The aim of this study was to determine whether a rowing training program improved the quantity and quality of physical activity and quality of life in female breast cancer survivors (stage I - 4.35%; II - 30.43%; III - 52.17%; and IV - 8.7%) diagnosed 6.57 ± 5.02 years previously, who had undergone a subsequent intervention (preservation 53.52%; total mastectomy 39.13% and double mastectomy 4.35%) and had a current mean age of 53.70 ± 7.88 years. The participants (N = 30) engaged in a 12-week training program, each week comprising three sessions and each session lasting 60-90 minutes. An anthropometric evaluation was performed before and after the program. The short form of the International Physical Activity Questionnaire (IPAQ-SF) and the Short Form 36 Health Survey (SF-36) were also administered. The results showed statistically significant improvements in levels of physical activity and in the dimensions of quality of life. We can conclude that a 12-week rowing training program tailored to women who have had breast cancer increases physical activity levels, leading to improved health status and quality of life.

The intracellular calcium concentration ([Ca2+]i) modulation plays a key role in the regulation of cellular growth and survival in normal cells and failure of [Ca2+]i homeostasis is involved in tumor initiation and progression. Here we show that inhibition of Furin by its naturally occurring inhibitor the prodomain ppFurin in the MDA-MB-231 breast cancer cells resulted in enhanced SOCE through TRPC6 activation that associated reduced cells malignant phenotype. Expression of ppFurin in a stable manner in MDA-MB-231 and the melanoma MDA-MB-435 cell lines inhibits Furin activity as assessed by in vitro digestion assays. Accordingly, cell transfection experiments, revealed that the ppFurin-expressing cells are unable to process adequately the PC substrates proVEGF-C and proIGF-1R. Compared to MDA-MB-435 cells, expression of ppFurin in MDA-MB-231 significantly induces Ca2+ entry which is impaired by silencing of TRPC6 expression. Analysis of TRPC6 activation revealed its up-regulated tyrosine phosphorylation in ppFurin-expressing MDA-MB-231 cells. The expression of ppFurin in MDA-MB-231 cells reduced their viability and ability to migrate and enhanced their sensitization to the apoptosis inducer hydrogen peroxide. These findings suggest that Furin inhibition by ppFurin may be a useful strategy to interfere with Ca2+ mobilization leading to breast cancer cells malignant phenotype repression and reduction of their resistance to treatments.

In this study, we described the most critical risk factors for different malignancies including: breast, prostate, lung, and colorectal carcinoma among others, with an emphasis on modifiable risk factors. We revised the literature review about risk factors involved in the genesis of cancer in various databases, including articles indexed in PUBMED, SCOPUS, PMC, and Google Scholar. Awareness of risk factors enables conscious decisions to be made in an effort to combat malignancies. Knowing risk factors is a mode of fighting malignancy. Diet, lifestyle, practises, and laboratory/clinical interventions were among risk factors of diverse malignancy. Diet, lifestyle, laboratory/clinical interventions all contribute to the genesis and prognosis in a variety of malignancies. We concluded that abstaining from risk factors can prevent the development of many malignancies in a century where this conundrum is raising disproportionately. By informing the public about modifiable risk factors cancer mortality rates can be reduced. It is treated here is to make the public aware of the modifiable risks of cancers.

Circulating tumor cells (CTCs) in the peripheral blood are the precursors to distant metastasis but the underlying mechanisms are poorly understood. This study aims at understanding the molecular features within CTCs in relation to their metastatic potential. Using in vitro CTC models, in which breast cancer cell lines are cultured in non-adherent conditions simulating the microenvironment in the blood stream, we found that suspension culture resulted in resistance to TNF-related apoptosis inducing ligand (TRAIL)-mediated cell death. Such a resistance was directly correlated with a reduction in surface and total levels of DR5 protein. In the non-adherent state, cells underwent rapid autophagic flux characterized by an accumulation of autophagosome organelles. Notably, DR5 was translocated to autophagosomes and underwent lysosomal degradation. Our data suggest that CTCs may evade TNF cytokine mediated immune surveillance through downregulation of DR expression. The data warrants further studies in cancer patients to find the status of DRs and other molecular features within primary CTCs in relation to disease progression or chemoresistance.

Background: Cancer stem cells (CSCs) exhibit self-renewal activity and give rise to other cell types in tumors. Due to the infinite proliferative potential of CSCs, drugs targeting these cells are necessary to completely inhibit cancer development. beta-lapachone (bL) has been widely used to treat cancer development, but its effect on cancer stem cells remain elusive. Thus, we investigated the effect of bL on mammosphere formation using breast cancer stem cell (BCSC) marker positive cells, MDA-MB-231. Methods: MDA-MB-231 Cells, which is negative for NQO1 expression, was constructed to stably express NQO1(NQO1 stable cells) to see the effect of bL. The effect of bL on cells were evaluated by wound healing and Transwell cell culture chambers, and ALDEFLUOR assay. Results: Here, we show that bL inhibited the proliferative ability of mammosphere derived from BCSC marker-positive cells, MDA-MB-231, in an NQO1-dependent manner. bL treatment efficiently downregulated expression level of BCSC markers CD44, ALDH1A1, and DLGAP5 that recently identified as a stem cell proliferation marker in both cultured cells and mammosphered cells. Moreover, bL efficiently downregulates cell proliferation and migration activities. Conclusions: These results strongly suggest that bL could be a therapeutic agent targeting breast cancer stem cells with proper NQO1 expression.

Background: Human epidermal growth factor receptor 2 (HER-2) overexpression can be found in 15-20% of breast cancers, and it strongly correlates with aggressive clinical behavior and adverse prognosis. The first-line treatment for HER-2 positive metastatic breast cancers is the combination of trastuzumab, pertuzumab, and taxane (PTH). ABP 980 is a biosimilar of the innovator trastuzumab and is characterized by highly comparable effectiveness. Methods: The group of 61 patients with HER-2 positive MBC received biosimilar ABP 980 plus pertuzumab and docetaxel from November, 18, 2018 to December, 24, 2019. The response to therapy, overall survival (OS), progression-free survival (PFS), metastases, and adverse effects among patients were determined and analyzed. Results: Initially, 42 women responded partially to the treatment and their median PFS was 27 months. Median PFS for the whole group was 18 months. Cardiotoxicity of treatment was noticed in all patients in the form of the reduction in left ventricular ejection fraction but only in 2 cases, it was the reason for withdrawing from therapy. Conclusion: Biosimilar ABP 980 is registered in the same indications as the innovator trastuzumab and their effectiveness, as well as side effects, are comparable. The costs of biosimilar make the therapy more accessible and thus more patients with MBC around the world can receive relevant treatment.

Sleep is essential for health. Indeed, poor sleep is consistently linked to the development of systemic disease, including depression, metabolic syndrome, and cognitive impairments. Further evidence has accumulated suggesting a role for sleep in cancer initiation and progression (primarily breast cancer). Indeed, patients with cancer and cancer survivors frequently experience poor sleep, manifested as insomnia, circadian misalignment, hypersomnia, somnolence syndrome, hot flushes, and nightmares. These problems are associated with a reduction in patients’ quality of life and increased mortality. Due to the heterogeneity among cancers, treatment regimens, patient populations, and lifestyle factors, the etiology of cancer-induced sleep disruption is largely unknown. Here, we discuss recent advances in understanding the pathways linking cancer and the brain and how this leads to altered sleep patterns. We describe a conceptual framework where tumors disrupt normal homeostatic processes, resulting in aberrant changes in physiology and behavior that are detrimental to health. Finally, we discuss how this knowledge can be leveraged to develop novel therapeutic approaches for cancer-associated sleep disruption, with special emphasis on host-tumor interactions.

Development of novel anti-cancer peptides requires a rapid screening process which can be accelerated by using appropriate in vitro tumor models. Breast carcinoma tissue is a three dimensional (3D) microenvironment, which contains a hypoxic center surrounded by dense proliferative tissue. Biochemical clues provided by such 3D cell mass cannot be recapitulated in conventional 2D culture systems. In this experiment, we evaluate the efficacy of the sandalwood peptide, cyclosaplin on established in vitro 3D silk breast cancer model using invasive MDA-MB-231 cell line. The anti-proliferative effect of the peptide on 3D silk tumor model is monitored by alamar blue assay, with conventional 2D culture as control. The proliferation rate, glucose consumed, LDH, and MMP-9 activity of Human breast cancer cells are higher in 3D constructs compared to 2D. A higher concentration of drug is required to achieve 50% cell death in 3D culture than 2D cultures. The cyclosaplin treated MDA-MB-231 cells showed significant decrease in MMP-9 activity in 3D constructs. Microscopic analysis revealed the formation of cell clusters evenly distributed in the scaffolds. The drug treated cells were less in number, smaller and showed unusual morphology. Overall, these findings indicate the role of cyclosaplin as a promising anti-cancer therapeutics.

Lipid-based drugs are emerging as an interesting class of novel anticancer drugs with the potential to target specific cancer cell metabolic pathway linked to their proliferation and invasiveness. In particular, ω−3 polyunsaturated fatty acids (PUFA) derivatives such as epoxides and their bioisosteres have demonstrated the potential to suppress growth and promote apoptosis in triple-negative human breast cancer cells MDA-MB-231. In this study 16-(4’-chloro-3’-trifluorophenyl)carbamoylamino]hexadecanoic acid (ClFPh-CHA), an anticancer lipid derived from ω−3,17,18-epoxyeicosanoic acid, was formulated as a stable nanoemulsion with size around 150 nm and narrow droplet size distribution (PDI<0.200) through phase-inversion emulsification process followed by high pressure homogenization in view of an oral administration. The ClFPh-CHA-loaded nanoemulsions were able to significantly decrease the relative tumor volume in mice bearing an intramammary tumor xenograft at all doses tested (2.5, 10 and 40 mg/kg) after 32 days of daily oral administration. Furthermore, absolute tumor weight was decreased to 50% of untreated control at 10 and 40 mg/kg, while intraperitoneal administration could achieve a significant reduction only at the highest dose of 40 mg/kg. Results suggest that oral administration of ClFPh-CHA formulated as a nanoemulsion has a sufficient bioavailability to provide an anticancer effect in mice and that the activity is at least equal if not superior to that obtained by a conventional parenteral administration of equivalent doses of the same drug.

Cancer cells are adept at reprogramming energy metabolism and the precise manifestation of this metabolic reprogramming exhibits heterogeneity across individuals (and from cell to cell). In this study, we analyzed the metabolic differences between interpersonal heterogeneous cancer phenotypes. We used divergence analysis on gene expression data of 1156 breast normal and tumor samples from The Cancer Genome Atlas (TCGA) and integrated this information with a genome-scale reconstruction of human metabolism to generate personalized, context-specific metabolic networks. Using this approach, we classified the samples into four distinct groups based on their metabolic profiles. Enrichment analysis of the subsystems indicated that amino acid metabolism, fatty acid oxidation, citric acid cycle, androgen and estrogen metabolism and ROS detoxification distinguished these four groups. Additionally, we developed a workflow to identify potential drugs that can selectively target genes associated with the reactions of interest. MG-132 (a proteasome inhibitor) and OSU-03012 (a celecoxib derivative) were the top-ranking drugs identified from our analysis and known to have anti-tumor activity. Our approach has the potential to provide mechanistic insights into cancer-specific metabolic dependencies, ultimately enabling the identification of potential drug targets for each patient independently, contributing to a rational personalized medicine approach.

Aims: To assess the occurrence of Chemotherapy-induced nausea and vomiting (CINV) after standard antiemetic therapy in the acute (24 h post-chemotherapy) and delayed (2–5 days post-chemotherapy) phases, as well as to identify risk factors for CINV in the acute and delayed phases. Methods: This prospective longitudinal and observational study analyzed the data of 400 breast cancer patients scheduled for chemotherapy over two cycles in two hospitals. The self-report survey was developed to assess the occurrence of CINV and their associated factors. CINV was evaluated with a Multinational Association of Supportive Care in Cancer Antiemetic Tool (MAT) on days 2 and 6 of chemotherapy. The incidence of acute and delayed CINV were presented by frequency and percentage. Generalized equation estimates (GEE) was used to identify risk factors of acute and delayed CINV. Results: There were 400 evaluable patients with complete Round 1 data, 334 for Round 2 data. Among 400 patients, 29.8% and 23.5% experienced acute and delayed CINV, respectively. Risk factors associated with for acute CINV were pain/insomnia, history of CINV, history of motion sickness (MS), and highly emetogenic chemotherapy regimen, while history of MS, CINV history, number of completed chemotherapy cycle number < 3, and the incidence of acute CINV were risk factors of delayed CINV (all p < 0.05). Conclusions: The findings may help nurses working for Chinese population in identifying patients at risk for CINV and in planning effective program to reduce the occurrence of CINV.

Translational medicine requires facile experimental systems to replicate the dynamic biological systems of diseases. Drug approval continues to lag, partly due to incongruencies in the research pipeline that traditionally involve 2D models, which could be improved with 3D models. The bone marrow (BM) poses challenges to harvest as an intact organ making it difficult to study disease processes such as breast cancer (BC) survival in BM, and to effective evaluation of drug response in BM. Furthermore, it is a challenge to develop 3D BM structures due to its weak physical properties, and complex hierarchical structure and cellular landscape. To address this, we leveraged 3D bioprinting to create a BM structure with varied methylcellulose (M):alginate (A) ratios. We selected hydrogels containing 4% (w/v) M and 2% (w/v) A, which recapitulates rheological and ultrastructural features of the BM while maintaining stability in culture. This hydrogel sustained the culture of two key primary BM microenvironmental cells found at the perivascular region, mesenchymal stem cells and endothelial cells. More importantly, the scaffold showed evidence of cell autonomous dedifferentiation of BC cells to cancer stem cell properties. This scaffold could be the platform to create BM models for various disease and also for drug screening.

Breast cancer is among the most common and fatal diseases for women, and no permanent treatment has been discovered. Thus, early detection is a crucial step to control and cure breast cancer that can save the lives of millions of women. For example, in 2020, more than 65% of breast cancer patients were diagnosed in early-stage of cancer, from whom all survived cancer. Although early detection is the most effective approach for cancer treatment, breast cancer screening conducted by radiologists is very expensive and time-consuming. More importantly, conventional methods of analyzing breast cancer images suffer from high false detection rates. Different breast cancer imaging modalities are used to extract and analyze the key features affecting diagnosis and treatment of breast cancer. These imaging modalities can be divided into subgroups such as mammograms, ultrasound, magnetic resonance imaging, histopathological images, or any combination of them. Radiologists or pathologists analyze images produced by these methods manually that leads to increase the risk of wrong decisions for cancer detection. Thus, utilization of new automatic methods to analyze all kinds of breast screening images to assist radiologists to interpret images is required. Recently, artificial intelligence (AI) has been widely utilized to automatically improve the early detection and treatment of different types of cancer, specifically breast cancer, thereby enhancing the survival chance of patients. Advances in AI algorithms, such as deep learning, and availability of datasets obtained from various imaging modalities have opened an opportunity to surpass limitations of current breast cancer analysis methods. In this article, we first review breast cancer imaging modalities, and their strengths and limitations. Then, we explore and summarize the most recent studies that employed AI in breast cancer detection using various breast imaging modalities. In addition, we report available datasets on the breast cancer imaging modalities which are important in developing AI-based algorithms and training deep learning models. In conclusion, this review paper tries to provide a comprehensive resource to help researchers working in breast cancer imaging analysis.

Breast cancer is a leading cause of death among women. Conventional screening methods, such as mammography, and ultrasound diagnosis are expensive and have significant limitations. Digital Image Elasto Tomography (DIET) is a new noninvasive breast cancer screening system that has a potential to be a low cost and reliable breast cancer screening tool. It is based on modal analysis of the breast mass, and stereographic 3D image analysis to detect the stiffer abnormal tissues. However, camera sensor noise, especially Gaussian noise is a major source of Optical Flow (OF) error in this approach to tumor detection. This work studies the performance of different conventional filters, including the standard Gaussian filter tool to remove this noise and produce more robust screening results. A radical approach, Multiple Frame Noise Removal (MFNR) is proposed, for use in this type of medical image processing instead of a Gaussian filter or other typical image noise removal tools. Its a multiple frame noise removal method where Probability Density Function (PDF) of noise is extracted from the multiple images by characterizing the same pixel positions in multiple images. The noise becomes deterministic, and hence easily removed. The proposed algorithm was applied to a data set from 10 phantom breast tests with a prototype DIET system, and 10 in-vivo samples from healthy women. Comparisons were made to an optimal Gaussian filter form that is commonly used. Reductions in OF error using these digitally imaged data sets was used to compare performance. Refinement of the images for medical applications requires higher PSNR, which was successfully achieved by using MFNR algorithm. In this study, the algorithm was used to improve the imaging results of a DIET system. The conventional wisdom that states that noise removal and detail preservation are contrasting effects is

The identification and molecular characterization of cellular hierarchies in complex tissues is key to understanding both normal cellular homeostasis and tumorigenesis. The mammary epithelium is a heterogeneous tissue consisting of two main cellular compartments, an outer basal layer containing myoepithelial cells and an inner luminal layer consisting of estrogen receptor-negative (ER⁻) ductal cells and secretory alveolar cells (in the fully functional differentiated tissue) and hormone-responsive estrogen receptor-positive (ER⁺) cells. Recent publications have used single-cell RNA-sequencing (scRNA-seq) analysis to decipher epithelial cell differentiation hierarchies in human and murine mammary glands, and reported the identification of new cell types and states based on the expression of the luminal progenitor cell marker KIT (c-Kit). These studies allow for comprehensive and unbiased analysis of the different cell types that constitute a heterogeneous tissue. Here we discuss scRNA-seq studies in the context of previous research in which mammary epithelial cell populations were molecularly and functionally characterized, and identified c-Kit⁺ progenitors and cell states analogous to those reported in the recent scRNA-seq studies.

Purpose: Recently introduced molecules namely long non-coding RNAs (lncRNAs) are associated with various diseases, including breast cancer, and they may have the potential to act as biomarkers. Invasive ductal carcinoma (IDC) is a frequently observed type of breast cancer that diagnosis through immunohistochemical methods. However, no reliable non-invasive markers such as circulating markers have been introduced for it, so far. Materials and methods: The relative quantitation (RQ) of two lncRNAs, RP11-445H22.4 and TINCR, was measured in tumoral tissues and paired adjacent non-tumoral tissues (PANTs) as well as in plasma samples using real-time polymerase chain reaction (RT-PCR). Furthermore, promoter methylation of the two lncRNAs genes was assessed using methylation-specific PCR (MSP). In order to compare the diagnostic values, plasma levels of CA 15-3 were measured as a conventional circulating biomarker using ELISA. The receiver operating characteristic (ROC) curve was used to illustrate the sensitivity and specificity of the potential biomarkers. Results: The RP11-445H22.4 and TINCR genes were upregulated in tumor tissues compared to PANTs (RQ_{RP11-445H22.4} = 2.7, RQ_TINCR = 4.4). Furthermore, the presence of RP11-445H22.4 and TINCR in the plasma of patients was significantly more than healthy controls (RQ_{c.RP11-445H22.4} = 4.12, RQ_c.TINCR = 4.16, P<0.001). The promoters of RP11-445H22.4 and TINCR genes were hypomethylated in the tumoral tissues with a negative correlation with their gene expression. Conclusion: Based on the findings, it can be speculated that the expression levels of these two lncRNAs as well as their promoter methylation can be considered as a therapeutic target and potential biomarker for breast carcinoma.

Background: Metastasis is a complex process that involves the spread of the tumor to distant parts of the body from its original site. Metastatic dissemination represents the main physiopathology of cancer. Soluble factors such as cytokines have been closely related to breast cancer (BC) metastasis. Bisphenol A (BPA) is an endocrine disrupting chemical compound with estrogenic properties, which exposure in the early stages of neonatal life leads to an increase in the size and weight of breast tumors and cellular changes in the tumoral immune microenvironment. Methods: Thus, we used female BALB/c mice that were exposed neonatally to a single dose of BPA. Once sexual maturity was reached, a mammary tumor was induced injecting 4T1 cells in situ. After 25 days of injection, we evaluated endocrine alterations, cytokine expression, tissue alterations denoted by macro and micro metastases in the lung, and metastasis-induced cell infiltration. Results: BPA neonatal treatment did not show significant endocrine alterations. Nevertheless, BPA induced a great rate of metastasis to the lung associated with higher intratumoral expression of IL-1b, IL-6, IFN-g, TNF-a and VEGF. Conclusions Our data suggest that cytokines are key players in BC metastasis induction, and that BPA is a risk factor to be considered. This knowledge must be considered with the aim of recognizing environmental pollution in the clinical history of patients to possibly counter BC metastases.

Immune checkpoint blockade (ICB)-based therapy is revolutionizing cancer treatment by fostering successful immune surveillance and effector cell responses against various types of cancers. However, patients with HER2+ cancers are yet to benefit from this therapeutic strategy. Precisely, several questions regarding the right combination of drugs, drug modality, and effective dose recommendations pertaining to the use of ICB-based therapy for HER2+ patients remain unanswered. In this study, we use a mathematical modeling-based approach to quantify the growth inhibition of HER2+ breast cancer (BC) cell colonies (ZR75) when treated with anti-HER2; trastuzumab (TZ) and anti-PD-1/PD-L1 (BMS-202) agents. Our data show that a combination therapy of TZ and BMS-202 can significantly reduce the viability of ZR75 cells and trigger several morphological changes. The combination decreased the cell’s invasiveness along with altering several key pathways, such as Akt/mTor and ErbB2 compared to monotherapy. In addition, BMS-202 causes dose-dependent growth inhibition of HER2+ BC cell colonies alone, while this effect is significantly improved when used in combination with TZ. Based on the in-vitro monoculture experiments conducted, we argue that BMS-202 can cause tumor growth suppression not only by mediating immune response but also by interfering with the growth signaling pathways of HER2+ BC. Nevertheless, further studies are imperative to substantiate this argument and to uncover the potential crosstalk between PD-1/PD-L1 inhibitors and HER2 growth signaling pathways in breast cancer.

Triple negative breast cancers (TNBCs) are molecularly heterogeneous, and the link between their aggressiveness with African ancestry is not established. We investigated primary TNBCs for gene expression among self-reported race (SRR) groups of African American (AA, n=42) and European American (EA, n=33) women. Using The Cancer Genome Atlas (TCGA) approaches, we analyzed RNA sequencing data to measure changes in genome-wide expression and used logistic regressions to identify ancestry-associated gene expression signatures. To determine global ancestry, GATK best practices were followed for variant calling, and used the 1000 Genomes Project as reference data. We identified >150 African ancestry-associated genes and found that, compared to SRR, quantitative genetic analysis was a more robust method to identify racial/ethnic-specific genes that were differentially expressed. A subset of African ancestry-specific genes that were upregulated in TNBCs of our AA patients were validated in TCGA data. In AA patients, there was a higher incidence of basal-like 2 tumors and altered TP53, NFB1, and AKT pathways. The distinct distribution of TNBC subtypes and altered oncologic pathways show that the ethnic variations in TNBCs are driven by shared genetic ancestry. Thus, to appreciate the molecular diversity of TNBCs, tumors from patients of various ancestral origins should be evaluated.

Background: Pathologic complete response (pCR) of breast cancer after neoadjuvant chemotherapy (NAC) is highly related to molecular subtypes. Patients who achieved tumor pCR after NAC have a better prognosis. However, despite of better prognosis, pCR patients have a potential for recurrence. There is little evidence of risk factors of recurrence in patients with pCR. We aim to analyze factors associated with tumor recurrence in patients who achieved pCR. Methods: This study retrospectively reviewed the data of patients diagnosed with breast cancer who achieved pCR after receiving NAC between January 2009 and December 2018 in Samsung Medical Center. pCR was defined as no residual invasive cancer in the breast and axillary nodes even if there is residual ductal carcinoma in situ (ypT0 or ypTis with ypN0). Breast cancers are classified into 4 subtypes based on hormone receptors (HR) and human epithelial growth factor receptor 2 (HER2) status. Patients who had bilateral breast cancer, inflammatory breast cancer, distant metastasis, unknown subtype, and histologically unique case were excluded from the study. Results: In total 483 patients were included in this study except for patients who corresponded to the exclusion criteria. The median follow-up duration was 59.0 months (range, 0.5-153.3 months). Breast cancer recurred in 4.1% of patients (20 of 483). There was a significant difference in clinical T (p = .004) and clinical N (p = .034) stage in the Kaplan-Meier curve for disease-free survival. Molecular subtypes (p = .573), Ki67 (p = 1.000), and breast surgery type (p = .574) were not associated with tumor recurrence in patients who achieved pCR after NAC. In the clinical T stage and clinical N stage, there was a significant difference between recurrence and no-recurrence groups (clinical T stage; p = .045, clinical N stage; p = .002). Univariable Cox regression revealed statistical significance in the clinical T stage (p = .049) and clinical N stage (p = .010), while multivariable Cox regression demonstrated non-significance in the clinical T stage (p = .320) and clinical N stage (p = .073). Conclusion: Results in this study showed that clinical T, clinical N stage, and molecular subtypes were not statistically significant predictors of recurrence in patients who achieved pCR after NAC. It is hypothesized that a multicenter-based study would lead to the identification of factors as predictors of recurrence after achieving pCR.

Gambogic acid, a common traditional Chinese medicine and widely distributed throughout South China, Vietnam, Cambodia, and Thailand. It is prenylated xanthone which is the significant bioactive compound of gamboge. Gambogic acid is known as a strong apoptotic inducer in cancer cells. It has been found as strong anticancer agent against various types of cancer cells lines such as breast cancer, pancreatic, and cervical cancer. It induces apoptosis, down regulates the anti-apoptotic proteins (survivin and BCL2,) and down regulates the activities of P-glycoprotein in drug sensitive human breast MCF-7 and drug-resistant MCF-7/ADR cells. Similarly, it also exerts alteration in P13K, AKT, p21, MMP-2 &-9, and phosphorylated-AKT expressions. The current review highlights the anticancer and chemo-preventive perspectives of gambogic acid and its mechanistic role against human and animal cancers.

Epidemiological studies on micronutrient consumption have reported protective associations in the incidence and/or progression of various cancer types. Supplementation with some of these micronutrients has been analyzed, showing chemoprotection, low toxicity, antiproliferation, and the ability to modify epigenetic signatures in various cancer models. The following review inves-tigates the reported effects of micronutrient intake or supplementation in breast cancer progres-sion. A PubMed search was conducted with the keywords “micronutrients breast cancer progres-sion,” and the results were analyzed. The selected micronutrients were: Vitamins (A, C, D, and E), Folic Acid, metals (Cu, Fe, Se, and Zn), fatty acids, polyphenols, and iodine. The majority of in vitro models showed antiproliferative, cell cycle arrest, and antimetastatic effects for almost all the micronutrients analyzed, but these effects do not reflect animal or human studies. Only one clinical trial with Vitamin D and one pilot study with molecular iodine showed favorable overall survival and disease-free interval.

Background: Circulating tumor cells (CTC) have relevance as prognostic markers in breast cancer. However, the functional properties of CTCs or their molecular characterization have not been well-studied. Experimental models indicate that only a few cells can survive in the circulation and eventually metastasize. Thus, it is essential to identify these surviving cells capable of forming such metastases. Methods: We isolated viable CTCs from 50 peripheral blood samples obtained from 35 patients with advanced metastatic breast cancer using RosetteSepTM for ex vivo culture. The CTCs were seeded and monitored on plates under low adherence conditions and with media supplemented with growth factors and Nanoemulsions. Phenotypic analysis was performed by immunofluorescence and gene expression analysis using RT-PCR and CTCs counting by Cellsearch® system. Results: We found that in 75% of samples the CTC cultures lasted more than 23 days, predicting a shorter Progression-Free Survival in these patients, independently of having ≥ 5 CTC by Cellsearch®. We also observed that CTCs before and after culture showed a different gene expression profile. Conclusions: the cultivability of CTCs is a predictive factor. Furthermore, the subset of cells capable of growing ex vivo show stem or mesenchymal features and may represent the CTC population with metastatic potential in vivo.

Purpose: Surgical site infection (SSI) is a significant complication of non-reconstructive and reconstructive breast. This study aimed to assess SSI after breast surgery over 5 years in a single center in Poland. The microorganisms responsible for SSI and their antibiotic susceptibility were determined. Materials/methods: Data of 2129 patients acquired over 5 years postoperatively by the [center] were analyzed. Results: SSI was diagnosed in 132 patients (6.2%) and was an early infection in most cases (65.2%). The incidence of SSI was highest in patients who underwent subcutaneous amputation with simultaneous reconstruction using an artificial prosthesis (14.6%) and breast reconstruction via the TRAM flap method (14.3%). Gram-positive bacteria were responsible for SSI in most cases (72.1%), and these were mainly Staphylococcus strains (53.6%). These strains were 100% susceptible to all beta-lactam antibiotics (except penicillin), but were less susceptible to macrolides and lincosamides. Conclusions: SSI is a serious problem, and attention should be focused on its prevention. Reconstruction using an artificial prosthesis or via the TRAM flap method is connected to increased SSI incidence. Further studies are required to prevent SSI following breast surgery.

Breast cancer develops from cells lining the milk ducts and slowly grows into a lump or a tumour. Breast cancer may be invasive or non-invasive. Invasive cancer spreads from the milk duct or lobule to other tissues in the breast, whereas, non-invasive ones lack the ability to invade other breast tissues. Non-invasive breast cancer is called in situ and may remain inactive for entire lifetime. Due to heterogeneity nature of breast, density as well as masses is variable in size and shape. A dataset of 18056 patients are collected from 20 Government Hospitals and 50 Private Hospitals in West Bengal before COVID-19 and after COVID-19. The classification of patients are made on three classes- Normal, Sign of Abnormality and Abnormality. The reports of MRIs of patients in January 2020 and February 2020 are collected from different hospitals. It is treated as dataset before COVID-19 . MRIS of patients in April 2020 and May 2020 are dataset during COVID-19. The entire datasets are accumulated for testing of any change in patients MRIS after the official announcement of new virus COVID-19 in March 2020. The aim of the paper is to make a comparison of any change in size and shape of masses of MRIs of patients before and after COVId-19. All collected MRIs reports are diagnosed by radiologists of hospitals.

Inherited mutations in BRCA1 and BRCA2 genes increase risks for breast, ovarian, and other cancers. Both genes encode proteins for accurately repairing chromosome breaks. If mutations inactivate this function, chromosome fragments may not be restored correctly. Resulting chromosome rearrangements can become critical breast cancer drivers. Because I had data from thousands of cancer structural alterations that matched viral infections, I wondered whether infections contribute to chromosome breaks and rearrangements in hereditary breast cancers. There are currently no interventions to prevent chromosome breaks because they are thought to be unavoidable. However, if chromosome breaks come from infections, they can be treated or prevented. I used bioinformatic analyses to test publicly available breast cancer sequence data around chromosome breaks for DNA similarity to all known viruses. Human DNA flanking breakpoints usually had the strongest matches to Epstein-Barr virus (EBV) tumor variants HKHD40 and HKNPC60. Many breakpoints were near sites that anchor EBV genomes, human EBV tumor-like sequences, EBV-associated epigenetic marks, and fragile sites. On chromosome 2, sequences near EBV genome anchor sites accounted for 90% of breakpoints (p<0.0001). On chromosome 4, 51/52 inter-chromosomal breakpoints were close to EBV-like sequences. Five EBV genome anchor sites were near breast cancer breakpoints at precisely defined, disparate gene or LINE locations. Breakpoint flanking regions resembled known EBV-cancers. Twenty-five breakpoints in breast cancers were within 1.25% of EBV cancer breakpoints. In addition to BRCA1 or BRCA2 mutations, all the breast cancers had mutated genes essential for immune responses. Because of this immune compromise, herpes viruses can activate and produce nucleases that break chromosomes. Alternatively, anchored viral episomes can obstruct break repairs, whatever the cause. The results, therefore, imply proactive treatment and prevention of herpes viral infections may prevent some chromosome breaks and benefit BRCA mutation carriers.

The epidermal growth factor receptor (EGFR) exon-19 deletion is one of the most common mutations detected in lung cancer patients. Although exon-19 deletion is frequently detected in adenocarcinoma, observing this mutation in germline cells is very rare. Besides, the co-occurrence of homozygous and heterozygous mutations in dual primary cancers in a person is very uncommon. This article presents a 53-year-old Iranian woman with no history of smoking who was diagnose with two primary cancers; invasive ductal carcinoma, and primary pulmonary lung adenocarcinoma. The case reported a history of breast cancer in her sister and a history of lung cancer in her father. To select the best choice of treatment the EGFR gene was analyzed with Sanger’s sequencing method from DNA extracted from the patient’s lung tissue sample. Observing two primary cancers in this patient and considering her family pedigree, germline cells were also analyzed using samples recruited from the patient’s peripheral blood to investigate any EGFR mutations in her germline cells. The obtained data revealed that the lung tissue of the patient carried a homozygous form of EGFR exon-19 deletion while her peripheral blood contained a heterozygous form of this mutation, which is exceptionally rare.

Neutrophil to lymphocyte ratio (NLR) is a promising predictive and prognostic factor in breast cancer. We investigated its ability to predict disease-free survival (DFS) and overall survival (OS) in patients with luminal A or luminal B-HER2-negative breast cancer who received neoadjuvant chemotherapy (NACT). Pre-treatment complete blood cell counts from 168 consecutive patients with luminal breast cancer were evaluated to assess NLR. The study population was stratified into NLRlow or NLRhigh according to a cut-off value established by receiving operator curve (ROC) analysis. Data on additional pre- and post-treatment clinical-pathological characteristics were also collected. Kaplan-Meier curves, log-rank tests, and Cox proportional hazards models were used for statistical analyses. Patients with pre-treatment NLRlow showed a significantly shorter DFS (HR 6.97, 95% CI 1.65-10.55, p= 0.002) and OS (HR 7.79, 95% CI 1.25-15.07, p= 0.021) compared to those with NLRhigh. Non-ductal histology, luminal B subtype, and post-treatment Ki67≥ 14% were also associated with worse DFS (p= 0.016, p= 0.002, and p= 0.001, respectively). In multivariate analysis, luminal B subtype, post-treatment Ki67≥ 14%, and NLRlow remained independent prognostic factors for DFS, while only post-treatment Ki67≥ 14% and NLRlow affected OS. The present study provides evidence that pre-treatment NLRlow helps identify women at higher risk of recurrence and death among patients affected by luminal breast cancer treated with NACT.

Patients diagnosed with unresectable locally advanced Triple Negative Breast Cancer (TNBC) usually have poor outcome for its aggressive clinical behaviour. Atezolizumab plus nanoparticle albumin-bound (nab)-Paclitaxel prolonged progression-free survival (PFS) and overall survival (OS) among patients with unresectable locally advanced TNBC but its use is hampered by the lack of reliable predictors of tumor response. Seventy-seven consecutive patients with unresectable locally advanced TNBC treated with Atezolizumab plus nab-Paclitaxel were studied by blood draws at baseline, 28 days and 56 days after initiation of treatment. Exosomal PD-L1 mRNA in plasma was determined using Bio-Rad QX100 digital droplet PCR system and exoRNeasy kit and objective responses were defined following the RECIST criteria v.1.1. The study evaluates whether PD-L1 mRNA copies per ml in plasma-derived exosomes may predict response to anti-PD-L1 antibodies early in the course of therapy. Our data showed patients with unresectable locally advanced TNBC and higher levels of PD-L1 mRNA expression in plasma-derived exosomes at baseline demonstrated greater response to atezolizumab plus nab-paclitaxel. Furthermore, the levels of mRNA decreased with successful treatment while the copy number increased in patients experiencing disease progression following atezolizumab plus nab-paclitaxel. For the first time, our data showed the usefulness of assessment of exosomal PD-L1 as non-invasive real-time biopsy in patients diagnosed with TNBC suggesting exosomal PD-L1 is significantly associated with outcome and response to Atezolizumab plus nab-Paclitaxel.

Wooden breast is a muscle disorder affecting modern commercial broiler chickens that causes a palpably firm pectoralis major muscle and severe reduction in meat quality. Most studies have focused on advanced stages of wooden breast apparent at market age, resulting in limited insights into the etiology and early pathogenesis of the myopathy. Therefore, the objective of this study was to identify early molecular signals in the wooden breast transcriptional cascade by performing gene expression analysis on the pectoralis major muscle of two-week-old birds that may later exhibit the wooden breast phenotype by market age at 7 weeks. Biopsy samples of the left pectoralis major muscle were collected from 101 birds at 14 days of age. Birds were subsequently raised to 7 weeks of age to allow sample selection based on the wooden breast phenotype at market age. RNA sequencing was performed on 5 unaffected and 8 affected female chicken samples, selected based on wooden breast scores (0 to 4) assigned at necropsy where affected birds had scores of 2 or 3 (mildly or moderately affected) while unaffected birds had scores of 0 (no apparent gross lesions). Differential expression analysis identified 60 genes found to be significant at an FDR-adjusted p value of 0.05. Of these, 26 were previously demonstrated to exhibit altered expression or genetic polymorphisms related to glucose tolerance or diabetes mellitus in mammals. Additionally, 9 genes have functions directly related to lipid metabolism and 11 genes are associated with adiposity traits such as intramuscular fat and body mass index. This study suggests that wooden breast disease is first and foremost a metabolic disorder characterized primarily by ectopic lipid accumulation in the pectoralis major.

The botanical species Ceratonia siliqua L., commonly referred to as the Carob tree, and locally as “L’Kharrûb”, holds significance as an agro-sylvo-pastoral species, and is traditionally utilized in Morocco for treating a variety of ailments. This current investigation aims to ascertain the antioxidant, antimicrobial, and cytotoxic properties of the ethanolic extract of C. siliqua leaves (CSEE). Initially, we analyzed the chemical composition of CSEE through high-performance liquid chromatography with Diode-Array Detection (HPLC-DAD). Subsequently, we conducted various assessments, including DPPH scavenging capacity, β-carotene bleaching assay, ABTS scavenging, and total antioxidant capacity assays, to evaluate the antioxidant activity of the extract. In this study, we investigated the antimicrobial properties of CSEE against five bacterial strains (two gram-positive, Staphylococcus aureus, and Enterococcus faecalis; and three gram-negative bacteria, Escherichia coli, Escherichia vekanda, and Pseudomonas aeruginosa) and two fungi (Candida albicans, and Geotrichum candidum). Additionally, we evaluated the cytotoxicity of CSEE on three human breast cancer cell lines (MCF-7, MDA-MB-231, and MDA-MB-436) and assessed the potential genotoxicity of the extract using the comet assay. Through HPLC-DAD analysis, we determined that phenolic acids and flavonoids were the primary constituents of the CSEE extract. The results of the DPPH test indicated a potent scavenging capacity of the extract with an IC50 of 302.78 ± 7.55 µg/mL, which was comparable to that of ascorbic acid with an IC50 of 260.24 ± 6.45 µg/mL. Similarly, the β-carotene test demonstrated an IC50 of 352.06 ± 12.16 µg/mL, signifying the extract's potential to inhibit oxidative damage. The ABTS assay revealed IC50 values of 48.13 ± 3.66 TE µmol/mL, indicating a strong ability of CSEE to scavenge ABTS radicals, and the TAC assay demonstrated an IC50 value of 165 ± 7.66 µg AAE/mg. The results suggest that the CSEE extract had potent antioxidant activity. Regarding its antimicrobial activity, the CSEE extract was effective against all five tested bacterial strains, indicating its broad-spectrum antibacterial properties. However, it only showed moderate activity against the two tested fungal strains, suggesting it may not be as effective against fungi. The CSEE exhibited a noteworthy dose-dependent inhibitory activity against all the tested tumor cell lines in vitro. The extract did not induce DNA damage at the concentrations of 6.25, 12.5, 25, and 50 µg/ml, as assessed by the comet assay. However, the 100 µg/ml concentration of CSEE resulted in a significant genotoxic effect compared to the negative control. A computational analysis was conducted to determine the physicochemical and pharmacokinetic characteristics of the constituent molecules present in the extract. The Prediction of Activity Spectra of Substances (PASS) test was employed to forecast the potential biological activities of these molecules. Additionally, the toxicity of the molecules was evaluated using the Protox II webserver.

A developed six-port reflectometry (SPR) system was integrated to measure the relative permittivity of tumor and normal breast tissue for medical diagnostic purpose. In order to obtain an accurate and precise measurement, the calibration process was done to the SPR using the well-known three-standard technique. Next, the studied dielectric probe was connected to the calibrated measurement-port of the SPR. The open end of the probe aperture was dibbed into the normal and tumor synthetic breast tissue samples to measure the synthetic breast tissues dielectric constant, ɛrʹ, and loss factor, ɛrʺ in the frequency range of 1.5 GHz to 3.3 GHz. Finally, the comparative studies were conducted between commercial VNA with Keysight 85070E dielectric probe and the studied SPR-probe system based on the measured magnitude of the reflection coefficient, phase shift, dielectric constant, and loss factor of the synthetic breast samples. The maximum absolute errors of the measured reflection coefficient magnitude, phase shift, dielectric constant, and loss factor were found to be 0.01, 1.07°, 1.12, and 0.75, respectively. It was ascertained that the predicted dielectric constant, ɛrʹ, is able to differentiate between normal, (ɛrʹ &lt; 50) and tumor, (ɛrʹ &gt; 50) breast tissues.

Endophytic fungi are a diverse group of microorganisms that colonize the inter- or intracellular spaces of plants for mutual benefits. The interactions with a host plant and other microbiomes are multidimensional and play a crucial role in the production of secondary metabolites. We screened bioactive compounds present in the extracts of Aspergillus flavus, an endophytic fungus isolated from the roots of the medicinal grass Cynodon dactylon, for its anticancer potential. Ethyl acetate extract from isolated A. flavus showed significant cytostatic effects (IC50: 16.25 μg mL−1) against breast cancer cells (MCF-7). Morphology of cells and DAPI stained nuclei along with the results of flow cytometry annexin V/PI assay suggested apoptosis to be the main process leading to cells’ death. While investigating the mechanism that triggers apoptosis, we found that the extract of A. flavus increased ROS generation and caused loss of mitochondrial membrane potential of MCF-7 cells. To identify the metabolites that might be responsible for the anticancer effect, the extract was examined using gas chromatography-mass spectrometry (GC-MS). Interestingly, nine phytochemicals were found to have potential inhibitory effects of anti-apoptotic protein (Bcl-2) in the breast cancer cells. In the in silico molecular docking and molecular dynamics simulation studies revealed that two compounds: 2,4,7-Trinitrofluorenone and 3alpha, 5alpha-Cyclo-ergosta-7,9(11),22t-triene-6beta-ol exhibited significant binding affinities (-9.20, and -9.50 Kcal mol-1, respectively) against Bcl-2 along with binding stability and intermolecular interactions of its ligand-Bcl-2 complexes. Overall, the study found that the endophytic A. flavus from C. dactylon contains plant-like bioactive compounds that have a promising effect in breast cancer.

Current oncological developments are based on improved understanding of genetics, and especially the discovery of genes whose alterations affect cell functions with consequences for the whole body. Our work is focused on the one of these genes, the BARD1 and its oncogenic role in breast cancer. Most importantly, the study points to new avenues in the treatment and prevention of the most frequent female cancer based on BARD1 research. The BARD1 and BRCA1 proteins have similar structures and functions, and they combine to form the new molecule BARD1-BRCA1 heterodimer. The BARD1-BRCA1 complex is involved in genetic stabilization at the cellular level. It allows to mark abnormal DNA fragments by attaching ubiquitin to them. In addition, it blocks (by ubiquitination of RNA polymerase II) the transcription of damaged DNA. Ubiquitination, as well as stabilizing chromatin, or regulating the number of centrosomes, confirms the protective cooperation of BARD1 and BRCA1 in the stabilization of the genome. The overexpression of the oncogenic isoforms BARD1β and BARD1δ permit cancer development. The introduction of routine tests, for instance, to identify the presence of the BARD1β isoform, would make it possible to detect patients at high risk of developing cancer. On the other hand, introducing BARD1δ isoform blocking therapy, which would reduce estrogen sensitivity, may be a new line of cancer therapy with potential to modulate responses to existing treatments. It is possible that the BARD 1 gene offers new hope for improving breast cancer therapy.

Molecular iodine (I2) induces apoptotic, antiangiogenic, and antiproliferative effects in breast cancer cells. Little is known about its effects on the tumor immune microenvironment. We studied the effect of oral (5 mg/day) I2 supplementation alone (I2) or together with conventional chemotherapy (Cht+I2) on the im-mune component of breast cancer tumors from a previously published pilot study conducted in Mexico. RNA-seq, I2 and Cht+I2 samples showed significant increases in expression of Th1 and Th17 pathways. Tumor immune composition determined by deconvolution analysis revealed significant increases in M0 macrophages and B lymphocytes in both I2 groups. Real-time RT-PCR showed that I2 tumors overexpress T-BET (p = 0.019) and interferon-gamma (IFNγ; p = 0.020) and silence tumor growth factor-beta (TGFβ; p = 0.049); whereas in Cht+I2 tumors, GATA3 is silenced (p = 0.014). Preliminary methylation analysis shows that I2 activates IFNγ gene promoter (by increasing its unmethylated form) and silences TGFβ in Cht+I2. In conclusion, our data showed that I2 supplements induce the activation of the immune response and that when combined with Cht, the Th1 pathways are stimulated. The molecular mechanisms involved in these responses are being analyzed, but preliminary data suggest that methylation/demethylation mechanisms could also participate.

Breast cancer is the most commonly diagnosed cancer in women worldwide. Approximately, 70 % of breast cancer patients express hormone receptors (HR) (Luminal subtype). Adjuvant endocrine treatments are the standard of care in HR+/HER2- breast cancer. Over time, about 50% of those patients develop endocrine resistance and metastatic breast cancer. Cyclin-dependent kinase inhibitors (CDKi) in combination with an aromatase inhibitor or fulvestrant have demonstrated superior efficacy increasing progression-free survival, with a safe toxicity profile, in HR+/HER2- metastatic breast cancer patients. CDKi blocks kinases 4/6 ATP-binding domain preventing G1/S cell cycle transition. Despite this, not all patients respond to CDKi and those who respond, finally develop resistance to combination therapy. Different studies, in tumour tissue or cell lines, have tried to elucidate the mechanisms underlying this progression, but there are still no conclusive data. In the last few years, liquid biopsy has contributed relevant information to this knowledge. Liquid biopsy can be performed in real-time, non-invasively and be repeated whenever needed. Circulating tumour material are potential prognostic markers in metastatic luminal breast cancer to determine patient prognosis, monitor disease and treatment selection. The objective of this review is to outline the different studies carried out in HR+ metastatic breast cancer patients treated with CDKi plus endocrine therapy using liquid biopsy approaches looking for possible resistance mechanisms.

Mitochondrial production of 2-hydroxyglutarate (R-2HG) can be catalyzed by wild-type isocitrate dehydrogenase 2 (IDH2) and alcohol dehydrogenase, iron-containing 1 (ADHFE1). We investigated whether biochemical background and substrate concentration in breast cancer cells promote 2HG production. To estimate its role in 2HG production, we analyzed 2HG levels and its enantiomers in breast cancer cells using analytical approaches for metabolomics. By manipulation of mitochondrial substrate fluxes, including glutaminolysis, using genetic and pharmacological approaches we demonstrated the existence of an active competition between 2HG producing enzymes, i.e. IDH2 and ADHFE1. Moreover, we show that distinct fractions of IDH2 enzyme molecules operate in distinct oxido-reductive modes, providing NADPH and producing 2HG simultaneously. We have also detected 2HG release into breast cancer patient´s urine undergoing adjuvant therapy and detected a correlation with stages of breast carcinoma development. In summary, we provide a background for vital mitochondrial production of 2HG in breast cancer cells with outcomes towards cancer biology and possible future diagnosis of breast carcinoma.

Measurement of breast cancer burden and identification of its influencing factors help in the development of public health policy and strategy against the disease. This study aimed to examine the variability of the excess mortality of female breast cancer patients in the North East Region of Peninsular Malaysia. This retrospective cohort study was conducted using breast cancer data from the Kelantan Cancer Registry between 2007 and 2011, and Kelantan general population mortality data. The breast cancer cases were followed up for five years until 2016. Out of 598 cases, 549 cases met the study criteria and were included in the analysis. Modelling of excess mortality was conducted using Poisson regression. Excess mortality of breast cancer varied according to age group (50 years old and below vs above 50 years old, Adj. EHR: 1.47; 95% CI: 1.31, 4.09; P=0.004), ethnicity (Malay vs non-Malay, Adj. EHR: 2.31; 95% CI: 1.11, 1.96; P=0.008), and stage (stage III and IV vs. stage I and II, Adj. EHR: 5.75; 95% CI: 4.24, 7.81; P<0.001). In conclusion, public health policy and strategy aim to improve cancer survival should focus more on patients presented at age below 50 years old, Malay ethnicity, and at a later stage.

This document summarizes the evidence currently available about the effects of the anesthetic agents and techniques used in primary cancer surgery and long-term oncologic outcomes, and the biomolecular mechanisms involved in their interaction..

Biomarker directed selection of targeted anti-neoplastic agents such as immune check-point inhibitors, small molecule inhibitors and monoclonal antibodies form an important aspect of cancer treatment. Immunohistochemistry (IHC) analysis of the tumor tissue is the method of choice to evaluate the presence of these biomarkers. However, a significant barrier to biomarker testing on tissue is the availability of an adequate amount of tissue and need for repetitive sampling due to tumor evolution. Also, tumor tissue testing is not immune to inter- and intra-tumor heterogeneity. We describe the analytical and clinical validation of a Circulating Tumor Cell (CTC) assay to accurately assess the presence of PD-L1 22C3 and PD-L1 28.8, ER, PR and HER2, from patients with solid tumors to guide the choice of suitable targeted therapies. Analytically, the test has high sensitivity, specificity, linearity and precision. Based on a blinded case control study, the clinical sensitivity and specificity for PD-L1 (22C3 and 28.8) was determined to be 90% and 100% respectively. The clinical sensitivity and specificity was 83% and 89% for ER; 80% and 94% for PR; 63% and 89% for HER2 (by ICC); and 100% and 92% for HER2 (by FISH), respectively. The performance characteristics of the test support its suitability and adaptability for routine clinical use.

Breast cancer (BC) is a heterogeneous disease representing a substantial economic burden. In order to develop policies that successfully decrease this burden, the factors affecting costs need to be fully understood. Evidence suggests that early detection in Stage I has a lower cost than late detection. We aim to provide conservative estimates of BC's stage-wise medical costs from German healthcare and the payer's perspective. To this end, we conducted a literature review of articles evaluating stage-wise costs of BC in Germany through PubMed, Web of Science, and Econ Lit databases supplemented by Google Scholar. We developed a decision tree model to estimate BC related medical costs in Germany using available treatment and cost information. The review generated seven studies; none estimated the stage-wise costs of BC. The studies were classified into two groups: (1) case scenarios (five studies) and two studies based on administrative data. The first sickness funds data study (Gruber, Stock, et al. 2012) used 1999 information to approach BC attributable cost; their results suggest a range between €3,929 and €11,787 depending on age. The second study (Kreis, Plöthner, et al. 2020) used 2011-2014 data and suggested an initial phase incremental cost of €21,499, an intermediate phase cost of €2,620, and a terminal phase cost of €34,513 per incident case. Our decision tree model based BC stage-wise cost estimates were €21,523 for Stage I, €25,679 for Stage II, €30,156 for Stage III, €42,086 for Stage IV. Alternatively, the modeled cost estimates are €20,284 for the initial phase of care, €851 for the intermediate phase of care, and €34,963 for the terminal phase of care. Our estimates for phases of care are consistent with recent German estimates provided by Kreis and Plöthner et al. Furthermore, the data collected by sickness funds are collected primarily for reimbursement purposes, where the German ICD-10 classification system defines a cancer diagnosis. As a result, claims data lack the clinical information necessary to understand stage-wise BC costs. Our model-based estimates fill the gap and inform future economic evaluations of BC interventions.

Breast cancer is the most widespread malignancy in women from corner to corner of the world. Nanostructured lipid carrier (NLC) proved its efficacy in the treatment of cancer. NLC loaded with Imatinib (IMA) (NANIMA) was prepared and evaluated for in vitro efficacy in MCF-7 breast cancer cells. Hot homogenization method was used for the preparation of NANIMAs. Aqueous solution of surfactants (hot) was mixed with molten mixture of stearic acid and sesame oil (hot) under homogenization. The prepared NANIMAs were characterized and evaluated for size, polydispersity index, zeta potential, encapsulation efficiency, release studies, stability studies and MTT assay (cytotoxicity studies). The optimized NANIMA revealed particle size of 104.63 ± 9.55 d.nm, PdI of 0.227 ± 0.06 and EE of 99.79 ± 0.03. All NANIMAs revealed slow and sustained release behaviour. The surfactants used in the preparation of NANIMAs exhibited their effects on particle size, zeta potential, encapsulation efficiency, stability studies and release studies. The cytotoxicity studies unveiled 8.75 times increase in cytotoxicity for optimized NANIMA (IC50 = 6 µM) when compared with IMA alone (IC50 = 52.5 µM) on MCF-7 breast cancer cells. After this, NLC containing IMA possibly will be employed for the cure of breast cancer. A lesser amount of IMA loaded NLC will be sufficient than IMA alone for the treatment of breast cancer. Moreover, the patient will exhibit not as much of adverse effects as in case of IMA alone. Consequently, NANIMA could prove to be useful for effective therapeutic outcome in breast cancer treatment.

Close to half (45.4%) of 2.3 million breast cancers (BC) diagnosed in 2020 were from Asia. While the burden of breast cancer has been examined on the level of broad geographic regions, literature on more in-depth coverage of the individual countries and subregions of the Asian continent is lacking. This review examines the breast cancer burden in 47 Asian countries. Breast cancer screening guidelines and risk-based screening initiatives are discussed.

(1) Background: Considering highly selected patients with ductal carcinoma in situ (DCIS), active surveillance is a valid alternative to surgery. Our study is aimed at showing the reliability of post-biopsy complete lesion removal, documented by mammogram, as additional criterion to select these patients. (2) Methods: 2173 Vacuum Assisted Breast Biopsies (VABB) documented as DCIS have been reviewed. Surgery has been performed in all cases. We retrospectively collected the reports of post-VABB complete lesion removal and the histological results of the biopsy and surgery. We calculated the rate of upgrade of DCIS identified on VABB upon excision for patients with post-biopsy complete lesion removal and for those showing residual lesion. (3) Results: We observed 2173 cases of DCIS: 408 classified as low grade; 1262 as intermediate grade; 503 as high grade. The overall upgrading rate to invasive carcinoma was 15.2% (330/2173). The upgrade rate was significantly lower (8.2%) when considering patients showing mammographically documented complete removal of the lesion. (4) Conclusion: The absence of mammographically documented residual lesion following VABB is associated to a lower upgrading rate of DCIS to invasive carcinoma on surgical excision and should be considered when deciding the proper management DCIS diagnosis.

Background. This study aims to estimate the rate of death by cancer, according to Radio Base Stations (RBS) radiofrequency exposure, especially for the types of breast, cervix, lung and esophagus cancer. Methods. We collected information about the number of deaths by cancer, gender, age group, Gross Domestic Product per capita, death year and the amount of exposure over the lifetime. We investigated all cancer types and some specific types (breast, cervix, lung and esophagus cancers). Results. In capitals where RBS radiofrequency exposure was higher than 2,000/antennas-year, the average mortality rate was 112/100,000 for all cancers. The adjusted analysis showed that the higher the exposure to RBS radiofrequency, the higher cancer mortality. The highest adjusted risk was observed for cervix cancer (Rate Ratio = 2.18). The spatial analysis showed that the highest RBS radiofrequency exposure was observed in a city in southern Brazil, which also showed the highest mortality rate for all types of cancer and specifically for lung and breast cancer. Conclusion. The balance of our results indicates that the exposure to radiofrequency electromagnetic fields from RBS increases the rate of death by all types of cancer.

The most common long-term complication of silicone breast implants (SMI) remains capsular fibrosis. The etiology of this exaggerated implant encapsulation is multifactorial but primarily induced by the host response towards the foreign material silicone. Identified risk factors included specific implant topographies. Of note, breast implant-associated anaplastic large cell lymphoma (BIA-ALCL), has only been observed in response to textured surface implants. We hypothesize that reduction of SMI surface roughness causes less host response hence better cosmetic outcome with fewer complications for the patient. A total of 7 patients received the routinely used CPX®4 breast expander (~60 µM Ra) and the novel SmoothSilk® (~ 4 µM Ra), fixed prepectoral with a titanised mesh pocket and randomized to the left or right breast after bilateral prophylactic NSME (nipple-sparing mastectomy). We aimed to compare the postoperative outcome regarding capsule thickness, seroma formation, rippling, implant dislocation as well as comfortability and practicability. Our analysis shows that surface roughness is an influential parameter in controlling fibrotic implant encapsulation. First time intra-individually compared in patients, our data confirm an improved biocompatibility with minor capsule formation around SmoothSilk® implants with an average shell roughness of 4 µM and in addition an amplification of host response by titanised implant pockets.

Computer-aided image diagnostics (CAD) have been used in many fields of diagnostic medicine. It relies heavily on classical computer vision and artificial intelligence. Quantum neural network (QNN) has been introduced by many researchers around the world and presented recently by research corporations such as Microsoft, Google, and IBM. In this paper, the investigation of the validity of using the QNN algorithm for machine-based breast cancer detection was performed. To validate the learnability of the QNN, a series of learnability tests were performed alongside with classical convolutional neural network (CCNN). QNN is built using the Cirq library to perform the assimilation of quantum computation on classical computers. Series of investigations were performed to study the learnability characteristics of QNN and CCNN under the same computational conditions. The comparison was performed for real Mammogram data sets. The investigations showed success in terms of recognizing the data and training. Our work shows better performance of QNN in terms of successfully training and producing a valid model for smaller data set compared to CCNN.

Given that 3-Phosphoinositide-dependent kinase 1 (PDK1) plays a crucial role in malignant biological behaviors of a wide-range of cancers, we further review the influence of PDK1 in breast cancer (BC). First, we describe the power of PDK1 in cellular behaviors and extensively demonstrate the interacting networks of PDK1 via PI3K-dependent/ PI3K-independent pathway. Then we enlighten the roles of PDK1 in carcinogenesis, growth and survival, metastasis, and chemoresistance in BC cells. More important, we sort the current preclinical or clinical trials of PDK1 targeted therapy in BC and find that even though at present no selective PDK1 inhibitor is available for BC therapy, but the combination trials of PDK1 targeted therapy and other agents have demonstrated some benefit. Thus, there is increasing anticipations that PDK1 targeted therapy will have its space in future therapeutic concepts of BC, and we hope to feature PDK1 in BC to the clinic and bring the new promising to patients for targeted therapies.

The resistance of cancer cell subpopulations, including cancer stem cell (CSC) populations, to apoptosis-inducing chemotherapeutic agents is a key barrier to improved outcomes for cancer patients. The cationic amphiphilic drug hexamethylene amiloride (HMA) has been previously demonstrated to efficiently kill bulk breast cancer cells independent of tumor subtype or species, but acts poorly toward non-transformed cells derived from multiple tissues. Here we demonstrate that HMA is similarly cytotoxic toward breast CSC-related subpopulations that are resistant to conventional chemotherapeutic agents, but poorly cytotoxic toward normal mammary stem cells. HMA inhibits the sphere-forming capacity of FACS-sorted human and mouse mammary CSC-related cells in vitro, specifically kills tumor but not normal mammary organoids ex vivo, and inhibits metastatic outgrowth in vivo, consistent with CSC suppression. Moreover, HMA inhibits viability and sphere formation by lung, colon, pancreatic, brain, liver, prostate and bladder tumor cell lines, suggesting that its effects may be applicable to multiple malignancies. Mechanistically, HMA elicits the permeabilization of the limiting lysosomal membrane, a hallmark feature of the lysosome-dependent cell death pathway. Our observations expose a key vulnerability intrinsic to cancer stem cells, and point to novel strategies for the exploitation of cationic amphiphilic drugs in cancer treatment.

Breast cancer is the leading cause of cancer deaths worldwide in women. This aggressive tumour can be categorized into two main groups: in situ and infiltrative, with the latter being the most common malignant lesions. The current use of Magnetic Resonance Imaging (MRI) was shown to provide highest sensitivity in the detection and discrimination between benign vs. malignant lesions, when interpreted by expert radiologists. In this article, we present the prototype of a Computer-Aided Detection/Diagnosis (CAD) system that could provide valuable assistance to the radiologist for the discrimination between in situ and infiltrating tumours. The system consists of two main processing levels: 1) Localization of possibly tumoral regions of interest (ROIs) through an iterative procedure based on intensity values (ROI Hunter) followed by a deep-feature extraction and classification method for false-positive rejection; 2) Characterization of the selected ROIs and discrimination between in situ and invasive tumour, consisting of Radiomics feature extraction and classification through a machine-learning algorithm. The CAD system was developed and evaluated using a DCE-MRI image database, containing at least one confirmed mass per image, as diagnosed by an expert radiologist. When evaluating the accuracy of the ROI Hunter procedure with respect to the radiologist-drawn boundaries, sensitivity to mass detection was found to be 75%. The AUC of the ROC curve for discrimination between in situ and infiltrative tumors was 0.70.

Patients with metastatic triple negative breast cancer (TNBC) need new therapies to improve the low survival rates achieved with standard treatments. In this work, we show that the survival of mice with metastatic TNBC can be markedly increased by replacing their normal diet with artificial diets in which the levels of amino acids (AAs) and lipids are strongly manipulated. After observing selective anticancer activity in vitro, we prepared five artificial diets and evaluated their anticancer activity in a challenging model of metastatic TNBC. The model was established by injecting 4T1 murine TNBC cells into the tail vein of immunocompetent BALB/cAnNRj mice. First-line drugs doxorubicin and capecitabine were used as positive controls. AA manipulation led to modest improvements in mice survival when the levels or lipids were normal. Reducing lipid levels to 1% markedly improved the activity of several diets with different AA content. Mice fed the artificial diets as monotherapy lived longer than mice treated with doxorubicin and capecitabine. An artificial diet without 10 non-essential AAs, with reduced levels of essential AAs, and with 1% lipids improved the survival not only of mice with TNBC but also of mice with other types of metastatic cancers.

Dietary pattern (DP) and its relationship with disease biomarkers has received recognition in nutritional epidemiology investigations. However, DP relationships with adipokines (i.e., adiponectin and leptin) among breast cancer survivors remain unclear. Therefore, we assessed relationships between DP with high molecular weight (HMW) adiponectin and leptin concentration among breast cancer survivors. This cross-sectional study involved 128 breast cancer survivors who attended the oncology outpatient clinic at two main government hospitals in East Coast of Peninsular Malaysia. The serum concentration of HMW adiponectin and leptin were measured using enzyme-linked immunosorbent assay (ELISA) kits. Reduced rank regression method was used to analyze DP. Relationships between DP with HMW adiponectin and leptin were examined using regression models. Findings showed that a one-unit increase in the ‘energy-dense, high-saturated fat and low-fiber’ DP z-score was associated with a 0.41 µg/mL lower HMW adiponectin (95% CI: -0.806, -0.014) which was independent of age, BMI, cancer stage, duration since diagnosis, education level and occupation status. A similar relationship with leptin concentration was not observed. In conclusion, ‘energy-dense, high-saturated fat and low-fiber’ DP, which is characterized by high sugar-sweetened drink and fat-based spread but low intake of fruits and vegetables, is an unhealthy dietary pattern and unfavorable for HMW adiponectin concentration but not for leptin. These findings could serve as a basis in developing specific preventive strategies that are tailored to the growing population of breast cancer survivors.

Triple negative breast cancer (TNBC) is an aggressive subtype of the disease with poor clinical outcomes and limited therapeutic options. Immune checkpoint blockade (CP) has surged to the forefront of cancer therapies with widespread clinical success in a variety of cancer types. However, the percentage of TNBC patients that benefit from CP as a monotherapy is low and clinical trials have shown the need for combined therapeutic modalities. Specifically, there has been interest in combining CP therapy with radiation therapy where clinical studies primarily with external beam have suggested their therapeutic synergy, contributing to the development of anti-tumor immunity. Here, we have developed a therapeutic platform combining radionuclide therapy (RT) and immunotherapy utilizing a radiolabelled biomolecule and CP in an E0771 murine TNBC tumor model. Survival studies show that while neither monotherapy is able to improve therapeutic outcomes, the combination of RT + CP extended overall survival. Histologic analysis showed that RT + CP increased necrotic tissue within the tumor and decreased levels of F4/80+ macrophages. Flow cytometry analysis of the peripheral blood also showed that RT + CP suppressed macrophages and myeloid-derived suppressive cells, both of which actively contribute to immune escape and tumor relapse.

TomoBreast hypothesized that hypofractionated 15 fractions/3 weeks image-guided radiation therapy (H-IGRT) can reduce lung-heart toxicity, as compared with normofractionated 25-33 fractions/5-7 weeks conventional radiation therapy (CRT). 123 women with stage I-II operated breast cancer were randomized to receive CRT (N=64) or H-IGRT (N=59). The primary endpoint used a four-items measure of the time to 10% alteration in any of patient self-reported measure, physician clinical evaluation, echocardiography or lung function tests, analyzed by intention-to-treat without exclusion. Results found comparable survivals, but H-IGRT significantly reduced the toxicity measured by lung diffusion capacity and alveolar volume as compared with CRT, G1 in 53% (31/59) versus 72% (44/61) patients, P=0.006; G2, 29% versus 48%, P=0.020. H-IGRT significantly reduced the risk of composite cardio-pulmonary alteration at 5 years, 10.2% versus 26.7%, P=0.024. In conclusion, TomoBreast is a proof-of-concept that image-guided radiation-therapy can improve the overall balance of lung-heart outcomes in breast cancer adjuvant therapy. Furthermore, the significance of the findings supports the efficacy of a small trial size design, which can be critical when clinical research resources are limited.

The aim of this study was to determine whether a rowing training program improved the quantity and quality of physical activity and quality of life in female breast cancer survivors (stage I - 4.35%; II - 30.43%; III - 52.17%; and IV - 8.7%) diagnosed 6.57 ± 5.02 years previously, who had undergone a subsequent intervention (preservation 53.52%; total mastectomy 39.13% and double mastectomy 4.35%) and had a current mean age of 53.70 ± 7.88 years. The participants (N = 30) engaged in a 12-week training program, each week comprising three sessions and each session lasting 60-90 minutes. An anthropometric evaluation was performed before and after the program. The short form of the International Physical Activity Questionnaire (IPAQ-SF) and the Short Form 36 Health Survey (SF-36) were also administered. The results showed statistically significant improvements in levels of physical activity and in the dimensions of quality of life. We can conclude that a 12-week rowing training program tailored to women who have had breast cancer increases physical activity levels, leading to improved health status and quality of life.

For decades since the central dogma, cancer biology research has been focusing on the involvement of genes encoding proteins. It has been not until more recent times that a new molecular class has been discovered, named non-coding RNA (ncRNA), which has been shown to play crucial roles in shaping the activity of cells. An extraordinary number of studies into shown that ncRNAs represent an extensive and prevalent group of RNAs, including both oncogenic or tumor suppressive molecules. Henceforth, various clinical trials involving ncRNAs as extra ordinary biomarkers or therapies have started to emerge. In this review, we will focus on the prognostic and diagnostic role of ncRNAs for breast cancer.

Complete pathologic response (pCR) predicts the long-term outcome of neoadjuvant treated (NAC) breast cancer (BC) but is reached in <10% of hormone-receptor-positive patients. Biomarkers able to guide adjustment or interruption of an ineffective therapy are desired. Here, we evaluated whether shifts in the serum concentration of thymidine kinase 1 (sTK1) during NAC could be utilized as a biomarker. In the PROMIX trial, women with localized HER2- BC received neoadjuvant epirubicin/docetaxel in six cycles. sTK1 was measured with an ELISA in 54 patients at cycles 1-4 and in a total of 131 patients before and 48h after cycle 1. The prognostic significance of the results was evaluated by log-rank tests of Kaplan–Meier estimates. Treatment resulted in a 2-fold increase of sTK1 before and 3-fold increase 48h after the cycles, except for the first cycle, where half of patients reacted with a decrease (post/pre sTK1- ratio <1.12) and the other half reacted with an increase (ratio >1.12). OS rates in ER+ patients with ratios of >1.12 and <1.12 were 97.7% and 78% (p=0.005), respectively, and DFS rates were 90.7% and 68% (p=0.006), respectively. Thus, response of sTK1 at the first cycle of chemotherapy could be used both as an early biomarker for guidance of chemotherapy and for the study of inherent tumor chemo-sensitivity, which could predict long-term outcome prior to therapy.

Breast self-Examination (BSE) is the cheapest most recommended Breast Cancer (BC) preventive tool for resource-deprived settings. There is paucity in the attitude research domain and comparative gender assessments of the BSE knowledge, attitude and performance (KAP) literature. Purpose: The purpose of this study was to assess the combined and exclusive gender BSE attitude of undergraduate health trainees and to determine significant differences between scores of both genders. Methodology: participants included 5 undergraduate health trainee classes purposively sampled from 2 faculties. Online cross-sectional method was used to assess BSE attitude of 336 purposively sampled Kwame Nkrumah University of Science and technology (KNUST) College of Health Sciences (CoHS) students. Data was analyzed using descriptive and inferential statistical analyses. Main findings: Compared to the construction groups’ average norm of 101.17 (SD = 9.55), our study participants’ (SPs) BSE attitude was lower (92.51; SD = 11.80). However, using popular mid-point and 3- part attitude scoring methods, our SPs’ attitude scores were comparable to sub-regional and national findings. Moreover,the male participants scored a generally high BSE attitude but significantly lower compared to their female counterparts (p < 0.5). Recommendations: There is the need to adjust the curriculum of all health trainees in developing nations to reflect relevant BC preventive measures. Furthermore, BSE research, education as well as advocacy should involve more males as important BC BSE stake holders.

Several studies have suggested that pre and/or postdiagnosis physical activity can reduce the risk of recurrence in breast cancer patients, however its effect according to follow-up time has not yet been investigated. We analyzed recurrence and mortality dynamics in randomized clinical trials (RCTs) from Australia and Canada. The combined Australian RCTs evaluated, at median follow-up of 8.3 years, an 8-month pragmatic exercise intervention in 337 women with newly diagnosed breast cancer, while the Canadian RCT evaluated, at median follow-up of 7.4 years, supervised aerobic or resistance exercise during chemotherapy in 242 patients. For each RCT, the control arm consisted of patients undergoing usual care. We estimated the event dynamics by the discrete hazard function, through flexible regression of yearly conditional event probabilities with generalized additive models. In the considered RCTs, the recurrence and mortality risk of patients enrolled in the physical activity arm was stably reduced at medium/long term after five year of follow-up. In the Australian RCTs where patients were recruited by urban versus rural area, the latter group did not display benefit from physical activity. Estimated Odds Ratios (95% Confidence Intervals) for Disease Free Survival (DFS) in urban women were 0.63 (0.22-1.85); 0.27 (0.079-0.90); 0.11 (0.013-0.96) at the 3rd, 5th and 7th year of follow-up, respectively. For rural women, DFS patterns were overlapping with ORs approximating 1 at the different years of follow-up. Although not reaching statistical evidence, the estimates in the Canadian trial were in line with the results from the Australian urban women with ORs (95% CI) forDFS of 0.70 (0.33-1.50); 0.47 (0.19-1.18); 0.32 (0.077-1.29) at 3rd, 5th, 7th follow-up year, respectively. While we acknowledge that the analyzed RCTs were not designed for investigating disease recurrence over time, these results support the evidence that physical activity reduces the risk of developing medium/long-term metastases. Additional translational research is needed to clarify the mechanisms underlying these observations.

Next Generation Sequencing based cancer risk screening with multigene panels has become the most successful method for programming cancer prevention strategies. ATM germ-line heterozygosity has been described as able to increase tumor susceptibility. In particular, families that carry heterozygous germ-line variants of ATM gene show a 5- to 9-fold risk of developing breast cancer. Recent studies identified ATM as the second most mutated gene after CHEK2 in BRCA-negative patients. Nowadays, more than 170 potential missense variants and several truncating mutations have been identified in ATM gene. Here we present the molecular characterization a new ATM deletion, identified thanks to the CNV algorithm implemented in the NGS analysis pipeline. An automated workflow implementing the SOPHiA Genetics’ Hereditary Cancer Solution (HCS) protocol was used to generate NGS libraries that were sequenced on Illumina MiSeq Platform. NGS data analysis allowed to identify a new inactivating deletion of exons 19-27 of ATM gene. DNA breakpoint was characterized both at DNA and RNA level

Development of targeted therapies for triple-negative breast cancer (TNBC) is an unmet medical need. Cisplatin has demonstrated its promising potential for the treatment of TNBC in clinical trials; however, cisplatin treatment is associated with hypoxia that in turn promotes cancer stem cell (CSC) enrichment and drug resistance. Therapeutic approaches to attenuate this may lead to increased cisplatin efficacy in the clinic for the treatment of TNBC. In this report, we analyzed clinical dataset of TNBC and found that TNBC patients possessed higher levels of EGFR and hypoxia gene expression. A similar expression pattern was also observed in cisplatin-resistant ovarian cancer cells. We thus developed a new therapeutic approach to inhibit EGFR and hypoxia by combination of metformin and gefitinib that sensitized TNBC cells to cisplatin and led to the inhibition of both CD44+/CD24- and ALDH+ CSCs. We demonstrated a similar inhibition efficacy on organotypic cultures of TNBC patient samples ex vivo. Since these drugs have already been used frequently in the clinic, this study illustrates a novel, clinically translatable therapeutic approach to treat patients with TNBC.

Breast cancer is a complex and heterogeneous disease that displays diverse molecular subtypes and clinical outcomes. Although it is known that the location of tumors can affect their biological behavior, the underlying mechanisms are not fully understood. In our previous study, we found a differential methylation profile and membrane potential between left (L) and right (R)-sided breast tumors. In this current study, we aimed to identify the ion channels responsible for this phenomenon and determine any associated phenotypic features. To achieve this, experiments were conducted in mammary tumors in mice, human patient samples, and with data from public datasets. The results revealed that L-sided tumors have a more depolarized state than R-ones. We identified a 6-ion channel-gene signature (CACNA1C, CACNA2D2, CACNB2, KCNJ11, SCN3A, and SCN3B) associated with side: L-tumors exhibit lower expression levels than R-ones. Additionally, in silico analyses show that the signature correlates inversely with DNA methylation writers and with key biological processes involved in cancer progression, such as proliferation and stemness. The signature also correlates inversely with patients’ survival rates. In an in vivo mouse model, we confirmed that KI67 and CD44 markers were increased in L-sided tumors and similar tendency for KI67 was found in patient L-tumors. Overall, this study provides new insights into the potential impact of anatomical location on breast cancer biology and highlights the need for further investigation into possible differential treatment options.

HER2-low and ultra-low breast cancer (BC) have been recently proposed as new subcategories of HER2 BC, re-considering the immunohistochemical negative score of 0, 1+ or score of 2+/in situ hybridization (ISH) negative phenotype. In the present review we have outlined the needed criteria to exactly distinguish HER2 low and ultra-low BC. Recent clinical trials have demonstrated significant clinical benefits of novel HER2 directing antibody-drug conjugates (ADCs) in treating these group sof tumors. In particular, Trastuzumab-deruxtecan (T-Dxd), a HER2-directing ADC has been recently approved by the U.S. Food and Drug Administration as the first targeted therapy to treat HER2-low BC. Furthermore, ongoing trials, such as the DESTINY-Breast06, are currently evaluating ADCs in patients with HER2-ultra low BC. Finally we hope that new guidelines may help to codify HER2 low and ultra-low BC, increasing our knowledge of tumor biology and improving a targetable new therapeutical treatment.

The use of multi-gene panels for germline testing in breast cancer enables the estimation of cancer risk and guides risk-reducing management options for tested individuals and their family members. We performed an analysis in our clinical database to identify breast cancer patients undergoing genetic testing with positive reports. We reviewed positive results with respect to the different levels of information provided in the reports; risk estimation and management, cascade family testing, information from secondary findings and actionable information for treatment decision-making. A total of 415 positive test reports were identified with 57.1%, 18.1%, 10.8% and 13.5% of individuals having pathogenic/likely pathogenic variants in high (BRCA1, BRCA2, PALB2, PTEN, TP53), moderate (ATM, CHEK2, NBN), low (BARD1, BRIP1, CHEK2, MLH1, MSH2, MSH6, NF1, RAD51C) and with insufficient evidence for breast cancer risk genes (FANCA, FANCM, NBN, MRE11, PMS2, RAD50, RAD51B, XRCC2, MUTYH), respectively. 6.7% of individuals were double heterozygotes with two pathogenic variants. Germline findings in 92% of individuals are linked to evidence-based treatment information and receive risk estimates for predisposition to breast and/or other cancer types. The use of germline findings for treatment decision making expands the indication of genetic testing to include individuals that could benefit from targeted treatments.

Congenital breast asymmetry represents a particular challenge to the classical techniques of plastic surgery due to a young group of patients. This study compares traditional breast augmentation using silicone implants to the more innovative lipograft technique regarding long-term results. To achieve this, we not only captured subjective parameters like satisfaction with outcome and symmetry, but also objective parameters such as breast volume and anthropometric measurements. Objective examination was performed manually and by using the Vectra® H2 photogrammetry scanning system. Patients who underwent implant augmentation and lipograft both showed no significant differences in patient´s satisfaction with surgical outcome (p = 0.55) and symmetry (p = 0.69). Furthermore, a breast symmetry of 93 % in both groups was reported. Likewise, no statistically significant volume difference between left and right breast was observed in both groups (p<0.41). However, on average, lipograft patients needed 1.3 procedures more until the desired result was achieved. In contrast, patients treated with implant-based breast augmentation usually need several implant changes during their life. In conclusion, both methods should be considered for patients with congenital breast asymmetry.

Background: transcriptome data provide a valuable resource for the study of cancer molecular mechanisms, but technical biases, samples’ heterogeneity and small sample sizes result in poorly reproducible lists of regulated genes. Additionally, the presence of multiple cellular components contributing to cancer development complicate the interpretation of bulk transcriptomic profiles. Methods: we collected 48 microarray datasets of laser capture microdissected breast tumors, and performed a meta-analysis to identify robust lists of genes differentially expressed in these tumors. We created a database with carefully harmonized metadata to be used as a resource for the research community. Results: combining the results of multiple datasets improved the statistical power, and the analysis of stroma and epithelium separately allows identifying genes with different contribution in each compartment. Conclusions: our database can profitably help biomarkers’ discovery and is readily accessible through a user-friendly web interface (https://aurorasavino.shinyapps.io/metalcm/).

Two related tumor suppressor genes, Brca1 and Brca2, attract a lot of attention from both fundamental and clinical points of view. Oncogenic hereditary mutations in these genes are firmly linked to the early onset of breast and ovarian cancers. However, the molecular mechanisms that drive extensive mutagenesis in these genes are not known. In this review we hypothesize that one of the potential mechanisms behind this phenomenon can be mediated by Alu mobile genomic elements. Linking mutations in the BRCA1 and BRCA2 genes to the general mechanism(s) of genome stability and DNA repair is critical to ensure the rationalized choice of anti-cancer therapy. Accordingly, we review the literature available on mechanisms of DNA damage repair where these proteins are involved in and how the inactivating mutations in these genes (BRCAness) can be exploited in anti-cancer therapy. We also propose a hypothesis that explains why breast and ovarian epithelial tissues are preferentially susceptible to mutations in BRCA genes. Finally, we discuss perspectives of novel therapeutic approaches for treating BRCAness cancers.

The association between autoimmune diseases, mostly rheumatoid arthritis, systemic lupus erythematous, celiac disease and Sjögren syndrome, and lymphoma has been widely demonstrated by several epidemiologic studies. By a not yet entirely elucidated mechanism, chronic activation/stimulation of the immune system, along with the administration of specific treatments, may lead to persistent stimulation of both of B- and T-cells, and to the onset of different types of lymphoma in such patients. Specifically, patients affected by may develop lymphomas may years after the original diagnosis. Several epidemiologic, hematologic and histological factors may anticipate the progression from Sjögren syndrome into lymphoma but, to the best of our knowledge, a definite pathogenetic mechanism for such progression is still missing. In fact, while the association between Sjögren syndrome and non-Hodgkin lymphoma, mostly diffuse large B-cell and extranodal marginal zone lymphomas is well established, many other variables, such as time of onset, gender predilection, sites of occurrence, subtype of lymphoma and predictive factors still remain unclear. We report on a rare case of primary breast lymphoma occurring three years after the diagnosis of Sjögren syndrome in a 57 y.o. patient. The diagnostic work-up, including radiograms, core needle biopsy and histological examination are discussed, along with emerging data from the recent literature, thus highlighting the usefulness of breast surveillance in Sjögren syndrome patients.

Neoadjuvant systemic therapy has now become the the standard in early breast cancer management. Chemotherapy in combination with trastuzumab +/- pertuzumab targeted therapy can improve rates of pathologic complete response (pCR) in patients with HER2-positive breast cancer. Achieving a pCR is considered a good prognostic factor, in particular in patients with more aggressive breast cancer subtypes such as TNBC or HER2 positive cancers. Furthermore, most studies demonstrate that chemotherapy in combination with trastuzumab and pertuzumab is well tolerated. The retrospective analysis presented here concentrates on neoadjuvant therapy with the TCbH-P regimen, with a particular emphasis on patients over 60 years of age. We analysed the factors affecting the achievement of pCR and presented adverse effects of the applied therapies, which opened a discussion about optimizing the therapy of older patients with HER-2 positive breast cancer.

Attempts to use computers to aid in the detection of breast malignancies date back more than 20 years. Despite significant interest and investment, this has historically led to minimal or no significant improvement in performance and outcomes with traditional computer aided detection. However, recent advances in artificial intelligence and machine learning are now starting to deliver on the promise of improved performance. There are at present more than 20 FDA approved AI applications for breast imaging, but adoption and utilization are widely variable and overall low. Breast imaging is unique and has aspects that create both opportunities and challenges for AI development and implementation. Breast cancer screening programs worldwide rely on screening mammography to reduce the morbidity and mortality of breast cancer and many of the most exciting research and available AI applications focus on cancer detection for mammography. There are however multiple additional potential applications for AI in breast imaging including decision support, risk assessment, breast density quantitation, workflow and triage, quality evaluation, response to neoadjuvant chemotherapy assessment, and image enhancement. In this review the current status, availability, and future directions of investigation of these applications are discussed, as well as the opportunities and barriers to more widespread utilization.

The HER2 overexpression occurs in 10–20% of breast cancer patients. HER2+ tumors are characterized by increase in Ki67, early relapse and increased metastasis. There is little known about factors influencing early stages of HER2- tumorigenesis and diagnostic markers. Previously, it was shown that deletion of NEDD9 in mouse models of HER2 cancer interferes with tumor growth, but the role of NEDD9 upregulation is currently unexplored. We report that NEDD9 is overexpressed in a significant subset of HER2+ breast cancers and correlates with limited response to anti-HER2 therapy. To investigate the mechanisms through which NEDD9 influences HER2-dependent tumorigenesis, we generated MMTV-Cre-NEDD9 transgenic mice. The analysis of mammary glands shows extensive ductal epithelium hyperplasia, increased branching, and terminal end bud expansion. The addition of oncogene Erbb2 (neu) leads to development of early hyperplastic benign lesions earlier (~16 weeks) with a significantly shorter latency than the control mice. Similarly, NEDD9 upregulation in MCF10A-derived acini leads to hyperplasia like DCIS. This phenotype is associated with activation of ERK1/2 and AURKA kinases leading to an increased proliferation of luminal cells. These findings indicate that NEDD9 is setting permissive conditions for HER2-induced tumorigenesis, thus identifying this protein as a potential diagnostic marker for early detection.

Possible alterations of maternal immune function due to psychological stress may reflect immunoactive factor levels in breast milk. This study aimed to assess the association between maternal distress and breast milk levels of secretory IgA (SIgA), IgM, IgG, and lactoferrin (LF). We hypothesized this association is moderated by maternal social support achieved from others during lactation. The study group included 103 lactating mothers and their healthy 5-months-old infants. Maternal distress was determined based on the State Anxiety Inventory and the level of salivary cortisol. Social support was assessed using Berlin Social Support Scales. Breast milk samples were collected to test for SIgA, IgM, IgG, and LF using the ELISA method. Milk immunoactive factors were regressed against maternal anxiety, social support, salivary cortisol, and infant gestational age using the general regression model. Maternal anxiety was negatively associated with milk levels of LF (β=-0.22, p<0.05) and SIgA (β=-0.29, p<0.01), while social support was positively associated with milk IgG (β=0.25, p<0.05). Neither anxiety nor social support was related to milk IgM. No association was found between the level of maternal salivary cortisol and immunoactive factors in milk. Our results suggest that maternal psychological well-being and social support may affect milk immune properties.

The Myc gene, widely studied in numerous cancer types, serves as a pivotal regulator of crucial cellular processes implicated in tumorigenesis, such as cell growth, proliferation, invasion, metastasis, and therapy resistance. LncRNAs have been identified as relevant partners of Myc. LncRNAs modulate chromatin structure and function, transcription, splicing, stability, and translation of mRNAs, thereby emerging as pivotal regulators in cell differentiation, metabolism, signaling. An intricate crosstalk exists between Myc and lncRNAs in a wide range of cancers, wherein they can physically and functionally interact through direct and indirect mechanisms. Some lncRNAs can regulate Myc activity at post-transcriptional level, affecting its stability, translation, or interactions with other proteins, thus acting as oncogenes, while others act as tumor suppressors. On the other hand, Myc can target numerous lncRNA genes and modulate their expression, affecting the expression of downstream targets involved in tumorigenesis. Given the significant role of the Myc-lncRNA network in various cancer types, exploring therapeutic strategies targeting these crucial cellular regulators is of utmost importance. This review article focuses on breast cancer, analyzing those lncRNAs influencing Myc as well as the Myc-regulated lncRNAs.

Up to 25% of early human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC) patients will relapse despite the improvement achieved by the introduction of HER2-targeted therapy. Beyond trastuzumab, other agents approved for early HER2+ BC include the monoclonal antibody pertuzumab, the antibody-drug conjugate (ADC) trastuzumab-emtansine (T-DM1) and the reversible HER2 inhibitor lapatinib. New agents, such as trastuzumab-deruxtecan or tucatinib in combination with capecitabine and trastuzumab, have also shown an improvement in the metastatic setting. Other therapeutic strategies to overcome treatment resistance have been explored in HER2+ BC, mainly in HER2+ that also overexpress estrogen receptors (ER+). One strategy has been to target the cyclin-dependent kinases 4/6 (CDK4/6) as they are downstream of HER2 and many of the cellular pathways associated with resistance to HER2-targeted therapies play a key role in cell cycle and proliferation. Different trials have explored these strategies with encouraging results, but definitive results are needed. In addition, HER2+ BC is known to be more immunogenic than other BC subgroups, with high variability between tumors. Different immunotherapeutic agents have been investigated in this setting, with promising but controversial results obtained to date.

Male breast cancers are uncommon, as men account for less than 1 percent of all breast carcinomas. Among the predisposing risk factors for male breast cancer, the following appear to be significant: a) breast/chest radiation exposure, b) estrogen use, diseases associated with hyper-estrogenism, such as cirrhosis or Klinefelter syndrome, and c) family health history. Furthermore, there are clear familial tendencies, with a higher incidence among men who have a large number of female relatives with breast cancer and d) major inheritance susceptibility. Moreover, in families with BRCA mutations, there is an increased risk of male breast cancer, although the risk appears to be greater with inherited BRCA2 mutations than with inherited BRCA1 mutations. Due to diagnostic delays, male breast cancer is more likely to present at an advanced stage. A core biopsy or a fine needle aspiration must be performed to confirm suspicious findings. Infiltrating ductal cancer is the most prevalent form of male breast cancer, while invasive lobular carcinoma is extremely uncommon. Male breast cancer is almost always positive for hormone receptors. A worse prognosis is associated with a more advanced stage at diagnosis for men with breast cancer. And randomized controlled trials which recruit both female and male patients should be developed in order to gain more consistent data on the optimal clinical approach.

Background: We previously found that QNBC tumors are more frequent in African Americans compared to TNBC tumors. To characterize this subtype further, we sought to determine the miRNA-mRNA profile in QNBC patients based on race. Methods: Both miRNA and mRNA expression data were analyzed from TCGA and validated using datasets from the METABRIC, TCGA proteomic, and survival analysis by KMPLOT. Results: miRNA-mRNAs which include FOXA1 and MYC (mir-17/20a targets); GATA3 and CCNG2 (mir-135b targets); CDKN2A, CDK6, and B7-H3 (mir-29c targets); and RUNX3, KLF5, IL1-β, and CTNNB1 (mir-375 targets) were correlated with basal-like and immune subtypes in QNBC patients and associated with a worse survival. Conclusion: Thus, QNBC tumors have an altered gene signature implicated in racial disparity and poor survival.

Breast cancer represents the most frequent cancer and the leading cause of cancer death among women. Thus, the prevention and early diagnosis of breast cancer appears to be of primary urgency as well as the development of new treatments able to improve its prognosis. Nerve Growth Factor (NGF) is a neurotrophic factor that plays a key role in the regulation of neuronal functions thought the binding to the Tropomyosin receptor kinase A (TrkA) and the Nerve Growth Factor receptor or Pan-Neurotrophin Receptor 75 (NGFR/p75NTR). Also, its precursor (pro-NGF) can extert biological activity by forming a trimeric complex with NGFR/p75NTR and sortilin or by binding to TrkA receptors with low affinity. Both in vitro and in vivo studies showed that NGF is synthesized and released by breast cancer cells and has mitogen, antiapoptotic and angiogenic effects on these cells through the activation of different signaling cascades that involve TrkA and NGFR/p75NTR receptors. Conversely, pro-NGF signaling has been related to breast cancer invasion and metastasis. Other studies suggested that NGF and its receptors could represent a good diagnostic and prognostic tool, as well as promising therapeutic targets for breast cancer. Here, we comprehensively summarize and systematically review the current experimental evidence on this topic.

Noninvasive and portable diagnoses via angle-resolved coherent spectral data are presented. ACTIRS (Angle- resolved coherent tomographic IR spectroscopy) through angle-coherent return spectra from photonic quantum ring laser of whispering gallery modes, which is not photocurrent-converted after the cortical, vascular or muscular diffuse paths, can be a new method for brain/heart studies. Also it will be eligible for frequent do-it-yourself diagnoses of breast cancer before hospital visits. The unique angle-coherent multi-spectra will eventually lead to study ionic or protein contents of cranial, arterial or lactiferous ducts that have been obtained only from uncomfortable biopsy, NMR, CT or mammography. The spectral data can be spatially or temporally improved and correlated for extracting more meaningful diagnostic conclusions

Breast cancer, although the most frequently diagnosed malignant tumour in humans, has a less clear aetiology compared to other frequent cancer types. Mouse-mammary tumour virus (MMTV) is involved in breast cancer in mice and dogs and might play a role in the aetiology of some breast cancers in humans, since it has been identified in 20-40% of breast cancer samples in Western Europe, USA, Australia and some other parts of the world population. The purpose of our study was to identify MMTV DNA sequences in breast tissue samples from breast cancer patients operated in our regional centre from Romania. We have selected 75 patients with non-metastatic breast cancer treated with curative intent and searched with PCR the MMTV-like DNA sequence in the breast cancer tissue and normal breast tissue obtained from the same patients. Since none of the examined samples was positive for MMTV-like target sequences on PCR we could not prove that MMTV plays a role in the aetiology of breast cancer in our patient group. This finding is similar to publications of other geographically related research groups and might be due to the fact that only the Mus musculus domesticus mouse species was proven to carry infectious MMTV, but not the Mus musculus musculus species, which is specific to South-Eastern Europe (including Romania) and some parts of Asia.

Hypoxia, a condition of low oxygenation frequently found in triple-negative breast tumors (TNBC), promotes extracellular vesicle (EV) secretion and favors cell invasion, a complex process in which cell morphology is altered, dynamic focal adhesion spots are created, and ECM is re-modeled. Here, we investigated the invasive properties triggered by TNBC-derived hypoxic small EV (SEVh) in vitro in cells cultured under hypoxic and normoxic conditions, using pheno-typical and proteomic approaches. SEVh characterization demonstrated increased protein abundance and diversity over normoxic SEV (SEVn), with enrichment in pro-invasive pathways. In normoxic cells, SEVh promotes invasive behavior through pro-migratory morphology, in-vadopodia development, ECM degradation and matrix metalloprotease (MMP) secretion. Pro-teome profiling of normoxic cells exposed to SEVh determined enrichment in metabolic processes and cell cycle, modulating cell health to escape apoptotic pathways. In hypoxia, SEVh was re-sponsible for proteolytic and catabolic pathway inducement, interfering with integrin availabil-ity and gelatinase expression. Overall, our results demonstrate the importance of hypoxic signal-ing via SEV in tumors for the early establishment of metastasis.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer that disproportionally accounts for the majority of breast cancer-related deaths due to the lack of specific targets for effective treatments. In this review, we highlight the complexity of the transforming growth factor-beta family (TGF-β) pathway and discuss how the dysregulation of the TGF-β pathway promotes oncogenic attributes in TNBC which negatively affects patient prognosis. Moreover, we discuss recent findings highlighting TGF-β inhibition as a potent method to target mesenchymal (CD44⁺/CD24^-) and epithelial (ALDH^high) cancer stem cell (CSC) populations. CSCs are associated with tumorigenesis, metastasis, relapse, resistance, and diminished patient prognosis; however, due to differential signal pathway enrichment and plasticity, these populations remain difficult to target and persist as a major barrier barring successful therapy. This review highlights the importance of TGF-β as a driver of chemoresistance, radioresistance and reduced patient prognosis in breast cancer and highlights novel treatment strategies which modulate TGF-β, impede cancer progression and reduce the rate of resistance generation via targeting the CSC populations in TNBC and thus reducing tumorigenicity. Potential TGF-β inhibitors targeting based on clinical trials are summarized for further investigation which may lead to the development of novel therapies to improve TNBC patient prognosis.

Background: We aimed to create a model of radiological and pathological criteria able to predict the upgrade rate of low-grade ductal carcinoma in situ (DCIS) to invasive carcinoma, in patients undergoing vacuum-assisted breast biopsy (VABB) and subsequent surgical excision. Methods: 3100 VABBs were retrospectively reviewed among which we reported 295 low-grade DCIS who subsequently underwent surgery. The association between patients’ features and the upgrade rate to invasive breast cancer (IBC) was evaluated by univariate analysis. Finally, we developed a predictive multivariable model based on the features which were significantly associated with the univariate analysis outcome. Results: the upgrade rate to invasive carcinoma was 10.8 %. At univariate analysis, the risk of upgrade was significantly lower in the absence of post- biopsy residual lesion (p<0.001), age > 50 (p=0.029), and in presence of low-grade DCIS only in specimens with microcalcifications (p=0.002). According to the final multivariable model, the predicted probability of diagnostic underestimation for a patient with all the three favourable features selected at univariate analysis was 1% (95% CI: 0.3%-4%). Conclusions: An easy to use predictive model of radiological and pathological criteria is able to identify patients with low-grade carcinoma in situ with low risk of upstaging to infiltrating carcinomas.

The National Breast and Cervical Cancer Early Detection Program (NBCCEDP) of Minnesota, “Sage”, provides breast cancer screening to uninsured women. We introduce a novel mapping technique, spatially adaptive filters (SAFs), to estimate utilization of Sage screening in Minnesota. Sage screenings (N = 74,712) were geocoded. The eligible population was modeled with the RTI synthetic population dataset. Between 2011 and 2015, 36,979 women a year were Sage eligible. Utilization was highly variable across Minnesota (M = 37.2%, range 0% - 131%, SD = 18.7%). This replicable approach modeled utilization rates to the neighborhood-level, allowing Sage to prioritize locations and engage communities.

Despite the recognized benefits of fecal occult blood test (FOBT) and mammography screenings, participation in breast (BC) and colorectal cancer (CRC) screening programs is still suboptimal. This study investigates municipal characteristics associated with their BC/CRC screening uptake profiles among women aged 55–69 years. Using data from 308 municipalities of Flanders from 2014 to 2017, a profile for each municipality based on its BC/CRC screening uptake compared with the median screening uptake was created. Logistic regression with generalized estimating equations was used to assess the associations between municipal characteristics and BC/CRC screening uptake profiles. The overall median uptake of cancer screening was higher for CRC (57.4%) than for BC (54.6%). The following municipal characteristics were associated with worse performance in terms of only CRC, only BC, or both CRC and BC screening uptake, respectively: foreign nationality, self-employment rate, (early) retirement rate, diabetes, disabilities; (early) retirement rate; age group 65–69, foreign nationality, self-employment rate, (early) retirement rate, wage-earners, diabetes. The following municipal characteristics were associated with better performance in terms of only CRC, only BC, or both CRC and BC screening uptake respectively: residential stability, having a partner, having children, jobseeker rate, GP visits, preventive dental visits; having children, GP visits; age group 55–59, residential stability, having a partner, having children, jobseeker rate, higher education, GP visits, preventive dental visits. This study’s results regarding the interrelation between the BC and CRC screening could be used to tailor interventions to improve the participation of the target population in both programs.

This study aimed to determine the feasibility of the development of an over-the-counter (OTC) screening model using machine learning for breast cancer screening in the Asian women population. Data were retrospectively collected from women who came to the Hospital Universiti Sains Malaysia, Malaysia. Five screening models were developed based on machine learning methods; random forest, artificial neural network (ANN), support vector machine (SVM), elastic-net logistic regression and extreme gradient boosting (XGBoost). Features used for the development of the screening models were limited to information from the patients’ registration form. The model performance was assessed across the dense and non-dense groups. SVM had the best sensitivity while elastic-net logistic regression had the best specificity. In terms of precision, both random forest elastic-net logistic regression had the best performance, while, in terms of PR-AUC, XGBoost had the best performance. Additionally, SVM had a more balanced performance in terms of sensitivity and specificity across the mammographic density groups. The three most important features were age at examination, weight and number of children. In conclusion, OTC models developed from machine learning methods can improve the prognostic process of breast cancer in Asian women.

Background: Liquid biopsy is widely recognised as an efficient diagnostic method in oncology for disease detection and monitoring. Though examination of circulating tumor cell (CTC) is mostly implemented for assessment of genomic aberrations, need of complex methodologies for their detection has impeded its acceptance in low resource settings. We evaluated the cell free DNA (cfDNA) as a liquid biopsy tool and investigated its utility in breast cancer patients. Methods: Total cell free DNA was extracted from plasma of breast cancer patients (n=167) with median follow up of more than 5 years, at various stages of the disease. Quantitative PCR was performed to estimate the copy numbers of two fractions of ALU repetitive elements (ALU 115 and ALU 247) and DNA Integrity (DI) was calculated as the ratio of ALU 247/115. Mutations in TP53 and PIK3CA in the cfDNA was estimated by next-gen sequencing (NGS) in a subset of samples. Association of the levels of both the ALU fragments with various clinico-pathological factors and disease-free survival at various stages were examined. Nomogram models were constructed with clinical variables and ALU 247 levels to predict disease-free survival and best performing model was evaluated by decision curve analysis. Results: DI and ALU 247 levels were significantly lower (p<0.0001) in the post-operative plasma when compared to their pre-surgery levels. DI and ALU 247 were found to be significantly higher in patients with metastasis (p<0.05). Patients with higher levels of ALU 247 in their post-operative plasma had significantly poor disease-free survival (p=0.005). Higher level of ALU 247 in circulation also correlated with low tumor-infiltrating lymphocytes (TIL) within their primary tumors in the ER-negative breast cancer subtype (p=0.01). Cox proportional hazard analysis confirmed ALU 247 as an independent variable of disease-free survival both in univariate and multivariate analysis [HR 1.3 (95% CI 1.047 to 1.613, p= 0.017)]. Nomogram model showed addition of ALU 247 with other variables significantly improved (C-index-0.823) the predictive ability of the model. Conclusion: Our results confirm the utility of cfDNA as an evolving liquid biopsy tool for molecular analysis. Evaluation of larger fragment of cfDNA estimated through ALU 247 can provide vital information concurrent with the pathological process of disease evolution in breast cancer and warrants expansion to other cancer types.

(1) Background: Breast cancer-associated lymphedema (BCRL) is a major complication of breast cancer treatment, affects the quality of life of breast cancer survivors who develop it. Manual lymphatic drainage has a beneficial result in combating lymphedema in patients who have undergone breast cancer surgery. The hypothesis consists in complete decongestive therapy reduces the lymphedema at the level of the upper limb on the side of mastectomy. (2) Methods: Twenty-five patients with radical mastectomy and upper limb lymphedema on the mastectomy side were included in this study. Upper limb circumferences were measured with a tape measure at the following levels: metacarpophalangeal joint; distal radioulnar joint; 10 cm distal to lateral epicondyle; 5 cm proximal to elbow joint; 10 cm proximal to lateral epicondyle. (3) Results: Patients received twice weekly manual lymphatic drainage, multi-layer compression bandaging and upper limb muscle stimulation exercises on the mastectomy side twice weekly. The circumference assessed at the level of the metacarpophalangeal joints and distal radio-carpal joint decreased at the final evaluation. Forearm perimetery - 5 and 10 cm distal to the lateral epicondyle the circumference decreased at the final assessment. (4) Conclusions: Patients with breast cancer-related lymphedema should receive comprehensive decongestive therapy in the early stage of lymphedema to achieve rapid clinical results and improved quality of life

Objective: Radiomics and deep transfer learning are two popular technologies used to develop computer-aided detection and diadnosis (CAD) schemes of medical images. This study aims to investigate and compare advantages and potential limitations of applying these two technologies in developing CAD schemes. Methods: A relatively large and diverse retrospective dataset including 3,000 digital mammograms is assembled in which 1,496 images depict malignant lesions and 1,054 images depict benign lesions. Two CAD schemes are developed to classify breast lesions. The first scheme is developed using four steps namely, applying an adaptive multi-layer topographic region growing algorithm to segment lesions, computing initial radiomics features, applying a principal component algorithm to generate an optimal feature vector, and building a support vector machine classifier. The second CAD scheme is built based a pre-trained residual net architecture (ResNet50) as a transfer learning model to classify breast lesions. Both CAD schemes are trained and tested using a 10-fold cross-validation method. Several score fusion methods are also investigated to classify breast lesions. CAD classification performance is evaluated by the area under ROC curve (AUC). Results: ResNet50 model-based CAD scheme yields AUC = 0.85±0.02, which is significantly higher than radiomics feature-based CAD scheme with AUC = 0.77±0.02 (p < 0.01). Additionally, fusion of classification scores generated by two CAD schemes does not further improve classification performance. Conclusion: This study indicates that using deep transfer learning is more efficient to develop CAD schemes and enables to yield higher lesion classification performance than CAD schemes developed using radiomics-based technology.

Fibroepithelial lesions (FL) of the breast, in particular Phyllodes tumors (PT) and fibroadenomas, pose a significant diagnostic challenge. There are no generally accepted criteria that distinguish benign, borderline, malignant PT, and FA. Combined genome-wide DNA methylation and copy number variant (CNV) profiling is an emerging strategy to classify tumors. We compiled a series of patient-derived archival biopsy specimens reflecting the FL spectrum and histological mimickers including clinical follow-up data. DNA methylation and CNVs were determined by well-established microarrays. Comparison of the patterns with a pan-cancer dataset assembled from public resources including "The Cancer Genome Atlas" (TCGA) and "Gene Expression Omnibus" (GEO) suggests that FLs form a methylation class distinct from both control breast tissue as well as common breast cancers. Complex CNVs were enriched in clinically aggressive FLs. Subsequent fluorescence in situ hybridization (FISH) analysis detected respective aberrations in the neoplastic mesenchymal component of FLs only, confirming that the epithelial component is non-neoplastic. Of note, our approach could lead to the elimination of the diagnostically problematic category of borderline PT and allow for optimized prognostic patient stratification. Furthermore, the identified recurrent genomic aberrations such as 1q gains (including MDM4), CDKN2a/b deletions and EGFR amplifications may inform therapeutic decision-making.

Inherited mutations in BRCA1 and BRCA2 genes increase risks for breast, ovarian, and other cancers. Both genes encode proteins for accurately repairing chromosome breaks. If mutations inactivate this function, broken chromosomes may not be restored correctly, allowing breaks to persist or rearrange chromosomes. These abnormalities are potentially catastrophic events that can originate from viral infections. I used bioinformatic analyses of publicly available breast cancer patient data to show that the distribution of chromosome breaks in hereditary breast cancers differs markedly from sporadic breast cancers. Then I tested hereditary breast cancer sequence data around chromosome breaks for DNA similarity to all known viruses. Human DNA flanking breakpoints usually had decisive matches to Epstein-Barr virus (EBV / HHV4) tumor variants HKHD40 and HKNPC60. Many breakpoints were near EBV genome anchor sites, human EBV tumor-like sequences, EBV-associated epigenetic marks, and some fragile sites. On chromosomes 2 and 12, sequences near EBV genome anchor sites accounted for 90% and 88% of breakpoints (p<0.0001), respectively. On chromosome 4, 51/52 inter-chromosomal breakpoints were close to EBV-like sequences in 19 hereditary breast cancers. In contrast, 19 sporadic breast cancers only had 12 interchromosomal breakpoint regions on chromosome 4 near EBV-like sequences. On various other chromosomes, five EBV genome anchor sites were near hereditary breast cancer breakpoints at precisely defined, disparate gene or LINE locations. Independent evidence further implicating EBV in hereditary breast cancer breakpoints is that 25 breast cancer break positions are within 1.25% of breakpoints in model EBV cancers. In addition to BRCA1 or BRCA2 mutations, all the hereditary breast cancers had mutated genes essential for immune responses. This compromise facilitates reactivation of herpes viruses which produce nucleases capable of breaking chromosomes. EBV also causes other deleterious effects: anchored EBV episomes can interfere with normal replication and obstruct DNA break repairs; even very early infection causes massive transcription changes. The results, therefore, imply proactive treatment and prevention of herpes viral infections may prevent some chromosome breaks and benefit BRCA mutation carriers.

We previously described a model of deep intrinsic resistance of breast cancer wherein we used a function-based approach to selection of cancer cells that can survive a variety of challenges in prolonged but reversible quiescence. Our experimental results suggested that resistant cancer cells possess a variety of mechanisms, including modifications of the epigenome and transcriptome, for generating a high degree of cellular heterogeneity. In the present study, we evaluated JIB-04, a small-molecule epigenetic inhibitor initially discovered to inhibit cancer growth, to determine its ability to affect deep intrinsic resistance in our breast cancer model. We found that long pretreatment with JIB-04 sensitized resistant triple-negative inflammatory breast cancer cells and their parental cell line SUM149 to the chemotherapeutic drugs doxorubicin and paclitaxel. Resistant cancer cells derived from another inflammatory breast cancer cell line, FC-IBC02, were considerably more sensitive to JIB-04 than was the parental cell line. Investigating a mechanism of sensitization, we found that JIB-04 exposure increased the expression of PD-L1 in resistant cells, suggesting that JIB-04 may also sensitize resistant breast cancer cells to anti-PD-L1 immune therapy. Finally, these results support the usefulness of our experimental strategy for evaluating anticancer agents such as JIB-04 that may halt cancer evolution and prevent development of cancer resistance to currently used therapies.

Given the broad and intense use of plastic, society is being increasingly affected by its degradation and by-products, particularly by microplastics (MPs) -fragments smaller than 5 mm in size-, and nanoplastics (NPs) -with sizes less than 1 µm. MPs and NPs may enter the body primarily through inhalation, consumption, and skin contact. Once ingested, MPs can penetrate tissues, deviating to other parts of the body, and hence potentially affecting important cellular pathways such as nonconforming chemokine receptors that control the communication between the fetus and the mother. Consequently, the potential health harm induced by MP internalization is a major issue, evidenced by multiple studies demonstrating harmful consequences in diverse animal models and human cells. Here, an overview of the various modes of exposure to MPs and NPs is presented, including inhalation, placental transfer, ingestion, breastmilk consumption, and skin absorption, as well as placental and fetal toxicity due to plastic particles based on animal and in vitro studies. Though MPs in our environment are becoming more recognized, their developmental toxicity is still scarcely known. Besides negatively affecting pregnancy, MPs and NPs have been shown to potentially harm the developing fetus, given their ability to cross the placental barrier. Still, considerable gaps remain in our understanding of the dispersion and toxicity of these particles in the environment, as well as the precise types of NPs and MPs bearing the greatest dangers. As a result, we advocate for larger-scale epidemiological investigations, the development of novel approaches for measuring NP and MP exposures, and the necessity of understanding the toxicity of various kinds of NPs to guide future research efforts.

The effect of the antioxidant vitamin C in cancer has been studied for over 30 years with conflict-ing results ranging from total absence of effect, to possible protective effect, to potential therapeutic effect when administered in high doses. The aim of the study was to define the effect of vitamin C in breast cancer and the possible involvement of sphingomyelin metabolism. Therefore, the effect of low and high dose of vitamin C on cells reproducing luminal A type (MCF7) and triple negative type (MB231) of breast cancer was analyzed. The results showed that high dose of vitamin C produced effects only in MCF7 cells such as decreased cell viability, modulation of cell cycle re-lated genes, unexpected change in cell phenotype due to estrogen receptor downregulation, catabo-lism of sphingomyelin with a large increase in ceramide. In conclusion, we demonstrated that high doses of VitC on the one hand reduce the growth of lu-minal A type breast cancer cells and on the other hand induce their phenotypic change towards hormone therapy resistant cells. The effect of vitamin C on therapeutic treatment failure of luminal A breast cancer and the possible involvement of high ceramide levels were discussed.

The aim of this study was to investigate the possible role of 99mTc-sestamibi in the regulation of cancer cell proliferation and apoptosis. To this end, Te in vivo values of 99mTc-sestamibi uptake have been associated to the in-situ expression of both Ki67 and caspase-3. For in vitro investiga-tions BT-474 cells were incubated with three different concentration of 99mTc-sestamibi: 10µg/ml –1µg/ml – 0,1µg/ml. Expression of caspase-3 and Ki67, as well as the ultrastructure of cancer cells, were evaluated at T0 and after 24, 48, 72 and 120 hours after 99mTc-sestamibi incubation. Ex vivo data strengthened the known association between the sestamibi uptake and the Ki67 expression. Linear regression analysis showed a significant association between the sestamibi uptake and the number of apoptotic cells evaluated as caspase-3 positive breast cancer cells. As concern the in vitro data, a significant decrease of the proliferation index was observed in breast cancer cells incubated with high concentration of 99mTc-sestamibi (10µg/ml). Amazingly, a significant increase in caspase-3 positive cells in cultures incubated with 10µg/ml 99mTc-sestamibi was observed. This study suggested the possible role of sestamibi in the regulation of pathophysiological process involved in breast cancer.

Early detection of breast cancer, one of the most common cancers in women worldwide, raises survival rates and lowers the cost of treatment. Although breast cancer detection and classification (CAD) tools have improved, some issues and restrictions still require further research. The creation of breast cancer CAD systems, particularly with deep learning models, was significantly impacted by recent advancements in machine learning and image processing techniques. The current deep learning-based CAD system to identify and categorize masses in mammography is presented in a structured manner in this survey. The survey provides the most popular breast cancer CAD system evaluation metrics, publicly available mammographic datasets, and current image modalities. The survey examines the available literature, emphasizing its strengths and limitations. The survey also emphasizes the difficulties and drawbacks of the current methods for classifying and detecting breast cancer. We point out research gaps and make suggestions for further study. This systematic review may be beneficial for clinicians using CAD systems to diagnose breast cancer early on and for researchers looking for knowledge gaps and making more contributions to the field.

Breast cancer (BC) is the most common malignancy and the second cause of cancer specific death in women from high-income countries. More than 70% of all breast cancer are hormone receptor-positive BC, and elevated estrogen circulating in blood has been proved to be a strong risk for BC development. This is due to its contribution to enhance proliferation of cancerous cells, angiogenesis and metastasis stimulation and therapy resistance. The estrogen (E) metabolism–gut microbiome axis is functional with underlying individual variations in E levels. It is reasonable that the estrobolome (bacterial genes whose products are capable of metabolizing E) could contribute to the risk of hormone-driven malignancies including BC and may serve as a potential biomarker and target. Gut microbial β -glucuronidase (GUS) enzymes have been suggested to be involved in the estrobolome. Furthermore, bacterial GUS enzymes within the gastrointestinal tract have been postulated to contribute to hormone breast cancer. In this review, we discuss the recent knowledge about the role of GUS enzyme in the pathogenesis of breast cancer. We focus on the role of GUS in (i)-the microbioma and estrogen metabolism, (ii) diet, estrobolome, and the BC development, (iii) other activities of the bacterial β-glucuronidase, and (iv) the new molecular target for BC therapeutic application.

PIK3CA is a gene usually mutated in breast cancer and has an important role in tumor progression and treatment. Therefore, there is required a technique to detect low-rate PIK3CA mutations improving the clinical conduct. This study aimed to compare chip-based dPCR and Sanger sequencing to detect PIK3CA mutations in breast cancer patients. Fifty-seven tumor samples from breast cancer patients were collected and analyzed by Sanger sequencing and dPCR for PIK3CA mutations (E545K, H1047R, and H1047L). Digital PCR sensitivity, specificity, and overall performance were estimated by contingency tables, receptor operator characteristic (ROC), and area under the curve (AUC). Sanger sequencing identified PIK3CA mutations in six patients (10.5%), two with H1047R, and four with E545K. Digital PCR confirmed those mutations and identified 19 additional patients with at least one mutation. Comparison between dPCR and Sanger sequencing showed a sensitivity of 100% (95% CI 53-100%), and a specificity of 84.2% (95% CI 83 - 84.2%). Besides, H1047R mutation showed a significant association with breast cancer phenotype (p =0.019) and lymphatic node infiltration (p =0.046). Digital PCR showed a high sensitivity to detect mutations in tumor samples and it might be capable to detect low-rate mutations and tumor subpopulations not detected by Sanger sequencing.

To gain new insights into the potential of mother-to-child transmission of Zika virus (ZIKV) through breast milk or breastfeeding practices, we systematically searched regional and international databases and screened 1,658 non-duplicate records describing women with suspected or confirmed ZIKV infection, intending to breastfeed or give breast milk to an infant. Fourteen studies met our inclusion criteria and inform this analysis. These studies reported on 97 mother-children pairs who provided breast milk for ZIKV assessment. Seventeen breast milk samples from different women were found positive for ZIKV via RT-PCR, and ZIKV replication was found in cell cultures from five out of seven breast milk samples from different women. Only three out of six infants who had ZIKV infection were breastfed, no evidence of clinical complications were found to be associated with ZIKV RNA in breast milk. This review updates our previous report by synthesizing the evidence from 12 new articles and we find no evidence of mother-to-child transmission through breast milk intake or breastfeeding. As the certainty of the present evidence is low, additional studies are still warranted to completely understand any potential of transmission of ZIKV through breastfeeding.

(1) Background: Mouse-mammary tumor virus (MMTV) might play a role in the etiology of some breast cancers in humans. The purpose of our study was to identify MMTV DNA sequences in breast tissue samples from breast cancer patients operated in our regional center from Romania. (2) Methods: We have selected 75 patients with non-metastatic breast cancer treated with curative intent and searched with PCR the MMTV-like DNA sequence in the breast cancer tissue and normal breast tissue obtained from the same patients. (3) Results: None of the examined samples was positive for MMTV-like target sequences on PCR. (4) Conclusions: We could not prove that MMTV plays a role in the etiology of breast cancer in our patient group. This finding is similar to findings of other geographically related research groups and might be due to the fact that only the Mus musculus domesticus mouse species was proven to carry infectious MMTV, but not the Mus musculus musculus species, which is specific to South-Eastern Europe and some parts of Asia.

The purpose of this study was to determine the change in overall survival (OS) for patients with de novo metastatic breast cancer (dnMBC) over time. We conducted a retrospective cohort study with 1981 patients with dnMBC diagnosed between January 1995 and December 2017 at The University of Texas MD Anderson Cancer Center. OS was measured from the date of diagnosis of dnMBC. OS was compared between patients diagnosed during different time periods: 5-year periods and periods defined according to when key agents were approved for clinical use. The median OS was 3.4 years. The 5- and 10-year OS rates improved over time across both types of time periods. A subgroup analysis showed that OS improved significantly over time for the estrogen-receptor-positive/HER2-positive (ER+/HER2+) subtype, and exhibited a tendency toward improvement over time for the ER-negative (ER-)/HER2+ subtype. Median OS was significantly longer in patients with non-inflammatory breast cancer (P = .02) and in patients with ER+ disease, progesterone-receptor-positive disease, HER2+ disease, lower nuclear grade, locoregional therapy, and metastasis to a single organ (all P &lt;.0001). These findings showed that OS at 5 and 10 years after diagnosis in patients with dnMBC improved over time. The significant improvements in OS over time for the ER+/HER2+ subtype and the tendency toward improvement for ER-/HER2+ subtype suggest the contribution of HER2-targeted therapy to survival.