Xiaochun Fei

Breast Cancer: Diffusion Kurtosis MR Imaging—Diagnostic Accuracy and Correlation with Clinical-Pathologic Factors

PURPOSE To assess diagnostic accuracy with diffusion kurtosis imaging (DKI) in patients with breast lesions and to evaluate the potential association between DKI-derived parameters and breast cancer clinical-pathologic factors. MATERIALS AND METHODS Institutional review board approval and written informed consent were obtained. Data from 97 patients (mean age ± standard deviation, 45.7 years ± 13.1; range, 19-70 years) with 98 lesions (57 malignant and 41 benign) who were treated between January 2014 and April 2014 were retrospectively analyzed. DKI (with b values of 0-2800 sec/mm(2)) and conventional diffusion-weighted imaging data were acquired. Kurtosis and diffusion coefficients from DKI and apparent diffusion coefficients from diffusion-weighted imaging were measured by two radiologists. Student t test, Wilcoxon signed-rank test, Jonckheere-Terpstra test, receiver operating characteristic curves, and Spearman correlation were used for statistical analysis. RESULTS Kurtosis coefficients were significantly higher in the malignant lesions than in the benign lesions (1.05 ± 0.22 vs 0.65 ± 0.11, respectively; P < .0001). Diffusivity and apparent diffusion coefficients in the malignant lesions were significantly lower than those in the benign lesions (1.13 ± 0.27 vs 1.97 ± 0.33 and 1.02 ± 0.18 vs 1.48 ± 0.33, respectively; P < .0001). Significantly higher specificity for differentiation of malignant from benign lesions was shown with the use of kurtosis and diffusivity coefficients than with the use of apparent diffusion coefficients (83% [34 of 41] and 83% [34 of 41] vs 76% [31 of 41], respectively; P < .0001) with equal sensitivity (95% [54 of 57]). In patients with invasive breast cancer, kurtosis was positively correlated with tumor histologic grade (r = 0.75) and expression of the Ki-67 protein (r = 0.55). Diffusivity was negatively correlated with tumor histologic grades (r = -0.44) and Ki-67 expression (r = -0.46). CONCLUSION DKI showed higher specificity than did conventional diffusion-weighted imaging for assessment of benign and malignant breast lesions. Patients with grade 3 breast cancer or tumors with high expression of Ki-67 were associated with higher kurtosis and lower diffusivity coefficients; however, this association must be confirmed in prospective studies.

Density of Tumor-Associated Macrophages Correlates with Lymph Node Metastasis in Papillary Thyroid Carcinoma

BACKGROUND Tumor-associated macrophages (TAMs) have recently been recognized as being important players in the tumoriogenesis of many cancers, including advanced thyroid cancer. However, a role in papillary thyroid carcinoma (PTC), the most prevalent thyroid cancer, has not been established. We hypothesized that TAMs also facilitate tumor progression in PTC. METHODS We investigated TAMs density in both benign thyroid lesions and PTC tumors by CD68 immunostaining. CD68-positive cell density was further associated with the clinicopathological characteristics of PTC patients. Finally, TAMs were isolated from PTC tumors and phenotyped by cytokine and receptor profiling. RESULTS The overall density of TAMs was found to be significantly higher in PTC tumors, compared with thyroid goiter and follicular adenoma. The density of TAMs was positively associated with lymph node metastasis in TNM (tumor-node-metastasis) stages III/VI compared with stages I/II. No association was observed in other common tumor features, including the BRAF mutation. The isolated TAMs presented with high levels of M2-associated cytokine and receptors, making M2 the predominant TAM phenotype. CONCLUSIONS TAMs may play a functional role in the progression of PTC.

The Impact of Androgen Receptor Expression on Breast Cancer Survival: A Retrospective Study and Meta-Analysis

Recent studies have highlighted the role of androgen receptor (AR) as a prognostic biomarker of breast cancer. However, its predictive role in disease free survival (DFS) and overall survival (OS) still remains inconclusive. The present study aimed to retrospectively investigate the association between AR and survival outcomes in breast cancer and also identify this association by a meta-analysis of published researches. Clinical data from 109 patients with breast cancer, who underwent surgery at Ruijin Hospital, Shanghai, were retrospectively analyzed for immunohistochemical AR expression measured by tissue microarray. For meta-analysis, articles available in Pubmed on the relationship between AR and breast cancer outcomes were included. Data obtained from both were combined and analyzed. Women with AR positive tumors in the retrospective study had a significantly better DFS (HR 0.24, 95% CI 0.07-0.88) and OS (HR 0.19, 95% CI 0.04-0.85) than women with AR negative ones. Meta-analysis showed that AR expression in breast tumors was an indicator of better DFS (HR 0.52, 95% CI 0.43-0.64). In subgroup analysis, AR could predict DFS outcome in estrogen receptor (ER) positive (HR 0.45, 95% CI 0.34-0.59), ER negative (HR 0.42, 95% CI 0.26-0.67), and triple negative breast cancer (HR 0.40, 95% CI 0.23-0.69). Moreover, in ER positive breast cancer patients, the expression of AR could predict better OS (HR 0.39, 95% CI 0.19-0.82). The present analysis indicated that AR expression was associated with lower risk of recurrence in patients with all breast cancer types and better OS in cases with ER positive.

Tumor-associated Macrophages Promote the Metastatic Potential of Thyroid Papillary Cancer by Releasing CXCL8

Tumor-associated macrophages (TAMs) can promote cancer initiation and progression by releasing cytokines. Previously, we have found the density of TAMs correlated with lymph node metastasis in papillary thyroid carcinoma (PTC). However, the mechanisms of how TAMs promote PTC progression remain unclear. In this study, we first showed that the TAMs density in the tumor core was associated with progressive PTC features and TAMs conditioned medium enhanced PTC cells invasion. Cytokine profiling identified a mixed M1/M2 phenotype and CXCL8 was the most consistently abundant cytokine in PTC-derived TAMs. CXCL8 receptors, CXCR1 and CXCR2, were positively stained in PTC cell lines and tissues, though no association with lymph node metastasis or extrathyroid extension. PTC cell invasion was abrogated by anti-CXCL8-neutralizing antibody, whereas addition of exogenous recombinant human CXCL8 enhanced the invasiveness. More importantly, CXCL8 promoted PTC metastasis in vivo. No difference was found for TAMs-derived CXCL8 expression in patients with and without lymph node metastasis or extrathyroid extension. These findings indicated that TAMs may facilitate PTC cell metastasis through CXCL8 and its paracrine interaction with CXCR1/2.

Preoperative core needle biopsy is accurate in determining molecular subtypes in invasive breast cancer

BackgroundEstrogen receptor (ER), progesterone receptor (PgR), HER2, and Ki67 have been increasingly evaluated by core needle biopsy (CNB) and are recommended for classifying breast cancer into molecular subtypes. However, the concordance rate between CNB and open excision biopsy (OEB) has not been well documented.MethodsPatients with paired CNB and OEB samples from Oct. 2009 to Feb. 2012 in Ruijin Hospital were included. ER, PgR, HER2, and Ki67 were determined by immunohistochemistry (IHC). Patients with HER2 IHC 2+ were further examined by FISH. Cutoff value for Ki67 high expression was 14%. Molecular subtypes were constructed as follows: Luminal A, Luminal B, Triple Negative, and HER2 positive.ResultsThere were 298 invasive breast cancer patients analyzed. Concordance rates for ER, PgR, and HER2 were 93.6%, 85.9%, and 96.3%, respectively. Ki67 expression was slightly higher in OEB than in CNB samples (29.3% vs. 26.8%, P = 0.046). Good agreement (κ = 0.658) was demonstrated in evaluating molecular subtypes between CNB and OEB, with a concordance rate of 77.2%. We also used a different Ki67 cutoff value (20%) for determining Luminal A and B subtypes in HR (hormone receptor) +/HER2- diseases and the overall concordance rate was 79.2%. However, using a cut-point of Ki67 either 14% or 20% for both specimens, there will be about 14% of HR+/HER2- specimens that are called Luminal A on CNB and Luminal B on OEB.ConclusionCNB was accurate in determining ER, PgR, and HER2 status as well as non-Luminal molecular subtypes in invasive breast cancer. Ki67 should be retested on OEB samples in HR+/HER2- patients to accurately distinguish Luminal A from B tumors.

Progesterone receptor status and Ki-67 index may predict early relapse in luminal B/HER2 negative breast cancer patients: a retrospective study.

Purpose Few studies has documented early relapse in luminal B/HER2-negative breast cancer. We examined prognostic factors for early relapse among these patients to improve treatment decision-making. Patients and Methods A total 398 patients with luminal B/HER2-negative breast cancer were included. Kaplan-Meier curves were applied to estimate disease-free survival and Cox regression to identify prognostic factors. Results Progesterone receptor (PR) negative expression was associated with higher tumor grade (p<.001) and higher Ki-67 index (p = .010). PR-negative patients received more chemotherapy than the PR-positive group (p = .009). After a median follow-up of 28 months, 17 patients (4.3%) had early relapses and 8 patients (2.0%) died of breast cancer. The 2-year disease-free survival was 97.7% in the PR-positive and 90.4% in the PR-negative groups (Log-rank p = .002). Also, patients with a high Ki-67 index (defined as >30%) had a reduced disease-free survival (DFS) when compared with low Ki-67 index group (≤30%) (98.0% vs 92.4%, respectively, Log-rank p = .013). In multivariate analysis, PR negativity was significantly associated with a reduced DFS (HR = 3.91, 95% CI 1.29–11.88, p = .016). Conclusion In this study, PR negativity was a prognostic factor for early relapse in luminal B/HER2-negative breast cancer, while a high Ki-67 index suggested a higher risk of early relapse.

USP2 promotes cell migration and invasion in triple negative breast cancer cell lines

Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer that is often associated with a poor prognosis. The aim of our study was to identify biomarkers predictive of TNBC progression. Primary TNBC breast tissue samples including four with metastasis and six without metastasis were subjected to Affymetrix GeneChip® analysis (human genome U133). Ubiquitin-specific protease 2 (USP2) was identified as an upregulated gene in the metastatic group, and its expression was analyzed by immunohistochemistry in 121 primary breast cancers, 13 paired normal tissues, and 13 paired metastatic lesions. Survival analysis was performed using the log-rank test and Cox regression hazard model. Matrigel migration and invasion assays in USP2-silenced and USP2-overexpressed breast cancer cell lines were used to investigate the mechanisms of USP2 in vitro. Positive immunostaining for USP2 was detected in breast tumors and was correlated with estrogen receptor (ER) and progesterone receptor (PR) statuses and TNBC subtype. USP2 was overexpressed in distant metastatic lesions compared with primary breast cancers. Survival analyses demonstrated that positive USP2 is a poor prognostic factor for disease-free survival. Silencing of USP2 expression decreased migration and invasion in LM2-4175 and SCP46 cells in association with the downregulation of matrix metalloproteinase-2 (MMP2) expression, whereas overexpression of USP2 in MDA-MB-468 and MDA-MB-231 cells enhanced migration and invasion and upregulated the expression of MMP2. The present study showed that USP2 expression is associated with TNBC cell line’s invasiveness and poor survival of breast cancer patients and may serve as a prognostic biomarker and therapeutic target for TNBC.

Axillary Staging of Early-Stage Invasive Breast Cancer by Ultrasound-Guided Fine-Needle Aspiration Cytology: Which Ultrasound Criteria for Classifying Abnormal Lymph Nodes Should Be Adopted in the Post-ACOSOG Z0011 Trial Era?

Ultrasound (US)‐guided fine‐needle aspiration cytology (FNAC) is able to identify patients with extensive node involvement before surgery. In this study, we aimed to establish the optimal US criterion to identify abnormal lymph nodes on US‐guided FNAC for detection of patients with 3 or more metastatic axillary nodes.

The importance of biopsy in clinically diagnosed metastatic lesions in patients with breast cancer

BackgroundReceptor status discordance, such as estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) status between primary breast cancer and metastatic lesions has been reported. The aim of this study was to evaluate the biopsy of clinically diagnosed metastatic lesions and to determine the changes in hormonal receptor and HER2 status of the metastatic lesions.MethodsSixty-three patients with clinically diagnosed metastatic breast cancer underwent an excisional biopsy or core needle aspiration guided by computed tomography/ultrasound. ER, PR and HER2 were assessed by immunohistochemistry (IHC).ResultsA total of 48 metastases (76.2%) and nine second primary malignancies (14.3%, seven primary lung cancers and two primary pancreatic cancers) were found. The discrepancies between ER, PR and HER2 status between the primary breast cancer and metastatic lesions were 14.6%, 16.7% and 8.3%, respectively. Six lesions (9.5%) were proved benign upon biopsy.ConclusionsThe biopsy of clinically suspicious metastatic lesions could histologically confirm the diagnosis of metastasis, evaluate discrepancies between ER, PR and HER2 status and exclude secondary malignancy, which might change the therapeutic strategy for breast cancer patients.

Prognostic and predictive value of Ki-67 in triple-negative breast cancer

This study was to investigate the prognostic role of Ki-67 in further classification of triple negative breast cancer (TNBC), and to test whether high expression level of Ki67 can predict benefit from carboplatin. From January 2004 to December 2012, 363 patients operated for TNBC were identified through the institutional clinical database. After a median follow-up time of 34 months (5.2–120.0 months), 62 patients (17.1%) had relapses and 33 patients (9.1%) died of breast cancer. In univariate analysis, high Ki-67 index as well as larger tumor size and lymph node involvement was associated with shorter disease-free survival (DFS) and overall survival (OS). In multivariate analysis, high Ki-67 is an independent risk factor for DFS (Risk Ratio, RR: 2.835, 95% confidence interval, 95% CI: 1.586–5.068, P < 0.001) and OS (RR: 3.180, 95% CI: 1.488–6.793, P = 0.003). When analyzing the 3-year DFS by Ki-67 distribution, Subpopulation Treatment Effect Pattern Plot analysis showed a beneficial effect of carboplatin in patients with high Ki-67 index. In conclusion, TNBC is probably a heterogeneous disease with different characteristics and prognosis, and may be further subdivided according to the Ki-67 expression levels. Patients in the high Ki- 67 group seem to benefit more from treatment with carboplatin, but this needs to be further verified.