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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. Cancer Res; 74(16); 4341–52. ©2014 AACR.

Supplementary Figure S3. miR-21 induces myofibroblast differentiation, proliferation and invasion of the stromal cells in PTs.

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.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.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.

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.

International audience; 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 (K-trans). 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.

MotivationSingle-cell RNA sequencing (scRNA-seq) techniques provide high-resolution data on cellular heterogeneity in diverse tissues, and a critical step for the data analysis is cell type identification. Traditional methods usually cluster the cells and manually identify cell clusters through marker genes, which is time-consuming and subjective. With the launch of several large-scale single-cell projects, millions of sequenced cells have been annotated and it is promising to transfer labels from the annotated datasets to newly generated datasets. One powerful way for the transferring is to learn cell relations through the graph neural network (GNN), while vanilla GNN is difficult to process millions of cells due to the expensive costs of the message-passing procedure at each training epoch.ResultsHere, we have developed a robust and scalable GNN-based method for accurate single cell classification (GraphCS), where the graph is constructed to connect similar cells within and between labelled and unlabelled scRNA-seq datasets for propagation of shared information. To overcome the slow information propagation of GNN at each training epoch, the diffused information is pre-calculated via the approximate Generalized PageRank algorithm, enabling sublinear complexity for a high speed and scalability on millions of cells. Compared with existing methods, GraphCS demonstrates better performance on simulated, cross-platform, and cross-species scRNA-seq datasets. More importantly, our model can achieve superior performance on a large dataset with one million cells within 50 minutes.

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 miR‑922, miR‑922-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.

Summary 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 Download : Download video (34MB)

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). 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. 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. 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.

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.

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.

This prospective cohort study aimed to compare the efficacy of cavity margins (CMs) and lumpectomy margins (LMs) for pathological assessment in breast-conserving surgery.We assessed the CMs and LMs of 163 breast cancer patients during breast-conserving surgery. We compared and analyzed the positivity rates of CM and LM.The positivity rate of CM at the case level and individual margin level was 30.7% and 8.0%, respectively. The positivity rate of LM was 12.3%, 33.1%, and 45.4% at the case level and 1.8%, 6.2%, and 9.1% at the individual margin level, when we used the National Surgical Adjuvant Breast and Bowel Project criteria (ink-free), 1 mm-free criteria and 2 mm-free criteria, respectively. The positivity rate of LM with 1 mm-free criteria was similar to that of CM. Delivery of neoadjuvant chemotherapy increased the positivity rate of CM (50.0% versus 25.2%; P0.01) but not LM (41.6% versus 30.7%; P0.05) at the case level, whereas the positivity rate of CM and LM both increased after neoadjuvant chemotherapy at the margin level (CMs: 15.5% versus 5.6%, P0.001; and LMs: 10.7% versus 4.9%, P0.001). In univariate and multivariate analysis, delivery of neoadjuvant chemotherapy, higher node-positive stage, and presence of ductal carcinoma in situ component were correlated with positive CM, whereas positive human epidermal growth factor receptor 2 status and higher node-positive stage were associated with positive LM.Ink-free criteria may be insufficient for LM assessment in breast-conserving surgery, and at least 1 mm width LM is suggested. After the delivery of neoadjuvant chemotherapy, CM assessment should be routinely performed in addition to LM assessment.

Tumor-associated epigenetic alterations including DNA methylation and histone modifications are important determinants in the initiation and progression of hepatocellular cancer (HCC) and represent promising biomarkers and therapeutic targets. Locus-specific trimethylation of histone H3 lysine 4 (H3K4me) is a well-known modification linked to the enhanced transcriptional expression of many genes activated in HCC. Our aim was to assess the cellular expression pattern of H3K4me3 in HCC and its association with clinicopathologic variables and outcome. Expression of H3K4me3 and the histone methyltransferase (HMT) SET and MYND domain-containing protein 3 (SMYD3) was studied by Western blotting and immunohistochemistry in cell lines and tumor tissue microarray from a well-characterized series of HCC patients (n = 168). The optimal cut-point of H3K4me3 expression for prognosis was determined by the X-tile program. The prognostic significance was evaluated using Kaplan-Meier survival estimates and log-rank tests. Tumor tissue microarray from another independent HCC patients cohort (n = 147) was used for validation studies. Expression of H3K4me3 and SMYD3 were enhanced in HCC cell lines. In tumor specimens, enhanced expression of H3K4me3 was correlated with reduced overall survival (P < .0001), especially in early-stage HCC patients (TNM I/II). Furthermore, both univariate and multivariate analyses revealed that H3K4me3 level was a significant and independent predictor of poor survival (hazard ratio, 3.592; 95% confidence interval, 2.302-5.605). In addition, H3K4m3 expression was positively correlated with SMYD3 expression in both testing and validation cohorts (P < .0001). In conclusion, H3K4me3 level defines unrecognized subsets of HCC patients with distinct epigenetic phenotype and clinical outcome and can thus be a novel predictor for poor prognosis of HCC patients, especially at TNM I/II stage.

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., Fibroblast activity is regulated by tissue macrophages. Here the authors show that two miRNAs regulated by IL-4 and IL-13 in macrophages target SOCS1 and PPARγ and modulate profibrogenic macrophage program in vitro and in vivo, and that alterations of these miRNAs are found in fibrosis.

Several models for predicting the risk of non-sentinel lymph node (NSLN) metastasis in breast cancer patients with positive sentinel lymph nodes (SLNs) have been developed. The purpose of this study was to validate and compare these models in Chinese patients. A total of 159 breast cancer patients with positive SLNs treated at our institution were included. Among them, 81 (50.9%) patients had at least one NSLN involvement. The Cambridge, Mou, Mayo, Tenon, MDA, Memorial Sloan-Kettering Cancer Center (MSKCC), Ljubljana, SNUH, Turkish, Louisville, Stanford, and Saidi models were evaluated and compared using receiver operating characteristic (ROC) curves, calibration plots, and false negative (FN) rates. The Cambridge and Mou models outperformed the others, both with area under the ROC curves (AUCs) of 0.73. The Mayo, Tenon, MDA, MSKCC, Turkish, Ljubljana, SNUH, and Louisville models had AUCs of 0.68, 0.66, 0.66, 0.64, 0.63, 0.62, 0.61, and 0.60, respectively. The Stanford and Saidi models did not present any discriminative capabilities, with AUCs of 0.54 and 0.50, respectively. The Cambridge, MSKCC, and Mayo models were well calibrated. With adjusted thresholds, the Mayo model outperformed the others by classifying the highest proportion of patients (20%) into the low-risk group. Our study revealed that the Cambridge and Mou models performed well in Chinese patients. The ROC curves, calibration plots, and FN rates should be used together for the accurate evaluation of prediction models. Selection of these models should be based on the clinicopathological features of the targeted population. The models specifically designed for patients with micrometastases or macrometastases of SLNs are needed in the future. (Cancer Sci 2012; 103: 274–281)

Background: Several models for predicting the risk of nonsentinel lymph node (NSLN) metastasis in breast cancer patients with positive sentinel lymph nodes (SLNs) have been developed. Independent validation of these models in different populations is necessary before clinical application. This study aimed to validate and compare these models in Chinese patients. Patients and Methods: A total of 159 breast cancer patients with positive SLNs treated at our institution were included. Chi-squared tests, RP-ROC, CART and multivariate logistic regression were used to analyze the risk factors for NSLN involvement in our population. ROC curves, calibration plots and false-negative (FN) rates were evaluated for 11 reported models. The threshold of each model for classifying patients into the low-risk group was adjusted to render the FN rate close to 10%. Results: In total, 81 (50.9%) patients had at least one NSLN involvement. Univariate and multivariate analyses revealed that the number of negative SLNs (P With adjusted thresholds, the Mayo model outperformed the others by classifying the highest proportion of patients (20%) into the low-risk group. The Cambridge, Mou and MDA models defined 17.0%, 14.5% and 15.1% of patients as low-risk, respectively. Conclusion: The Cambridge and Mou models performed well in Chinese patients. ROC curves, calibration plots and FN rates should be used together for the accurate evaluation of prediction models. The analysis of the clinicopathological features of the targeted population is critical for the selection of the most appropriate model. The models specifically designed for patients with micrometastases or macrometastases of SLNs are needed in the future. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-07-13.

With the purpose of minimizing arm lymphedema after axillary staging surgeries in breast cancer patients, the axillary reverse mapping (ARM) technique has been developed to identify and preserve arm drainage system during axillary surgery. This study aimed to clarify risk factors for metastasis in arm lymphatic drainage system in breast cancer patients with clinically negative axillary nodes. Sixty-nine patients who underwent successful both sentinel lymph node (SLN) biopsy (SLNB) and ARM from October 2009 to August 2010 were enrolled in this study. Radioactive tracer was used for SLN localization and blue dye was used for ARM. All of the identified SLNs and ARM nodes were sent for pathological assessment. ARM nodes metastasis occured in 6 of 69 patients. Age, pathological tumor size (pT) and pathological lymph node status (pN) were not associated with ARM nodes metastasis (P > 0.01). Interestingly, in these 6 patients, all metastatic ARM nodes coincided with SLN-ARM nodes (hot SLN and blue ARM node were the same lymph node). In 50 of 69 patients whose ARM nodes did not coincided with SLNs, all ARM nodes were negative, even in 12 patients with metastatic SLNs. Crossover between breast and ipsilateral arm lymphatic drainage system contributes for ipsilateral arm lymph node metastasis. When ARM and SLNB are simultaneously performed in a patient, selectively preservation of the ARM nodes that do not coincided with SLNs would be safe, even if the SLNs are positive. Pathological lymph node status does not account for the occurrence of metastasis in ARM nodes. ARM nodes could be preserved safely, independent of the pathological lymph node status.

Ubiquitin-conjugating enzyme 9 (Ubc9), the sole conjugating enzyme for sumoylation, regulates protein function and plays an important role in tumorigenesis. Whether Ubc9 is involved in the chemoresistance of breast cancer remains unknown. In this study, we aimed to evaluate the contribution of Ubc9 in the chemoresistance of breast cancer. Immunohistochemistry (IHC) was used to examine the expression level of Ubc9. Chi-square test, Wilcoxon test, and one-way ANOVA were applied to analyze the relationship between Ubc9 expression, clinicopathologic features, and clinical response to neoadjuvant chemotherapy. The significance of variables for survival was analyzed by the Cox proportional hazards model in a multivariate analysis. Kaplan-Meier survival curves were plotted and log-rank test was performed. The proportion of Ubc9-positive cells was higher in invasive ductal carcinoma than in normal breast tissues [(48.48 ± 17.94)% vs. (5.82 ± 2.80)%, P < 0.001]. High Ubc9 expression was associated with poor differentiation (Χ² = 6.538, P = 0.038), larger tumor size (Χ² = 4.701, P = 0.030), advanced clinical stage (Χ² = 4.651, P = 0.031), lymph node metastasis (Χ² = 9.913, P = 0.010), basal-like phenotype (Χ² = 8.660, P = 0.034), and poor clinical response to neoadjuvant chemotherapy (Χ² = 11.09, P = 0.001). The expected 6-year cumulative disease-free survival rate was 87.32% in patients with low Ubc9 expression compared to 68.78% in those with high Ubc9 expression (Χ² = 4.289, P = 0.038). These data indicate that high Ubc9 expression correlates with poor response to chemotherapy and poor clinical prognosis.

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.

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.

Supplemental Digital Content is available in the text, 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.

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. Cancer Res; 74(16); 4341–52. ©2014 AACR.

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.

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. 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. 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. 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.

Background: Breast cancer patients with high proportion of cancer stem cells (BCSCs) are more chemotherapy-resistant and have unfavorable clinical outcomes. MicroRNAs (miRNAs) can function as oncogenes or tumor suppressor genes, which regulate key features of BCSCs. Since BCSCs have unique miRNA expression profile, we hypothesized that a biology-driven model based on BCSC-associated miRNAs could provide prognostic information for low recurrent-risk HR+HER2- breast cancer patients. Methods: A systematic literature reviewing suggested 50 BCSC-associated miRNAs that regulate the BCSC features. We excluded 15 of these miRNAs as they were not constantly detectable in the 40 paraffin embedded tumor samples by qRT-PCR (A pilot assay). A total of 35 BCSC-associated miRNAs were identified. We randomly assigned 303 patients into a training group (n = 202) and an internal validation (n = 101) group. We built a 10-miRNA-based classifier using a LASSO Cox model in the training group and validated its prognostic in the internal validation group, and two external independent groups of 308 patients. Results: In this multicenter study, we developed build a 10-miRNA classifier to predict disease-relapse free survival (DRFS). With this classifier, HR+HER2- breast cancer patients were classified into high-risk and low-risk group of diseases recurrence. The DFS was significantly different between these two groups in all of the patient groups. In the training group, the 5-year DRFS was 90.83% and 35.0% for the low-risk and the high-risk group, respectively (hazard ratio [HR] 15.85, 95% CI 8.15-30.82; p Interpretation: Our 10-miRNA-based classifier provides a reliable prognostic model for disease recurrence in HR+HER2- breast cancer patients. This classifier may facilitate patient counseling and serve in personalized treatment for breast cancer patients. Citation Format: Chang Gong, Weige Tan, Kai Chen, Na You, Shan Zhu, Wei Luo, Xinhua Xie, Yunjie Zeng, Nengtai Ouyang, Zhihua Li, Mushen Zeng, ShiMei Zhuang, Wan-Yee Lau, Qiang Liu, Fengxi Su, Xueqin Wang, Erwei Song. Prognostic value of a BCSC-associated microRNA signature in hormone receptor-positive her2-negative breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-139.

532Background: Breast cancer patients with high proportion of cancer stem cells (BCSCs) are more chemotherapy-resistant and have unfavorable clinical outcomes. MicroRNAs (miRNAs) can function as on...

Background In premenopausal women, endocrine adjuvant therapy for breast cancer primarily consists of tamoxifen alone or with ovarian suppressive strategies. Toremifene is a chlorinated derivative of tamoxifen, but with a superior risk-benefit profile. In this retrospective study, we sought to establish the role of toremifene as an endocrine therapy for premenopausal patients with estrogen and/or progesterone receptor positive breast cancer besides tamoxifen. Methods Patients with early invasive breast cancer were selected from the breast tumor registries at the Sun Yat-Sen Memorial Hospital (China). Premenopausal patients with endocrine responsive breast cancer who underwent standard therapy and adjuvant therapy with toremifene or tamoxifen were considered eligible. Patients with breast sarcoma, carcinosarcoma, concurrent contralateral primary breast cancer, or with distant metastases at diagnosis, or those who had not undergone surgery and endocrine therapy were ineligible. Overall survival and recurrence-free survival were the primary outcomes measured. Toxicity data was also collected and compared between the two groups. Results Of the 810 patients reviewed, 452 patients were analyzed in the study: 240 received tamoxifen and 212 received toremifene. The median and mean follow up times were 50.8 and 57.3 months, respectively. Toremifene and tamoxifen yielded similar overall survival values, with 5-year overall survival rates of 100% and 98.4%, respectively (p = 0.087). However, recurrence-free survival was significantly better in the toremifene group than in the tamoxifen group (p = 0.022). Multivariate analysis showed that recurrence-free survival improved independently with toremifene (HR = 0.385, 95% CI = 0.154-0.961; p = 0.041). Toxicity was similar in the two treatment groups with no women experiencing severe complications, other than hot flashes, which was more frequent in the toremifene patients (p = 0.049). No patients developed endometrial cancer. Conclusion Toremifene may be a valid and safe alternative to tamoxifen in premenopausal women with endocrine-responsive breast cancer.

The aim of this study was to determine whether estrogen receptor (ER)/progesterone receptor (PR) and human epidermal growth factor receptor type 2 (HER2) statuses between primary tumors and paired liver metastatic localizations of breast carcinoma were modified by treatment or during the natural metastatic process.ER, PR, and HER2 expressions were analyzed on paired tissue specimens taken from the primary and the liver metastatic tumors in breast cancer patients. The first group included 46 women who presented with T1-T4, N0-N3, M0 breast carcinoma when first diagnosed and were treated by neoadjuvant therapy or directly underwent surgery, then received postoperative treatment and developed liver metastasis several months/years later. The second group included 12 patients with liver metastatic breast carcinoma when first diagnosed for breast cancer. HER2 status was determined by immunohistochemistry as well as fluorescence in situ hybridization.Among the 46 patients in the first group, the ER/PR and HER2 statuses (when considered as a whole histological subtype) were changed between primary tumor and liver metastatic lesions in 12 patients (26.1%). While ER and PR status were modified in 14 (30.4%) and 25 (54.3%) patients, respectively, there were only 5 (10.9%) cases showed a discrepancy in the HER2 status. In the second group, the ER/PR and HER2 statuses (when considered as a whole subtype) were consistent between primary and liver metastatic tumor in 10 of 12 (83.3%) patients. ER, PR, and HER2 statuses were modified in 0 of 12 (0%), 4 of 12 (33.3%), and 1 of 12 (8.3%) cases, respectively.ER/PR and HER2 statuses between primary and liver metastatic lesions of breast carcinoma can be modified after treatment but are stable in most cases during the natural metastatic process.

This study describes a modified intraoperative method for cavity margin (CM) assessment in place of lumpectomy margin assessment in patients undergoing breast-conserving surgery (BCS).This is a retrospective review of 422 breast cancer patients undergoing BCS with intraoperative CM assessment. After an initial lumpectomy with intent to obtain ≥1-cm margins, separate specimens 1 × 1 cm, 0.5-cm thick were taken from the cavity margin circumferentially. These were frozen without reference to the side of the new margin as a time-saving measure, and parallel sections of the resected surface were evaluated.After a median follow-up of 55.5 months, a cumulative 5-year locoregional recurrence-free survival rate of 95.3%, metastasis-free survival rate of 97.8%, disease-free survival rate of 88.3%, and overall survival rate of 96.0%, was achieved. The CM positivity rates were of no statistical difference when7, 7-8, and8 CMs were assessed. The second operation rate was 3.5% because of the false-negative results of the frozen section analysis on CMs. Univariate and multivariate analysis revealed that a higher pN stage and cT stage as well as a lack of adjuvant chemotherapy or radiation demonstrated significantly worse clinical outcomes. Locoregional recurrences and metastasis are both correlated with worse overall survival. The number of the CMs assessed was not associated with clinical outcomes.The modified CM assessment presented here is a rapid, accurate, and oncologically safe approach for margin evaluation in BCS patients. Lumpectomy margin assessment might be spared when this method is used.

Background The aim of this study was to evaluate the clinical outcomes of 1,578 patients with breast benign diseases after excisions and the risk factors. Methods and results With a median follow-up of 34 months, 69 patients were identified to have recurrence (local recurrence: 45; new lesion: 24). Univariate and multivariate analyses revealed that multiple lesions, a larger lesion size, and a hematoma were independent risk factors for recurrence. Patients with in situ recurrence tended to have fewer lesions and more samples taken per lesion. Patients with new lesions tended to have multiple lesions. After re-excisions, there was no second recurrence events observed in the patients with local recurrence (0/30), whereas 5 patients with new lesions (5/14) were noted to have second recurrence events. Conclusions Ultrasound-guided vacuum-assisted biopsy for the complete excision of breast benign diseases is safe and effective. Local recurrence and new lesions may have different clinicopathological features and underlying mechanisms. Different management might be given to patients with a different pattern of recurrence.

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 Note: This abstract was not presented at the meeting. Citation Format: Shaohua Liu, Yunjie Zeng, Nengtai Ouyang. Targetting VPAC1 for intestinal cancer prevention. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4163. doi:10.1158/1538-7445.AM2015-4163

To study the predictive factors that are associated with intraoperative identification of the sentinel lymph node (SLN).Lymphatic mapping using blue dye was performed in 108 patients with stage I and II operable primary breast cancer. Subsequently the patients received operations of breast cancer including axillary dissection. Clinical and histological factors were assessed to determine those that were associated with intraoperative identification of the SLN.The sentinel node was identified at the time of surgery in 84 patients (77.78%). Of the clinical factors assessed, age(y)50 (chi(2) = 7.447, P0.01), tumour in the upper quadrant (chi(2) = 6.330, P0.05), diagnosis by preoperative biopsy (chi(2) = 5.509, P0.05), successful mapping of the lymphatic duct (chi(2) = 13.125, P0.01) were significant in identifying the sentinel node at operation. No histological factor was associated with intraoperative identification of the sentinel node.There are the possibility of failure of SLN identification at sentinel lymph node biopsy. Our results suggest that the best predictor of intraoperative sentinel node identification is the visualization of the lymphatic duct on mapping by blue dye. Other factors such as age, tumour site as well as diagnostic method are also important in determining the success of the procedure.

Highlights • Biology-driven strategy can be used in development of prognostic model. • The BCSC-associated miRNA classifier can predict prognosis for HR + HER2 − breast cancer. • The BCSC-associated miRNA classifier outperforms IHC4 scoring and 21-gene RS. • Chemotherapy can improve DRFS in patients predicted as high-risk. Breast cancer patients with high proportion of cancer stem cells (BCSCs) have poor clinical outcomes. MiRNAs regulate key features of BCSCs as oncogenes or tumor suppressors. Although hormone receptor (HR)-positive, HER2-negative breast cancers are the most common subtype, current methods are inadequate to predict its clinical outcome. In this multicenter study, we identified and validated a 10 BCSC-associated-miRNA classifier that can predict survival for HR + HER2 − patients. Retrospective analysis showed that this classifier outperformed IHC4 scoring and 21-gene Recurrence Score (RS), and chemotherapy could improve survival in high-risk patients determined by this classifier. This model may facilitate personalized clinical decision for HR + HER2 − individuals., 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.

The objection of this study is to investigate whether the cavity margin (CM) status has different predictive efficacy for local-regional recurrence (LRR) in patients who have received or have not received neoadjuvant chemotherapy (NAC) before breast-conserving surgery. We identified 61 patients who received NAC before breast-conserving surgery. A nonrandomized unmatched cohort of 295 patients without history of receiving NAC were also included in this study. Clinicopathological features and follow-up data were abstracted and analyzed. Patients in the NAC-treated group had more advanced diseases when compared with patients in the non NAC-treated group. With a median follow-up of 42 months, the LRR-free survival rate of patients with positive CMs was significantly lower than that of patients with negative CMs in the NAC-treated group. This distinction was not observed in the nonNAC-treated group. Univariate and multivariate analysis revealed that positive CM was the only independent predictive factor for LRR in the NAC-treated group but not in nonNAC-treated patients. CM status had different predictive efficacy for LRR in different settings. Association between CM status and LRR was observed in NAC-treated patients rather than nonNAC-treated patients. More extensive surgical treatment might be needed in NAC-treated patients when their CMs are positive.

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