Exosomal microRNA-92b Is a Diagnostic Biomarker in Breast Cancer and Targets Survival-Related MTSS1L to Promote Tumorigenesis.

Exosomal microRNAs (miRNAs) are novel, non-invasive biomarkers for facilitating communication and diagnosing cancer. However, only a few studies have investigated their function and role in the clinical diagnosis of breast cancer. To address this gap, we established a stable cell line, MDA-MB-231-CD63-RFP, and recruited 112 female participants for serum collection. We screened 88 exosomal miRNAs identified through microarray analysis of 231-CD63 and literature screening using real-time PCR; only exosomal miR-92b-5p was significantly increased in patients with breast cancer. It had a significant correlation with stage and discriminated patients from the control with an AUC of 0.787. Exosomal miR-92b-5p impacted the migration, adhesion, and spreading ability of normal human mammary epithelial recipient cells through the downregulation of the actin dynamics regulator MTSS1L. In clinical breast cancer tissue, the expression of MTSS1L was significantly inversely correlated with tissue miR-92b-5p, and high expression of MTSS1L was associated with better 10-year overall survival rates in patients undergoing hormone therapy. In summary, our studies demonstrated that exosomal miR-92b-5p might function as a non-invasive body fluid biomarker for breast cancer detection and provide a novel therapeutic strategy in the axis of miR-92b-5p to MTSS1L for controlling metastasis and improving patient survival.

Combination of FAK inhibitor and cytokine-induced killer cell therapy: An alternative therapeutic strategy for patients with triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is characterized by the loss of expression of several biomarkers, which limits treatment strategies for the disease. In recent years, immunotherapy has shown promising results in the treatment of various tumors. Emerging evidence demonstrated that TNBC is an immune-activated cancer, suggesting that immunotherapy could be a feasible treatment option for TNBC. Cytokine-induced killer (CIK) cell therapy is considered as a potential treatment for cancer treatment. However, it is still not approved as a standard treatment in the clinical setting. Our previous study demonstrated that focal adhesion kinase (FAK) plays important role in regulating the sensitivity of TNBC cells to CIK cells. In this study, we further verify the role of FAK in regulating the immune response in vivo. Our in vitro study indicated that knockdown of FAK in TNBC cells or treat with the FAK inhibitor followed by co-culture with CIK cells induced more cell death than CIK cells treatment only. RNA-seq analysis indicated that suppression of FAK could affect several immune-related gene expressions in TNBC cells that affects the immune response in the tumor microenvironment of TNBC cells. The combination of FAK inhibitor and CIK cells significantly suppressed tumor growth than the treatment of FAK inhibitor or CIK cells alone in vivo. Our findings provide new insights into the cytotoxic effect of CIK cell therapy in TNBC treatment and indicate that the combination of CIK cell therapy with FAK inhibitors may be an alternative therapeutic strategy for patients with TNBC.

Breast infiltrating ductal carcinoma with metastasis to stomach: A case report.

The most common metastatic sites in breast cancer include the liver, bone, the lungs, and the brain. Metastasis to the gastrointestinal system is rare and can occur years after breast cancer diagnosis. This case report features a woman who was diagnosed with infiltrating ductal carcinoma 10 years ago and was discovered to have stomach metastasis this year. Immunohistochemical staining was employed to distinguish the metastasis from primary gastric cancer. This case is presented to raise awareness of the risk of gastric metastasis from breast cancer after years of breast cancer therapy.

Precise application of sentinel lymph node biopsy in patients with ductal carcinoma in situ: A systematic review and meta-analysis of real-world data.

PURPOSE: Although ductal carcinoma in situ (DCIS) seldom involves lymph nodes, some patients may upstage to invasive disease, thus requiring a second surgery for sentinel lymph node (SLN) biopsy (SLNB). However, the indications of SLNB remain inconclusive and clinical trials are rarely available. Our aim is to systematically review the real-world data to evaluate whether SLNB is precisely applied in patients with a high risk of upstaging from DCIS to invasive carcinoma. METHODS: PubMed, EMBASE, and Cochrane library databases were searched. Prospective and retrospective cohort studies that evaluated the pathological outcomes of SLNB and the upstaging rate in women with DCIS were included. The primary outcomes were the upstaging and SLN-positive rates of patients initially diagnosed as having DCIS. We analyzed factors, namely biopsy methods, clinical presentations, histological patterns, and hormone receptor status, that potentially indicate nodal involvement risk. RESULTS: We retrieved 43 prospective and 69 retrospective studies including 44,001 patients. The pooled estimates of upstaging and SLN-positive rates were 25.8% (95% confidence interval [CI]: 0.230-0.286) and 4.9% (95% CI: 0.042-0.055), respectively. In subgroup analysis, the upstaging rate was significantly higher in patients with estrogen receptor-negative status, palpable mass, tumor size >2 cm on imaging, and high-nuclear grade and those who received a preoperative diagnosis through core needle biopsy. CONCLUSION: The upstaging and SLN-positive rates of DCIS were 25.8% and 4.9%, respectively. By selecting patients with high risk DCIS, surgeons may increase the precision of and reduce the excess and incomplete treatment rates of SLNB.

Comprehensive Transcriptomic and Proteomic Analyses Identify a Candidate Gene Set in Cross-Resistance for Endocrine Therapy in Breast Cancer.

Endocrine therapy (ET) of selective estrogen receptor modulators (SERMs), selective estrogen receptor downregulators (SERDs), and aromatase inhibitors (AIs) has been used as the gold standard treatment for hormone-receptor-positive (HR+) breast cancer. Despite its clinical benefits, approximately 30% of patients develop ET resistance, which remains a major clinical challenge in patients with HR+ breast cancer. The mechanisms of ET resistance mainly focus on mutations in the ER and related pathways; however, other targets still exist from ligand-independent ER reactivation. Moreover, mutations in the ER that confer resistance to SERMs or AIs seldom appear in SERDs. To date, little research has been conducted to identify a critical target that appears in both SERMs/SERDs and AIs. In this study, we conducted comprehensive transcriptomic and proteomic analyses from two cohorts of The Cancer Genome Atlas Breast Invasive Carcinoma (TCGA-BRCA) to identify the critical targets for both SERMs/SERDs and AIs of ET resistance. From a treatment response cohort with treatment response for the initial ET regimen and an endocrine therapy cohort with survival outcomes, we identified candidate gene sets that appeared in both SERMs/SERDs and AIs of ET resistance. The candidate gene sets successfully differentiated progress/resistant groups (PD) from complete response groups (CR) and were significantly correlated with survival outcomes in both cohorts. In summary, this study provides valuable clinical implications for the critical roles played by candidate gene sets in the diagnosis, mechanism, and therapeutic strategy for both SERMs/SERDs and AIs of ET resistance for the future.

Synchronous surgery and immediate reconstruction of double primary cancers of the ovary and breast.

INTRODUCTION: There has been an ongoing debate about the benefits and risks between synchronous surgery and two independent surgery of ovary tumor removal and breast reconstruction. Here we report a synchronous oncological surgery and immediate postmastectomy reconstruction of double primary cancers of the ovary and breast. PATIENT CONCERNS: A 58-year-old woman presented with a right breast lump and ascites. DIAGNOSIS: Computed tomography (CT) indicated synchronous breast and ovarian cancer with multiple metastases. Double primary mammary and ovarian cancer was confirmed after a series of evaluations, such as core needle biopsy of the breast tumor. INTERVENTIONS AND OUTCOMES: Synchronous surgery and immediate reconstruction of double primary cancers of the ovary and breast were performed. Post-operative results showed complete resection of ovarian tumor, no post-operative complication, and excellent life quality. CONCLUSION: Synchronous surgery is warranted as a treatment option for selected cases of double primary cancer. The surgery not only achieved complete removal of one cancer and reduction of the other but also reached excellent breast reconstruction and body shape recovery.

Invasive lobular carcinoma enclosed by a benign phyllodes tumor: A case report.

INTRODUCTION AND IMPORTANCE: Phyllodes tumors (PT) account for approximately 1% of all breast tumors. The coexistence of phyllodes tumor and invasive lobular carcinoma in the ipsilateral breast is extremely rare with fewer than six cases reported worldwide in the last 20 years. We hereby present the first in Taiwan. CASE PRESENTATION: A 43-year-old female was presented with a protruding tumor with bleeding tendency over left breast in 2016. Breast sonography revealed highly suspected malignancy (ACR BI-RADS category 5). Computed tomography scan disclosed a protruding mass occupying the left breast. Core needle biopsy showed a fibroepithelial lesion favoring fibroadenoma. Considering clinicopathological discrepancy, a nipple-sparing mastectomy was conducted. Pathology report revealed a benign PT with an incidental finding of invasive lobular carcinoma (pT1cN0) within the tumor. Due to tumor recurrence, the patient received re-operation of total mastectomy in 2017, and is under regular adjuvant hormonal therapy without cancer recurrence to date. CLINICAL DISCUSSION: Physicians could easily overlook carcinomas enclosed by PTs due to its occult property. However, when carcinomatous changes arise from within or along with the PT, the proposed therapeutical course may be altered. Moreover, invasive carcinoma components in PTs possess potential for lymph node metastasis. Multidisciplinary cooperation is key in detecting and managing PT with synchronous carcinomatosis. CONCLUSION: Thorough examination of the excised tumor specimen and ensuring an adequate surgical margin is necessary. Sentinel lymph node biopsy (SLNB) should be considered whenever suspicious clinical features occur in PT patients. This may aid in the detection of microscopic invasive carcinomatous change.

FAK Regulates VEGFR2 Expression and Promotes Angiogenesis in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) remains a significant clinical challenge because of its high vascularity and metastatic and recurrent rates. Tumor angiogenesis is considered an important mediator in the regulation of tumor cell survival and metastasis in TNBC. Angiogenesis is induced by the binding of vascular endothelial growth factor to vascular endothelial growth factor receptor 2 (VEGFR2). Focal adhesion kinase (FAK) plays an important role in regulating various cell functions in normal and cancer cells. Previous studies have focused on investigating the function of endothelial FAK in tumor cell angiogenesis. However, the association between tumor FAK and VEGFR2 in tumor angiogenesis and the possible mechanisms of this remain unclear. In this study, we used a public database and human specimens to examine the association between FAK and VEGFR2. At the same time, we verified the association between FAK and VEGFR2 through several experimental methods, such as quantitative real-time polymerase chain reaction, Western blotting, and next-generation sequencing. In addition, we used the endothelial cell model, zebrafish, and xenograft animal models to investigate the role of FAK in TNBC angiogenesis. We found that FAK and VEGFR2 were positively correlated in patients with TNBC. VEGFR2 and several other angiogenesis-related genes were regulated by FAK. In addition, FAK regulated VEGFR2 and VEGF protein expression in TNBC cells. Functional assays showed that FAK knockdown inhibited endothelial tube formation and zebrafish angiogenesis. An animal model showed that FAK inhibitors could suppress tumor growth and tumor vascular formation. FAK promotes angiogenesis in TNBC cells by regulating VEGFR2 expression. Therefore, targeting FAK could be another antiangiogenic strategy for TNBC treatment.

Comprehensive profiles and diagnostic value of menopausal-specific gut microbiota in premenopausal breast cancer.

In Western countries, breast cancer tends to occur in older postmenopausal women. However, in Asian countries, the proportion of younger premenopausal breast cancer patients is increasing. Increasing evidence suggests that the gut microbiota plays a critical role in breast cancer. However, studies on the gut microbiota in the context of breast cancer have mainly focused on postmenopausal breast cancer. Little is known about the gut microbiota in the context of premenopausal breast cancer. This study aimed to comprehensively explore the gut microbial profiles, diagnostic value, and functional pathways in premenopausal breast cancer patients. Here, we analyzed 267 breast cancer patients with different menopausal statuses and age-matched female controls. The α-diversity was significantly reduced in premenopausal breast cancer patients, and the ß-diversity differed significantly between breast cancer patients and controls. By performing multiple analyses and classification, 14 microbial markers were identified in the different menopausal statuses of breast cancer. Bacteroides fragilis was specifically found in young women of premenopausal statuses and Klebsiella pneumoniae in older women of postmenopausal statuses. In addition, menopausal-specific microbial markers could exhibit excellent discriminatory ability in distinguishing breast cancer patients from controls. Finally, the functional pathways differed between breast cancer patients and controls. Our findings provide the first evidence that the gut microbiota in premenopausal breast cancer patients differs from that in postmenopausal breast cancer patients and shed light on menopausal-specific microbial markers for diagnosis and investigation, ultimately providing a noninvasive approach for breast cancer detection and a novel strategy for preventing premenopausal breast cancer.

Transarterial chemoembolization as a part of multi-modality treatment with drug-eluting beads for locally advanced breast cancer: A case report.

Locally advanced breast cancer (LABC) is generally treated with combined-modality therapy including systemic chemotherapy, surgery, radiotherapy, and targeted therapy due to its nature of rapid onset of metastatic disease and poor prognosis. In this case report, we present a 61-year-old female who suffered from a huge protruding breast mass (16.2cm) with superficial ulcerative wound noted for three months. LABC was diagnosed via core needle biopsy and PET-CT examination. Initially, she received combined systemic chemotherapy, hormone therapy and radiation therapy; however, severe necrosis caused rupture in part of the breast mass and extensive wound discharge resulting in difficulty in wound care and prolonged disease course. Trans-arterial chemoembolization with drug-eluting beads (DEB-TACE) was applied as a part of combined-modality therapy for shortening the time before surgery. HepaSphere (as one of the DEB) loaded with high dose of epirubicin (total 80mg) was infused intra-arterially due to the nature of slow-releasing effect and longer duration of ischemic effect. Shortly after DEB-TACE following in about 40 days, surgery was smoothly performed. Post-operative adjuvant target therapy and adjuvant chemotherapy with taxane were administered. There was no evidence of local recurrence or distal metastases after 9 months of follow-up. It is suggested that performing DEB-TACE prior to surgery becomes a part of multimodality treatment of LABC to achieve better local control, better wound care and shortened treatment course.

Comprehensive Transcriptomic Analysis Identifies ST8SIA1 as a Survival-Related Sialyltransferase Gene in Breast Cancer.

Hypersialylation caused by the overexpression of sialyltransferases (STs) is a common feature in cancer that is associated with several characteristics of tumorigenesis. Thus, identifying cancer-associated STs is critical for cancer therapy. However, ST screening has been frequently conducted in cell line models. In this study, we conducted a comprehensive analysis of STs in the clinical database and identified the STs related with the survival of breast cancer patients. RNA sequencing (RNA-Seq) data of 496 patients were obtained from The Cancer Genome Atlas Breast Invasive Carcinoma (TCGA-BRCA). Of the eight mapped STs, ST3GAL5, and ST8SIA1 met the acceptable area under the curve (AUC) criteria for overall survival (OS). Using Kaplan-Meier methods, we determined that high expression of ST8SIA1 was associated with poor 10-year OS in all patients, triple-negative breast cancer (TNBC), and non-TNBC patients, and poor disease-free survival (DFS) rates particularly in TNBC. ST8SIA1 also had superior AUC values in terms of OS/DFS. High ST8SIA1 levels showed a higher risk for poor OS in different groups of patients and a higher risk for poor DFS particularly in TNBC. In summary, we conducted a comprehensive analysis of STs from the clinical database and identified ST8SIA1 as a crucial survival-related ST, which might be a potential therapeutic target for breast cancer and TNBC patients.

Effects of Fibrin Sealant on Seroma Reduction for Patients with Breast Cancer Undergoing Axillary Dissection: Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Seroma formation is common in patients with breast cancer after axillary dissection. Fibrin sealant, containing fibrinogen and thrombin, has been developed to improve wound healing. We conducted a systematic review and meta-analysis to evaluate the efficacy of fibrin sealants in reducing seroma among patients with breast cancer undergoing axillary dissection. METHODS: We searched the PubMed, EMBASE, and Cochrane Library databases for randomized controlled trials (RCTs) published up to April 2020. Pooled estimates of the outcomes were computed using a random-effects model. The primary outcomes were incidence and volume of seroma, while the secondary outcomes were volume and duration of drainage, incidence of infection, and length of hospital stay. RESULTS: We reviewed 23 RCTs that included 1640 patients. Compared with the control group, the fibrin sealant group had no significant differences in the incidence of seroma, length of hospital stay, or incidence of surgical site infection. Significant intergroup differences were discovered in lower volume of seroma (weighted mean difference [WMD] - 71.88, 95% confidence interval [CI] - 135.58 to - 8.19), volume of drainage (WMD - 73.24, 95% CI - 107.32 to - 39.15), and duration of drainage (WMD - 0.84, 95% CI - 1.50 to - 0.19). CONCLUSIONS: Fibrin sealants provide limited benefits in reducing the volume of seroma and the volume and duration of drainage. Therefore, after shared decision making, surgeons may apply fibrin sealants to patients with breast cancer undergoing axillary dissection.

Transumbilical versus periumbilical incision for laparoscopic surgery: A meta-analysis.

BACKGROUND: Whether a transumbilical or periumbilical incision is beneficial for the initial peritoneal access in laparoscopic abdominal surgery has been debated. Our aim is to determine whether a transumbilical or periumbilical incision is a better route for the initial umbilical trocar. METHODS: PubMed, Embase, and Cochrane Library databases were searched for articles published before March 2020. The meta-analysis calculated the pooled effect size by using a random effects model. RESULTS: Five trials involving 783 patients were reviewed. The transumbilical group significantly reduced operation time (mean difference: -7.73; 95% confidence interval: -13.10 to -2.35) when compared to the periumbilical group. The length of hospital stay, mean pain scores on operation day and postoperation day 1 did not differ significantly between the two groups. Moreover, the incidence of surgical site infection, cosmetic satisfaction, and complication rate did not differ significantly between groups. CONCLUSION: A transumbilical incision is better than a periumbilical incision for laparoscopic surgery as it saves operation time. Hence, we suggest transumbilical incisions for the initial peritoneal access in laparoscopic abdominal surgery.

Effects of yam dioscorin interventions on improvements of the metabolic syndrome in high-fat diet-induced obese rats.

BACKGROUND: The metabolic syndrome (MS) is termed a cluster of multiple metabolic risk criteria which is positively correlated with cardiovascular disease and type 2 diabetes mellitus (DM). Yam dioscorins have been reported to exhibit biological activities, however, little is known their preventive effects on the MS. Therefore, a high-fat (HF) diet was used to induce Wistar rat obesity and then yam dioscorin (50 mg/kg, dio50) was intervened daily concurrent HF diet (HF diet + dio50) for five weeks to check the changes of weights of body and tissues, blood pressures, and impaired glucose tolerances. The in vitro peptic hydrolysates of dioscorin with molecular mass between 3 kDa and 10 kDa and less than 3 kDa were used to determine dipeptidyl peptidase IV (DPP IV) inhibitory activities which DPP IV inhibitor has been reported to prevent and treat type 2 DM. RESULTS: There were no significant difference in body weights, feed intakes, feed conversion, and weights of adipose tissues of obese rats in groups of HF and (HF diet + dio50). However, the systolic blood pressures in obese rats of 2-, 3- and 4-week dioscorin interventions were showed significantly lower (P < 0.05) compared to the HF group. The dioscorin intervention (HF+ dio50) was showed significantly different (P < 0.05) and improved the impaired glucose tolerances compared to HF group in obese rats by the oral glucose tolerance tests. It was also found that the fraction with different molecular mass of dioscorin peptic hydrolysates (5 mg/ml) showed inhibitory activities against DPP IV using sitagliptin phosphate as positive controls. CONCLUSIONS: Yam dioscorins exhibit improved MS activities in obese rats which the related mechanisms may need further investigations.

Learned resourcefulness, quality of life, and depressive symptoms for patients with breast cancer.

PURPOSE/OBJECTIVES: To investigate the relationships among learned resourcefulness, quality of life, and depressive symptoms of women with breast cancer. In addition, the direct and indirect effects of learned resourcefulness among disease characteristics and quality of life and depressive symptoms were examined. DESIGN: Descriptive, correlational, and predictive. SETTING: Two teaching hospitals in southern Taiwan. SAMPLE: 150 women with breast cancer. METHODS: Participants completed demographic information concerning disease characteristics and learned resourcefulness via the Center for Epidemiological Studies-Depression questionnaire and the SF-36 health survey during visits to the outpatient oncology department. MAIN RESEARCH VARIABLES: Learned resourcefulness, depressive symptoms, and quality of life. FINDINGS: About 35% of the participants had depressive symptoms. Participants with lower income and those undergoing adjuvant therapy displayed more depressive symptoms. Learned resourcefulness was a strong predictor of depressive symptoms and quality of life, but no mediating effects of resourcefulness on depressive symptoms existed. In addition, when participants had better income and were at a lower stage, a better quality of life was evident. CONCLUSIONS: A high amount of patients with breast cancer experience depressive symptoms. Learned resourcefulness can be a method of helping patients to improve their self-control behaviors and change their negative thoughts. IMPLICATIONS FOR NURSING: Nurses and healthcare professionals can apply resourcefulness strategies to promote quality of life and to prevent depressive symptoms in women with breast cancer.