetic expression of several oncogenic pathways. In this study, the feasibility of using nanoscale delivery systems to control release and prolong mammary tissue persistence of a lipophilic metal complex of CPX and Zinc (CPXZn) after intraductal administration was investigated. METHODS: CPX and CPX-Zn nanosuspensions (NSs) were prepared using an evaporative nanoprecipitation-ultra-sonication method. Flash nanoprecipitation was used to prepare PLGA nanoparticles (NPs) loaded with CPXZn. Our established orthotopic DCIS rat model was used to evaluate efficacy. Briefly, two days after 13762 Mat B III cell intraductal inoculation, rats were divided into treatment groups and a single intraductal injection of CPX NS, CPX-Zn NS or CPX-Zn NPs was administered. In the first study arm, the efficacy of CPX NS (1, 3, 5 mg/duct) was evaluated. In the second arm, the in vivo efficacy of CPX NS, CPX-Zn NS and CPX-Zn loaded NPs was evaluated and compared at equivalent CPX doses. The mammary persistence of CPX from CPX NS, CPX-Zn NS, and CPX-Zn PLGA NPs was also assessed. RESULTS: CPX-Zn complex was successfully synthesized and characterized by several spectral analyses. CPX release was slowed from the CPX-Zn NS and further slowed by incorporating CPX-Zn into PLGA NPs as compared to the CPX NS with release half times following the order: CPX NS < CPX-Zn NS << CPX-Zn NP. Intraductal CPX NS administration was dose and time dependent in suppressing tumor initiation suggesting prolonged mammary exposure may improve efficacy. In the second arm, mammary tissue persistence of CPX followed the rank order CPX NS < CPX-Zn NS << CPX-Zn NP at 6 h and 48 h post-administration. Prolonged mammary CPX exposure was highly correlated to improved efficacy. Prolonged CPX tissue persistence, attributed to slower release from the zinc complex and the PLGA NPs, resulted in a 5-fold dose reduction compared to the CPX NS. CONCLUSIONS: The current results demonstrate that slowing drug release in the mammary duct after intraductal administration overcomes the rapid ductal clearance of CPX, prolongs mammary tissue persistence, improves efficacy against DCIS lesions in vivo, and requires 5-fold less CPX to achieve equivalent efficacy. The studies also provide a strategic path forward for developing a locally administered drug delivery system for treating DCIS, for which no primary chemotherapy option is available.

Side effects from acute myeloid leukemia treatment: results from a national survey.

Objective: Acute myeloid leukemia (AML) is experiencing a therapeutic renaissance due to the heightened biomedical understanding of AML and patient-focused drug development (PFDD). Many AML patients now live long-term with the side effects of treatment. This study documents the prevalence and severity of AML treatment-related side effects. Methods: A national cross-sectional survey designed with the Leukemia & Lymphoma Society assessed patients' experiences with short-term (nausea/vomiting, diarrhea, hair loss, mouth sores, infection, rash) and long-term (organ dysfunction, chemobrain, fatigue, neuropathy) treatment side effects. Patient and caregiver participants rated side effect severity (none-severe). Results: Survey participants (n = 1182) were mostly female (65%), AML patients (76%), and had undergone chemotherapy (94%). Eighty-seven per cent of participants reported severe short-term effects, and 33% reported severe long-term effects of treatment. Only 11% of respondents did not have any severe effects. Hair loss and fatigue were the most common severe short- and long-term side effects (78%, 33%). There was a moderate correlation between having short- and long-term adverse effects (r = 0.41, p < 0.001). Caregivers were more likely than patients to report severe organ dysfunction, fatigue, and neuropathy (p-values < 0.05). Conclusions: Survivors experience a high burden of side effects from AML treatments highlighting the need for the development of less toxic therapies. Differences in patients' and caregivers' experiences illustrate the importance of sampling from diverse sources to understand the full burden of AML treatment, and the need for less toxic drugs. This study informs patients, patient-advocacy groups, clinicians, and regulators about AML treatment burdens and provides the community with information to inform PFDD.

Evaluation of intraductal delivery of poly(ethylene glycol)-doxorubicin conjugate nanocarriers for the treatment of ductal carcinoma in situ (DCIS)-like lesions in rats.

Ductal carcinoma in situ is the most commonly diagnosed early stage breast cancer. The efficacy of intraductally delivered poly(ethylene glycol)-doxorubicin (PEG-DOX) nanocarriers, composed of one or more DOX conjugated to various PEG polymers, was investigated in an orthotopic ductal carcinoma in situ-like rat model. In vitro cytotoxicity was evaluated against 13762 Mat B III cells using MTT assay. The orthotopic model was developed by inoculating cancer cells into mammary ducts of female Fischer 344 retired breeder rats. The ductal retention and in vivo antitumour efficacy of two of the six nanocarriers (5 kDa PEG-DOX and 40 kDa PEG-(DOX)4) were investigated based on in vitro results. Mammary retention of DOX and PEG-DOX nanocarriers was quantified using in vivo imaging. Histopathologic effects of DOX and PEG-DOX nanocarriers on mammary ductal structure were also investigated. Cytotoxicities of small linear PEG-DOX nanocarriers (5 and 10 kDa) were not different from DOX whereas larger PEG-DOX nanocarriers showed reduced potency. The order of mammary retention was 40 kDa PEG-(DOX)4 > 5 kDa PEG-DOX >> DOX, in normal and tumour-bearing rats. Intraductally administered PEG-DOX nanocarriers and DOX were effective in reducing tumour incidence and increasing survival rate, with no significant differences found among the three treatment groups. However, nanocarriers administered intravenously at the same doses were not effective, and intraductally administered free DOX caused severe local toxicity. Intraductal administration of PEG-DOX nanocarriers is effective and less toxic than that of free DOX, as well as IV DOX/PEG-DOX. Furthermore, PEG-DOX nanocarriers demonstrate the added benefit of prolonging DOX ductal retention, which would necessitate less frequent dosing.

Impact of apolipoprotein E genotypes on vitamin E and memantine treatment outcomes in Alzheimer's disease.

INTRODUCTION: Because apolipoprotein E (APOE) genotypes are known risk factors for Alzheimer's disease (AD), they have been measured in clinical trial participants to determine their effect on treatment outcome. METHODS: We determined APOE genotypes in a subset of subjects (N = 415) who participated in a randomized controlled trial of vitamin E and memantine in 613 veterans with mild-to-moderate AD. RESULTS: Similar to the primary study, substudy participants receiving vitamin E also had slower functional decline than those receiving placebo. Overall, there was no difference in the rate of functional decline between APOE ε4 allele carriers and noncarriers. A significant interaction was observed between treatment and the APOE genotype on AD progression: ε4 carriers declined faster than noncarriers in the vitamin E plus memantine treatment arm. DISCUSSION: APOE genotypes may modulate AD treatment response and should be included in the design of future randomized controlled trials.

Palpable Breast Lump Triage by Minimally Trained Operators in Mexico Using Computer-Assisted Diagnosis and Low-Cost Ultrasound.

Purpose In low- to middle-income countries (LMICs), most breast cancers present as palpable lumps; however, most palpable lumps are benign. We have developed artificial intelligence-based computer-assisted diagnosis (CADx) for an existing low-cost portable ultrasound system to triage which lumps need further evaluation and which are clearly benign. This pilot study was conducted to demonstrate that this approach can be successfully used by minimally trained health care workers in an LMIC country. Patients and Methods We recruited and trained three nonradiologist health care workers to participate in an institutional review board-approved, Health Insurance Portability and Accountability Act-compliant pilot study in Jalisco, Mexico, to determine whether they could use portable ultrasound (GE Vscan Dual Probe) to acquire images of palpable breast lumps of adequate quality for accurate computer analysis. Images from 32 women with 32 breast masses were then analyzed with a triage-CADx system, generating an output of benign or suspicious (biopsy recommended). Triage-CADx outputs were compared with radiologist readings. Results The nonradiologists were able to acquire adequate images. Triage by the CADx software was as accurate as assessment by specialist radiologists, with two (100%) of two cancers considered suspicious and 30 (100%) of 30 benign lesions classified as benign. Conclusion A portable ultrasound system with CADx software can be successfully used by first-level health care workers to triage palpable breast lumps. These results open up the possibility of implementing practical, cost-effective triage of palpable breast lumps, ensuring that scarce resources can be dedicated to suspicious lesions requiring further workup.

Neuropsychiatric Symptoms and Caregiver Burden in Individuals With Alzheimer's Disease: The TEAM-AD VA Cooperative Study.

OBJECTIVES: To assess the prevalence of neuropsychiatric symptoms (NPS) in mild-to-moderate Alzheimer disease (AD) and their association with caregiver burden. METHODS: Secondary analyses of baseline data from the Trial of Vitamin E and Memantine in Alzheimer's Disease (TEAM-AD) (N=613). Neuropsychiatric Inventory were used to measure severity of NPS and caregiver activity survey to measure caregiver burden. RESULTS: A total of 87% of patients displayed at least 1 NPS; 70% displayed clinically meaningful NPS. The most common symptoms were apathy (47%), irritability (44%), agitation (42%), and depression (40%). Those with moderate AD had more severe NPS than those with mild AD ( P = .03). Neuropsychiatric symptoms were significantly associated with caregiver time after adjusting for age, education, cognitive function, and comorbidity ( P-value < .0001) with every point increase in NPS associated with a 10-minute increase in caregiver time. CONCLUSION: Neuropsychiatric symptoms were prevalent in both mild and moderate AD, even in patients receiving treatment with an acetylcholinesterase inhibitors, and were more severe in moderate AD and associated with greater caregiver time.

Metastatic Breast Cancer Collateral Damage Project (MBCCD): Scale development and preliminary results of the Survey of Health, Impact, Needs, and Experiences (SHINE).

PURPOSE: Until recently, people with metastatic breast cancer (MBC) had a very poor prognosis. New treatment approaches have prolonged the time that people with MBC live, but their quality of life has received less attention. Consequently, the needs and concerns across financial, vocational, psychological, social, and physical domains in MBC patients are poorly understood-particularly regarding the collateral damage or longer-term, life-altering impacts of MBC and its treatments. This study's aims were to characterize MBC-related collateral damage, identify groups most likely to experience collateral damage, and examine its associations with psychological health, illness management, and health behaviors. METHODS: Participants (N = 515) with MBC were recruited from Dr. Susan Love Research Foundation's Army of Women® and other advocacy organizations. Participants completed questionnaires of MBC-related collateral damage, depressive symptoms, anxiety, self-efficacy for managing oncologic treatments and physical symptoms, sleep, and physical activity. RESULTS: Eight domains of MBC-related collateral damage, as well as MBC-related benefit finding, were reliably characterized. Concerns about mortality/uncertainty were most prominent. Participants also endorsed high levels of benefit finding. Participants younger than 50 years, with limited financial resources, or with children under 18 at home reported the most collateral damage. Collateral damage was associated significantly with compromised psychological health, lower illness management efficacy, and poorer health behaviors, beyond sociodemographic and medical characteristics. CONCLUSIONS: Subgroups of MBC patients report long-term, life-altering consequences of MBC and its treatments, which relate to important health outcomes. Clinical implications and recommendations are discussed.

The effect of size and polymer architecture of doxorubicin-poly(ethylene) glycol conjugate nanocarriers on breast duct retention, potency and toxicity.

Although systemic administration of chemotherapeutic agents is routinely used for treating invasive breast cancer, the only therapeutic options for ductal carcinoma in situ (DCIS) are surgery and radiation. Treating DCIS by delivering drugs locally to the affected milk duct offers significant advantages over systemic administration, including reduced systemic and breast toxicities, as well as a greatly reduced need for surgery and radiation. In this study, mammary gland retention and toxicity of intraductally administered poly(ethylene) glycol-doxorubicin (PEG-DOX) polymeric conjugate nanocarriers of varying molecular sizes and architectures were investigated. Nanocarriers were formed by conjugating one or more copies of doxorubicin to PEG polymers, of varying molecular weights (5, 10, 20, and 40 kDa) and architectures (linear, four-arm and eight-arm). Cytotoxicity against MCF7 cells, a human breast cancer cell line, was assessed, and IC50 values were calculated. The nanocarriers were intraductally administered into the mammary glands of female retired breeder Sprague-Dawley rats. Whole body images were captured using in vivo optical imaging, and changes in ductal structure as well local inflammation were monitored. Fluorescence intensities were monitored, over time, to evaluate nanocarrier mammary gland retention half-lives (t1/2). The IC50 values of PEG-DOX nanocarriers against MCF7 cells were 40 kDa PEG-(DOX)4 (1.23 µM) < 5 kDa PEG-DOX (1.76 µM) < 40 kDa PEG-(DOX)8 (3.49 µM) < 10 kDa PEG-DOX (3.86 µM) < 20 kDa PEG-DOX (8.96 µM) < 40 kDa PEG-DOX (18.11 µM), whereas the IC50 of free DOX was only 0.14 µM. The t1/2 of linear 5, 20, and 40 kDa nanocarriers were 2.2 ±â€¯0.3, 3.6 ±â€¯0.6, and 13.1 ±â€¯3.4 h, whereas the retention t1/2 of 4- and 8-arm 40 kDa nanocarriers were 14.9 ±â€¯5.6 h and 11.9 ±â€¯2.9 h, respectively. The retention t1/2 of free doxorubicin was 2.0 ±â€¯0.4 h, which was significantly shorter than that of the linear and branched 40 kDa PEG-DOX nanocarriers. Increased molecular weight and decreased branching both demonstrated a strong correlation to enhanced mammary gland retention. Intraductally administered free doxorubicin resulted in ductal damage, severe inflammation and generation of atypical cell neoplasms, whereas PEG-DOX nanocarriers induced only minor and transient inflammation (i.e., damaged epithelial cells and detached cellular debris). The 40 kDa 4-arm PEG-DOX nanocarrier demonstrated the longest ductal retention half-life, the lowest IC50 (i.e., most potent), and minimal ductal damage and inflammation. The current results suggest that PEG-DOX nanocarriers with prolonged ductal retention may present the best option for intraductal treatment of DCIS, due to their low local toxicity and potential for sustained therapeutic effect.

Characterization of the microbiome of nipple aspirate fluid of breast cancer survivors.

The microbiome impacts human health and disease. Until recently, human breast tissue and milk were presumed to be sterile. Here, we investigated the presence of microbes in the nipple aspirate fluid (NAF) and their potential association with breast cancer. We compared the NAF microbiome between women with a history of breast cancer (BC) and healthy control women (HC) using 16S rRNA gene amplicon sequencing. The NAF microbiome from BC and HC showed significant differences in community composition. Two Operational Taxonomic Units (OTUs) showed differences in relative abundances between NAF collected from BC and HC. In NAF collected from BC, there was relatively higher incidence of the genus Alistipes. By contrast, an unclassified genus from the Sphingomonadaceae family was relatively more abundant in NAF from HC. These findings reflect the ductal source DNA since there were no differences between areolar skin samples collected from BC and HC. Furthermore, the microbes associated with BC share an enzymatic activity, Beta-Glucuronidase, which may promote breast cancer. This is the first report of bacterial DNA in human breast ductal fluid and the differences between NAF from HC and BC. Further investigation of the ductal microbiome and its potential role in breast cancer are warranted.

Examination of Duct Physiology in the Human Mammary Gland.

BACKGROUND: The human breast comprise several ductal systems, or lobes, which contain a small amount of fluid containing cells, hormones, proteins and metabolites. The complex physiology of these ducts is likely a contributing factor to the development of breast cancer, especially given that the vast majority of breast cancers begin in a single lobular unit. METHODS: We examined the levels of total protein, progesterone, estradiol, estrone sulfate, dehydroepiandrosterone sulfate, and macrophages in ductal fluid samples obtained from 3 ducts each in 78 women, sampled twice over a 6 month period. Samples were processed for both cytological and molecular analysis. Intraclass correlation coefficients and mixed models were utilized to identify significant data. RESULTS: We found that the levels of these ductal fluid components were generally uncorrelated among ducts within a single breast and over time, suggesting that each lobe within the breast has a distinct physiology. However, we also found that estradiol was more correlated in women who were nulliparous or produced nipple aspirate fluid. CONCLUSIONS: Our results provide evidence that the microenvironment of any given lobular unit is unique to that individual unit, findings that may provide clues about the initiation and development of ductal carcinomas.

Peri-operative biology in primary breast cancer: a credible therapeutic target.

Over the last 25 years, there has been a growing body of basic science, modeling, and clinical data suggesting that the peri-operative period in the treatment of primary breast cancer is dynamic and can be manipulated to improve long-term outcomes. Clinical data have demonstrated early peaks of hazards for recurrence and emphasized the relationship of these to peri-operative events. More recently, clinical trial data with surgical oophorectomy at different times in the menstrual cycle, peri-operative progesterone, and anti-inflammatory drugs suggest that interventional studies are particularly well justified, given the increasing recognition of the costs both financially and clinically of current systemic regimens.