A randomized Phase I pre-operative window trial of transdermal endoxifen in women planning mastectomy: Evaluation of dermal safety, intra-mammary drug distribution, and biologic effects.

Breast cancer prevention only requires local exposure of the breast to active drug. However, oral preventive agents entail systemic exposure, causing adverse effects that limit acceptance by high-risk women. Drug-delivery through the breast skin is an attractive option, but requires demonstration of dermal safety and drug distribution throughout the breast. We formulated the tamoxifen metabolite (E/Z)-endoxifen for transdermal delivery and tested it in a placebo-controlled, double-blinded Phase I trial with dose escalation from 10 to 20 mg daily. The primary endpoint was dermal toxicity. Thirty-two women planning mastectomy were randomized (2:1) to endoxifen-gel or placebo-gel applied to both breasts for 3-5 weeks. Both doses of endoxifen-gel incurred no dermal or systemic toxicity compared to placebo. All endoxifen-treated breasts contained the drug at each of five sampling locations; the median per-person tissue concentration in the treated participants was 0.6 ng/g (IQR 0.4-1.6), significantly higher (p < 0.001) than the median plasma concentration (0.2 ng/mL, IQR 0.2-0.2). The median ratio of the more potent (Z)-isomer to (E)-isomer at each breast location was 1.50 (IQR 0.96-2.54, p < 0.05). No discernible effects of breast size or adiposity on tissue concentrations were observed. At the endoxifen doses and duration used, and the tissue concentration achieved, we observed a non-significant overall reduction of tumor proliferation (Ki67 LI) and significant downregulation of gene signatures known to promote cancer invasion (FN1, SERPINH1, PLOD2, PDGFA, ITGAV) (p = 0.03). Transdermal endoxifen is an important potential breast cancer prevention agent but formulations with better dermal penetration are needed.

Glycyrrhizic acid delivery system Chitosan-coated liposome as an adhesive anti-inflammation.

Nowadays, medicinal plants are used to overcome the side effects of prescription drugs in modern medicine. Glycyrrhizic acid (GA) derived from the root of the licorice plant is one of the plant compounds whose effectiveness has been confirmed in the treatment of inflammatory bowel disorders (IBD). Liposome thin film hydration method was used to synthesize chitosan-coated liposomes containing GA. In the present study, chitosan-coated liposome was characterized by dynamic light scattering (DLS), zeta potential, scanning electron microscope (SEM) and Fourier transforms infrared spectroscopy (FTIR). The FTIR spectrum confirmed the coating of liposomes by chitosan polymer.  Liposome coating leads to an increase in the size and values of zeta potential. The 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay of chitosan-coated liposomes containing GA confirmed that it has no cytotoxicity toward fibroblasts cell line, therefore confirming their cytocompatibility. Overall, drug loading, release and cytotoxicity were evaluated and it was found that chitosan decreased the release rate of GA. It seems; chitosan-coated liposomes may be a suitable system for delivering liposomal GA in the treatment of IBD.

Exploring the biological application of Penicillium fimorum-derived silver nanoparticles: In vitro physicochemical, antifungal, biofilm inhibitory, antioxidant, anticoagulant, and thrombolytic performance.

This study showed the anti-candida, biofilm inhibitory, antioxidant, anticoagulant, and thrombolytic properties of biogenic silver nanoparticles (AgNPs) fabricated by using the supernatant of Penicillium fimorum (GenBank accession number OQ568180) isolated from soil. The biogenic AgNPs were characterized by using different analytical techniques. A sharp surface plasmon resonance (SPR) peak of the colloidal AgNPs at 429.5 nm in the UV-vis spectrum confirmed the fabrication of nanosized silver particles. The broth microdilution assay confirmed the anti-candida properties of AgNPs with a minimum inhibitory concentration (MIC) of 4 µg mL-1. In the next step, the protein and DNA leakage assays as well as reactive oxygen species (ROS) assay were performed to evaluate the possible anti-candida mechanisms of AgNPs representing an increase in the total protein and DNA of supernatant along with a climb-up in ROS levels in AgNPs-treated samples. Flow cytometry also confirmed a dose-dependent cell death in the AgNPs-treated samples. Further studies also confirmed the biofilm inhibitory performance of AgNPs against Candia albicans. The AgNPs at the concentrations of MIC and 4*MIC inhibited 79.68 ± 14.38% and 83.57 ± 3.41% of biofilm formation in C. albicans, respectively. Moreover, this study showed that the intrinsic pathway may play a significant role in the anticoagulant properties of AgNPs. In addition, the AgNPs at the concentration of 500 µg mL-1, represented 49.27%, and 73.96 ± 2.59% thrombolytic and DPPH radical scavenging potential, respectively. Promising biological performance of AgNPs suggests these nanomaterials as a good candidate for biomedical and pharmaceutical applications.

Menstrual Phase and Menopausal Status Classification of Benign Breast Tissue Using Hormone-Regulated Gene Expression and Histomorphology: A Validation Study.

BACKGROUND: The validation of breast cancer risk biomarkers in benign breast samples (BBS) is a long-sought goal, hampered by the fluctuation of gene and protein expression with menstrual phase (MP) and menopausal status (MS). Previously, we identified hormone-related gene expression and histomorphology parameters to classify BBS by MS/MP. We now evaluate both together, to validate our prior results. PATIENTS AND METHODS: BBS were obtained from consenting women (86 premenopausal, 55 postmenopausal) undergoing reduction mammoplasty (RM) or contralateral unaffected breast (CUB) mastectomy. MP/MS was defined using classical criteria for menstrual dates and hormone levels on the day of surgery. BBS gene expression was measured with reverse transcription quantitative polymerase chain reaction (RT-qPCR) for three luteal phase (LP) genes (TNFSF11, DIO2, MYBPC1) and four menopausal genes (PGR, GREB1, TIFF1, CCND1). Premenopausal samples were classified into LP or non-LP, using published histomorphology parameters. Logistic regression and receiver-operator curve analysis was performed to assess area under the curve (AUC) for prediction of MP/MS. RESULTS: In all 131 women, menopausal genes plus age > 50 years predicted true MS [AUC 0.93, 95% confidence interval (CI) 0.89, 0.97]. Among premenopausal women, high TNFSF11 expression distinguished non-LP from LP samples (AUC 0.80, 95% CI 0.70, 0.91); the addition of histomorphology improved the prediction nonsignificantly (AUC 0.87, 95% CI 0.78, 0.96). In premenopausal subsets, addition of histomorphology improved LP prediction in RM (AUC 0.95, 95% CI 0.87, 1.0), but not in CUB (0.84, 95% CI 0.72, 0.96). CONCLUSIONS: Expression of five-gene set accurately predicts menopausal status and menstrual phase in BBS, facilitating the development of breast cancer risk biomarkers using large, archived sample repositories.

Z-Endoxifen prevents aggressive mammary cancers in mice by inhibiting cell proliferation and creating a tumor suppressive microenvironment.

Aggressive estrogen receptor (ER) positive breast cancer is frequently tamoxifen-resistant; alternative endocrine approaches exist for therapy, but not for prevention, particularly in premenopausal women. We examined the efficacy of the selective ER modulator (Z-endoxifen) as monotherapy and in combination with the selective progesterone receptor modulators (onapristone and ulipristal acetate) in the tamoxifen-insensitive C3(1)/SV40TAg mouse mammary tumorigenesis model. Unlike tamoxifen at human equivalent dose (HED) 101 mg/day, endoxifen at HED 24 mg/day significantly increased latency and reduced tumor growth relative to untreated controls. Ulipristal acetate (UPA) at HED 81 mg/day also significantly increased latency however failed to inhibit tumor growth, while onapristone (HED 98 mg/day) had no tumor prevention efficacy in this model. Addition of UPA to endoxifen did not enhance preventive efficacy over endoxifen alone. The expression of genes associated with cell cycle, cell proliferation and extracellular matrix remodeling was similarly repressed by endoxifen and UPA however only endoxifen significantly downregulated prominent genes associated with poor prognosis (Col11a1, Il17b, Pdgfa, Tnfrsf11a). Our results indicate that endoxifen can prevent breast cancers, even when tamoxifen-resistant, through its role in favorable tissue remodeling and immunomodulation.

Clindamycin removal from aqueous solution by non-thermal air plasma treatment: performance, degradation pathway and ensuing antimicrobial activity.

The present study set out to investigate clindamycin (CLN) removal from aqueous solution using non-thermal plasma (NTP) under atmospheric air conditions and to address the effects of some variables including pH, initial concentration of CLN, and working voltage on CLN degradation. The result showed that the NTP system exhibited excellent degradation rate and mineralization efficiency on CLN in 15 min under neutral conditions, which exceeded 90 and 45%, respectively, demonstrating its conversion to other organic by-products. Furthermore, CLN degradation was largely dependent upon the initial pH of solution, applied voltage, and reaction time. Specifically, under acidic conditions (pH = 3), working voltage of 24 kV and after 15 min of reaction, almost 100% of CLN was degraded. NTP-initiated CLN degradation products through LC-MS/MS analysis, determined within 10 min of reaction, inferred that the complex structure of CLN has undergone deterioration by active radical species which subsequently generated small molecular organic compounds. Chemical processes involved in CLN degradation were found to be demethylation, desulfonylation, dechlorination, hydroxylation and deamination. Lastly, antimicrobial susceptibility tests revealed that the activity of CLN was reduced following NTP treatment, which is also in good agreement with the minimum inhibitory concentration (MIC) values obtained from microdilution analyses.

The Effect of Barbed Sutures on Complication Rates Post Colectomy: A Retrospective Case-Matched Review.

Background and objective Colectomies are common general surgical procedures performed for a variety of gastrointestinal disorders ranging from benign to malignant. Early definitive fascial closure has been shown to improve outcomes in patients following abdominal surgery. Conventional loop sutures and their accompanying knots present several disadvantages and require technical expertise. Reducing complications has been a strong driver for innovations such as the use of barbed sutures. Barbed sutures consist of axially spaced barbed segments on each side of a midpoint at which the barbs change directions. This study is a retrospective case-matched review that evaluates the effects of barbed sutures compared to non-barbed sutures on the rates and severity of postoperative complications following colectomies for abdominal fascial closure. Materials and methods The study enrolled 151 patients who underwent open and minimally invasive colorectal abdominal surgeries from January 1, 2017, to November 30, 2019. Primary outcome measures included operative time, length of hospital stay, and postoperative complications compared between barbed and non-barded suture types. The sub-analysis further compared the surgical approach (open vs. robotic/laparoscopic) and incision type (Pfannenstiel vs. midline and other) between the suture types. Results The mean operative time for barbed sutures was 177 minutes, while it was 157 minutes for non-barbed sutures, resulting in a significant difference (p=0.0264). No significant difference was noted in postoperative complications between the groups. Conclusions The results of this study indicate that the use of barbed sutures in colorectal surgery does not increase the chances of postoperative infections, prolonged hospital stays, or other postoperative complications. Barbed sutures resulted in fewer class IV complications and more class I complications when compared to non-barbed sutures. Barbed sutures have proven to be beneficial in cases that require good wound approximation in high-tension areas and they eliminate the need for knots.

Correlation between echocardiographic measurements and right heart hemodynamic parameters in patients undergoing evaluation for pulmonary hypertension.

Echocardiograms provide important information for the evaluation and management of patients with pulmonary hypertension. Right ventricular free wall strain measurements provide additional information about the longitudinal contractile function of the right ventricle. Clinical information, including echocardiographic measurements and right heart hemodynamic parameters, on patients undergoing right heart catheterization for evaluation of possible pulmonary hypertension was collected retrospectively. This study included 60 patients (35 women) with a mean age of 62.6 ± 14.8 years. For World Health Organization categories, 32 patients were in Group 1, 12 in Group 2, 4 in Group 3, 3 in Group 4, and 7 had mixed clinical features of both Group 2 and Group 3. The mean pulmonary artery pressure was 40.6 ± 13.2 mm Hg. The right atrial volume index had significant positive correlations with the brain natriuretic peptide level, right ventricular volume index, left atrial volume index, and right atrial pressure and negative correlations with the cardiac index and mixed venous oxygen saturation. The mean right ventricular free wall strain was -17.85 ± 5.56%; it did not have significant correlations with right heart hemodynamic parameters. Therefore, the right atrial volume index but not the right ventricular strain index provides important objective information for the evaluation of patients with possible pulmonary hypertension.

The Utility of Brain Natriuretic Peptide in Patients Undergoing an Initial Evaluation for Pulmonary Hypertension.

Introduction: Brain natriuretic peptide (BNP) is a polypeptide released from the cardiac ventricles and has been used as a diagnostic marker in cardiovascular diseases. Some patients with pulmonary hypertension have significant increases in BNP levels. This study wanted to determine whether the BNP levels in patients referred for evaluation of possible pulmonary hypertension were associated with a particular functional class or diagnostic group. Methods: Data were collected on patients from the Pulmonary Vascular Disease clinic undergoing right heart catheterization between 1/1/2019 and 5/20/2020. Clinical information, laboratory results including BNP, and hemodynamic parameters were recorded. Results: This study included 117 patients referred for evaluation for PH with measured BNP levels. The mean age was 63; the female to male ratio was 2:1, 25.4% of the patients were Hispanic. The average BNP level for the entire cohort was 4127.1 ± 11761.98 pg/ml. Patients in higher WHO functional classes tended to have higher levels of BNP, but statistical analysis BNP showed no differences between the functional classes. Patients in WHO Group 4 had significantly higher BNP levels than other WHO groups. Hemodynamic group classification demonstrated significant differences in BNP values between the low, intermediate, and high composite score patients. Conclusions: Patients undergoing evaluation for pulmonary hypertension had a wide range of BNP values. Patients with more abnormal composite hemodynamic scores higher BNP levels. Measurement of BNP provides an independent test to help interpret patients' descriptions of their functional limitations and to identify patients with more abnormal hemodynamic parameters.

Ruptured Hepatic Hemangioma in the Third Trimester of Pregnancy: A Rare Case Report.

Hepatic hemangiomas are considered the most common benign mesenchymal hepatic tumors. Most cases are asymptomatic. However, giant hemangiomas can present with a variety of clinical presentations, with a rupture being the most catastrophic outcome. Only a few cases of ruptured perinatal hepatic hemangiomas have been reported. Accelerated growth of hepatic hemangiomas caused by increased estrogen in pregnancy, increased intra-abdominal pressure, and direct contact with a gravid uterus are possible mechanisms for increased risk of rupture during pregnancy. The safety of either non-operative or surgical treatment of symptomatic giant hemangioma during pregnancy has not been adequately investigated. We present a rare case of a 28-year-old G1P0 female at 33 weeks gestation that presented with a ruptured hepatic hemangioma treated with damage control surgery followed by nonanatomic surgical resection.

Targeting EGFR Tyrosine Kinase: Design, Synthesis and Biological Evaluation of Novel Quinazolinone Derivatives.

Impaired cell cycle regulation and disturbance in signal transduction pathway are two major causes of a condition defined as cancer, one of the significant reasons for mortality worldwide. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have been commonly used as anticancer agents, and the majority of this medications possess quinazoline moiety as a heteroaromatic core. In this study, two novel series of EGFR-TKIs containing quinazolinone core were designed and synthesized. Most compounds showed reasonable inhibitory activity against EGFR-TK compared to that of erlotinib, a reversible inhibitor of this enzyme. Compound 8b, 2-((2-chlorobenzyl)amino)-6-phenoxyquinazolin-4(1H)-one, with an IC50 value of 1.37 nM exhibited the highest potency. Molecular docking study of compound 8b showed that it had the same direction of erlotinib and formed proper hydrogen bonds and hydrophobic interactions with the important amino acid residues of the active site. Based on in-silico calculations of ADME properties, our novel compounds have the potential to be orally active agents.

Increasing Fecal Immunochemical Test Return Rates by Implementing Effective "Reminder to Complete Kit" Communication With Participants: A Quality Improvement Study.

Background The incidence of colorectal cancer (CRC) in the United States is increasing. It remains the second leading cause of cancer death in the United States for men and women combined, mainly due to underutilization of screening methods. The American Cancer Society now recommends that adults aged 45 years and older with an average risk of CRC undergo regular screening with either a high-sensitivity stool-based test or structural (visual) examination, depending on patient preference and test availability. The primary objective of this quality improvement project was to determine if reminder methods, such as telephone or letter reminders, increased the return rate of fecal immunochemical tests (FIT) for CRC screening. Methodology At public outreach events and daily clinics in the West Texas Panhandle area, participants in the GET FIT program were provided with FIT kits after completing the education on CRC. Participants who fit the inclusion criteria and had received a FIT kit from the program were included. They were instructed on how to perform the test and mail it back. Participants who did not return the completed kits within two weeks were reminded either through (1) a reminder letter, (2) telephone, or (3) a combination of letter reminder and telephone call every two weeks (±three days) for 60 days or five attempts to contact. We de-identified and analyzed the FIT kit return data from April-September 2019 before analyzing these reminder methods. We then calculated the change in return rates from October 2019 to March 2020. Our goal was to increase the FIT return rates by 25% compared to the baseline return rate. Results The pre-intervention return rate of kits for April-September 2019 was 61.52%, and the post-intervention return rate for October 2019-March 2020 was 71.85%. This rate was equal to an approximately 16.79% increase in return rates that was statistically significant (p < 0.01). There was a significant difference in the method of reminder between the two groups, but no significant differences in gender and race/ethnicity between the two groups. There was a significant difference in return rates between race/ethnicities in the October-March cohort with black and Hispanic participants having the highest return rates of 82.3% and 77.25%, respectively. Conclusions FIT remains one of the primary options for CRC screening. Due to its lower cost and noninvasiveness, FIT was offered to patients at average risk. We demonstrated an increase in return rates, although we did not meet our target return rate goal for this project. This study was limited due to a gradual increase in coronavirus disease 2019 (COVID-19) cases and a subsequent shift and conversation of ongoing research into COVID-19.

Primary-Site Local Therapy for Patients with De Novo Metastatic Breast Cancer: An Educational Review.

BACKGROUND: Until 2001, the paradigm guiding the management of women with de novo metastatic breast cancer (dnMBC) stipulated that primary-site locoregional therapy (PSLT) did not alter the course of metastatic disease and was necessary only for palliation of symptoms. Since 2002, retrospective data have begun questioning this paradigm. However, selection biases driving an observed survival advantage associated with PSLT in dnMBC were quickly recognized and led to several randomized clinical trials (RCTs) addressing this question. METHODS AND RESULTS: Four published RCTs have since tested the value of PSLT added to systemic therapy (ST) or not, with overall survival (OS) as the primary end point. The results of three published trials show no OS benefit for the addition of PSLT: Indian Tata Memorial, U.S./Canada E2108, and Austrian POSYTIVE (although POSYTIVE did not reach full accrual). The fourth RCT (Turkey, MF07-01) shows an OS benefit for PSLT at 5 years (42 % vs 24 % in the ST arm; hazard ratio [HR], 0.66; 95 % confidence interval [CI], 0.49-0.88). However, the 5-year survival in the PSLT arm of MF07-01 is similar to that in both arms of E2108, suggesting that the worse survival in the ST arm of MF07-01 is a result of biologically worse disease (from imbalanced randomization). Locoregional control was improved by PSLT in all trials, but without improvement in quality of life. CONCLUSIONS: The current evidence fails to refute the 20th century paradigm guiding management of de novo metastatic breast cancer. Discussion continues regarding the survival value of PSLT for patients with bone-only disease or oligometastases, but unbiased evidence is lacking.

The clinical associations with cardiomegaly in patients undergoing evaluation for pulmonary hypertension.

BACKGROUND: Chest radiographs can identify important abnormalities in patients undergoing diagnostic evaluation for cardiovascular diseases. Cardiomegaly often reflects cardiac chamber dilation, or cardiac muscle hypertrophy, or both conditions. The clinical implications of cardiomegaly depend on the underlying clinical disorder. Does cardiomegaly have any clinical, laboratory, echocardiographic, and right heart catheterization associations in patients undergoing evaluation for pulmonary hypertension? METHODS: Patients referred to a pulmonary vascular disease clinic for possible pulmonary hypertension underwent a comprehensive evaluation that included right heart catheterization. These patients also had chest radiographs, laboratory studies, and echocardiograms. The patients were divided into two groups based on the presence or absence of cardiomegaly. RESULTS: This study included 102 patients (63.7% female) with a mean age of 62.3 ± 15.0 years. Patients with cardiomegaly (n = 64) had elevated BNP, BUN, and creatinine levels. They had elevated right atrial pressures, right ventricular pressures, and pulmonary artery pressures and reduced cardiac indices and reduced mixed venous oxygen saturations. There were no differences in echocardiographic parameters between the two groups. CONCLUSIONS: This study demonstrates that the presence of cardiomegaly on chest radiographs has important clinical implications, including increased BNP levels and increased right heart pressures, in patients undergoing evaluation for pulmonary hypertension. Consequently, the presence of cardiomegaly supports the need for additional evaluation, including right heart catheterization, and provides useful information for primary care physicians and specialists.

Selective progesterone receptor blockade prevents BRCA1-associated mouse mammary tumors through modulation of epithelial and stromal genes.

Pharmacological approaches to breast cancer risk-reduction for BRCA1 mutation carriers would provide an alternative to mastectomy. BRCA1-deficiency dysregulates progesterone signaling, promoting tumorigenesis. Selective progesterone receptor (PR) modulators (SPRMs) are therefore candidate prevention agents. However, their efficacy varies in different BRCA1-deficient mouse models. We examined chemopreventive efficacy of telapristone acetate (TPA), ulipristal acetate (UPA) and mifepristone (MFP) in mice with a conditional knockout of the Brca1 C-terminal domain. The SPRMs displayed a spectrum of efficacy: UPA was most effective, TPA less, and MFP ineffective. Compared to no-treatment controls, UPA reduced tumorigenesis (p = 0.04), and increased tumor latency (p = 0.03). In benign mammary glands, UPA decreased Ki67 (p < 0.001) and increased PR expression (p < 0.0001). RNA sequencing analysis revealed distinct gene expression in response to UPA and MFP. UPA downregulated glycolysis and extracellular matrix-inflammation genes (Fn1, Ptgs2, Tgfb2, Tgfb3) whereas MFP downregulated claudin genes and upregulated amino acid metabolism and inflammation genes. The anti-glucocorticoid effects of MFP appeared not to be tumor-protective, while altering estrogen receptor signaling and NF-kB activation. Our study points to an important role of epithelial PR and its paracrine action on the microenvironment in BRCA1-deficient mammary tumorigenesis, and prevention.

The Diagnostic Competence of Glial Fibrillary Acidic Protein in Mild Traumatic Brain Injury and Its Prognostic Value in Patient Recovery.

AIM: To show whether the glial fibrillary acidic protein (GFAP) levels are significantly higher in the serum of patients with mild traumatic brain injury or not. MATERIAL AND METHODS: The level of serum GFAP was measured in 176 patients suffering from brain trauma. The ability of GFAP in predicting the presence of intracranial lesions and the need for neurosurgical intervention was analyzed using the area under the receiver (AUC) operating characteristic (ROC). By passing three months from mild TBI, the Post-Concussion Symptoms Questionnaire (PCSQ) as well as the physical and mental evaluations were performed using the SF-36 questionnaire. RESULTS: Of 176 patients included, 79.5% had no complications and symptoms by passing three months from traumatic brain injury. The AUC for GFAP was 72.6%, which revealed a good accuracy in predicting the need for neurosurgical intervention. CONCLUSION: GFAP, as a predictive factor in people with mild TBI diagnosis who need neurosurgical operation, expressed a favorable diagnostic effect.

Local Transdermal Delivery of Telapristone Acetate Through Breast Skin, Compared With Oral Treatment: A Randomized Double-Blind, Placebo-Controlled Phase II Trial.

Oral breast cancer prevention medications entail systemic exposure, limiting acceptance by high-risk women. Delivery through the breast skin, although an attractive alternative, requires demonstration of drug distribution throughout the breast. We conducted a randomized double-blind, placebo-controlled phase II clinical trial comparing telapristone acetate, a progesterone receptor antagonist, administered orally (12 mg/day) or transdermally (12 mg/breast) for 4 ± 1 weeks to women planning mastectomy. Plasma and tissue concentrations, measured at five locations in the mastectomy specimen using liquid chromatography tandem mass spectrometry were compared. In 60 evaluable subjects, median drug concentration (ng/g tissue) was 103 (interquartile range (IQR): 46.3-336) in the oral vs. 2.82 (IQR: 1.4-5.5) in the transdermal group. Despite poor dermal permeation, within-breast drug distribution pattern was identical in both groups (R2  = 0.88, P = 0.006), demonstrating that transdermally and orally delivered drug is distributed similarly through the breast, and is strongly influenced by tissue adiposity (P < 0.0001). Other skin-penetrant drugs should be tested for breast cancer prevention.