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.

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.

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.

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.

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.

Social media and gamification: Engaging vulnerable parents in an online evidence-based parenting program.

The aim of this study was to examine the feasibility (accessibility, engagement and impact) of adding social media and gaming features (e.g., social sharing with anonymity, badges to incentivize skills practice, an accredited facilitator for support) and access via smartphones to an evidenced-based parenting program, Triple P Online. The highly vulnerable population included 155 disadvantaged, high-risk parents (e.g., 76% had a family annual income of less than $15,000; 41% had been incarcerated; 38% were in drug/alcohol treatment; and 24% had had a child removed due to maltreatment). The ethnic groups most commonly identified were African American (24%) and Hispanic (66%). Respondents were primarily mothers (86%) from five community programs in Los Angeles. The study used a single group repeated measures design (pre, post, 6-month follow-up). Data collected included standardized self-report measures, post-intervention focus groups and interviews, website usage reports, and Google Analytics. Significant multivariate ANOVA time effects were found, demonstrating reductions in child behavioral problems, reduced lax/permissive and over-reactive parenting, and decreased parental stress. No effects were found for parental confidence, attributions, or depression and anxiety (which were in the normal range at baseline). Positive effects were maintained or improved at 6-month follow-up. The participants engaged in the online community and valued its flexibility, anonymity, and shared learning. This foundational implementation trial provides support for future rigorous evaluation of social media and gaming features as a medium for increasing parental engagement in evidence-based parenting programs online--a public health approach to protect and improve the development of vulnerable children.

The safety parameters of the study on intraductal cytotoxic agent delivery to the breast before mastectomy.

BACKGROUND: Intraductal administration of cytotoxic agents has been shown to inhibit the development of breast cancer in animal models. The object of this study was to demonstrate the safety of intraductal delivery cytotoxic agents in patients prior to mastectomy. This method is hopeful to be developed as a chemoprevention approach in patients with pre-malignant or non-invasive ductal lesions to prevent breast cancer which will be further developed. METHODS: TWO DRUGS, PEGYLATED LIPOSOMAL DOXORUBICIN (PLD) AND CARBOPLATIN WERE ADMINISTERED AT THREE DOSE LEVELS (PLD: 10, 20, 50 mg and carboplatin 60, 120, 300 mg). There were five subjects in each group with 15 subjects treated with each drug once. Venous blood samples were obtained for pharmacokinetic analysis. The breast was removed surgically 2-5 days post administration and the treated ducts were marked to enable identification on pathological evaluation. RESULTS: Intraductal administration was generally well-tolerated with mild, transient breast discomfort. In the carboplatin arm, three women at the 300 mg dose experienced mild nausea and vomiting. In the PLD arm most women had mild erythema and swelling of the breast over the 72 hours following the drug administration. Patients receiving the 50 mg dose experienced local erythema until the time of surgery. Pharmacokinetic analysis showed that carboplatin rapidly entered systemic circulation with an early peak time (Tmax ~30 min) with a corresponding plasma ultrafiltrate area under the curve (AUC) consistent with the Calvert Formula using estimated glomerular filtration rate (GFR). Total plasma doxorubicin had delayed peak concentration times (Tmax >48 hours) with a linear dose response and peak concentrations substantially lower than expected from equivalent intravenous injection dosing. No doxorubicinol metabolite was detected in the plasma. CONCLUSIONS: This study demonstrates that cytotoxic drugs can be safely administered into breast ducts with minimal toxicity.

Enhancing Accessibility and Engagement in Evidence-Based Parenting Programs to Reduce Maltreatment: Conversations With Vulnerable Parents.

11 focus groups (N = 160) of high-risk parents in Los Angeles County were asked to assess the value of social media to deliver an evidence-based parenting program, Triple P-Positive Parenting Program, to reduce child maltreatment. For feasibility, (N = 238) parents were surveyed regarding their internet use. Parents responded enthusiastically to the online program, and expressed the importance of a sense of community and learning through the experiences of others. 78% of the young, high-poverty, minority parents used the internet. An online evidence-based parenting program delivered in social media could enhance accessibility and engagement of high-risk parents - a powerful tool to reduce child maltreatment.

Intraductal therapy of ductal carcinoma in situ: a presurgery study.

INTRODUCTION: Ductal carcinoma in situ (DCIS) is a noninvasive breast cancer wherein malignant cells are confined within a ductal lobular unit. Although less than half the cases of DCIS will progress to invasive disease, most women are treated aggressively with surgery, radiation, and/or hormone therapy due to the inability to clinically evaluate the extent and location of the disease. Intraductal therapy, in which a drug is administered directly into the mammary duct through the nipple, is a promising approach for treating DCIS, but the feasibility of instilling drug into a diseased duct has not been established. PATIENTS AND METHODS: Four to 6 weeks before their scheduled surgery, 13 women diagnosed with DCIS were subjected to cannulation of the affected duct. After both the absence of perforation and presence of dye in the duct were confirmed by ductogram, pegylated liposomal doxorubicin was instilled. Histopathologic assessment was performed after surgery to assess the treatment effects. RESULTS: Of the 13 women enrolled in the study, 6 had their DCIS duct successfully cannulated without perforation and instilled with the drug. The treatment was well tolerated, and no serious adverse events have been reported. Biomarker studies indicated a general decrease in Ki-67 levels but an increase in annexin-1 and 8-hydroxydeoxyguanosine in the lumen of DCIS-containing ducts, which suggests a local response to pegylated liposomal doxorubicin treatment. CONCLUSIONS: Intraductal therapy offers a nonsurgical strategy to treat DCIS at the site of disease, potentially minimizing the adverse effects of systemic treatment while preventing development of invasive cancer.

A feasibility study of the intraductal administration of chemotherapy.

Preclinical data have shown the potential of the intraductal administration of chemotherapy for breast cancer prevention. Direct translation of this work has been stymied by the anatomical differences between rodents (one duct per teat) and women (5-9 ductal systems per breast). The objective of this phase I study was to show the safety and feasibility of intraductal administration of chemotherapy drugs into multiple ducts within one breast in women awaiting mastectomy for treatment of invasive cancer. Thirty subjects were enrolled in this dose escalation study conducted at a single center in Beijing, China. Under local anesthetic, one of two chemotherapy drugs, carboplatin or pegylated liposomal doxorubicin (PLD), was administered into five to eight ducts at three dose levels. Pharmacokinetic analysis has shown that carboplatin was rapidly absorbed into the bloodstream, whereas PLD, though more erratic, was absorbed after a delay. Pathologic analysis showed marked effects on breast duct epithelium in ducts treated with either drug compared with untreated ducts. The study investigators had no difficulty in identifying or cannulating ducts except in one case with a central cancer with subareolar involvement. This study shows the safety and feasibility of intraductal administration of chemotherapy into multiple ducts for the purpose of breast cancer prevention. This is an important step toward implementation of this strategy as a "chemical mastectomy", where the potential for carcinogenesis in the ductal epithelium is eliminated pharmacologically, locally, and without the need for surgery.

Global breast cancer: the lessons to bring home.

Breast cancer is the most common cancer affecting women globally. This paper discusses the current progress in breast cancer in Western countries and focuses on important differences of this disease in low- and middle-income countries (LMCs). It introduces several arguments for applying caution before globalizing some of the US-adopted practices in the screening and management of the disease. Finally, it suggests that studies of breast cancer in LMCs might offer important insights for a more effective management of the problem both in developing as well as developed countries.

The physiology of the normal human breast: an exploratory study

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The physiology of the nonlactating human breast likely plays a key role in factors that contribute to the etiology of breast cancer and other breast conditions. Although there has been extensive research into the physiology of lactation, few reports explore the physiology of the resting mammary gland, including mechanisms by which compounds such as hormones, drugs, and potential carcinogens enter the breast ducts. The purpose of this study was to explore transport of exogenous drugs into ductal fluid in nonlactating women and determine if their concentrations in the fluid are similar to those observed in the breast milk of lactating women. We selected two compounds that have been well characterized during lactation, caffeine and cimetidine. Caffeine passively diffuses into breast milk, but cimetidine is actively transported and concentrated in breast milk. After ingestion of caffeine and cimetidine, 14 nonlactating subjects had blood drawn and underwent ductal lavage at five time points over 12 h to measure drug levels in the fluid and blood. The concentrations of both caffeine and cimetidine in lavage fluid were substantially less than those observed in breast milk. Our results support recent evidence that the cimetidine transporter is not expressed in the nonlactating mammary gland, and highlight intriguing differences in the physiology and molecular transport of the lactating and nonlactating breast. The findings of this exploratory study warrant further exploration into the physiology of the nonlactating mammary gland to elucidate factors involved in disease initiation and progression (AU)

The physiology of the normal human breast: an exploratory study.

The physiology of the nonlactating human breast likely plays a key role in factors that contribute to the etiology of breast cancer and other breast conditions. Although there has been extensive research into the physiology of lactation, few reports explore the physiology of the resting mammary gland, including mechanisms by which compounds such as hormones, drugs, and potential carcinogens enter the breast ducts. The purpose of this study was to explore transport of exogenous drugs into ductal fluid in nonlactating women and determine if their concentrations in the fluid are similar to those observed in the breast milk of lactating women. We selected two compounds that have been well characterized during lactation, caffeine and cimetidine. Caffeine passively diffuses into breast milk, but cimetidine is actively transported and concentrated in breast milk. After ingestion of caffeine and cimetidine, 14 nonlactating subjects had blood drawn and underwent ductal lavage at five time points over 12 h to measure drug levels in the fluid and blood. The concentrations of both caffeine and cimetidine in lavage fluid were substantially less than those observed in breast milk. Our results support recent evidence that the cimetidine transporter is not expressed in the nonlactating mammary gland, and highlight intriguing differences in the physiology and molecular transport of the lactating and nonlactating breast. The findings of this exploratory study warrant further exploration into the physiology of the nonlactating mammary gland to elucidate factors involved in disease initiation and progression.

The intraductal approach to the breast: raison d'être.

Opportunities for the detection, prediction, and treatment of breast cancer exist at three biological levels: systemically via the blood, at the whole organ level, and within the individual ductal lobular structures of the breast. This review covers the evaluation of approaches targeted to the ductal lobular units, where breast cancer begins. Studies to date suggest the presence of 5 to 12 independent ductal lobular systems per breast, each harboring complex cellular fluids contributed by local and systemic processes. New techniques for accessing and interrogating these systems offer the potential to gauge the microenvironment of the breast and distill biological risk profiles.

The Fourth International Symposium on the Intraductal Approach to Breast Cancer, Santa Barbara, California, 10-13 March 2005.

Intraductal approaches encompass procedures and technologies that are designed to access and interrogate the ductal-alveolar systems of the human breast, and include nipple aspiration, ductal lavage, random periareolar fine needle aspiration, and ductoscopy. These approaches are being used to collect and analyze fluids and cells to develop methods for breast cancer detection and risk assessment; to introduce imaging technologies to explore the mammary tree for abnormalities; to administer therapeutic and/or preventive agents directly to the breast tissue; and to explore the biology of the normal mammary gland. The latest research findings in these areas, presented at The 4th International Symposium on the Intraductal Approach to Breast Cancer in 2005, are summarized in this report.

Anatomy of the nipple and breast ducts revisited.

BACKGROUND: Increasing interest in the intraductal approach to the breast has necessitated revisiting the anatomy of the breast. METHODS: Using six different complementary in vivo and in vitro approaches, the authors determined the number, distribution, and anatomic properties of the ductal systems of the breast, which extend from the nipple orifices to the terminal duct lobular units. RESULTS: More than 90% of all nipples examined contained 5-9 ductal orifices, generally arranged as a central group and a peripheral group. Each nipple orifice communicated with a separate, nonanastomosing ductal system, which extended to the terminal duct lobular unit. CONCLUSIONS: Increased knowledge of the ductal anatomy of the breast and the ability to access the nipple ductal orifices will provide a foundation for the intraductal approach to the breast.