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Purpose: To establish a preoperative nomogram incorporating morphological and dynamic contrast-enhanced (DCE) features to individually predict the risk of malignancy in patients with breast tumor. Methods A total of 447 consecutive female patients who were divided into the primary cohort (n=326) and the validation cohort (n=121) were enrolled between March 2015 to January 2018. Univariate and multivariate logistic regression analyses were used to identify the potential independent indicators of malignancy. An MRI-based nomogram integrating morphological features and kinetic curves was developed to achieve individualized risk prediction of malignancy in patients with breast masses. The discrimination, calibration ability and clinical utility of the MRI-based model were assessed using C-index, calibration curve and decision curve analysis. Results: Age, tumor size, margin, internal enhancement characteristics, and kinetic curve were confirmed as the independent predictors of malignancy. The AUC of MRI-based nomogram was 0.940 (95% CI: 0.911-0.970) and 0.894 (95% CI: 0.816-0.974) in the primary cohort and validation cohort, respectively. 447 patients were subdivided into the low-risk group (n=107) and high-risk group (n=340) based on the optimal cut-off value of 21.704. The high-risk patients had a higher likelihood of harboring malignancy. Conclusion: The MRI-based nomogram can be used to achieve an accurate individualized risk prediction of malignancy and reduce unnecessary breast biopsy.

Background This study aimed to investigate whether an immunohistochemical prognostic model (IHC4 score) can predict the prognosis and the chemotherapy benefit in patients with estrogen receptor‐positive (ER+)/human epidermal growth receptor 2–negative (HER2−) metastatic breast cancer (MBC). Materials and Methods We developed a method to calculate the modified IHC4 (mIHC4) scores based on routine pathological reports and compared them with the original IHC4 scores that were much more difficult to calculate. Univariate and multivariate analyses were used to study the prognostic factors of progression‐free survival (PFS) and overall survival (OS). The predictive value of mIHC4 score was also investigated. Results The Sun Yat‐sen Memorial Hospital data set included 315 patients with newly diagnosed ER+ MBC with a median follow‐up of 25.6 months. Univariate and multivariate analysis showed that higher mIHC4 scores in metastatic lesions, but not the ones in primary tumors, were significantly associated with worse PFS and OS. The prognostic value of mIHC4 scores for PFS was validated using an independent Chinese Society of Clinical Oncology‐ Breast Cancer (CSCO‐BC) data set. More importantly, subpopulation treatment effect pattern plot analysis showed that first‐line endocrine therapy achieved better PFS and OS than chemotherapy in low‐risk patients with ER+/HER2− MBC, whereas first‐line chemotherapy was associated with improved PFS and OS compared with endocrine therapy in high‐risk ones. The predictive value of mIHC4 score for PFS in selecting first‐line endocrine therapy versus chemotherapy was also confirmed in the CSCO‐BC data set. Conclusion mIHC4 scores in metastatic lesions are prognostic for the PFS and OS in patients with ER+ MBC. Low or high mIHC4 score may indicate the survival benefit in choosing first‐line endocrine therapy or chemotherapy in patients with ER+/HER2− MBC, respectively. Implications for Practice The modified IHC4 (mIHC4) score is easy to implement and able to predict patients with advanced and/or metastatic breast cancer. In addition, with the help of the mIHC4 score, physicians might be able to recommend chemotherapy or endocrine therapy as the first‐line treatment for patients with high and low risk as predicted by the mIHC4 score., A method to reliably predict prognosis for patients with metastatic breast cancer is needed. This article reports an immunohistochemical prognostic model (IHC4 score) that can predict the prognosis and chemotherapy benefit in patients with ER+/HER2– metastatic breast cancer.

Background Triple negative breast cancer (TNBC) is an aggressive and heterogeneous disease. Nomograms predicting outcomes of TNBC are needed for risk management. Methods Nomograms were based on an analysis of 296 non-metastatic TNBC patients treated at Sun Yat-sen Memorial Hospital from 2002 to 2014. The end points were disease-free survival (DFS) and overall survival (OS). Predictive accuracy and discriminative ability were evaluated by concordance index (C-index), area under the curve (AUC) and calibration curve, and compared with the American Joint Committee on Cancer (AJCC) staging system, PREDICT and CancerMath. Models were subjected to bootstrap internal validation and external validation using independent cohorts of 191 patients from the second Xiangya Hospital and Peking University Shenzhen Hospital between 2007 and 2012. Results On multivariable analysis of training cohort, independent prognostic factors were stromal tumor-infiltrating lymphocytes (TILs), tumor size, node status, and Ki67 index, which were then selected into the nomograms. The calibration curves for probability of DFS and OS showed optimal agreement between nomogram prediction and actual observation. The C-index of nomograms was significantly higher than that of the seventh and eighth AJCC staging system for predicting DFS (training: 0.743 vs 0.666 (P = 0.003) and 0.664 (P = 0.024); validation: 0.784 vs 0.632 (P = 0.02) and 0.607 (P = 0.002)) and OS (training: 0.791 vs 0.683 (P = 0.004) and 0.677 (P

Surgery, steroids, and/or observations alone have been proposed for patients with nonlactational mastitis (NLM), but most of these studies were retrospective. The optimal treatment for these patients remains unclear. This prospective, single-arm, proof-of-concept trial aimed to evaluate the feasibility and safety of ductal lavage as a novel treatment for patients with NLM.Eligible patients with NLM received an intraductal infusion of corticosteroids and antimicrobial agents and returned the next day for a breast massage. This cycle was repeated for 2 wk, and we followed up these patients for 1 y. Patients did not receive surgery or steroids after ductal lavage. The primary endpoint was the time to complete response (CR).This trial included 32 patients with a median (range) age of 32 (20-53). Skin erythema and tenderness were the major symptoms. The median (range) visual analog score was 5 (0-9). There were 21 (65.6%), 4 (12.5%), and 7 (21.9%) patients diagnosed as idiopathic granulomatous mastitis, periductal mastitis, and unspecific NLM, respectively. During the ductal lavage, the median (range) number of cannulated ducts at first attempt was 5 (3-8). Ductal lavage significantly reduced the visual analog score and mastitis score (M-score) (P 0.01). Within a median follow-up of 15.6 mo, 93.8% (30/32) of patients achieved CR. The median (range) time to CR was 6 (0.5-21) mo. Three patients (10.0%) relapsed. No adverse events associated with ductal lavage were observed.Ductal lavage for patients with NLM is feasible and safe, and a definitive randomized controlled trial for further investigation is warranted.ClinicalTrials.gov, NCT02794688.

Background Mitogen-activated protein kinase 10 (Mapk10) is a member of the c-jun N-terminal kinases (jnk) subgroup in the MAPK superfamily, and was proposed as a tumor suppressor inactivated epigenetically. Its role in hepatocellular carcinoma (HCC) has not yet been illustrated. We aimed to investigate the expression and epigenetic regulation of mapk10 as well as its clinical significance in HCC. Results Mapk10 was expressed in almost all the normal tissues including liver, while we found that the protein expression of MAPK10 was significantly downregulated in clinical samples of HCC patients compared with these levels in adjacent normal tissues (29/46, P < 0.0001). Clinical significance of MAPK10 expression was then assessed in a cohort of 59 HCC cases, which indicated its negative expression was significantly correlated with advanced tumor stage (P = 0.001), more microsatellite nodules (P = 0.025), higher serum AFP (P = 0.001) and shorter overall survival time of HCC patients. Methylation was further detected in 58% of the HCC cell lines we tested and in 66% of primary HCC tissues by methylation-specific PCR (MSP), which was proved to be correlated with the silenced or downregulated expression of mapk10. To get the mechanisms more clear, the transcriptional silencing of mapk10 was reversed by pharmacological demethylation, and ectopic expression of mapk10 in silenced HCC cell lines significantly inhibited the colony formation ability, induced apoptosis, or enhanced the chemosensitivity of HCC cells to 5-fluorouracil. Conclusion Mapk10 appears to be a functional tumor suppressor gene frequently methylated in HCC, which could be a valuable biomarker or a new diagnosis and therapy target in a clinical setting.

Background The prognosis of ductal carcinoma in situ (DCIS) is reportedly well. Extremely rare patients with DCIS develop distant breast cancer metastasis without locoregional or contralateral recurrence. This is the first report of multiple bones and sigmoid colon metastases from DCIS after mastectomy. Case presentation A 43-year-old woman was diagnosed with DCIS, and she received mastectomy, followed by endocrine therapy and target therapy. During the following-up, convulsions and pain on the legs were complaint. Therefore, Computed Tomography (CT) on bones and positron emission tomography (PET) for whole body were examined in order. Multiple bones and sigmoid colon were under the suspect of metastases, which were then verified by biopsy in the left ilium and colonoscopy respectively. Conclusions This case reveals the heterogeneous behavior and the potential poor outcome of DCIS, regular examination and surveillance are necessary even though the distant metastasis rate in DCIS is low.

Patients with ductal carcinoma in situ with microinvasion (DCISM) have worse cancer-specific survival, disease-free survival and overall survival, and a higher mortality rate compared with patients with ductal carcinoma in situ (DCIS). Distinguishing DCISM from DCIS via preoperative imaging could help to predict the prognosis of patients. The present study compared the sonographic and mammographic features of patients with DCIS and DCISM. A total of 147 women (94 patients with DCIS and 53 patients with DCISM) were retrospectively included. The sonographic lesions were classified as either masses or non-mass abnormalities. The lesions observed on mammography were classified as calcifications only, mass, asymmetry or architectural distortion. Statistical comparisons were performed using the Mann-Whitney U test, χ2 test, Fisher's exact test and multiple logistic regression analysis. Univariate and multivariate analyses showed that the presence of calcifications (P=0.038) and vascularity (P=0.025) on sonography were associated with DCISM. Furthermore, a lager distribution of calcifications was associated with a higher likelihood of DCISM (P=0.002). In conclusion, the presence of calcifications and vascularity on sonography or a lager distribution of calcifications on mammography may suggest DCISM.

Purpose To evaluate the value of T2, T1rho, and diffusion metrics in assessment of liver fibrosis in rats. Materials and Methods Liver fibrosis in a rat model (n = 72) was induced by injection of carbon tetrachloride (CCl4) at 3T. T2, T1rho, and diffusion parameters (apparent diffusion coefficient (ADC), Dtrue) via spin echo (SE) diffusion-weighted imaging (DWI) and stimulated echo acquisition mode (STEAM) DWI with three diffusion times (DT: 80, 106, 186 msec) were obtained in surviving rats with hepatic fibrosis (n = 52) and controls (n = 8). Liver fibrosis stage (F0–F6) was identified based on pathological results using the traditional liver fibrosis staging method for rodents. Nonparametric statistical methods and receiver operating characteristic (ROC) curve analysis were employed to determine the diagnostic accuracy. Results Mean T2, T1rho, ADC, and Dtrue with DT = 186 msec correlated with the severity of fibrosis with r = 0.73, 0.83, −0.83, and −0.85 (all P < 0.001), respectively. The average areas under the ROC curve at different stages for T1rho and diffusion parameters (DT = 186 msec) were larger than those of T2 and SE DWI (0.92, 0.92, and 0.92 vs. 0.86, 0.82, and 0.83). The corresponding average sensitivity and specificity for T1rho and diffusion parameters with a long DT were larger (89.35 and 88.90, 88.36 and 89.97, 90.16 and 87.13) than T2 and SE DWI (90.28 and 79.93, 85.30 and 77.64, 78.21 and 82.41). The performances of T1rho and Dtrue (DT = 186 msec) were comparable (average AUC: 0.92 and 0.92). Conclusion Among the evaluated sequences, T1rho and STEAM DWI with a long DT may serve as superior imaging biomarkers for assessing liver fibrosis and monitoring disease severity. Level of Evidence: 1 J. Magn. Reson. Imaging 2017;45:741–750.

e17040 Background: PD-1/PD-L1 blockade significantly improved survival for bladder cancer. PD-L1 expression might not be an ideal marker for patient selection in isolation. Several studies demonstrated that alternative markers such as NLR, a biomarker of systemic inflammation response to therapy, correlated with outcomes in a variety of cancers including bladder cancer, might be a predictor for patient selection and the response to immunotherapy. However, no reporters have been made combination of NLR and PD-L1 in predicting prognosis in bladder cancer. Methods: Suitable tissue of 100 FFPE blocks of bladder cancer patients treated in Sun Yat-Sen Memorial Hospital Sun Yat-sen University were stained with PD-L1 antibody. Clinicopathological data and pretreatment complete blood count were retrospectively collected. All patients were classified into high NLR group and low NLR group at cut-off 3.0. Kaplan-Meier and Cox proportional hazard models analyses were used to assessed the predictor of combined PD-L1/NLR for disease-free survival (DFS) and overall survival (OS). Results: Patients were mostly male (79%) with high grade () lymph node positive (21%), T3-4 (33%) . The positivity of PD-L1 expression was 22% (22/100) at cut-off 1%. Univariate analysis showed that PD-L1 expression was positively associated with larger tumor size, higher grade, positive lymph node metastases. Median DFS and OS were 35 months and 37 months, respectively. Both PD-L1 expression and NLR were associated with DFS and OS. COX analysis model showed that PD-L1 and NLR were independent prognostic factors for tumor prognosis. Of interest, when patients were divided in two groups based on PD-L1/NLR: patients with PD-L1+/high NLR as group 1 and other patients as group 2, group1 had significantly shorter DFS and OS (DFS, X2 = 4.146, P = 0.042; OS, X2 = 10.274, P = 0.001). COX proportional hazards regression models indicated that PD-L1+/high NLR was correlated with a significantly shorter DFS and OS (DFS, hazard ration [ HR] = 2.572, P = 0.05; OS, HR = 3.811, P = 0.003). Conclusions: The study indicated that combined use of PD-L-1/ NLR as predictive biomarker for survival. This feasible panel may be optional maker applied to select patients for immunotherapy.

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.

Chromosome region 3p12‐14 is an important tumour suppressor gene (TSG) locus for multiple cancers. ADAMTS9, a member of the metalloprotease large family, has been identified as a candidate 3p14.2 TSG inactivated by aberrant promoter CpG methylation in several carcinomas, but little known about its expression and function in breast cancer. In this report, ADAMTS9 expression and methylation was analysed in breast cancer cell lines and tissue samples. ADAMTS9 RNA was significantly down‐regulated in breast cancer cell lines (6/8). After treating the cells with demethylation agent Aza and TSA,ADAMTS9 expression was dramatically increased. Bisulphite genomic sequencing and methylation‐specific PCR detected promoter methylation, which was associated with decreased ADAMTS9 expression. Hypermethylation was also detected in 130/219 (59.4%) of primary tumours but only in 4.5% (2/44) of paired surgical margin tissues. Ectopic expression of ADAMTS9 in tumor cells induced significant growth suppression, cell cycle arrest at the G0/G1 phase, enhanced apoptosis and reduced cell migration and invasion. Conditioned culture medium from ADAMTS9‐transfected BT549 cells markedly disrupted tube formation ability of human umbilical vein endothelial cell (HUVEC) in Matrigel. Furthermore, ADAMTS9 inhibited AKT signaling and its downstream targets (MDM2, p53, p21, p27, E‐cadherin, VIM, SNAIL, VEGFA, NFκB‐p65 and MMP2). In addition, we demonstrated, for the first time, that ADAMTS9 inhibits AKT signaling, through suppressing its upstream activators EGFR and TGFβ1/TβR(I/II) in breast cancer cells. Our results suggest that ADAMTS9 is a TSG epigenetically inactivated in breast cancer, which functions through blocking EGFR‐ and TGFβ1/TβR(I/II)‐activated AKT signaling.

// Yi-wang Zhang 1 , Xiao-xiao Zhao 1 , Cui Tan 4 , Zhi-gang Zhang 1 , Ye Jiang 1 , Jian-ning Chen 1 , Hong-bo Wei 2 , Ling Xue 3 , Hai-gang Li 4 , Hong Du 5 and Chun-kui Shao 1 1 Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China 2 Department of Gastrointestinal Surgery, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China 3 Department of Pathology, The First Affiliated Hospital, Sun Yat-sen University, Zhongshan Guangzhou, Guangdong Province, China 4 Department of Pathology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China 5 Department of Pathology, Guangzhou First Municipal People’s Hospital, Guangzhou, Guangdong Province, China Correspondence: Chun-kui Shao, email: // Keywords : EBVaGC; HER2; LMP2A; TWIST; YB-1 Received : August 20, 2014 Accepted : November 06, 2014 Published : November 06, 2014 Abstract To explore HER2 expression in Epstein-Barr virus-associated gastric carcinoma (EBVaGC) and the possible mechanisms causing down-regulation of HER2 expression in EBVaGC, we first evaluated HER2 and LMP2A expression on a clinicopathological-features matched cohort including 78 EBVaGC and 216 EBV-negative gastric carcinoma (EBVnGC) cases by immunohistochemistry. Cases with high HER2 expression in EBVaGC were significantly less than in EBVnGC (5.1% versus 23.7%; p

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.

This study evaluated the associations of HER2 protein, HER2 gene amplification, and positivity for p-AKT, p-ERK, and p-PLCγ proteins with clinicopathological status and overall survival (OS) of patients who had Epstein-Barr virus-associated gastric cancer (EBVaGC; n = 58) or EBV-negative GC (EBVnGC; n = 329). Tissue samples were subjected to immunohistochemistry and fluorescence in situ hybridization (FISH). Results showed that EBVaGC less expressed HER2 and amplified HER2 gene. p-AKT (p = 0.035) and p-ERK (p = 0.001) were inhibited in EBVaGC than in EBVnGC, while p-PLCγ (p = 0.034) was upregulated. Among EBVaGC patients, p-ERK positivity was associated with Lauren classification (p = 0.023), and p-PLCγ positivity was inversely associated with TNM stage (p = 0.041) and lymph node metastasis (p = 0.041). In contrast, among EBVnGC patients, HER2 expression was associated with distant metastasis (p = 0.043) and p-AKT positivity was associated with intestinal subtype (p 0.004), lymph node metastasis (p = 0.031), distant metastasis (p 0.001), and elder age (60y, p 0.004). Overall analysis showed that EBVaGC patients presented better OS than EBVnGC patients (p = 0.044). Among EBVaGC patients, p-AKT positivity (p = 0.008) was associated with worse OS; as well as, HER2 high expression (p 0.001), p-AKT positivity (p = 0.010), and p-PLCγ (p 0.001) were associated with worse OS in EBVnGC patients. Multivariate analysis showed that distant metastasis (95% CI: 1.559 to 4.028, p 0.001), HER2 high expression (95% CI: 1.058 to 2.454, p = 0.026), and p-PLCγ positivity (95% CI: 1.056 to 2.435, p = 0.027) were independent prognostic predictors of OS in EBVnGC patients. Our results indicated that p-AKT positive patients presented worse OS than p-AKT negative ones in EBVaGC, as well as, HER2, p-AKT, and p-PLCγ are prognostic biomarkers for OS in EBVnGC patients.

Background Breast cancer (BrCa) is a complex disease driven by aberrant gene alterations and environmental factors. Recent studies reveal that abnormal epigenetic gene regulation also plays an important role in its pathogenesis. Ubiquitin carboxyl- terminal esterase L1 (UCHL1) is a tumor suppressor silenced by promoter methylation in multiple cancers, but its role and alterations in breast tumorigenesis remain unclear. Methodology/Principal Findings We found that UCHL1 was frequently downregulated or silenced in breast cancer cell lines and tumor tissues, but readily expressed in normal breast tissues and mammary epithelial cells. Promoter methylation of UCHL1 was detected in 9 of 10 breast cancer cell lines (90%) and 53 of 66 (80%) primary tumors, but rarely in normal breast tissues, which was statistically correlated with advanced clinical stage and progesterone receptor status. Pharmacologic demethylation reactivated UCHL1 expression along with concomitant promoter demethylation. Ectopic expression of UCHL1 significantly suppressed the colony formation and proliferation of breast tumor cells, through inducing G0/G1 cell cycle arrest and apoptosis. Subcellular localization study showed that UCHL1 increased cytoplasmic abundance of p53. We further found that UCHL1 induced p53 accumulation and reduced MDM2 protein level, and subsequently upregulated the expression of p21, as well as cleavage of caspase3 and PARP, but not in catalytic mutant UCHL1 C90S-expressed cells. Conclusions/Significance UCHL1 exerts its tumor suppressive functions by inducing G0/G1cell cycle arrest and apoptosis in breast tumorigenesis, requiring its deubiquitinase activity. Its frequent silencing by promoter CpG methylation may serve as a potential tumor marker for breast cancer.