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Metastatic breast cancer dominates the female cancer-related mortality. Tumour-associated molecules represents a crucial for early disease detection and identification of novel therapeutic targets. Nanomaterial technologies provide promising novel approaches to disease diagnostics and therapeutics. In the present study we extend the investigations of antitumoral properties of Carbon Dots prepared from N-hydroxyphthalimide (CD-NHF) precursor. We evaluate the effect of CD-NHF on tumour cell migration and invasion in vitro and their impact on tumour progression using an in vivo model. Furthermore, we investigate the molecular mechanisms involved in CD-NHF antitumour effects. In vivo mammary tumours were induced in Balb/c female mice by injecting 4T1 cells into the mammary fat pad. Conditional treatment with CD-NHF significantly impair both migration and invasion of metastatic breast cancer cells. The presence of CD-NHF within the 3D cell cultures strongly inhibited the malignant phenotype of MDA-MB-231, 4T1 and MCF-7 cells in 3D culture, resulting in culture colonies lacking invasive projections and reduction of mammospheres formation. Importantly, breast tumour growth and metastasis dissemination was significantly reduced upon CD-NHF treatments in a syngeneic mouse model and is associated with down-regulation of Ki67 and HSP90 expression. CD-NHF nanostructures provide exciting perspective for improving treatment outcome in breast cancer. [ABSTRACT FROM AUTHOR]

Purpose: Endocrine therapy (ET) used to reduce the risk of recurrence in hormone receptor-expressing disease (75% of breast cancers) is associated with worsening of climacteric symptoms with a negative impact on quality of life (QoL). Homeopathy might allow a better management of hot flushes (HF).Methods: In this multicenter randomized double-blind placebo-controlled phase III study ( ClinicalTrials.gov NCT01246427), we enrolled ≥ 18 years old women with histologically proven non metastatic localized breast cancer, with Eastern Cooperative Oncology Group-Performance Status (ECOG-PS) ≤ 1, treated for at least 1 month with adjuvant ET, and complaining about moderate to severe HF. Patients should not be scheduled for chemotherapy or radiotherapy, and had no associated pathology known to induce HF. After a 2- to 4-week placebo administration, we randomly assigned (1:1) patients with HFS ≥ 10 using an interactive web-based centralized platform to BRN-01 homeopathic medicine complex (Actheane®) in arm A or Placebo (Arm P). Randomization was stratified by adjuvant ET (taxoxifen/aromatase inhibitor) and recruiting site. HF scores (HFS) were calculated as the mean of HF frequencies before randomization, at 4, and at 8 weeks post-randomization (pre-, 4w,- and 8w-) weighted by a 4-level intensity scale. Primary endpoint was assessed at 4-week post-randomization, as the variation between pre- and 4w-HFS. Secondary endpoints included HFS variation between pre- and 8w-HFS, compliance and tolerance assessed 8 weeks after randomization, and QoL and satisfaction assessed at 4- and 8-week post-randomization.Results: Two hundred ninety-nine patients were included, and 138 (46.2%) randomized (A, 65; P, 73). Median 4w-HFS absolute variation (A, - 2.9; P, - 2.5 points, p = 0.756) and relative decrease (A, - 17%; P, - 15%, p = 0.629) were not statistically different. However, 4w-HFS decreased for 46 (75%) in A vs 48 (68%) patients in P arm. 4w-QoL was stable or improved for respectively 43 (72%) vs 51 (74%) patients (p = 0.470).Conclusions: The efficacy endpoint was not reached, and BRN-01 administration was not demonstrated as an efficient treatment to alleviate HF symptoms due to adjuvant ET in breast cancer patients. However, the study drug administration led to decreased HFS with a positive impact on QoL. Without any recommended treatment to treat or alleviate the HF-related disabling symptoms, Actheane® could be a promising option, providing an interesting support for better adherence to ET, thereby reducing the risk of recurrence with a good tolerance profile. [ABSTRACT FROM AUTHOR]

Purpose: To prevent febrile neutropenia (FN), European Organisation for Research and Treatment of Cancer (EORTC) guidelines recommend primary prophylaxis with granulocyte colony-stimulating factors (PPG) for patients at high risk (≥ 20%) of FN. In Belgium, the use of PPG is restricted by specific reimbursement criteria. The impact of these criteria on PPG use and adherence to guidelines is unknown.Methods: This multicentre, cross-sectional, observational study aimed to describe PPG use by FN risk category in breast cancer patients who were scheduled to receive myelosuppressive chemotherapy in outpatient clinics in Belgium during a 2-week period between 13 October and 12 December 2014.Results: In total, 490 patients were enrolled. Median age was 57.0 years. Based on their chemotherapy regimen, 53.9, 5.1 and 41.0% of patients were at a low, intermediate and high risk of FN, respectively. Overall, 39.8% of patients received PPG (17.0, 12.0 and 73.1% of those receiving low-, intermediate- and high-risk regimens, respectively). In the high-risk category, PPG was used in 89.9% of dose-dense and in 25.0% of classical chemotherapy regimens. PPG use was adherent to EORTC guidelines in 75.3% of patients (30.6% appropriate use, 44.7% appropriate non-use). EORTC guidelines would recommend PPG use in 46.1% of this study population (n = 226), and its use was reimbursable in Belgium in 76.1% of these patients (n = 172), but only 66.4% of them received PPG (n = 150).Conclusions: Both Belgian reimbursement criteria and physician decision-making led to a proportion of patients for whom PPG treatment was recommended but finally not receiving it. [ABSTRACT FROM AUTHOR]

Although adjuvant aromatase inhibitor (AI) therapy is widely used in postmenopausal women with hormone receptor-positive breast cancer, it is known to be associated with bone loss and increased fracture risk. Denosumab, a fully human monoclonal antibody against the receptor activator of nuclear factor-κB ligand, has been shown to protect against AI-induced bone loss. However, the efficacy of denosumab in the treatment of AI-associated bone loss has not been prospectively evaluated in Japan. We prospectively monitored bone mineral density (BMD) of the lumbar spine and bilateral femoral necks in 100 postmenopausal women with hormone receptor-positive postoperative breast cancer of clinical stage I-IIIA in whom treatment with AI as adjuvant endocrine therapy was planned or had been ongoing. Study participants received supplemental calcium and vitamin D every day and denosumab (60 mg) subcutaneously every 6 months. At enrollment, patients were required to have evidence of low bone mass without meeting the criteria for osteoporosis. The primary endpoint was percentage change from baseline in lumbar spine BMD at month 12. At 6 and 12 months, lumbar spine BMD increased by 3.3 and 4.7%, respectively. BMD of the femoral necks also increased. Hypocalcemia of grade ≥2, osteonecrosis of the jaw, and non-traumatic clinical fracture did not occur. In conclusion, semi-annual treatment with denosumab was associated with increased BMD in Japanese women receiving adjuvant AI therapy, regardless of prior AI treatment. [ABSTRACT FROM AUTHOR]

Background: Exemestane (EXE), exemestane + everolimus (EXE + EVE), toremifene (TOR), and fulvestrant (FUL) are second-line endocrine therapies for postmenopausal hormone receptor-positive (HR +)/human epidermal growth factor receptor 2-negative (HER2 -) metastatic breast cancer (mBC) in Japan. Although the efficacy of these therapies has been shown in recent studies, cost-effectiveness has not yet been determined in Japan.Objective: This study aimed to examine the cost-effectiveness of second-line endocrine therapies for the treatment of postmenopausal women with HR + and HER2 - mBC.Methods: A Markov model was developed to analyze the cost-effectiveness of the therapies over a 15-year time horizon from a public healthcare payer's perspective. The efficacy and utility parameters were determined via a systematic search of the literature. Direct medical care costs were used. A discount rate of 2% was applied for costs and outcomes. Subgroup analysis was performed for non-visceral metastasis. A series of sensitivity analyses, including probabilistic sensitivity analysis (PSA) and threshold analysis were performed.Results: Base-case analyses estimated incremental cost-effectiveness ratios (ICERs) of 3 million and 6 million Japanese yen (JPY)/quality-adjusted life year (QALY) gained for TOR and FUL 500 mg relative to EXE, respectively. FUL 250 mg and EXE + EVE were dominated. The overall survival (OS) highly influenced the ICER. With a willingness-to-pay (WTP) threshold of 5 million JPY/QALY, the probability of TOR being cost-effective was the highest. Subgroup analysis in non-visceral metastasis revealed 0.4 and 10% reduction in ICER from the base-case results of FUL5 500 mg versus EXE and TOR versus EXE, respectively, while threshold analysis indicated EVE and FUL prices should be reduced 73 and 30%, respectively.Conclusion: As a second-line therapy for postmenopausal women with HR +/HER2 - mBC, TOR may be cost-effective relative to other alternatives and seems to be the most favorable choice, based on a WTP threshold of 5 million JPY/QALY. FUL 250 mg is expected to be as costly and effective as EXE. The cost-effectiveness of EXE + EVE and FUL 500 mg could be improved by a large price reduction. However, the results are highly sensitive to the hazard ratio of OS. Policy makers should carefully interpret and utilize these findings. [ABSTRACT FROM AUTHOR]

Purpose: L-Thyroxine is one of the most commonly prescribed drugs and accordingly used by many breast cancer patients with thyroid disorders. Hence, potential interactions of chemotherapy with L-thyroxine, possibly contributing to fatigue, would be of high clinical relevance. Therefore, we investigated fatigue and underlying pathways in L-thyroxine-using breast cancer patients during chemotherapy.Methods: Thyroid-stimulating hormone (TSH), L-triiodothyronine (T3), and diurnal salivary cortisol patterns were analyzed in breast cancer patients in the beginning and at the end of adjuvant chemotherapy within the control group (n = 41) of a randomized exercise intervention trial. Additionally, relationships in the exercising group (n = 45) as well as in healthy women (n = 25) were explored. Regression and mediation analyses were performed.Results: L-Thyroxine use was significantly associated with lower TSH (median = 0.33 mU/l, interquartile range = (0.15-0.48)), whereas patients not using L-thyroxine had TSH comparable to healthy women (0.51 mU/l (0.37-0.74)). T3 significantly declined during chemotherapy in L-thyroxine users but not in non-users. However, the group difference failed statistical significance. L-Thyroxine treatment was significantly associated with increased physical fatigue during chemotherapy (p = 0.004) in the non-exercising group. This association appeared to be partly mediated by TSH. Further, TSH appeared to affect fatigue partly via increased cortisol levels. In the exercise group, there was no significant association between L-thyroxine and fatigue.Conclusions: L-Thyroxine treatment during chemotherapy might result in hormonal dysregulations that can contribute to increased physical fatigue. Therefore, breast cancer patients on L-thyroxine treatment may need special monitoring of their thyroid levels and of fatigue during chemotherapy and should be encouraged to exercise.Trial Registration: ClinicalTrials.gov NCT01106820. [ABSTRACT FROM AUTHOR]

Introduction: Cancer treatment-induced bone loss (CTIBL) is a long-term side effect of breast cancer therapy. Both calcitriol and weight-bearing exercise improve bone metabolism for osteoporotic patients, but are unproven in a breast cancer population. We used a novel high-dose calcitriol regimen with an individualized exercise intervention to improve bone metabolism in breast cancer survivors.Methods: We accrued 41 subjects to this open label, 2 × 2 factorial, randomized feasibility trial. Breast cancer survivors were randomized to receive the following: (1) calcitriol (45 micrograms/week), (2) individualized exercise with progressive walking and resistance training, (3) both, or (4) a daily multivitamin (control condition) for 12 weeks. Primary outcomes included changes in biomarkers of bone formation, bone resorption, and the bone remodeling index, a composite measure of bone formation and resorption. Safety measures included clinical and biochemical adverse events. A main effect analysis was used for these endpoints.Results: Hypercalcemia was limited to three grade I cases with no grade ≥ 2 cases. Among exercisers, 100% engaged in the prescribed aerobic training and 44.4% engaged in the prescribed resistance training. Calcitriol significantly improved bone formation (Cohen's d = 0.64; p < 0.01), resulting in a non-significant increase in the bone remodeling index (Cohen's d = 0.21; p = 31). Exercise failed to improve any of the bone biomarkers.Conclusions: Both calcitriol and exercise were shown to be feasible and well tolerated. Calcitriol significantly improved bone formation, resulting in a net increase of bone metabolism. Compliance with the exercise intervention was sub-optimal, which may have led to a lack of effect of exercise on bone metabolism. [ABSTRACT FROM AUTHOR]

Purpose: We conducted a retrospective study to assess the outcomes of capecitabine for advanced breast cancer (ABC) after perioperative fluoropyrimidines (FPs).Methods: The charts of patients with ABC who received capecitabine between 2008 and 2016 at the National Cancer Center Hospital (Tokyo, Japan) were reviewed. Progression-free survival (PFS), overall survival (OS), tumor response, and adverse events (AEs) were compared between two groups: an FP group (prior perioperative FP use) and a non-FP group (no prior FP use).Results: Overall, 288 patients (FP n = 105; non-FP n = 183) were analyzed. The two groups had similar patient characteristics. The FP group had significantly poorer PFS than the non-FP group (multivariate hazard ratio [HR] 1.33; 95% confidence interval [CI] 1.02-1.73; p = 0.036), although the OS did not differ significantly between the groups (multivariate HR 1.00; 95% CI 0.67-1.50; p = 0.994). With different cut-off values (relapse-free interval [RFI] = 3, 4, and 5 years), multivariate HRs for PFS were 1.32-1.67 (short RFI), and 1.00-1.25 (long RFI). A trend for a larger HR in the FP group compared to the non-FP group with short RFI than in that with long RFI was also seen for OS. Response rate (RR) and disease control rate (DCR) did not differ significantly between the groups (RR in FP vs non-FP 13.8 vs 21.0%; p = 0.173; DCR 54.0 vs 59.9%; p = 0.418). No significant difference in AEs existed between the groups.Conclusions: Extra caution is needed when capecitabine is considered for patients with ABC who used perioperative FP, especially those who had early recurrence. [ABSTRACT FROM AUTHOR]

Purpose: To determine the maximum tolerated dose (MTD) of BEZ235, an oral inhibitor of class I PI3K and mTOR complexes 1 and 2.Methods: We performed a phase I/Ib, multicenter, open-label study of oral BEZ235 administered in a continuous daily schedule. The study consisted of two parts: dose-escalation part and safety-expansion part. BEZ235 was administered as a single agent to patients with solid tumors or in combination with trastuzumab for HER2+ advanced breast cancer (aBC). Primary end points were MTD, safety, and tolerability. The secondary end point was pharmacokinetics. Other formulations of BEZ235, solid dispersion system (SDS) sachet, and SDS capsules were also assessed.Results: One hundred and eighty-three patients were enrolled; single-agent BEZ235 was administered as hard gelatin capsule (n = 59), SDS capsules A and B (n = 33), and SDS sachet (n = 61), amongst which SDS sachet was chosen as the preferred formulation. The monotherapy MTD for capsule A and SDS sachet was determined to be 1000 and 1200 mg/day, respectively. Thirty patients with HER2+ aBC received BEZ235 in combination with trastuzumab. The MTD of BEZ235 in combination with trastuzumab was 600 mg/day. A total of four patients (13.3%) achieved partial response across the different groups. Most frequent AEs in single agent and combination cohorts included nausea (80.3 and 93.3%), diarrhea (75.4 and 80.0%), and vomiting (63.9 and 63.3%).Conclusions: The MTD of BEZ235 as single agent was 1200 and 600 mg/day with trastuzumab. Pharmacokinetic profiles showed low-to-moderate variability at low dose (10 mg) and high variability at high doses (100 mg and above). Gastrointestinal AEs were frequent at high doses. [ABSTRACT FROM AUTHOR]

Purpose: Despite its widespread use as primary febrile neutropenia (FN) prophylaxis during chemotherapy for early-stage breast cancer, the optimal duration of daily filgrastim is unknown. Using the minimum effective duration may improve patient comfort and acceptability while reducing costs. Yet, suboptimal dosing may also negatively impact patient care. A survey was performed to obtain information regarding current practices for granulocyte colony-stimulating factor (G-CSF) use.Methods: Canadian oncologists involved in the treatment of breast cancer patients, as well as patients who had received neo/adjuvant chemotherapy for breast cancer, were surveyed. Standardized surveys were designed to collect information on perceived reasons for G-CSF use and current practices.Results: The surveys were completed by 38/50 (76%) physicians and 95/97 (98%) patients. For physicians, there was variability in the choice of chemotherapy regimens that required G-CSF support, the dose of filgrastim prescribed and the number of days prescribed. The majority of physicians reported using 5 (31.6%), 7 (47.4%), or 10 (13.2%) days of therapy. Nearly half of the patients (46.3%) recalled having experienced at least one of the chemotherapy-related complications including chemotherapy delays, dose reductions, and FN. While on filgrastim, 66.3% of patients reported myalgia and bone pain. Both physicians and patients expressed interest in participating in clinical trials designed to optimize the duration of filgrastim administration.Conclusions: Significant variability in practice exists with respect to filgrastim administration. Definitive studies are therefore required to standardize and improve care, as this has the potential to impact treatment outcomes, patient quality of life, and cost savings. [ABSTRACT FROM AUTHOR]

The composition of vaginal microbiome in menopause and cancer survivor women changes dramatically leading to genitourinary syndrome of menopause (GSM) in up to 70% of patients. Recent reports suggest that laser therapy may be valuable as a not hormonal therapeutic modality. The aim of the present study was to evaluate the effects of fractional CO2 laser treatment on the vaginal secretory pathway of a large panel of immune mediators, usually implicated in tissue remodeling and inflammation, and on microbiome composition in postmenopausal breast cancer survivors. The Ion Torrent PGM platform and the Luminex Bio-Plex platform were used for microbiome and immune factor analysis. The significant reduction of clinical symptoms and the non-significant changes in vaginal microbiome support the efficacy and safety of laser treatment. Moreover, the high remodeling status in vaginal epithelium is demonstrated by the significant changes in inflammatory and modulatory cytokine patterns. Laser therapy can be used for the treatment of GSM symptoms and does not show any adverse effects. However, further studies will be needed to clarify its long-term efficacy and other effects. [ABSTRACT FROM AUTHOR]

Background: The mammalian target of rapamycin (mTOR) inhibitor everolimus is used in the treatment of breast cancer, neuroendocrine tumors, and renal cancer. The approved 10 mg once-daily dose is associated with considerable adverse effects and it has been suggested that these are associated with the maximum concentration (C max) of everolimus. Twice-daily dosing might be an alternative strategy with improved tolerability; however, a direct pharmacokinetic comparison of 10 mg once-daily with 5 mg twice-daily dosing is lacking.Methods: We performed a prospective, randomized, pharmacokinetic, crossover trial comparing everolimus 10 mg once daily with 5 mg twice daily. Patients received the first dose schedule for 2 weeks and then switched to the alternative regimen for 2 weeks. Pharmacokinetic sampling was performed on days 14 and 28.Results: Eleven patients were included in the study, of whom 10 were evaluable for pharmacokinetic analysis. On the 10 mg once-daily schedule, C max, minimum concentration (C min), and area under the concentration-time curve from time zero to 24 h (AUC24) were 61.5 ng/mL [mean percentage coefficient of variation (CV%) 29.6], 9.6 ng/mL (CV% 35.0), and 435 ng h/mL (CV% 28.1), respectively. Switching to the 5 mg twice-daily schedule resulted in a reduction of C max to 40.3 ng/mL (CV% 46.6) (p = 0.013), while maintaining AUC24 at 436 ng h/mL (CV% 34.8) (p = 0.952). C min increased to 13.7 ng/mL (CV% 53.9) (p = 0.018). The overall reduction in C max was 21.2 ng/mL, or 32.7%. The C max/C min ratio was reduced from 6.44 (CV% 36.2) to 3.18 (CV% 35.5) (p < 0.001).Conclusions: We demonstrated that switching from a once-daily to a twice-daily everolimus dose schedule reduces C max without negatively impacting C min or AUC24. These results merit further investigation of the twice-daily schedule in an effort to reduce everolimus toxicity while maintaining treatment efficacy.Registration: This trial was registered in the EurdaCT database (2014-004833-25) and the Netherlands Trial Registry (NTR4908). [ABSTRACT FROM AUTHOR]

Purpose: Although eribulin is a suitable option for early-line treatment of metastatic breast cancer (MBC), data on first- or second-line use of eribulin for human epidermal growth factor receptor 2 (HER2)-negative MBC are still limited. Therefore, we conducted a phase II trial to investigate the efficacy and safety of eribulin for first- or second-line chemotherapy for HER2-negative MBC.Materials and Methods: We performed a phase II, open-label, single-arm, multicenter study in Japan. Eligible patients were women with histologically confirmed HER2-negative MBC without chemotherapy or only one chemotherapy line for MBC. The primary endpoint was the overall response rate (ORR) and the secondary endpoints included the clinical benefit rate (ORR + stable disease for 6 months; CBR), progression-free survival (PFS), overall survival (OS), duration of response (DOR), safety, and health-related quality of life (HRQoL).Results: A total of 35 patients with HER2-negative MBC were enrolled between March 2013 and February 2017 (data cut-off July 31, 2017). The ORR was 37.1% (95% CI 21.1-53.2%). The CBR was 54.3% (95% CI 37.8-70.8%). The median PFS was 6.2 months (95% CI 2.7-9.4 months) and median OS was 21.4 months (95% CI 11.5-32.9 months). Common grade 3/4 adverse events were neutropenia (42.9%) but febrile neutropenia (2.9%). Although the majority of non-hematological adverse events were mild in severity, one patient died of pneumonitis. In HRQoL analysis, eribulin appeared to maintain HRQoL of many patients.Conclusions: Eribulin as first- or second-line chemotherapy is effective and has manageable toxicity for patients with HER2-negative MBC. [ABSTRACT FROM AUTHOR]

Purpose: Etirinotecan pegol (EP), a long-acting topoisomerase-1 inhibitor, is a polyethylene glycol conjugate of irinotecan, with an intended indication for treatment of breast cancer with brain metastases. The objective of this study was to develop a population pharmacokinetic (popPK) model of EP and four of its metabolites (irinotecan, SN38, SN38-glucuronide, and APC) and determine covariates affecting their pharmacokinetics.Methods: Data from 83 cancer patients enrolled in phase 1 studies were used. The model was developed in two stages: (1) concentration-time data were analyzed with a 3-analyte model for EP, irinotecan, and SN38; and (2) a 5-analyte model developed based on expansion of 3-analyte model to include concentration-time data for SN38 glucuronide and APC with parameter values from 3-analyte model fixed. Covariate relationships with parameters were selected based on Wald's test within the Wald's Approximation Method approach, first for the 3-analyte model then the 5-analyte model.Results: The final integrated popPK model for the five analytes was a two-compartment per analyte model that followed the metabolic cascade of EP to irinotecan, followed by metabolism of irinotecan to the previously known metabolites, but with altered exposures as compared to administration of irinotecan. With the model developed based on total dose of EP, the population estimates of EP clearance and central volume were 0.237 L/h and 5.5 L, respectively. Patient age, body surface area (BSA), and estimated glomerular filtration rate were found to correlate with EP clearance and BSA with EP central volume. Individuals who were homozygous for UGT1A1*28 genotype had modestly reduced elimination capacity of SN38 compared to heterozygous and wild-type genotypes. Simulations evaluating the clinical importance of significant covariates indicated minimal change in areas under the curve and peak concentrations of EP and SN38.Conclusions: The pharmacokinetics of EP and four metabolites including the active metabolite SN38 were described by an integrated popPK model. Other than BSA, which was already accounted by a BSA-based dosing scheme, no other covariates were deemed to have clinical implications. No EP starting dose adjustment based on patient demographics and other covariates was deemed necessary. [ABSTRACT FROM AUTHOR]

Background: Dehydroepiandrosterone (DHEA) is helpful for treating vaginal symptoms. This secondary analysis evaluated the impact of vaginal DHEA on hormone concentrations, bone turnover, and vaginal cytology in women with a cancer history.Methods: Postmenopausal women, diagnosed with breast or gynecologic cancer, were eligible if they reported at least moderate vaginal symptoms. Participants could be on tamoxifen or aromatase inhibitors (AIs). Women were randomized to 3.25 versus 6.5 mg/day of DHEA versus a plain moisturizer (PM) control. Sex steroid hormone levels, biomarkers of bone formation, vaginal pH, and maturation index were collected at baseline and 12 weeks. Analysis included independent t tests and Wilcoxon rank tests, comparing each DHEA arm with the control.Results: Three hundred forty-five women contributed evaluable blood and 46 contributed evaluable cytology and pH values. Circulating DHEA-S and testosterone levels were significantly increased in those on vaginal DHEA in a dose-dependent manner compared to PM. Estradiol was significantly increased in those on 6.5 mg/day DHEA but not in those on 3.25 mg/day DHEA (p < 0.05 and p = 0.05, respectively), and not in those on AIs. Biomarkers of bone formation were unchanged in all arms. Maturation of vaginal cells was 100% (3.25 mg/day), 86% (6.5 mg/day), and 64% (PM); pH decreased more in DHEA arms.Conclusion: DHEA resulted in increased hormone concentrations, though still in the lowest half or quartile of the postmenopausal range, and provided more favorable effects on vaginal cytology, compared to PM. Estrogen concentrations in women on AIs were not changed. Further research on the benefit of vaginal DHEA is warranted in hormone-dependent cancers. [ABSTRACT FROM AUTHOR]

Breast cancer is the major cause of death by cancer in women worldwide and in spite of the many drugs for its treatment, there is still the need for novel therapies for its control. Ocimum species have been used by traditional medicine to control several diseases, including cancer. We have previously characterized the antidiabetic properties of the unfractionated aqueous leaf extracts of Ocimum basilicum (OB) and Ocimum gratissimum (OG), modulating glucose metabolism in diabetic mice. Since glucose metabolism is primordial for cancer cells survival, we hypothesized that these extracts are effective against cancer cells. The unfractionated aqueous leaf extracts of OB and OG were chemically characterized and tested for their cytotoxic, cytostatic and anti-proliferative properties against the human breast cancer cell line MCF-7. Both extracts presented cytostatic effects with an 80% decrease in MCF-7 cell growth at 1 mg/mL. However, only OB promoted cytotoxic effects, interfering with the cell viability even after interruption of the treatment. Moreover, OB but not OG affected the cell proliferation and metabolism, evaluated in terms of lactate production and intracellular ATP content. After 24 h of treatment, OB treated cells presented an apoptotic profile, while OG treated cells were more necrotic. The treatment with both extracts also activated AMPK, but OB was much more efficient than OG in promoting this. The activation of mTOR signaling, another survival pathway was promoted by OB, whereas OG failed to activate it. In the end, we conclude that OB extract is efficient against the human breast cancer cell line. [ABSTRACT FROM AUTHOR]

Background: Everolimus is the hydroxyethyl derivative of sirolimus and a strong inhibitor of mammalian target of rapamycin (mTOR). This drug has immunosuppressive and anticancer activities and the present in vitro study was aimed at identifying the cellular and molecular profiles of breast cancer cells predictive of sensitivity to everolimus.Materials and Methods: MCF-7, T-47D, ZR-75-1, CAMA-1, HCC-1500 and MCF-10A cells were used and viability was assessed using WST-1 dye. Sensitivity to everolimus was correlated with phosphorylation of AKT (Ser473/Thr308), mTOR (Ser2448), and ERK1/2 (Thr202/Tyr204) and mutational profile of KRAS, NRAS, BRAF, PIK3CA, PTEN, TSC1, TSC2 and FRAP genes. Protein phosphorylation was evaluated by AlphaScreen SureFire, while the mutational status was examined by digital droplet PCR and Sanger sequencing.Results: Everolimus showed a transient growth inhibition in non-tumorigenic cells, while in tumorigenic lines the drug suppressed the proliferation in a concentration-dependent manner but with different potency (IC50) and efficacy (Emax), being ZR-75-1 the most sensitive and T47D the least sensitive. MCF-7, T47D and HCC1500 had activating mutations in PIK3CA gene, while loss-of-activity PTEN mutations were detected in sensitive cell lines, including ZR-75-1, which showed no changes or minimal increase in the amount of p-AKT(Ser473/Thr308) and p-ERK1/2(Thr202/Tyr204) induced by everolimus compared to the resistant cell line T47D in which phosphorylation of AKT and ERK was increased.Conclusions: Cellular levels of p-AKT(Ser473/Thr308) and p-ERK1/2(Thr202/Tyr204), activating mutations of PIK3CA and inactivating mutations of PTEN may predict response to everolimus in breast cancer cells; these findings have potential applications for treatment personalization of everolimus in breast cancer patients. [ABSTRACT FROM AUTHOR]

Purpose: Neoadjuvant chemotherapy is commonly used to treat patients with locally advanced breast cancer and a common option for primary operable disease. However, systemic toxicity including cardiotoxicity and inefficient delivery are significant challenges form any chemotherapeutics. The development of targeted treatments that lower the risk of toxicity has, therefore, become an active area of research in the field of novel cancer therapeutics. Mesoporous silica nanoparticles (MSNs) have attracted significant attention as efficient drug delivery carriers, due to their high surface area and tailorable mesoporous structures. Eph receptors are the largest receptor tyrosine kinase family, which are divided into the A- and the B-type. Eph receptors play critical roles in embryonic development and human diseases including cancer. EphA2 is expressed in breast cancer cells and has roles in carcinogenesis, progression and prognosis of breast cancer.Methods: A homing peptide with the sequence YSAYPDSVPMMSK (YSA) that binds specifically to EphA2 was used to functionalize MSN. We focus on a novel EphA2-targeted delivery MSN system for breast cancer cells.Results: We show that the EphA2 receptor is differentially expressed in breast cancer cells and highly expressed in the HER2-negative breast cancer cell line MCF7. Our results suggest that EphA2-targeted MSN for doxorubicin delivery (MSN-YSA-DOX) are more effective than MSN-DOX in treating breast cancer cell lines in vitro.Conclusions: Our preliminary observations suggest that the EphA2-targeted MSN delivery system may provide a strategy for enhancing delivery of therapeutic agents to breast cancer cells expressing EphA2, and potentially reduce toxicity while enhancing therapeutic efficacy. [ABSTRACT FROM AUTHOR]

Immunotherapy has been suggested as a compelling alternative approach for conventional breast cancer treatment methods. Despite the paramount rolesof T cells in this approach, insufficient numbers of them in the combat against progressive tumor growth still remain to be dealt with. Super antigens are a class of antigens, capable of eliciting T cell proliferation response against desired antigens. Staphylococcal enterotoxin B (SEB) is categorized as a super antigen, its anti-tumor properties has been previously reported. However, to the best our knowledge, SEB has not been ever administered as a DNA construct. In the present study, we exploited bioinformatics tools to assess the immunoreactivity of a SEB-coding DNA construct that serves as a DNA vaccine for breast cancer therapy. Potential B and T (MHC class I and II binders) cell epitopes of the hypothetically expressed protein, along with its sub cellular localization were predicted. Moreover, probable glycosylation and phosphorylation sites within the protein sequence were determined. The gene sequence was optimized according to murine model codon bias and its mRNA stability was analyzed. Employing an integrative in silico approach, we revealed that apparently the construct could be efficiently expressed in mouse model. Moreover, the hypothetically expressed protein could act as an amenable adjuvant in cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Purpose: Breast cancer is the leading cause of death from cancer in women and the most common cancer in the world [1]. To date, many patients with estrogen-receptor-positive (ER+) breast cancer are overtreated with chemotherapy when the rationale for adjuvant chemotherapy is based on clinicopathologic parameters. Different studies were able to demonstrate that a 21-gene expression assay (Oncotype DX® Genomic Health, Redwood City, CA) can predict the benefit from adjuvant chemotherapy in ER+ breast cancers [2, 3] and provide additional prognostic information independent of clinicopathological features [4].Results: Data from all patients with ER+ Her2neu- breast cancer undergoing Oncotype DX® testing between 2011 and 2014 at a tertiary referral center in Germany were analyzed. Oncotype DX® was performed in 69 cases, in 2 cases data were missing and in 3 cases Oncotype DX® could not be performed by the company. The results showed a low risk in 39 cases, an intermediate risk in 22 cases and a high risk in 3 cases. Based on Oncotype results, treatment recommendations were changed in 39 of 64 patients (61%). Before Oncotype DX® testing, chemotherapy was recommended in 67 patients, afterwards only in 25 patients. Data from 44 of 67 patients were matched to controls for stage, tumor grade, menopausal and hormone receptor status. Within a mean observation time of 19.7 months, cancer recurrence was observed in two patients.Conclusions: Oncotype DX® testing can be recommended for risk-tailored chemotherapy. Results should be validated in larger prospective studies. [ABSTRACT FROM AUTHOR]

Background: Our goal was to compare the survival advantage of tamoxifen (TAM) and aromatase inhibitor (AI) in female (FBC) and male breast cancer (MBC).Patients and methods: We performed a retrospective study of 2785 FBC and 257 MBC patients treated with hormonal therapy.Results: The median follow-up was 106 months (range 3–151 months) and 42 months (range 2–115 months) for FBC and MBC, respectively. The patients were divided into two groups according to the hormonal therapy used: TAM-treated and AI-treated. MBC was characterized by older age, advanced tumor stage, and higher rate of lymph node metastases, in comparison with FBC. Matching analysis was performed using six prognostic criteria: patient age, tumor stage, tumor grade, lymph node status, human epidermal growth factor receptor (HER2) status, and administration of chemotherapy. The female and male patients were matched 2:1. In this analysis, 316 women and 158 men treated with TAM, and 60 women and 30 men treated with AI, were included. The overall survival (OS) was estimated by the Kaplan–Meier method and was compared between FBC and MBC. TAM-treated FBC and MBC patients had similar 5-year OS, 85.1 and 89.2%, respectively (p = 0.972). Notably, FBC patients treated with AI had significantly greater 5-year OS (85.0%) in comparison with AI-treated MBC patients (5-year OS of 73.3%; p = 0.028).Conclusions: The OS of TAM-treated patients with MBC was similar to the OS of TAM-treated FBC patients, whereas AI treatment is associated with poorer survival of MBC patients. [ABSTRACT FROM AUTHOR]

Biosimilars are biological medicines that have been shown to be similar to a reference biological medicine that has already been approved for use. Development of biosimilars is based on a "totality of evidence" approach that involves a series of steps by which biosimilars must demonstrate similarity to a reference product in all aspects of the drug and eliminate any remaining uncertainties. Clinical studies are then considered confirmatory and are performed to show that there are no clinically meaningful differences compared with the reference product in a sensitive patient population. The recombinant human granulocyte colony-stimulating factor (G-CSF) biosimilar EP2006/Zarxio® (filgrastim-sdnz) became the first FDA-approved biosimilar in 2015. This review evaluates how clinical equivalence can be demonstrated with G-CSF biosimilars through the identification of "sensitive" study populations and endpoints. Patients with non-metastatic breast cancer treated in the (neo)adjuvant setting represent a potentially homogenous population, making this a suitable sensitive indication for assessing filgrastim and pegfilgrastim biosimilars compared with reference products. This review includes clinical trials of G-CSF biosimilars in breast cancer, focusing on key aspects of the trials that were necessary to accurately demonstrate clinical equivalence and enable extrapolation to relevant indications, based on guidelines and biostatistical principles. [ABSTRACT FROM AUTHOR]

Breast cancer 1 (BRCA1), as a tumor suppressor, exerts an effective influence on protecting DNA integrity to suppress the development of breast cancer (BC). BRCA1 expression is induced in response to DNA-damaging agents such as etoposide. Germline BRCA1 gene mutations are associated with development of hereditary BC. However, besides BRCA-mutated BCs, some sporadic cancers may also exhibit a BRCA-like phenotype, displaying so-called 'BRCAness'. This common phenotype may respond to similar therapeutic approaches as BRCA-mutated tumors and may thus have important implications for the clinical management of these cancers. In order to determine whether and how etoposide regulates the protein levels of BRCA1 in BC cells, we exposed a panel of five selected cell lines to etoposide, compared the results to untreated control cells, and then stained the cells with the specific, reliable, and reproducible MS110 antibody directed against phosphorylated Ser1423 BRCA1. By evaluating cytoplasmic BRCA1 protein levels, we were able to distinguish three aggressive BC subtypes with BRCAness characteristics. In addition, determination of early and late apoptosis helped to complete the analysis of BRCA1 functions in the DNA damage pathway of aggressive BC. In conclusion, our study suggested that high cytoplasmic BRCA1 protein levels could be considered as a potential predictive marker for response to chemotherapy in both sporadic and hereditary BC. Tumors with either BRCAness phenotype or germline BRCA1 mutation are both aggressive BCs associated with poor prognosis and could both be subjected to targeted therapies against BRCA1-mutated BC in future clinical management strategies. [ABSTRACT FROM AUTHOR]

Breast cancer is a hormone-dependent malignancy and is the most prevalent cause of cancer-related mortality among females. Radiation therapy and chemotherapy are common treatments of breast cancer. However, tumor relapse and metastasis following therapy are major clinical challenges. The importance of B-lymphoma Moloney murine leukemia virus insertion region-1 (BMI-1) was implicated in cell proliferation, stem cell maintenance, and tumor initiation. We established radio- and temozolomide (TMZ)-resistant (IRC-R) MCF-7 and MDA-MB-231 cell lines to investigate the mechanism involved in therapeutic resistance. Cell proliferation and sphere number were dramatically elevated, and BMI-1 was remarkably upregulated, in IRC-R cells compared to parental cells. Silencing BMI-1 by RNA interference only affected the cell proliferation of IRC-R but not parental cells, suggesting the critical role of BMI-1 in radio- and TMZ resistance. We used a xenograft mice model to elucidate that BMI-1 was necessary in tumor development by assessing tumor volume and Ki67 expression. We found that Hedgehog (Hhg) signaling exerted synergized functions together with BMI-1, implicating the importance of BMI-1 in Hhg signaling. Downregulation of BMI-1 could be an effective strategy to suppress tumor growth, which supports the potential clinical use of targeting BMI-1 in breast cancer treatment. [ABSTRACT FROM AUTHOR]

Purpose: Letrozole as a steroidal anticancer drug with hydrophobic nature is usually administrated by oral route for patient treatment and the injectable formulation for this drug has not still been reported. In this study, a new letrozole incorporated folate-conjugated polymer - lipid hybrid nanoparticles - is introduced for cancer treatment. Methods: Nanoparticles were fabricated via modified oil in water ionic gelation method using optimization parameters and then were coupled to folic acid using carbodiimide activation. The physicochemical characterization in vitro drug release, cytotoxicity, and then ex vivo study of obtained carrier was investigated. Results: Both thermal and crystallography studies proved the amorphous loading of drug in the nanocarrier. The cytotoxicity investigation with an average IC value of 79 ± 2.40 nM proved the efficiency of the coupled folic acid carrier for the intracellular uptake of letrozole on the breast cancer line. Ex vivo , the study proved the positive effect of the letrozole entrapment on the drug bioavailability. Conclusions: The obtained targeted nanocarrier could overcome the limitations associated with the LTZ as a potent non-steroidal drug. Both the entrapment and therapeutic efficiency of letrozole in the amphiphilic carrier were increased using the lipid nanoparticles and the surface modification, respectively. [ABSTRACT FROM AUTHOR]

Purpose: In the phase III EMILIA study, trastuzumab emtansine (T-DM1) significantly improved progression-free survival (PFS) and overall survival (OS) versus capecitabine plus lapatinib (control) in previously treated human epidermal growth factor receptor 2-positive advanced breast cancer. Using EMILIA data, we evaluated the T-DM1 exposure-response relationship.Methods: Exposure-response relationships were examined with four exposure metrics [model-predicted and observed minimum concentration (C min) and area under the concentration-time curve from time zero to day 21 of T-DM1 at cycle 1] and multiple efficacy (OS, PFS, objective response rate) and safety (grade ≥ 3 adverse events, grade ≥ 3 thrombocytopenia, grade ≥ 3 hepatotoxicity) endpoints.Results: An apparent exposure-response trend was observed between model-predicted exposure metrics and efficacy; trends for observed exposure metrics were shallower and often not significant. Although median OS and PFS were numerically longer in patients with higher versus lower model-predicted cycle 1 C min, OS and PFS hazard ratios for T-DM1-treated patients in the lowest exposure quartile (Q1) versus control were < 1 after adjusting for baseline risk factors (e.g., ECOG status, tumor burden, measurable disease, and number of disease sites). No meaningful exposure-response relationship was observed for any safety endpoints.Conclusion: Exposure-response relationships for efficacy were inconsistent across exposure metrics; model-predicted cycle 1 C min showed the strongest exposure-response trend. The Q1 subgroup based on model-predicted cycle 1 C min had numerically similar or better OS and PFS versus control following covariate adjustment. The approved T-DM1 dose (3.6 mg/kg every 3 weeks) has a positive benefit-risk ratio versus control, even for the T-DM1 Q1 subgroup. [ABSTRACT FROM AUTHOR]

Over two-thirds of women with breast cancer have positive tumors for hormone receptors, and these patients undergo treatment with endocrine therapy, tamoxifen being the most widely used agent. Despite being very effective in breast cancer treatment, tamoxifen is associated with side effects that include cognitive impairments. However, the specific aspects and mechanisms underlying these impairments remain to be characterized. Here, we have investigated the effects of tamoxifen and interaction with estrogen receptors on formation of memory for inhibitory avoidance conditioning in female rats. In the first experiment, Wistar female rats received a single oral dose of tamoxifen (1, 3, or 10 mg/kg) or saline by gavage immediately after training and were tested for memory consolidation 24 h after training. In the second experiment, rats received a single dose of 1 mg/kg tamoxifen or saline by gavage 3 h after training and were tested 24 h after training for memory consolidation. In the third experiment, rats received a subcutaneous injection with estrogen receptor α agonist or estrogen receptor beta agonist 30 min before the training. After training, rats received a single oral dose of tamoxifen 1 mg/kg or saline and were tested 24 h after training. In the fourth experiment, rats were trained and tested 24 h later. Immediately after test, rats received a single dose of tamoxifen (1 mg/kg) or saline by gavage and were given four additional daily test trials followed by a re-instatement. Tamoxifen at 1 mg/kg impaired memory consolidation when given immediately after training and the estrogen receptor alpha agonist improved the tamoxifen-related memory impairment. Moreover, tamoxifen impairs memory consolidation of the test. These findings indicate that estrogen receptors regulate the early phase of memory consolidation and the effects of tamoxifen on memory consolidation. [ABSTRACT FROM AUTHOR]

Purpose: Hepatic arterial infusion chemotherapy (HAIC) is an option for patients with liver-predominant metastatic breast cancer (LMBC), when no further systemic treatment is available. But systematic reports are limited. Here we conducted a retrospective analysis of LMBC patients treated at an expert center. Methods: Individual patient data were retrieved from the clinical data base of the West German Cancer Center. Primary endpoints included hepatic response (RECIST), progression-free survival (PFS), overall survival (OS), and toxicity. A score based on LDH, AST, ALT and bilirubine was developed to estimate the hepatic metastasis load. Results: Data from 70 consecutive patients were included. All patients were heavily pretreated (median 7 treatment lines for LMBC). HAIC protocols included mitomycin/5-FU (70%), mitomycin (14.3%), melphalan (12.9%) and 5-FU (7.1%), with selection based on patient characteristics. Partial hepatic remission was obtained as best response in 14 patients (20.0%), stable disease in 27 patients (38.6%), and progressive disease in 29 patients (41.4%). Median PFS and OS from initiation of HAIC were 2 (range 0-10) and 7 months (range 1-37). Mainly hepatic and hematopoietic HAIC-related toxicities were observed; there was no treatment-related death. The hepatic metastasis score effectively separated two prognostic groups: Patients with a score <3 had significantly superior PFS (15 vs 7 weeks, p = 0.017) and OS (12 vs 5 months, p = 0.002). Conclusion: HAIC offers a safe and effective salvage treatment strategy in heavily pretreated patients with LMBC and no further treatment options. The hepatic metastasis score may help to identify patients with sustained clinical benefit. [ABSTRACT FROM AUTHOR]

Purpose: The approval of injectable generic drugs does not require bioequivalence testing. However, although generic products contain the same level of the active compound, the levels and types of additives present can differ from those used in the original product. Since docetaxel is highly lipophilic, polysorbate 80 (PS80), polyethylene glycol (PEG), and ethyl alcohol are employed to solubilize this anticancer agent. This retrospective study compared the safety of five docetaxel products (Taxotere, Docetaxel Hospira, Docetaxel Sandoz, Docetaxel Sawai, and Docetaxel EE). Methods: The incidence and severity of adverse events were analyzed using the medical records of operable breast cancer patients ( n = 363) treated with docetaxel (75 mg/m) in Showa University Hospital, Japan, from Jan 2013 to Mar 2016. Toxicities were graded using the Common Terminology Criteria for Adverse Events, version 4.0. Results: Significant product-related differences were observed in the following non-hematological adverse events: injection site reaction ( P = 0.0012), hand-foot syndrome (≥grade 3) ( P = 0.0003), and oral mucositis (≥grade 3) ( P = 0.0080). Multivariate logistic regression analyses of the associations between these adverse events and the total additive administered (g/m) identified significant negative effects of PS80 and ethyl alcohol. Conclusions: Injectable docetaxel products had different adverse event profiles, which showed negative associations with the amounts of PS80 and ethyl alcohol present. This finding indicated that there might be additive-related pharmacokinetic and physiochemical differences among these products, suggesting a need for further pre- or post-approval testing of injectable generic products containing noticeable different levels of additives. [ABSTRACT FROM AUTHOR]

Purpose: Breast cancer is the most common invasive type of cancer among women. Role of different microRNAs (miRNAs) and poly(ADP-ribose) polymerases (PARPs) in breast cancer has been well established. This study aimed to explore the effects of miR-891b on sensitizing breast cancer cells to alkylating chemotherapeutic drugs through PARPs.Methods: The expression of miR-891b and PARP1 in human breast cancer cells HCC1806 was overexpressed by transfection with their mimics or expressing vector. Then, the transfected cells were exposed to 40 µM N-methyl-N-nitro-N-nitrosoguanidine (MNNG) for 1 h. The correlation between miR-891b and PARP1 was detected by RT-qPCR, western blot, and dual-luciferase reporter assay. Besides, MTT assay and Annexin V assay were done to measure cell proliferation and apoptosis, respectively.Results: PARP1 was a target of miR-891b, and it was negatively regulated by miR-891b. MiR-891b increased the sensitivity of the HCC1806 cells to the cytotoxic effects of MNNG through suppressing cell proliferation and increasing the percentage of apoptotic cells. Restoration of PARP1 activity in the HCC1806 cells led to loss of miR-891b mediated sensitivity of the HCC1806 cells to MNNG.Conclusion: MiR-891b increases the sensitivity of the breast cancer cells (HCC1806) to the cytotoxic effects of the chemotherapeutic agent MNNG by suppressing the expression of PARP1. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to evaluate the pharmacokinetics (PK) of trastuzumab emtansine (T-DM1) and relevant analytes in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer and hepatic impairment.Methods: Patients were enrolled in three independent parallel cohorts based on hepatic function per Child-Pugh criteria: normal hepatic function, mild hepatic impairment, and moderate hepatic impairment. Patients received T-DM1 3.6 mg/kg intravenously every 3 weeks. PK samples were collected during cycles 1 and 3, and the PK of T-DM1 and relevant analytes were characterized and compared across cohorts.Results: Compared with patients with normal hepatic function (n = 10), T-DM1 clearance at cycle 1 was 1.8- and 4.0-fold faster in the mild (n = 10) and moderate (n = 8) cohorts, respectively. The trend of faster clearance was less apparent in cycle 3, with similar T-DM1 clearance across cohorts (mean ± standard deviation 8.16 ± 3.27 [n = 9], 9.74 ± 3.62 [n = 7], and 8.99 and 10.2 [individual values, n = 2] mL/day/kg for the normal, mild, and moderate cohorts, respectively). T-DM1 clearance at cycle 1 correlated significantly with baseline albumin, aspartate aminotransferase, and HER2 extracellular domain concentrations (p < 0.05). Plasma concentrations of DM1 and DM1-containing catabolites were low and were comparable across cohorts.Conclusions: No increase in systemic DM1 concentration was observed in patients with mild or moderate hepatic impairment versus those with normal hepatic function. The faster T-DM1 clearance observed at cycle 1 in patients with hepatic impairment appeared to be transient. After repeated dosing (three cycles), T-DM1 exposure in patients with mild and moderate hepatic impairment was within the range seen in those with normal hepatic function. [ABSTRACT FROM AUTHOR]

The toxicity of Salvia officinalis L. on different cancer cell lines has been reported extensively, but an in vivo evaluation on breast cancer has not been conducted. Therefore, in vivo and in vitro studies of are evaluated in this study. The hydro-alcoholic extract of Salvia officinalis L. was studied in female Wistar rats in three groups: one control (Con) group ( n = 7) and two 7, 12-dimethylbenz[a]anthracene cancer-induced groups (CI) that were gavaged either with distilled water (Con-CI) or 30 mg/kg sage hydro-alcoholic extract (SHE-CI) for 30 days ( n = 34). A mammary gland whole mount was prepared, and the number of alveolar buds and lobules were scored. Histomorphometrical changes and apoptosis were examined in mammary gland sections. Chromatin condensation, cell viability, apoptosis, and toxicity induction were monitored in 4T1 mouse mammary carcinoma cells treated by different doses of SHE. IC of the 4T1 cell-treated SHE were examined by MTT assay. A decrease in alveolar buds, number of ducts and lobules, ductal diameters, and epithelial cells was observed in whole mount and histological sections of mammary glands in SHE-CI compared to the Con-CI group. Apoptotic cells were increased in SHE-CI compared to the Con-CI group. A decrease in cell viability and increase in chromatin condensation were observed in a dose-dependent manner in SHE-treated cultures. MTT assay revealed IC of the 4T1 cell-treated SHE reduced significantly compared to the NIH cell line from the fibroblast as a normal cell. Salvia officinalis might prevent breast cancer under both in vivo and in vitro conditions. [ABSTRACT FROM AUTHOR]

Introduction: Prognosis of Her2-positive breast cancer has changed since the introduction of trastuzumab for treatment in metastatic and early breast cancer. It was described to be even better compared to prognosis of Her2-negative metastatic breast cancer. The purpose of this study was to evaluate the effect of trastuzumab in our cohort. Besides the effect of adjuvant pretreatment with trastuzumab on survival of patients with metastatic Her2-positive breast cancer was analyzed.Methods: All patients with primary breast cancer of the Regional Breast Cancer Center Dresden diagnosed during the years 2001-2013 were analyzed for treatment with or without trastuzumab in the adjuvant and in the metastatic treatment setting using Kaplan-Meier survival estimation and Cox regression. Age and tumor stage at time of first diagnosis of breast cancer as well as hormone receptor status, grading, time, and site of metastasis at first diagnosis of distant metastatic disease were analyzed.Results: Of 4.481 female patients with primary breast cancer, 643 presented with metastatic disease. Her2-positive status was documented in 465 patients, including 116 patients with primary or secondary metastases. Median survival of patients with Her2-positive primary metastatic disease was 3.0 years (95% CI 2.3-4.0). After adjustment for other factors, survival was better in patients with Her2-positive breast cancer with trastuzumab therapy compared to Her2-negative metastatic disease (HR 2.10; 95% CI 1.58-2.79). Analysis of influence of adjuvant therapy with and without trastuzumab by Kaplan-Meier showed a trend for better survival in not pretreated patients. Median survival was highest in hormone receptor-positive Her2-positive (triple-positive) primary metastatic breast cancer patients with 3.3 years (95% CI 2.3-4.6).Conclusion: Prognosis of patients with Her2-positive metastatic breast cancer after trastuzumab treatment is more favorable than for Her2-negative breast cancer. The role of adjuvant chemotherapy with or without trastuzumab warrants further research. Survival is best in triple-positive metastatic breast cancer. This will effect counseling at the time of first diagnosis of metastatic breast cancer. [ABSTRACT FROM AUTHOR]

Purpose: The hydrazide backbone is a well-known structural core system found in a broad range of biologically activated compounds. Among which, the compounds with anticancer activity have been cited in a number of studies. With this object in mind, we focused on the in vitro and in vivo anticancer potential of two novel hydrazide derivatives bearing furan or thiophen substituents (compounds 1 and 2).Methods: The cytotoxic property was evaluated using MTT assay against MCF-7 human breast adenocarcinoma cell line, while the in vivo antitumor activity was investigated in BALB/c mice bearing 4T1 mammary carcinoma cells. Flow cytometry was used for cell cycle analysis, and detection of apoptosis was examined by Annexin-V-FLUOS/PI assay. Protein expression of Bax, Bcl-2 and procaspase-3 was estimated by Western blotting.Results: Compounds 1 and 2 were found to be cytotoxic towards breast cancer cells presenting IC50 values of 0.7 and 0.18 µM, respectively, and selectivity over normal fibroblast cells. Our findings further indicated that 2 × IC50 concentrations of both compounds induce early stage apoptosis and increase percentage of sub-G1 population in MCF-7 cells at 48 h. An elevation in Bax/Bcl-2 ratio and caspase-3 cleavage suggested that apoptosis induced by the two compounds is through a caspase- and mitochondrial-dependent pathway. In the in vivo study, compounds 1 and 2 at doses of 10 and 1 mg/Kg/day, respectively, significantly hindered the growth of tumor after 3 weeks of i.p. administration, when compared to vehicle-treated mice.Conclusion: Collectively, the great potential exhibited by compound 2 could make it a promising chemotherapeutic candidate for human cancers, especially for breast cancer. [ABSTRACT FROM AUTHOR]

Purpose: Because of its aggressive characteristics and poor prognosis, triple-negative breast cancer (TNBC) has become a hot topic in cancer research. Chemotherapy is currently the only treatment for patients with TNBC. The transcription factor FOXC1 has been associated with TNBC prognosis, but little is known about its effect on chemosensitivity. The aim of this study was to investigate the effects of FOXC1 on chemosensitivity.Methods: A case-control study was performed on 25 TNBC patients who experienced relapse and/or metastasis. Another 25 patients without relapse or metastasis were randomly selected as controls. Medical records were reviewed for relevant information, and immunohistochemistry was performed to measure FOXC1 levels. The Kaplan-Meier method and Cox analysis were used to analyze differences in disease-free survival (DFS) and overall survival (OS). The correlation of FOXC1 expression with chemosensitivity was analyzed. Data were analyzed using SPSS 21.0 software, and a P value <0.05 was considered to be statistically significant.Results: In 15 of 22 case patients, FOXC1 was overexpressed, whereas only 8 control patients exhibited FOXC1 overexpression (P < 0.05). FOXC1 expression had no correlation with pathological indicators. An anthracycline-based regimen was administered to 21 study patients and 23 control patients. FOXC1 expression was significantly associated with a worse DFS (HR 2.62, 95% CI 1.05-6.50, P = 0.038) but presented no correlation with OS (HR 2.53, 95% CI 0.76-8.40, P = 0.131) among these 44 patients.Conclusions: This study shows that FOXC1 is correlated with chemosensitivity to anthracycline and could be used as an indicator of chemosensitivity in sporadic TNBC. [ABSTRACT FROM AUTHOR]

Purpose: The present study aims to analyze a cohort of advanced breast cancer patients in Germany to assess their interest in complementary and alternative medicine (CAM) and patient's use of most frequent CAM methods.Patients and Methods: Based on the PREGNANT real-time breast cancer registry which is a multicenter study in Germany, questionnaires of 580 patients with advanced breast cancer were evaluated. The implemented questionnaire for CAM asked for general interest in CAM and for patient's use of different CAM methods at present and in the past. The interest and application of CAM were analyzed for association with patients' characteristics such as tumor, patient, and therapy characteristics.Results: In total, 436 out of 580 (75%) patients claimed to be interested in CAM. Further, interest in CAM is significantly correlated with younger age and absence of metastasis at the time of diagnosis. Multivariate analysis confirmed the patient's age and distant disease status at the time of diagnosis as related to interest in CAM. A total of 56.4% of patients applied any CAM method in the past. Moreover, with increasing lines of therapies, the more frequent use of CAM was observed. Hereby, praying, vitamin supplements, and other food supplements were most frequently applied.Conclusion: Our data demonstrate high overall interest and frequent use of CAM in advanced breast cancer patients supporting a strong demand of breast cancer patients for complementary counseling and treatments additional to the established cancer therapies. It is indispensable to implement counseling and evidence-based complementary treatments into clinical routine of cancer centers and to adapt postgraduate medical education, respectively. [ABSTRACT FROM AUTHOR]

Purpose: Combination of anthracyclines with trastuzumab is hampered by cardiotoxicity. Pegylated liposomal doxorubicin and lapatinib could represent a safer alternative to combination therapy.Methods: In this phase Ib study with 3 + 3 dose escalation design, patients with HER2-positive advanced breast cancer received pegylated liposomal doxorubicin 30 mg/m2 intravenously on day 1 plus lapatinib 1250 (level 1) or 1500 (level 2) mg/day orally on days 1-21 of each 21-day cycle. The aims were to establish the maximum tolerated dose at first cycle, and the activity and safety of multiple cycles.Results: Nine patients out of 11 enrolled were evaluable: 3 at level 1 and 6 at level 2. No dose-limiting toxicities occurred at dose level 1, while 1 (grade 3 diarrhea) occurred at dose level 2, leading to the expansion of this cohort to 6 patients, with no further dose-limiting toxicities. Main grade 1-2 toxicities at first cycle were leucopenia, diarrhea, elevated transaminases, mucositis. Three patients had grade 3 toxicities at subsequent cycles, including colitis, anorexia, stomatitis plus hand-foot syndrome. One partial response, 5 disease stabilizations, and 3 disease progressions were reported.Conclusions: Combination of pegylated liposomal doxorubicin and lapatinib is feasible and potentially active in pretreated HER2-positive advanced breast cancer patients.Trial Registration: NCT02131506 (ClinicalTrials.gov identifier). [ABSTRACT FROM AUTHOR]

Purpose: Providers' communication skills play a key role in encouraging breast cancer survivors to report symptoms and adhere to long-term treatments such as adjuvant endocrine therapy (AET). The purpose of this study was to examine provider perspectives on patient-provider communication regarding AET symptom management and to explore whether provider perspectives vary across the multi-disciplinary team of providers involved in survivorship care.Methods: We conducted three one-hour focus groups with a multi-disciplinary group of health care providers including oncology specialists, primary care physicians, and non-physician providers experienced in caring for breast cancer survivors undergoing AET (n = 13). Themes were organized using Epstein and Street's (2007) Framework for Patient-Centered Communication in Cancer Care.Results: The findings of this study suggest providers' communication behaviors including managing survivors' uncertainty, responding to survivors' emotions, exchanging information, and enabling self-management influences the quality of patient-provider communication about AET symptoms. Additionally, lack of systematic symptom assessment tools for AET requires providers to use discretion in determining which symptoms to discuss with survivors resulting in approaches that vary based on providers' discipline.Conclusion: There may be AET-specific provider communication skills and behaviors that promote effective patient-provider communication but additional research is needed to identify practices and policies that encourage these skills and behaviors among the many providers involved in survivorship care. Efforts are also needed to coordinate AET symptom assessment across providers, clarify providers' roles in symptom assessment, and determine best practices for AET symptom communication. [ABSTRACT FROM AUTHOR]

Postmenopausal women with breast cancer on aromatase inhibitor (AI) treatment are at increased risk of bone mineral density loss, which may lead to minimal trauma fractures. We examined the cost-effectiveness of dual energy X-ray absorptiometry (DXA) with antiresorptive (AR) therapy compared with fracture risk assessment, lifestyle advice, and vitamin supplementation. We used a hypothetical Markov cohort model of lifetime duration for 60-year-old women with early stage breast cancer receiving AIs. The data to inform the model came from medical literature, epidemiological reports, and costing data sets. Two eligibility scenarios for AR therapy were considered: (A) osteoporosis and (B) osteopenia or osteoporosis. The main outcomes were incremental cost per quality-adjusted life years gained and cumulative fractures per 1000 women, calculated relative to the comparator. Key aspects of the model were explored in sensitivity analyses. Due to relatively low effectiveness gains, the outcomes were primarily driven by the costs. The incremental cost per quality-adjusted life year gained was A$47,556 and A$253,000 for scenarios A and B, respectively. The numbers of fractures avoided were 56 and 77 per 1000 women, respectively. The results were most sensitive to the initial probability of osteoporosis, baseline risk of fracture, and cohort starting age. Compared with risk assessment and lifestyle advice only, a DXA scan followed by an AR treatment is potentially cost-effective for women aged 60 and over undergoing AI therapy for early breast cancer. However, the number of fractures averted through this intervention is small. [ABSTRACT FROM AUTHOR]

Purpose: To compare the effectiveness of trastuzumab-modified gold nanoparticles (AuNP) labeled with Lu (trastuzumab-AuNP-Lu) targeted to HER2 with non-targeted AuNP-Lu for killing HER2-overexpressing breast cancer (BC) cells in vitro and inhibiting tumor growth in vivo following intratumoral (i.t.) injection. Methods: AuNP (30 nm) were modified with polyethylene glycol (PEG) polymers linked to trastuzumab or to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelators to complex Lu. The binding and internalization of trastuzumab-AuNP-Lu in HER2-positive SK-BR-3, BT-474 and MDA-MB-361 human BC cells were studied. Clonogenic survival and DNA double-strand breaks (DSBs) were measured after exposure of SK-BR-3 or MDA-MB-361 cells to trastuzumab-AuNP-Lu or AuNP-Lu. NOD/SCID mice with s.c. MDA-MB-361 tumor xenografts were treated by i.t. injection of 3 MBq (0.15 mg) of trastuzumab-AuNP-Lu, AuNP-Lu or normal saline. Tumor growth was measured over 16 days and normal tissue toxicity evaluated. Results: Trastuzumab-AuNP-Lu was bound and internalized by HER2 positive BC cells (K = 7.6 ± 2.0 nM). Trastuzumab-AuNP-Lu was 42.9 and 2.6-fold more effective than AuNP-Lu at decreasing the clonogenic survival of SK-BR-3 (1.3 × 10 HER2/cell) and MDA-MB-361 (5.1 × 10 HER2/cell) cells, respectively, exposed overnight to these agents (1.5 nM; 20 MBq/mg Au). Under the same treatment conditions, 10-fold and 2.8-fold more DNA DSBs were observed in SK-BR-3 and MDA-MB-361 cells, respectively, exposed to trastuzumab-AuNP-Lu than AuNP-Lu. Trastuzumab-AuNP-Lu was 1.8-fold more effective at inhibiting tumor growth than AuNP-Lu. No or minimal normal tissue toxicity was observed for trastuzumab-AuNP-Lu or AuNP-Lu treatments. Conclusion: Trastuzumab-AuNP-Lu enables an efficient local radiation treatment of HER2-positive BC. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to determine the quality of life (QOL) and symptom burden (SB) among breast cancer patients.Methods: Patients with DCIS, early stage, locally advanced, or metastatic breast cancer completed the Edmonton Symptom Assessment System (ESAS) and the Functional Assessment of Cancer Therapy for Breast Cancer (FACT-B). Patients were divided into subsequent cohorts based on their last day of treatment, age at enrollment, radiation, chemotherapy, and hormone therapy.Results: A total of 1513 patients were enrolled. Metastatic patients had a lower QOL and greatest SB compared to all other patient groups. Patients ≤50 years old with early stage or locally advanced breast cancer had a lower QOL and greater SB for fatigue, depression, and anxiety compared to all other age cohorts. Patients with early stage breast cancer who received chemotherapy had a lower QOL and greater SB. Patients taking selective estrogen receptor modulator (SERM) had greater SB for depression and lower QOL compared to those not on SERM. Patients 2-10 years post-treatment had a lower QOL compared to patients ≥10 years post-treatment.Conclusion: Patients ≤50 years old, 2-10 years post-treatment, treated with chemotherapy or SERM had increased SB and decreased QOL. Individualized interventions and programs can be developed to tailor to physical, educational, and psychosocial needs identified across the breast cancer continuum. [ABSTRACT FROM AUTHOR]

Purpose: Evaluation of [18F]fluoromisonidazole ([18F]FMISO)-positron emission tomography (PET) imaging as a metric for evaluating early response to trastuzumab therapy with histological validation in a murine model of HER2+ breast cancer.Procedures: Mice with BT474, HER2+ tumors, were imaged with [18F]FMISO-PET during trastuzumab therapy. Pimonidazole staining was used to confirm hypoxia from imaging.Results: [18F]FMISO-PET indicated significant decreases in hypoxia beginning on day 3 (P < 0.01) prior to changes in tumor size. These results were confirmed with pimonidazole staining on day 7 (P < 0.01); additionally, there was a significant positive linear correlation between histology and PET imaging (r 2  = 0.85).Conclusions: [18F]FMISO-PET is a clinically relevant modality which provides the opportunity to (1) predict response to HER2+ therapy before changes in tumor size and (2) identify decreases in hypoxia which has the potential to guide subsequent therapy. [ABSTRACT FROM AUTHOR]

Purpose: This study was conducted a promising approach to surface functionalization developed for lipid-core nanocapsules and the merit to pursue new strategies to treat solid tumors. Methods: Bromelain-functionalized multiple-wall lipid-core nanocapsules (Bro-MLNC-Zn) were produced by self-assembling following three steps of interfacial reactions. Physicochemical and structural characteristics, in vitro proteolytic activity (casein substrate) and antiproliferative activity (breast cancer cells, MCF-7) were determined. Results: Bro-MLNC-Zn had z-average diameter of 135 nm and zeta potential of +23 mV. The complex is formed by a Zn-N chemical bond and a chelate with hydroxyl and carboxyl groups. Bromelain complexed at the nanocapsule surface maintained its proteolytic activity and showed anti-proliferative effect against human breast cancer cells (MCF-7) (72.6 ± 1.2% at 1.250 μg mL and 65.5 ± 5.5% at 0.625 μg mL). Comparing Bro-MLNC-Zn and bromelain solution, the former needed a dose 160-folds lower than the latter for a similar effect. Tripan blue dye assay corroborated the results. Conclusions: The surface functionalization approach produced an innovative formulation having a much higher anti-proliferative effect than the bromelain solution, even though both in vitro proteolytic activity were similar, opening up a great opportunity for further studies in nanomedicine. [ABSTRACT FROM AUTHOR]

Background: Despite decades of clinical success, tamoxifen therapy is complicated by inter-individual variability due to CYP450 polymorphism and resistance attributed to ERα/HER2 crosstalk. Direct administration of endoxifen shows promise in circumventing obligatory CYP450 bioactivation while maintaining efficacy. Separately, disruption of the crosstalk using probe antagonists against ERα (tamoxifen) and HER2 (e.g., lapatinib) has been explored clinically. However, the efficacy of this combination may be confounded by lapatinib, a potent inactivator of CYP3A4/5 which could negate the bioactivation of tamoxifen to the active metabolite endoxifen. Additionally, in a manner analogous to tamoxifen, endoxifen is similarly not immune to the development of ERα/HER2 crosstalk that could result in resistance. Simultaneous antagonism of ERα and HER2 using endoxifen and lapatinib could overcome these problems.Methods: Metabolism studies were performed in human liver microsomes to determine the extent of inhibition of tamoxifen bioactivation by lapatinib. Synergism of endoxifen and lapatinib was assessed using the combination index design in a panel of cell models exhibiting either a priori ERα/HER2 crosstalk (BT474) or acquired ERα/HER2 crosstalk (TAM-R and MCF-7/HER2).Results: Lapatinib inhibited tamoxifen bioactivation by up to 1.8-fold. Synergistic activity was uncovered for lapatinib and endoxifen against BT474, TAM-R and MCF-7/HER2 models of ERα/HER2 crosstalk. Western blot confirmed that endoxifen and lapatinib disrupted this crosstalk.Conclusion: This forward-looking study extends the success of tamoxifen by exploring the effectiveness of combining the next-generation tamoxifen derivative, endoxifen with an anti-HER2 agent to combat ERα/HER2 crosstalk, and at the same time provides a solution to the predicted pharmacokinetic antagonism between lapatinib and tamoxifen. [ABSTRACT FROM AUTHOR]

Purpose: The present study aimed to discover a new potent BCRP inhibitor overcoming multidrug resistance.Methods: Effects of LW6 on the functional activity and gene expression of two major efflux transporters, BCRP and P-gp, were evaluated by using MDCKII cells overexpressing each transporter (MDCKII-BCRP and MDCKII-MDR1). Its effects on the cytotoxicity and pharmacokinetics of co-administered anticancer drugs were also evaluated in transfected cells and rats, respectively.Results: In MDCKII-BCRP cells overexpressing BCRP, LW6 enhanced significantly (p < 0.05) the cellular accumulation of mitoxantrone, a BCRP substrate, and was more potent than Ko143, a well-known BCRP inhibitor. LW6 also down-regulated BCRP expression at concentrations of 0.1-10 µM. Furthermore, cells became more susceptible to the cytotoxicity of anticancer drugs in the presence of LW6. The CC50 values of mitoxantrone and doxorubicin were reduced by three- and tenfold, respectively, in MDCKII-BCRP cells, while LW6 did not affect the cytotoxicity of anticancer drugs in MDCKII-mock cells lacking BCRP transporter. Furthermore, LW6 improved the oral exposure of methotrexate by twofold in rats. In contrast to BCRP, LW6 had no inhibition effect on the functional activity and gene expression of P-gp.Conclusion: LW6 was newly identified as a potent BCRP inhibitor and could be useful to reduce the multidrug resistance of cancer cells via the inhibition of BCRP-mediated drug efflux as well as the down-regulation of BCRP expression. [ABSTRACT FROM AUTHOR]

Background: Transparent reporting of validation efforts of health economic models give stakeholders better insight into the credibility of model outcomes. In this study we reviewed recently published studies on seasonal influenza and early breast cancer in order to gain insight into the reporting of model validation efforts in the overall health economic literature.Methods: A literature search was performed in Pubmed and Embase to retrieve health economic modelling studies published between 2008 and 2014. Reporting on model validation was evaluated by checking for the word validation, and by using AdViSHE (Assessment of the Validation Status of Health Economic decision models), a tool containing a structured list of relevant items for validation. Additionally, we contacted corresponding authors to ask whether more validation efforts were performed other than those reported in the manuscripts.Results: A total of 53 studies on seasonal influenza and 41 studies on early breast cancer were included in our review. The word validation was used in 16 studies (30 %) on seasonal influenza and 23 studies (56 %) on early breast cancer; however, in a minority of studies, this referred to a model validation technique. Fifty-seven percent of seasonal influenza studies and 71 % of early breast cancer studies reported one or more validation techniques. Cross-validation of study outcomes was found most often. A limited number of studies reported on model validation efforts, although good examples were identified. Author comments indicated that more validation techniques were performed than those reported in the manuscripts.Conclusions: Although validation is deemed important by many researchers, this is not reflected in the reporting habits of health economic modelling studies. Systematic reporting of validation efforts would be desirable to further enhance decision makers' confidence in health economic models and their outcomes. [ABSTRACT FROM AUTHOR]

Adoptive T cell immunotherapy is a promising approach to cancer treatment that currently has limited clinical applications. DNA methyltransferase inhibitors (DNAMTi) have known potential to affect the immune system through multiple mechanisms that could enhance the cytotoxic T cell responses, including: upregulation of tumor antigen expression, increased MHC class I expression, and blunting of myeloid derived suppressor cells (MDSCs) expansion. In this study, we have investigated the effect of combining the DNAMTi, decitabine, with adoptive T cell immunotherapy in the murine 4T1 mammary carcinoma model. We found that expression of neu, MHC class I molecules, and several murine cancer testis antigens (CTA) was increased by decitabine treatment of 4T1 cells in vitro. Decitabine also increased expression of multiple CTA in two human breast cancer cell lines. Decitabine-treated 4T1 cells stimulated greater IFN-gamma release from tumor-sensitized lymphocytes, implying increased immunogenicity. Expansion of CD11b + Gr1 + MDSC in 4T1 tumor-bearing mice was significantly diminished by decitabine treatment. Decitabine treatment improved the efficacy of adoptive T cell immunotherapy in mice with established 4T1 tumors, with greater inhibition of tumor growth and an increased cure rate. Decitabine may have a role in combination with existing and emerging immunotherapies for breast cancer. [ABSTRACT FROM AUTHOR]

Background: Taxane acute pain syndrome (TAPS) is characterized by myalgias and arthralgias starting 24-48 h after taxane-based chemotherapy and lasting for 5-7 days. Relatively little is known about its incidence and impact on quality of life.Objectives: A systematic review was conducted evaluating the incidence of TAPS in breast cancer patients receiving taxane-based chemotherapy.Methods: Embase, Cochrane, and Ovid MEDLINE were searched from 1947 to July 2015. Data was sought from randomized controlled trials (RCTs), prospective and retrospective observational studies. Two reviewers independently screened citations and full text articles. Outcomes of interest were the incidence of TAPS and its impact on quality of life.Results: Of 980 citations identified, 51 relevant studies (27,007 patients) were included. Data came from RCTs (12,357 patients), retrospective (6566 patients) and prospective observational studies (6210 patients). Study sample sizes ranged from 14 to 4149 patients (median 152). Given the significance between study heterogeneity, a meta-analysis was not performed. The incidence of TAPS varied between taxanes: paclitaxel (median 13.1 %, range 0.9-86 %), docetaxel (median 10.5 %, range 3.6-70 %), and nab-paclitaxel (26 %, range 14-43 %). In the metastatic setting, median incidence was 30 % (range 5.4-73 %), compared with 11.3 % (range 0.9-86 %) in the adjuvant setting. Three out of eight studies assessing quality of life demonstrated pain interference with daily activities.Conclusions: The incidence of TAPS varies between taxanes, regimens, and disease settings. In order to identify patients at the greatest risk of TAPS, and hence optimize its prevention and management, standardized methods of diagnosing and measuring TAPS are needed. [ABSTRACT FROM AUTHOR]

Raloxifene is a selective estrogen receptor modulator that has been approved for treating osteoporosis and breast cancer in high-risk postmenopausal women. However, recent evidence suggests that raloxifene adjunct therapy improves cognition and reduces symptom severity in men and women with schizophrenia. In animal models, raloxifene increases forebrain neurogenesis and enhances working memory and synaptic plasticity. It may consequently repair the neuronal and synaptic connectivity that is disrupted in schizophrenia. It also reduces oxidative stress and neuroinflammation, which are potent etiological factors in the neuropathology of schizophrenia. Furthermore, in postmenopausal women, raloxifene reduces the risks for atherosclerosis, diabetes mellitus, and weight gain, which are serious adverse effects associated with long-term antipsychotic treatment in schizophrenia; therefore, it may improve the safety and efficacy of antipsychotic drugs. In this review, recent insights into the neurocognitive, neuroprotective, and cardiometabolic effects of raloxifene in relation to therapeutic outcomes in schizophrenia are discussed. [ABSTRACT FROM AUTHOR]

Neutrophil elastase (NE) is an innate immune cell-derived inflammatory mediator that we have shown increases the presentation of tumor-associated peptide antigens in breast cancer. In this study, we extend these observations to show that NE uptake has a broad effect on enhancing antigen presentation by breast cancer cells. We show that NE increases human leukocyte antigen (HLA) class I expression on the surface of breast cancer cells in a concentration and time-dependent manner. HLA class I upregulation requires internalization of enzymatically active NE. Western blots of NE-treated breast cancer cells confirm that the expression of total HLA class I as well as the antigen-processing machinery proteins TAP1, LMP2, and calnexin does not change following NE treatment. This suggests that NE does not increase the efficiency of antigen processing; rather, it mediates the upregulation of HLA class I by stabilizing and reducing membrane recycling of HLA class I molecules. Furthermore, the effects of NE extend beyond breast cancer since the uptake of NE by EBV-LCL increases the presentation of HLA class I-restricted viral peptides, as shown by their increased sensitivity to lysis by EBV-specific CD8+ T cells. Together, our results show that NE uptake increases the responsiveness of breast cancer cells to adaptive immunity by broad upregulation of membrane HLA class I and support the conclusion that the innate inflammatory mediator NE enhances tumor cell recognition and increases tumor sensitivity to the host adaptive immune response. [ABSTRACT FROM AUTHOR]