Pyrotinib with trastuzumab and aromatase inhibitors as first-line treatment for HER2 positive and hormone receptor positive metastatic or locally advanced breast cancer: study protocol of a randomized controlled trial.

BACKGROUND: HER2 dual-blockade combined with aromatase inhibitors (AI) is a promising strategy to improve progression-free survival (PFS) in hormone receptor (HR) positive, metastatic breast cancer (MBC). Pyrotinib is a novel irreversible epidermal growth factor receptor/HER2 dual tyrosine kinase inhibitor. However, there is scarcity of data on the effectiveness and safety of pyrotinib combined with trastuzumab and AI as first-line treatment in a metastatic setting. METHODS/DESIGN: The present study is a prospective, randomized, open-label trial. 198 patients with HER2+/HR+ MBC will be recruited. Eligible patients will be allocated (2:1) to either an experimental group (pyrotinib + trastuzumab + AI) or a control group (trastuzumab + AI). Allocation will be stratified by 1) time since adjuvant hormone therapy (≤ 12 months/> 12 months/no prior hormone therapy); 2) lesion sites (visceral / non-visceral). The primary endpoint is PFS. DISCUSSION: To our knowledge, this is the first prospective randomized controlled trial to assess dual HER2-blockade with pyrotinib in the metastatic setting. This study will provide valuable evidence regarding the efficacy and safety of pyrotinib when combined with trastuzumab and an AI as first-line treatment for MBC. Moreover, it will also evaluate the feasibility of endocrine therapy as an alternative to chemotherapy in providing de-escalation therapy with less toxicity for advanced HR+/HER2+ patients. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT03910712 . Registered on 10 Apr. 2019.

Binding affinity and decontamination of dermal decontamination gel to model chemical warfare agent simulants.

Six chemical warfare agent simulants (trimethyl phosphate, dimethyl adipate, 2-chloroethyl methyl sulfide, diethyl adipate, chloroethyl phenyl sulfide and diethyl sebacate) were studied in in vitro human skin to explore relationship between dermal penetration/absorption and the mechanisms of simulant partitioning between stratum corneum (SC) and water as well as between dermal decontamination gel (DDGel) and water. Both binding affinity to and decontamination of simulants using DDGel were studied. Partition coefficients of six simulants between SC and water (Log PSC/w ) and between DDGel and water (Log PDDGel/w ) were determined. Results showed that DDGel has a similar or higher binding affinity to each simulant compared to SC. The relationship between Log P octanol/water and Log PSC/w as well as between Log P octanol/water and Log PDDGel/w demonstrated that partition coefficient of simulants correlated to their lipophilicity or hydrophilicity. Decontamination efficiency results with DDGel for these simulants were consistent with binding affinity results. Amounts of percentage dose of chemicals in DDGel of trimethyl phosphate, dimethyl adipate, 2-chloroethyl methyl sulfide, diethyl adipate, chloroethyl phenyl sulfide and diethyl sebacate were determined to be 61.15, 85.67, 75.91, 53.53, 89.89 and 76.58, with corresponding amounts absorbed in skin of 0.96, 0.65, 1.68, 0.72, 0.57 and 1.38, respectively. In vitro skin decontamination experiments coupled with a dermal absorption study demonstrated that DDGel can efficiently remove chemicals from skin surface, back-extract from the SC, and significantly reduced chemical penetration into skin or systemic absorption for all six simulants tested. Therefore, DDGel offers a great potential as a NextGen skin Decon platform technology for both military and civilian use.

Prognostic Value of PD-L1 in Breast Cancer: A Meta-Analysis.

Programmed cell death 1 ligand 1 (PD-L1) is a promising therapeutic target for cancer immunotherapy. However, the correlation between PD-L1 and breast cancer survival remains unclear. Here, we present the first meta-analysis to investigate the prognostic value of PD-L1 in breast cancer. We searched Pubmed, Embase, and Cochrane Central Register of Controlled Trials databases for relevant studies evaluating PD-L1 expression and breast cancer survival. Fixed- and random-effect meta-analyses were conducted based on heterogeneity of included studies. Publication bias was evaluated by funnel plot and Begg's test. Overall, nine relevant studies with 8583 patients were included. PD-L1 overexpression was found in 25.8% of breast cancer patients. PD-L1 (+) associated with several high-risk prognostic indicators, such as ductal cancer (p = 0.037), high tumor grade (p = 0.000), ER negativity (p = 0.000), PR negativity (p = 0.000), HER2 positivity (p = 0.001) and aggressive molecular subtypes (HER2-rich and Basal-like p = 0.000). PD-L1 overexpression had no significant impact on metastasis-free survival (HR 0.924, 95% CI = 0.747-1.141, p = 0.462), disease-free survival (HR 1.122, 95% CI = 0.878-1.434, p = 0.357) and overall specific survival (HR 0.837, 95% CI = 0.640-1.093, p = 0.191), but significantly correlated with shortened overall survival (HR 1.573, 95% CI = 1.010-2.451, p = 0.045). PD-L1 overexpression in breast cancer associates with multiple clinicopathological parameters that indicated poor outcome, and may increase the risk for mortality. Further standardization of PD-L1 assessment assay and well-controlled clinical trials are warranted to clarify its prognostic and therapeutic value.

Vehicle effects on human stratum corneum absorption and skin penetration.

This study evaluated the effects of three vehicles-ethanol (EtOH), isopropyl alcohol (IPA), and isopropyl myristate (IPM)-on stratum corneum (SC) absorption and diffusion of the [14C]-model compounds benzoic acid and butenafine hydrochloride to better understand the transport pathways of chemicals passing through and resident in SC. Following application of topical formulations to human dermatomed skin for 30 min, penetration flux was observed for 24 h post dosing, using an in vitro flow-through skin diffusion system. Skin absorption and penetration was compared to the chemical-SC (intact, delipidized, or SC lipid film) binding levels. A significant vehicle effect was observed for chemical skin penetration and SC absorption. IPA resulted in the greatest levels of intact SC/SC lipid absorption, skin penetration, and total skin absorption/penetration of benzoic acid, followed by IPM and EtOH, respectively. For intact SC absorption and total skin absorption/penetration of butenafine, the vehicle that demonstrated the highest level of sorption/penetration was EtOH, followed by IPA and IPM, respectively. The percent doses of butenafine that were absorbed in SC lipid film and penetrated through skin in 24 h were greatest for IPA, followed by EtOH and IPM, respectively. The vehicle effect was consistent between intact SC absorption and total chemical skin absorption and penetration, as well as SC lipid absorption and chemical penetration through skin, suggesting intercellular transport as a main pathway of skin penetration for model chemicals. These results suggest the potential to predict vehicle effects on skin permeability with simple SC absorption assays. As decontamination was applied 30 min after chemical exposure, significant vehicle effects on chemical SC partitioning and percutaneous penetration also suggest that skin decontamination efficiency is vehicle dependent, and an effective decontamination method should act on chemical solutes in the lipid domain.

Antifungal ME1111 in vitro human onychopharmacokinetics.

This study determined ME1111 onychopharmacokinetics and possible topical antifungals' clinical efficacy in human great toenails using an in vitro finite dose model. ME1111 topical formulations in 1, 5, 10 or 15% for 3 days observation and 1, 5 or 10% for 14 days observation, respectively, were used to determine ME1111 penetration rate and transungual kinetics. ME1111 concentrations in the deeper nail (ventral/intermediate layers) and a cotton pad/nail bed, were several orders of magnitude greater than MIC90 and MFC90 for three major dermatophytes. ME1111 concentrations 3 days after a single and 14 days after multiple dosing of 10% formulation were 253 and 7991 µg/g nail, respectively, and superior to those of 8% ciclopirox control. ME1111 concentration (µg equivalent/cm3) in the cotton pad following 10% ME1111 multiple applications increased linearly throughout the 336 h experiment and was significantly greater than that of 8% ciclopirox. Flux rate of ME1111 averaged as 50.9 µg/cm3/day, which was ca. two orders of magnitude greater than the MIC90 values. The novel antifungal ME1111 penetrated well into human nail plate and its concentrations in the deeper nail and cotton pad after application of 10% formulation were significantly greater than those of ciclopirox.

Proposed human stratum corneum water domain in chemical absorption.

Compounds with varying physical and chemical properties may have different affinities to the stratum corneum (SC) and/or its intercellular lipids, keratin protein, and possible water domains. To better understand the mechanism of percutaneous absorption, we utilized 21 carbon-14 labeled chemicals, with wide hydrophilicity (log P = -0.05 to 6.17), and quantified their absorption/adsorption properties for a short incubation time (15 min) with regards to intact SC membrane, delipidized SC membrane and SC lipid. A facile method was developed for SC/lipid absorption, providing a more equivalent procedure and comparable data. SC lipid absorption of chemical solutes positively correlated with the octanol/water partition coefficient (log P). Differences between the percent dose of chemical absorption to intact SC and the total percent dose contributed by the protein and lipid domains suggest the possibility and significance of a water domain. Absorption rate experiments showed a longer lag time for intact SC than for delipidized SC or SC lipid, suggesting that the water domain may delay chemical binding to protein and lipid domains, and may be a factor in the resistance of many chemicals to current decontamination methods. Copyright © 2015 John Wiley & Sons, Ltd.

Effects of soap-water wash on human epidermal penetration.

Skin decontamination is a primary interventional method used to decrease dermal absorption of hazardous contaminants, including chemical warfare agents, pesticides and industrial pollutants. Soap and water wash, the most common and readily available decontamination system, may enhance percutaneous absorption through the "wash-in effect." To understand better the effect of soap-water wash on percutaneous penetration, and provide insight to improving skin decontamination methods, in vitro human epidermal penetration rates of four C(14) -labeled model chemicals (hydroquinone, clonidine, benzoic acid and paraoxon) were assayed using flow-through diffusion cells. Stratum corneum (SC) absorption rates of these chemicals at various hydration levels (0-295% of the dry SC weights) were determined and compared with the results of the epidermal penetration study to clarify the effect of SC hydration on skin permeability. Results showed accelerated penetration curves of benzoic acid and paraoxon after surface wash at 30 min postdosing. Thirty minutes after washing (60 min postdosing), penetration rates of hydroquinone and benzoic acid decreased due to reduced amounts of chemical on the skin surface and in the SC. At the end of the experiment (90 min postdosing), a soap-water wash resulted in lower hydroquinone penetration, greater paraoxon penetration and similar levels of benzoic acid and clonidine penetration compared to penetration levels in the non-wash groups. The observed wash-in effect agrees with the enhancement effect of SC hydration on the SC chemical absorption rate. These results suggest SC hydration derived from surface wash to be one cause of the wash-in effect. Further, the occurrence of a wash-in effect is dependent on chemical identity and elapsed time between exposure and onset of decontamination. By reducing chemical residue quantity on skin surface and in the SC reservoir, the soap-water wash may decrease the total quantity of chemical absorbed in the long term; however, the more immediate accelerated absorption of chemical toxins, particularly chemical warfare agents, may be lethal. Copyright © 2015 John Wiley & Sons, Ltd.

Stratum corneum reservoir as a predictive method for in vitro percutaneous absorption.

Interaction between drug and proteins and lipids in stratum corneum (SC) is an important pharmacokinetic parameter in early steps of absorption. Previous in vivo studies showed that the total amount of compound, regardless of properties, penetrating over a 96 h period could be predicted by the amount present in SC 30 min after application by a linear relationship. Validating this linear relationship through in vitro study would facilitate testing of transdermal drug delivery platforms. We aimed to determine in vitro penetration behavior across SC of humans by determining the relationship between quantity present in SC reservoir 30 min after application with 24 h skin absorption and penetration. In this study, use of the SC reservoir effect to predict absorption and penetration of topical compounds is reaffirmed with in vitro models involving human skin. These results indicate the amount in short-term (30 min) SC reservoir predict long-term (24 h) skin absorption and penetration, as characterized by statistically significant linear relationships determined via regression. This may be explained by the fact that SC is a rate-limiting barrier to percutaneous drug transport. After molecules diffuse through SC barrier, passage into deeper dermal layers and systemic uptake occur relatively quickly. These results enable one to measure quantity in SC reservoir shortly after topical application as a proxy for absorption and penetration over longer periods. With respect to drug development and risk assessment of toxic substances, this may simplify assays attempting to quantitate penetration capacity. Further investigation with a larger range of compounds is needed to clarify the observations recorded here. Copyright © 2015 John Wiley & Sons, Ltd.

Depth-dependent stratum corneum permeability in human skin in vitro.

The stratum corneum (SC), a permeable membrane, limits percutaneous penetration. As SC chemical and structural properties responsible for skin barrier function appear depth-related, we conducted an in vitro dermatopharmacokinetic study on intact and adhesive tape-stripped skin samples to clarify whether SC is a homogeneous barrier for chemical transport. SC concentration-thickness profiles were determined for four C-14 labeled model chemicals, panthenol, benzoic acid, paraoxon and butenafine, using the tape-stripping approach. Data analysis with the unsteady-state diffusion equation of Fick's second law permitted a chemical diffusion coefficient in SC. To evaluate the consistency of SC permeability from its surface to lower levels, the skin was tape-stripped five to 10 times to remove the upper cell layers before chemical application, such that diffusion coefficients could be determined from three SC depth levels (0, 5 and 10 tape strips). Results suggested the depth-dependency of SC permeability to panthenol, benzoic acid and butenafine; the diffusion coefficient of panthenol decreased significantly after the first five tape strips and subsequently remained consistent. A progressive increase in diffusion coefficients of benzoic acid and butenafine was observed as tape-stripping levels increased. The removal of superficial SC did not result in a significant difference in the paraoxon diffusion coefficient. For individual chemicals, a variation in the diffusion coefficient from SC surface to deeper layers agreed with the change of the diffusion coefficient over time in intact skin. Characterization of the SC properties contributing to the depth-dependent SC permeability will hopefully provide further insight to skin penetration/decontamination. Copyright © 2016 John Wiley & Sons, Ltd.

Analysis of the browning reaction in a sorbitol/glycine model: Formation and degradation of precursors, glucose and α-dicarbonyl compounds during heating.

Browning can occur in the matrices of alditol and amino acids due to heating or long-term storage, which poses challenges in achieving the desired appearance stability. To investigate the mechanism of browning in the sorbitol-glycine system, we evaluated the evolution of typical intermediates, including glucose and α-dicarbonyl compounds (α-DCs), during heating at 100 ˚C. The browning index and intermediate products of the sorbitol-glycine system increased more rapidly compared to those of the sorbitol system. After heating for 10 h, the browning index of the sorbitol-glycine system was eight times higher than that of sorbitol alone. In the presence of glycine, sorbitol underwent continuous conversion into glucose. After 10 h of heating, the concentration of glucose in the sorbitol-glycine system reanched 726.6 mg/L, which was approximately 63 times higher than that in the sorbitol system. Mass spectrometry analysis revealed the presence of α-DCs such as 3-deoxyglucosone (3-DG), glyoxal (GO), methylglyoxal (MGO), 2,3-butanedione (2,3-BD), in the sorbitol-glycine system. These compounds were precursors of melanoidins, indicating the occurrence of the Maillard reaction and resulting in the browning of the system. Therefore, the browning process in the sorbitol-glycine system involved two stages of reactions: the conversion of sorbitol to glucose and the Maillard reaction between glucose and glycine.

The Prognostic and Clinical Value of Tumor-Associated Macrophages in Patients With Breast Cancer: A Systematic Review and Meta-Analysis.

Background: The prognostic and clinical value of tumor-associated macrophages (TAMs) in patients with breast cancer (BCa) remains unclear. We conducted the current meta-analysis to systematically evaluate the association of CD68+ and CD163+ TAM density with the prognosis and clinicopathologic features of BCa patients. Methods: Searches of Web of Science, PubMed, and EMBASE databases were performed up to January 31, 2022. The meta-analysis was conducted using hazard risks (HRs) and 95% confidence intervals (CIs) for survival data including overall survival (OS), disease-free survival (DFS), and BCa specific survival. Sensitivity and meta-regression analyses were also conducted to identify the robustness of the pooled estimates. Results: Our literature search identified relevant articles involving a total of 8,496 patients from 32 included studies. Our analysis indicates that a high CD68+ TAM density in the tumor stoma was significantly linked with poor OS (HR 2.46, 95% CI, 1.83-3.31, P<0.001) and shorter DFS (HR 1.77, 95% CI, 1.08-2.89, P=0.02) compared to low CD68+ TAM density. A significant association was also found in the tumor nest. Analysis of CD163+ TAM density showed similar results (all P<0.001). Notably, the pooled analysis with multivariate-adjusted HRs for OS and DFS also found that a high TAM density was significantly related to poorer outcomes for BCa patients (all P<0.05). In addition, BCa patients with high TAM density were more likely to have larger tumors, no vascular invasion, and positive estrogen receptor expression (all P<0.05). Conclusion: This meta-analysis indicates that a high CD68+ and CD163+ TAM density is associated with poor OS and shorter DFS in BCa patients. Further clinical studies and in vivo experiments are needed to elucidate the underlying mechanism of TAMs. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022304853, identifier CRD42022304853.

Efficacy and Safety Profile of Histone Deacetylase Inhibitors for Metastatic Breast Cancer: A Meta-Analysis.

Introduction: Acquired resistance to endocrine therapy (ET) remains a big challenge in the management of metastatic breast cancer (MBC). A novel therapeutic agent, histone deacetylase inhibitors (HDACi), targets the abnormal epigenetic modification and may overcome acquired resistance. However, HDACi efficacy and the safety profile for hormone receptor (HoR)-positive/human epidermal growth factor receptor 2 (HER2)-negative MBC remain controversial. Methods: Two independent reviewers searched PubMed, Embase, and Cochrane Central Register of Controlled Trials databases for relevant studies on HDACi and HoR+/HER2- MBC. Demographic and clinicopathological parameters were extracted and presented as means and proportions, and between-group differences were assessed by Pearson chi-square test. Fixed- or random-effects models were used for meta-analysis based on inter-study heterogeneity. Pooled results were presented as L'Abbé plot and forest plot. Funnel plot and Egger's test were employed for evaluation of publication bias. Results: Four studies with 1,457 patients were included for meta-analysis. The overall objective response rates (ORRs) of HDACi + ET (HE) and placebo + ET (PE) groups were 11.52% and 6.67%, respectively. The HE regimen significantly increased ORR (odds ratio [OR] 1.633, 95% confidence interval [CI] = 1.103-2.418, p < 0.05) and showed higher clinical benefit rate (CBR) than the PE regimen (HE vs. PE groups: 38.82% vs. 30.58%, OR 1.378, 95% CI = 1.020-1.861, p < 0.05). Additionally, the HE regimen was associated with prolonged progression-free survival (PFS) (hazard ratio [HR] 0.761, 95% CI = 0.650-0.872, p < 0.001) and overall survival (OS) (HR 0.849, 95% CI = 0.702-0.996, p < 0.001). Regarding safety profile, the HE regimen had increasing toxicity in terms of higher overall adverse event (AE), Grade ≥3 AE, dose modification, and discontinuation rate. Conclusions: This meta-analysis validated that the HE regimen had superior efficacy over control in terms of ORR, CBR, PFS, and OS, but was accompanied with increasing toxicity. HDACi plus ET could serve as an important option in managing HoR+/HER2- MBC. Future studies may focus on the clinical difference among different HDACi and AE managements to enhance tolerability.

Breast-conserving therapy for breast cancer with BRCA mutations: a meta-analysis.

BACKGROUND: BRCA1/2 mutated breast cancer accounts for 3 to 12% of all women with breast cancer and significantly increases the lifetime risk of breast cancer. However, the optimal local treatment for breast cancer with BRCA germline mutation remains controversial. Here we present a meta-analysis to evaluate the impact of breast-conserving therapy (BCT) on the prognosis of breast cancer with BRCA mutation. METHODS: Two independent reviewers searched Pubmed, Embase and Cochrane Central Register of Controlled Trials databases for relevant studies on BCT and BRCA mutated breast cancer. Fixed or random effect models were used for meta-analyses based on whether significant heterogeneity existed among included studies. Funnel plot and Begg's test were employed for the evaluation of publication bias. RESULTS: Totally, four studies with five cohorts and a totally 1254 patients were included for meta-analyses. The BCT group involved more T0/T1 (BCT 63.7% Vs. M 48.9%, p < 0.001), N0 (BCT 70.5% Vs. M 56.2%, p < 0.001) and ER negative (BCT 58.8% Vs. M 49.3% p < 0.01) tumors than M group. Patients who received M tended to have prophylactic contralateral mastectomy (BCT 16.5% Vs. M 35.8%, p < 0.001). BCT had a significant higher risk for local recurrence than M (HR 3.838, 95% CI = 2.376-6.201, p < 0.001). The pooled results revealed no significant impact of BCT on disease-free survival (DFS), metastasis-free survival (MFS), breast cancer-specific survival (BCSS) and overall survival (OS). CONCLUSIONS: The present meta-analysis suggested that BCT had increasing local recurrence risk, but did not significantly impact patient survival in terms of DFS, MFS, BCSS and OS. BCT may serve as a safe alternative to mastectomy for breast cancer with BRCA mutation. Further high-quality randomized control trials are warranted to explore the optimal surgical management for BRCA mutation carriers.

T1a triple negative breast cancer has the worst prognosis among all the small tumor (<1 cm) of TNBC and HER2-rich subtypes.

BACKGROUND: Triple negative breast cancer (TNBC), accounting for 15% of all breast cancer cases, was usually considered as the most aggressive subtype. The present study evaluated the prognosis of T1a TNBC and the impact of tumor size on T1 TNBC survival in large-scale population. METHODS: This retrospective study enrolled T1a/T1b/T1c TNBC and HER2+/hormone receptor (HoR)- patients diagnosed between 2010 to 2012 from the Surveillance, Epidemiology, and End Results database. The following information was extracted for further analyses: demographic variables including age at diagnosis, race, marital status, laterality, histological grade, T/N stage, American Joint Committee on Cancer (AJCC) stage, radiation therapy, survival and cause of death. Kaplan-Meier method and Cox regression were engaged for breast cancer specific survival (BCSS) and overall survival (OS) analyses. RESULTS: In all, the present study enrolled 6,953 TNBC and 2,648 HER2+/HoR- patients. T1a TNBC which generally omitted adjuvant chemotherapy had worse prognosis than T1a HER2+/HoR- [BCSS: hazard ratio (HR) 3.23, 95% confidence interval (CI): 1.05-9.09, P=0.03; OS: HR 2.63, 95% CI: 1.25-5.56, P=0.01] and T1b HER2+/HoR- (BCSS: HR 5.26, 95% CI: 1.61-16.7, P=0.006; OS: HR 3.03, 95% CI: 1.27-7.14, P=0.013) tumors which both were recommended by the National Comprehensive Cancer Network (NCCN) guideline to have chemotherapy. T1a TNBC also showed a trend with poorer prognosis than T1b TNBC, but did not reach statistical significance. CONCLUSIONS: T1a TNBC had the worst prognosis among all small tumors (<1 cm) of TNBC and HER2+/HoR- subtypes, indicating the necessity of more intensive adjuvant treatment.

Platinum-Based Neoadjuvant Chemotherapy for Breast Cancer With BRCA Mutations: A Meta-Analysis.

BACKGROUND: Triple-negative breast cancer (TNBC) is one of the most aggressive subtypes of breast cancer and the major phenotype of BRCA related hereditary breast cancer. Platinum is a promising chemotherapeutic agent for TNBC. However, its efficacy for breast cancer with BRCA germline mutation remains inconclusive. Here we present a meta-analysis to evaluate the effect of platinum agents for breast cancer patients with BRCA mutation in neoadjuvant setting. MATERIALS AND METHODS: Pubmed, Embase, and Cochrane Central Register of Controlled Trials databases were searched for relevant studies on neoadjuvant platinum treatment and BRCA related breast cancer. Fixed- and random-effect models were adopted for meta-analyses. Heterogeneity investigation was conducted by sensitivity and subgroup analyses. Publication bias was evaluated by funnel plot and Begg's test. RESULTS: In all, five studies with 363 patients were included for meta-analysis. The pooled pathological complete response (pCR) rates were 43.4% (59/136) and 33.9% (77/227) for platinum and control groups, respectively. Adding platinum to neoadjuvant regimen did not significantly improved pCR rate (odds ratio [OR]: 1.340, 95% confidence interval [CI] = 0.677-2.653, p = 0.400). Sensitivity analyses also revealed platinum did not significantly increase pCR rate in either TNBC or HER2- patients (TNBC subgroup: OR: 1.028, 95% CI = 0.779-1.356, p = 0.846; HER2- subgroup: OR: 0.935, 95% CI = 0.716-1.221, p = 0.622). CONCLUSIONS: Our meta-analysis suggested that the addition of platinum to neoadjuvant chemotherapy did not significantly improve pCR rate for patients with BRCA mutations. Further large-scale randomized control trial with survival data may provide more robust evidence on therapeutic value of platinum for breast cancer neoadjuvant treatment.

Validation of CTS5 model in large-scale breast cancer population and the impact of menopausal and HER2 status on its prognostic value.

Clinical Treatment Score post-5 years (CTS5) is a promising prognostic tool to evaluate late recurrence risk for breast cancer. Our study aimed to validate its prognostic value in large-scale population and explore the impact of menopausal and HER2 status on CTS5 model. We performed a retrospective cohort study using the Surveillance, Epidemiology, and End Results (SEER) database. Survival analyses were conducted to assess the prognostic value of CTS5 in different breast cancer subgroups in terms of overall survival (OS) and breast cancer specific survival (BCSS) after five years. A total of 23,168 breast cancer patients with positive hormone receptor (HoR) were enrolled. Postmenopausal and premenopausal patients were 13,686 and 9,482, respectively. Taking CTS5 score as a continuous variable, it had significant positive correlation with poor prognosis beyond five years in both postmenopausal and premenopausal subgroups. Nevertheless, for HER2+ postmenopausal patients, the model has less effective prognostic value on long-term BCSS [HR1.177 (95%CI 0.960-1.443), p = 0.117]. Using CTS5 score as a categorical variable, HER2- patients with high-risk level revealed significant poor survival in terms of both BCSS and OS, irrespective of menopausal status. Our study showed the CTS5 model could be a useful prognostic tool for predict long-term survival in HoR+/HER2- patients. And further large-scale studies are warranted to assess its prognostic value for HER2+ patients and develop novel prediction model for late recurrence risk estimation.

The impact of pre-existed and SERM-induced non-alcoholic fatty liver disease on breast cancer survival: a meta-analysis.

Background: Non-alcoholic fatty liver disease (NAFLD) is a common disorder and a frequent side effect of endocrine therapy (ET) for breast cancer treatment. This was the first meta-analysis to investigate the impact of NAFLD on breast cancer survival. Material and Methods: We searched Pubmed, Embase and Cochrane Central Register of Controlled Trials database for relevant studies that investigated the correlation between NAFLD and breast cancer survival. Fixed- and random-effect meta-analyses were conducted according to the heterogeneity of enrolled studies. Subgroup analyses were performed based on whether NAFLD was induced by ET administration Results: Eight cohorts from six studies including 3684 breast cancer patients were enrolled. NAFLD was significantly associated with advanced age (p < 0.001), obesity (p < 0.001), lymph node metastases (p = 0.003) and hormone receptor positivity (p < 0.001). NAFLD had no significant impact on disease free survival (DFS) [hazard ratio (HR) 1.07, 95% confidence interval (CI) = 0.64-1.77, p = 0.81] and overall survival (OS) (HR 1.29, 95% CI = 0.68-2.44, p = 0.44). In subgroup analyses, ET-associated NAFLD showed no significant impact on DFS and OS. Nonetheless, non-ET-associated NAFLD had a strong prognostic correlation with poor OS (HR 1.92, 95% CI = 1.09-3.41, p = 0.02). Conclusion: NAFLD had no significant impact on breast cancer survival. However, non-ET-associated NAFLD implied increasing death risk. Future large-scale studies are warranted to further elucidate the correlation between NAFLD and breast cancer prognosis.

In vitro human skin permeation and decontamination of 2-chloroethyl ethyl sulfide (CEES) using Dermal Decontamination Gel (DDGel) and Reactive Skin Decontamination Lotion (RSDL).

This study compared the efficiency for in vitro human skin decontamination using DDGel and RSDL. Experiments were performed using in vitro human skin models, in which skin was mounted onto Flow-Through diffusion cells. The mass of 14-C CEES removed from skin surface after decontamination was quantitated by measuring radioactivity with a liquid scintillation spectrometer. Both decontaminants removed more than 82% of CEES from skin. DDGel skin decontamination significantly reduced toxicant amount when compared to RSDL. Mean CEES remaining in stratum corneum (SC), viable epidermis, dermis, and systemic absorption of DDGel and RSDL were, 0.12 and 0.55% (P < 0.01), 0.31 and 0.95% (p < 0.01), 1.08 and 2.92% (p < 0.05), 3.13 and 6.34% (p < 0.05), respectively. DDGel showed higher decontamination efficiency (twice decontamination efficacy factor, DEF) than RSDL and efficiently removed chemicals from the skin surface, importantly back-extracted from the SC, and significantly reduced both chemical penetration into skin and systemic absorption. Thus, DDGel can offer a potential as a next generation skin decontamination platform technology for military and civilian applications.