Pretrained subtraction and segmentation model for coronary angiograms.

This study introduces a novel self-supervised learning method for single-frame subtraction and vessel segmentation in coronary angiography, addressing the scarcity of annotated medical samples in AI applications. We pretrain a U-Net model on a large dataset of unannotated coronary angiograms using an image-to-image translation framework, then fine-tune it on a limited set of manually annotated samples. The pretrained model excels at comprehensive single-frame subtraction, outperforming existing DSA methods. Fine-tuning with just 40 samples yields a Dice coefficient of 0.828 for vessel segmentation. On the public XCAD dataset, our model sets a new state-of-the-art benchmark with a Dice coefficient of 0.755, surpassing both unsupervised and supervised learning approaches. This method achieves robust single-frame subtraction and demonstrates that combining pretraining with minimal fine-tuning enables accurate coronary vessel segmentation with limited manual annotations. We successfully apply this approach to assist physicians in visualizing potential vascular stenosis sites during coronary angiography. Code, dataset, and a live demo will be available available at: https://github.com/newfyu/DeepSA .

Efficacy and safety of Xuefu Zhuyu Granules combined with western medicine in the treatment of angina pectoris of coronary heart disease: A study protocol of a randomized, double-blind, placebo-controlled clinical trial.

BACKGROUND: Despite advances in treatment strategies for coronary heart disease, angina pectoris remains a major cardiovascular disease causing death worldwide. For patients with angina pectoris of coronary heart disease, new or adjuvant treatment regimens are needed. The available evidence suggests that Xuefu Zhuyu Granules combined with Western medicine has advantages in the treatment of angina pectoris of coronary heart disease, but whether its efficacy has a placebo effect and whether it can be used as an adjuvant regimen for the treatment of angina pectoris of coronary heart disease remains controversial. METHODS: This is a prospective, randomized, double-blind, placebo-controlled trial to study the efficacy and safety of Xuefu Zhuyu Granules combined with Western medicine in the treatment of angina pectoris of coronary heart disease. Participants will be randomly divided into a treatment group or a control group, and all patients will receive Western medicine treatment based on guideline recommendations. On this basis, the treatment group orally takes Xuefu Zhuyu Granules and the control group orally takes Xuefu Zhuyu Granules mimic, and are followed up for 24 weeks after 12 weeks of continuous treatment. The observation indexes include: cardiac function parameters (left ventricular end-diastolic diameter; left ventricular end-systolic diameter; left ventricular ejection fraction, blood lipid levels (total cholesterol; triacylglycerol; low-density lipoprotein cholesterol; high-density lipoprotein cholesterol), the number of angina attacks per week, total amount of nitroglycerin tablets taken, and adverse reactions. Finally, SPSS22.0 (IBM Company, New York, NY) software will be used for statistical analysis of the data. DISCUSSION: This study will evaluate the efficacy and safety of Xuefu Zhuyu Granules combined with Western medicine in the treatment of angina pectoris of coronary heart disease. The results of this study will verify whether the efficacy of Xuefu Zhuyu Granules in the treatment of angina pectoris of coronary heart disease belongs to the placebo effect, which will also provide a reference for the clinical use of Xuefu Zhuyu Granules as a supplementary scheme for the treatment of angina pectoris of coronary heart disease.

Multivessel vs. Culprit Vessel-Only Percutaneous Coronary Intervention for ST-Segment Elevation Myocardial Infarction in Patients With Cardiogenic Shock: An Updated Systematic Review and Meta-Analysis.

Background: The optimal revascularization strategy in patients with ST-segment elevation myocardial infarction (STEMI) complicating by cardiogenic shock (CS) remains controversial. This study aims to evaluate the clinical outcomes of multivessel percutaneous coronary intervention (MV-PCI) compared to culprit vessel-only PCI (CO-PCI) for the treatment, only in patients with STEMI with CS. Methods: A comprehensive literature search was conducted. Studies assessed the efficacy outcomes of short (in-hospital or 30 days)/long-term mortality, cardiac death, myocardial reinfarction, repeat revascularization, and safety outcomes of stroke, bleeding, acute renal failure with MV-PCI vs. CO-PCI in patients with STEMI with CS were included. The publication bias and sensitivity analysis were also performed. Results: A total of 15 studies were included in this meta-analysis. There was no significant difference in short- and long-term mortality in patients treated with MV-PCI compared to CO-PCI group [odds ratio (OR) = 1.17; 95% confidence interval (CI), 0.92-1.48; OR = 0.86; 95% CI, 0.58-1.28]. Similarly, there were no significant differences in cardiac death (OR = 0.67; 95% CI, 0.44-1.00), myocardial reinfarction (OR = 1.24; 95% CI, 0.77-2.00), repeat revascularization (OR = 0.75; 95% CI, 0.40-1.42), bleeding (OR = 1.53; 95% CI, 0.53-4.43), or stroke (OR = 1.42; 95% CI, 0.90-2.23) between the two groups. There was a higher risk in acute renal failure (OR = 1.33; 95% CI, 1.04-1.69) in patients treated with MV-PCI when compared with CO-PCI. Conclusion: This meta-analysis suggests that there may be no significant benefit for patients with STEMI complicating CS treated with MV-PCI compared with CO-PCI, and patients are at increased risk of developing acute renal failure after MV-PCI intervention.

A 10-miRNA risk score-based prediction model for pathological complete response to neoadjuvant chemotherapy in hormone receptor-positive breast cancer.

Patients with hormone receptor (HR)-positive tumors breast cancer usually experience a relatively low pathological complete response (pCR) to neoadjuvant chemotherapy (NAC). Here, we derived a 10-microRNA risk score (10-miRNA RS)-based model with better performance in the prediction of pCR and validated its relation with the disease-free survival (DFS) in 755 HR-positive breast cancer patients (273, 265, and 217 in the training, internal, and external validation sets, respectively). This model, presented as a nomogram, included four parameters: the 10-miRNA RS found in our previous study, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) status, and volume transfer constant (Ktrans). Favorable calibration and discrimination of 10-miRNA RS-based model with areas under the curve (AUC) of 0.865, 0.811, and 0.804 were shown in the training, internal, and external validation sets, respectively. Patients who have higher nomogram score (>92.2) with NAC treatment would have longer DFS (hazard ratio=0.57; 95%CI: 0.39-0.83; P=0.004). In summary, our data showed the 10-miRNA RS-based model could precisely identify more patients who can attain pCR to NAC, which may help clinicians formulate the personalized initial treatment strategy and consequently achieves better clinical prognosis for patients with HR-positive breast cancer.

Potential Acupoint Prescriptions and Outcome Reporting for Acupuncture in Atopic Eczema: A Scoping Review.

BACKGROUND: Acupuncture is considered a complementary therapy for atopic eczema. The aim of this scoping review is to identify, examine, and summarize the potential acupoint prescriptions and outcome reporting regarding the clinical trials of acupuncture for eczema. METHODS: We searched different databases from inception to September 30, 2020. The data were screened and extracted to identify the potential acupuncture prescription and examine the variation in outcome reporting, outcome measurement instruments (OMIs), and measurement time points in clinical trials of acupuncture. RESULTS: A total of 116 clinical studies were included. The acupoint combination of LI11 and SP10 was used frequently. The core acupoint association networks were acupoints LI11, SP10, ST36, SP6, and LI4. For clinical trials of acupuncture, a total of 6 outcome distinct domains were identified in the 32 outcome measurements. The most frequently reported outcome was the eczema area, which was reported 97 times (83.6%, 97/116). Immune system outcomes were assessed in 15 outcome measurements, which totally reported 37 times. Adverse events were reported 51 times. TCM syndrome, which could reflect the characteristics of TCM, was reported 4 times. 29 outcomes (90.6%, 29/32) were provided definitions or OMIs. Among these outcomes, the outcome measurement times ranged from 0 to 34. CONCLUSIONS: This scoping review provides potential knowledge that should be considered as priority in future research of acupuncture for eczema.

Complement Signals Determine Opposite Effects of B Cells in Chemotherapy-Induced Immunity.

Understanding molecular mechanisms that dictate B cell diversity is important for targeting B cells as anti-cancer treatment. Through the single-cell dissection of B cell heterogeneity in longitudinal samples of patients with breast cancer before and after neoadjuvant chemotherapy, we revealed that an ICOSL+ B cell subset emerges after chemotherapy. Using three immunocompetent mouse models, we recapitulated the subset switch of human tumor-infiltrating B cells during chemotherapy. By employing B-cell-specific deletion mice, we showed that ICOSL in B cells boosts anti-tumor immunity by enhancing the effector to regulatory T cell ratio. The signature of ICOSL+ B cells is imprinted by complement-CR2 signaling, which is triggered by immunogenic cell death. Moreover, we identified that CD55, a complement inhibitory protein, determines the opposite roles of B cells in chemotherapy. Collectively, we demonstrated a critical role of the B cell subset switch in chemotherapy response, which has implications in designing novel anti-cancer therapies. VIDEO ABSTRACT.

Blocking the recruitment of naive CD4+ T cells reverses immunosuppression in breast cancer.

The origin of tumor-infiltrating Tregs, critical mediators of tumor immunosuppression, is unclear. Here, we show that tumor-infiltrating naive CD4+ T cells and Tregs in human breast cancer have overlapping TCR repertoires, while hardly overlap with circulating Tregs, suggesting that intratumoral Tregs mainly develop from naive T cells in situ rather than from recruited Tregs. Furthermore, the abundance of naive CD4+ T cells and Tregs is closely correlated, both indicating poor prognosis for breast cancer patients. Naive CD4+ T cells adhere to tumor slices in proportion to the abundance of CCL18-producing macrophages. Moreover, adoptively transferred human naive CD4+ T cells infiltrate human breast cancer orthotopic xenografts in a CCL18-dependent manner. In human breast cancer xenografts in humanized mice, blocking the recruitment of naive CD4+ T cells into tumor by knocking down the expression of PITPNM3, a CCL18 receptor, significantly reduces intratumoral Tregs and inhibits tumor progression. These findings suggest that breast tumor-infiltrating Tregs arise from chemotaxis of circulating naive CD4+ T cells that differentiate into Tregs in situ. Inhibiting naive CD4+ T cell recruitment into tumors by interfering with PITPNM3 recognition of CCL18 may be an attractive strategy for anticancer immunotherapy.

miR-922 regulates CYLD expression and promotes the cell proliferation of human hepatocellular carcinoma.

Evidence reveals that microRNAs (miRNAs) play essential roles in hepatocellular carcinoma (HCC) tumorigenesis. In the present study, we identified an essential role for miR-922 in the development of HCC. We found that miR-922 was significantly upregulated in HCC cells and clinical tissues. Gain and loss of function studies indicated that miR-922 significantly promoted HCC cell proliferation. We subsequently identified that cylindromatosis (CYLD) was a target gene of miR-922. Moreover, miR-922 decreased CYLD expression, subsequently upregulating the expression of c-Myc and cyclin D1, while downregulating p-Rb expression. Furthermore, knockdown of CYLD expression by siRNA partially counteracted the tumor suppressive effect of the inhibitor of miR­922, miR­922-in. Taken together, our findings indicate that miR-922 plays a key role in the promotion of HCC cell proliferation, and strongly suggest that exogenous miR-922 may have therapeutic value for treating HCC.

Prognostic Value of a BCSC-associated MicroRNA Signature in Hormone Receptor-Positive HER2-Negative Breast Cancer.

PURPOSE: Breast cancer patients with high proportion of cancer stem cells (BCSCs) have unfavorable clinical outcomes. MicroRNAs (miRNAs) regulate key features of BCSCs. We hypothesized that a biology-driven model based on BCSC-associated miRNAs could predict prognosis for the most common subtype, hormone receptor (HR)-positive, HER2-negative breast cancer patients. PATIENTS AND METHODS: After screening candidate miRNAs based on literature review and a pilot study, we built a miRNA-based classifier using LASSO Cox regression method in the training group (n=202) and validated its prognostic accuracy in an internal (n=101) and two external validation groups (n=308). RESULTS: In this multicenter study, a 10-miRNA classifier incorporating miR-21, miR-30c, miR-181a, miR-181c, miR-125b, miR-7, miR-200a, miR-135b, miR-22 and miR-200c was developed to predict distant relapse free survival (DRFS). With this classifier, HR+HER2- patients were scored and classified into high-risk and low-risk disease recurrence, which was significantly associated with 5-year DRFS of the patients. Moreover, this classifier outperformed traditional clinicopathological risk factors, IHC4 scoring and 21-gene Recurrence Score (RS). The patients with high-risk recurrence determined by this classifier benefit more from chemotherapy. CONCLUSIONS: Our 10-miRNA-based classifier provides a reliable prognostic model for disease recurrence in HR+HER2- breast cancer patients. This model may facilitate personalized therapy-decision making for HR+HER2- individuals.

Benign Phyllodes Tumor of the Breast Diagnosed After Ultrasound-Guided Vacuum-Assisted Biopsy: Surgical Excision or Wait-and-Watch?

BACKGROUND: The role of tumor-free resection in the treatment of benign phyllodes tumors (PTs) is still unknown. Ultrasound-guided vacuum-assisted biopsy (UGVAB) has been used for complete removal of benign breast lesions. This retrospective study aimed to compare the risk of relapse between patients with benign PT who undergo UGVAB and those who receive surgical excision (SE). METHODS: Benign PT patients with a pathology diagnosis who had received treatment between 2005 and 2013 at the authors' hospital were identified. The patients who received UGVAB did not receive any SE. In the SE group, wide local excision or mastectomy was performed when appropriate. The Kaplan-Meier curve and Cox proportional hazards regression were used to analyze and compare the relapse-free survival (RFS) between the patients in the two groups. RESULTS: The study enrolled 225 female patients with benign PT. The patients in the UGVAB group (n = 108) had significantly smaller tumors, more fibroadenoma, a higher body mass index (BMI), and a lower Breast Imaging-Reporting and Data System classification than the patients in the SE group (n = 117). The 5-year cumulative RFS was 81.6 and 88.7 % (p = 0.11) respectively for the patients receiving UGVAB and SE during a median follow-up period of 35.5 months. After adjustment for age, tumor size, BMI, or presence of fibroadenoma, treatment (UGVAB vs. SE) was not associated with increased risk for relapse events (hazard ratio 0.34; 95 % confidence interval 0.08-1.43; p = 0.14). No distant metastasis or death events occurred. CONCLUSIONS: The patients with benign PT who received UGVAB alone did not have a significantly more compromised RFS than those who underwent SE. A prospective, randomized study is needed to confirm this observation.

CCL18/PITPNM3 enhances migration, invasion, and EMT through the NF-κB signaling pathway in hepatocellular carcinoma.

Chemokine ligand 18 (CCL18) has been associated with hepatocellular carcinoma (HCC) metastasis. Here, we demonstrated a novel mechanism through which CCL18 enhances cell migration, invasion, and epithelial-mesenchymal transition (EMT) in HCC. (1) Using immunohistochemistry, we analyzed the expression of PITPNM3, a molecule that correlated with CCL18 signaling, in 149 HCC tissue specimens. The results showed that PITPNM3 expression is highly associated with tumor metastasis and differentiation; (2) in vitro experiments showed that CCL18 enhances cell migration, invasion, and EMT in PITPNM3((+)) HCC cells but not in PITPNM3((-)) cells. Silencing of PITPNM3 by short interfering RNA (siRNA) inhibited the induction of cell migration, invasion, and EMT by CCL18; (3) Cell migration, invasion, and EMT induced by CCL18 accompanied with the phosphorylation of IKK and IKBα as well as p65 nuclear translocation in PITPNM3((+)) HCC cells, but not in the cells that PITPNM3 is silenced with siRNA, implying that the activation of NF-κB signaling is involved in the action of CCL18/PITPNM3. These results suggest that CCL18 enhances HCC cell migration, invasion, and EMT through the expression of PITPNM3 and the activation of the NF-κB signaling pathway.

miR-142-5p and miR-130a-3p are regulated by IL-4 and IL-13 and control profibrogenic macrophage program.

Macrophages play a pivotal role in tissue fibrogenesis, which underlies the pathogenesis of many end-stage chronic inflammatory diseases. MicroRNAs are key regulators of immune cell functions, but their roles in macrophage's fibrogenesis have not been characterized. Here we show that IL-4 and IL-13 induce miR-142-5p and downregulate miR-130a-3p in macrophages; these changes sustain the profibrogenic effect of macrophages. In vitro, miR-142-5p mimic prolongs STAT6 phosphorylation by targeting its negative regulator, SOCS1. Blocking miR-130a relieves its inhibition of PPARγ, which coordinates STAT6 signalling. In vivo, inhibiting miR-142-5p and increasing miR-130a-3p expression with locked nucleic acid-modified oligonucleotides inhibits CCL4-induced liver fibrosis and bleomycin-induced lung fibrosis in mice. Furthermore, macrophages from the tissue samples of patients with liver cirrhosis and idiopathic pulmonary fibrosis display increased miR-142-5p and decreased miR-130a-3p expression. Therefore, miR-142-5p and miR-130a-3p regulate macrophage profibrogenic gene expression in chronic inflammation.

CCL18 from tumor-associated macrophages promotes angiogenesis in breast cancer.

The infiltration of tumor-associated macrophages (TAMs) is associated with extensive angiogenesis, which contributes to a poor prognosis in breast cancer. However, anti-angiogenic therapy with VEGF-specific monotherapy has been unsuccessful in treating breast cancer, and the molecular mechanisms associated with chemoresistance remain unclear. Here, we investigated whether CCL18, a chemokine produced by TAMs, can stimulate angiogenesis in breast cancer, as well as the underlying mechanisms. Double immunohistochemical staining for CCL18 and CD34/CD31/vWF was performed in 80 breast cancer samples to study the correlation between CCL18+ TAMs and microvascular density (MVD). Cocultures of TAMs with human umbilical vein endothelial cells (HUVECs) were used to model the inflammatory microenvironment, and CCL18-induced angiogenesis was evaluated both in vitro and in vivo. We demonstrated that CCL18+ TAM infiltration positively associated with MVD in breast cancer samples, which was correlated with tumor metastasis and poor prognosis. We confirmed, both in vitro and in vivo, that CCL18 and VEGF synergistically promoted endothelial cell migration and angiogenesis. Conversely, blocking CCL18 or VEGF with neutralizing antibodies synergistically inhibited the promigratory effects of TAMs. Silencing PITPNM3, a putative CCL18 receptor, on the surface of HUVECs abrogated CCL18-mediated promigration and the enhancement of HUVEC tube formation, independently of VEGFR signaling. Moreover, CCL18 exposure induced the endothelial-mesenchymal transformation and activated ERK and Akt/GSK-3ß/Snail signaling in HUVECs, thereby contributing to its pro-angiogenic effects. In conclusion, our findings suggest that CCL18 released from TAMs promotes angiogenesis and tumor progression in breast cancer; thus, CCL18 may serve as a novel target for anti-angiogenic therapies.

Paraneoplastic pemphigus associated with follicular dendritic cell sarcoma: report of a case and review of literature.

Follicular dendritic cell sarcoma (FDCS) is a rare tumor associated with paraneoplastic pemphigus. It is Blame drenchs auxiliary cell tumor which is derived from the peripheral lymphoid tissues. Throughout the world, several patients of paraneoplastic pemphigus associated follicular dendritic cell sarcoma were reported in the literature, but mostly originated from the neck lymph nodes, and extranodal origin of follicular dendritic sarcoma was rarely reported. Also, so far we have found that the malignant degree of all patients diagnosed with malignant tumors have been reported were low and after combined treatment of surgery, radiotherapy and chemotherapy, most of the prognosis was good. However, here we present a patient of paraneoplastic pemphigus associated with follicular dendritic cell sarcoma origined from outside of the lymph nodes and had high tumor malignant degree for its unclear cell boundaries, obvious atypia and mitoses and the patient's state became progressively deteriorate after operation.

Nerve fibers in breast cancer tissues indicate aggressive tumor progression.

Emerging evidence has indicated nerve fibers as a marker in the progression of various types of cancers, such as pancreatic cancer and prostate cancer. However, whether nerve fibers are associated with breast cancer progression remains unclear. In this study, we evaluated the presence of nerve fibers in 352 breast cancer specimens and 83 benign breast tissue specimens including 43 cases of cystic fibrosis and 40 cases of fibroadenoma from 2 independent breast tumor center using immunohistochemical staining for specific peripheral nerve fiber markers.In all, nerve fibers were present in 130 out of 352 breast cancer tissue specimens, while none were detected in normal breast tissue specimens. Among 352 cases, we defined 239 cases from Sun Yat-Sen Memorial Hospital, Guangzhou, China, as the training set, and 113 cases from the First Affiliated Hospital of Shantou University, Guangdong, China, as the validation set. The thickness of tumor-involving nerve fibers is significantly correlated with poor differentiation, lymph node metastasis, high clinical staging, and triple negative subtype in breast cancer. More importantly, Cox multifactor analysis indicates that the thickness of tumor-involving nerve fibers is a previously unappreciated independent prognostic factors associated with shorter disease-free survival of breast cancer patients. Our findings are further validated by online Oncomine database. In conclusion, our results show that nerve fiber involvement in breast cancer is associated with progression of the malignancy and warrant further studies in the future.

HER-2 positive breast cancer is associated with an increased risk of positive cavity margins after initial lumpectomy.

BACKGROUND: The effect of breast cancer subtype on margin status after lumpectomy remains unclear. This study aims to determine whether approximated breast cancer subtype is associated with positive margins after lumpectomy, which could be used to determine if there is an increased risk of developing local recurrence (LR) following breast-conserving surgery. METHODS: We studied 1,032 consecutive patients with invasive cancer who received lumpectomies and cavity margin (CM) assessments from January 2003 to November 2012. The following data were collected: patient age, cT stage, pT stage, grade, status of CM, lymph node status, menopausal status, ER, PR, HER-2, and Ki67, as well as the presence of extensive intraductal component (EIC) and lymphovascular invasion (LVI). A χ2 test was used to compare categorical baseline characteristics. Univariate and multivariate logistic regression analyses were performed to evaluate associations between pathologic features of CM status. Kaplan-Meier actuarial cumulative rates of LR (ipsilateral in-breast) were calculated. RESULTS: A total of 7,884 pieces of marginal tissue were collected from 1,032 patients, and 209 patients had positive CMs. Of the patients tested, 52.3% had luminal A subtype, 14.9% were luminal B, 12.8% were luminal-HER-2, 8.1% were HER-2 enriched, and 11.8% were triple negative. Univariate analysis showed that EIC (P < 0.001), LVI (P = 0.026), pN stage (N1 vs. N0: P = 0.018; N3 vs. N0: P < 0.001), and luminal B (P = 0.001) and HER-2 (P < 0.001) subtypes were associated with positive CMs. Multivariable analysis indicated that only EIC (P < 0.001), pN stage (P = 0.003), and HER-2 subtype (P < 0.001) were significantly correlated with positive CMs. On multivariable analysis, HER-2 subtype was an independent prognostic factor in LR (P = 0.031). CONCLUSIONS: The HER-2 subtype was the predictive factor most associated with positive CMs and an independent prognostic factor for LR. This result suggests that the increased risk of LR in HER-2 breast cancer is due to an increased microscopic invasive tumor burden, which is indicated by margin status after lumpectomy.

Restoration of miR-193b sensitizes Hepatitis B virus-associated hepatocellular carcinoma to sorafenib.

BACKGROUND: Chronic infection with Hepatitis B virus (HBV) is the major risk factor of Hepatocellular Carcinoma (HCC). This study is to explore the mechanism of sorafenib resistance and find an effective strategy to sensitize HBV-associated HCC to sorafenib. METHODS: Cytotoxicity to sorafenib was evaluated in HBV-positive/negative HCC cell lines. Expression of miR-193b and myeloid cell leukemia-1 (Mcl-1) protein were assessed by Q-PCR, in situ hybridization and western blot, immunohistochemistry, respectively. A luciferase reporter of Mcl-1 3'-UTR was used for validation as a target of miR-193b. Cell apoptosis was measured by flow cytometry, caspase-3 activity assay and DAPI staining. RESULT: The IC50 to sorafenib was significantly higher in HBV-positive HCC cells than those without HBV infection. Significant downregulation of miR-193b and a higher level of Mcl-1 were observed in HBV-positive HCC cells and tissues. The activity of Mcl-1 3'-UTR reporter was inhibited by co-transfection with miR-193b mimic. Restoring the expression of miR-193b sensitized HBV-associated HCC cells to sorafenib treatment and facilitated sorafenib-induced apoptosis. CONCLUSIONS: Modulation of miRNAs expression might be a potential way to enhance response to sorafenib in HBV-associated HCC.

miR-21 induces myofibroblast differentiation and promotes the malignant progression of breast phyllodes tumors.

Phyllodes tumors of breast, even histologically diagnosed as benign, can recur locally and have metastatic potential. Histologic markers only have limited value in predicting the clinical behavior of phyllodes tumors. It remains unknown what drives the malignant progression of phyllodes tumors. We found that the expression of myofibroblast markers, α-smooth muscle actin (α-SMA), fibroblast activation protein (FAP), and stromal cell-derived factor-1 (SDF-1), is progressively increased in the malignant progression of phyllodes tumors. Microarray showed that miR-21 was one of the most significantly upregulated microRNAs in malignant phyllodes tumors compared with benign phyllodes tumors. In addition, increased miR-21 expression was primarily localized to α-SMA-positive myofibroblasts. More importantly, α-SMA and miR-21 are independent predictors of recurrence and metastasis, with their predictive value of recurrence better than histologic grading. Furthermore, miR-21 mimics promoted, whereas miR-21 antisense oligos inhibited, the expression of α-SMA, FAP, and SDF-1, as well as the proliferation and invasion of primary stromal cells of phyllodes tumors. The ability of miR-21 to induce myofibroblast differentiation was mediated by its regulation on Smad7 and PTEN, which regulate the migration and proliferation, respectively. In breast phyllodes tumor xenografts, miR-21 accelerated tumor growth, induced myofibroblast differentiation, and promoted metastasis. This study suggests an important role of myofibroblast differentiation in the malignant progression of phyllodes tumors that is driven by increased miR-21.

VPAC1 overexpression is associated with poor differentiation in colon cancer.

Vasoactive intestinal peptide (VIP) is a neurotransmitter that primarily functions as a vasodilator. VIP plays its role through binding to its receptors known as VIP/pituitary adenylate cyclase-activating peptide receptors (VPACs). In this study, we examined the expression of VPAC1 in human colon cancer tissues, analyzed the relationship between VPAC1 expression and cancer malignancy, and explored the possible mechanisms using immunohistochemistry and immunofluorescence double staining. The results showed that (1) poorly differentiated colon cancers have significantly higher VPAC1 expression than well-differentiated colon cancers do (p < 0.01); (2) phospho-epithelial growth factor receptor (EGFR) overexpression/activation in the cytoplasm of cancer cells is related to VPAC1 overexpression; (3) blood vessels surrounding colon cancer have significantly more VPAC1-positive than normal colon mucosa does; (4) tumor-associated macrophages (TAMs) of colon cancer have a higher level of VPAC1 expression than macrophages in normal colon mucosa do. These data suggest that VPAC1 overexpression is associated with poorer differentiation of colon cancer, which is likely caused by subsequent EGFR activation in cancer cells. In addition, VPAC1 overexpression in both blood vessels and macrophages in tumors may also play an important role in the development of aggressive cancer.

Impact of atypical hyperplasia at margins of breast-conserving surgery on the recurrence of breast cancer.

PURPOSE: Atypical hyperplasia (AH) is associated with a relatively higher risk of subsequent development of cancer. It remains controversial whether it is necessary to re-excise AH found at surgical margins during breast-conserving surgery (BCS). The aim of this study was to determine the impact of atypical ductal/lobular hyperplasia found at the margins during BCS on the prognosis of early-stage breast cancer patients. METHODS: A retrospective analysis comparing patients with AH and receiving no further surgical treatment (n = 233) to those without AH at the margins during BCS (n = 158) was performed. RESULTS: At a median follow-up of 76 months, the 5- and 8-year rates of ipsilateral breast tumor recurrence (IBTR) were 3.26 and 8.79% for women with AH and 2.56 and 8.95% for women without AH, respectively. There were no significant differences between the two groups in terms of IBTR (p = 0.803), distant-metastasis-free survival (DMFS) (p = 0.749), or overall survival (OS) (p = 0.165). Moreover, no significant differences were found in IBTR, DMFS, or OS between patients with severe atypical hyperplasia (n = 86) and those without AH (n = 158) (p = 0.81, 0.82, and 0.78, respectively). Additionally, young women or those with ductal carcinoma in situ or triple-negative breast cancer with AH involving margins did not have a higher IBTR rate when compared to similar patients without AH. CONCLUSIONS: This study suggests that AH found at the margins during BCS does not increase the risk of subsequently developing an IBTR. There is not enough evidence for re-excision of AH found at the margins during BCS in patients with early-stage breast cancer.