[Analysis of clinicopathological factors associated with false-negative rate of sentinel lymph node biopsy in breast cancer patients: experience of a single center].

OBJECTIVE: The purpose of this study was to investigate the clinicopathologic factors associated with false-negative rate of sentinel lymph node biopsy (SLNB) in breast cancer, and to explore how to reduce the false-negative rate of SLNB. METHODS: The clinicopathological data of 2265 patients with invasive breast carcinoma who underwent sentinel lymph nodes biopsy (SLNB) in Shandong Cancer Hospital between November 1999 and December 2011 were retrospectively analyzed. We screened 1228 patients who received axillary lymph node dissection after SLNB, and studied the clinicopathological factors that could be associated with false-negative rate of SLNB. RESULTS: The false negative rate of this group was 10.7% (73/683), accuracy rate was 94.1% (1155/1228), and negative predictive value was 88.2% (545/618). Clinical tumor size (all P < 0.05), calendar year of surgery (all P < 0.05) and numbers of detected SLNs (all P < 0.05) were significantly related with false negative rate and accuracy rate of SLNB, determined by single factor analysis. Logistic regression model analysis showed that calendar year of surgery (P = 0.034) and numbers of detected SLNs (P = 0.012) were independent predictive factors for the false negative rate of SLNB. CONCLUSIONS: False negative rate and accuracy rate of SLNB are significantly related to the calendar year of surgery and number of detected SLNs. Strict case selection, standard operation procedure, increaseing numbers of detected SLNs, and improvement of the skill of operators are effective measures to reduce the false negative rate of SLNB.

[Value of sentinel lymph node metastasis status in predicting the presence of residual disease in the non-sentinel lymph node of breast cancer patients].

OBJECTIVE: To explore the value of sentinel lymph nodes (SLN) metastasis status in predicting the presence of residual disease in non-sentinel lymph nodes (nSLN) and the feasibility of avoiding or reducing the scope of axillary lymph node dissection (ALND) for patients with single positive SLN. METHODS: A retrospective study was conducted for 2265 patients with invasive breast carcinomas undergoing sentinel lymph nodes biopsy (SLNB) at Shandong Cancer Hospital between November 1999 and December 2011. And 1228 patients with axillary dissection were screened and divided into 5 groups of (-), (1/n), (1/1), (n/N), (n/n) (n ≥ 2, N ≥ 3, N > n) according to the status of SLN metastasis. RESULTS: The nSLN metastasis rate of SLN(-), (1/n), (1/1), (n/N) and (n/n) groups was 11.8%(73/618), 25.2%(65/258), 49.6%(67/135), 48.4%(60/124)and 65.6%(61/93)respectively. A comparison of SLN(-), (1/n), (1/1), (n/N), and (n/n) groups of nSLN metastasis showed a significant difference (P = 0.000). The differences of nSLN metastasis between SLN(-) and other groups (including 1/n, 1/1, n/N, n/n group) were significant (P = 0.000). This difference was also significant between SLN (1/n) and other positive groups (include 1/1, n/N, n/n group) (P = 0.000), but not significant between SLN(1/1), (n/N) and (n/n) groups (P = 0.842, 0.017, 0.042 respectively, Chi-square segmentation). No significant difference existed between axillary lymph node metastasis on Level II and III of SLN 1/n group and SLN(-) group (P = 0.012, 0.570,χ(2) segmentation). CONCLUSIONS: The status of SLN metastasis is one of influencing factors for the nSLN metastasis of patients with invasive breast cancer. The possibility of non-sentinel lymph node involvement for patients with single SLN metastasis was smaller than that of other SLN-positive patients. It is safe for some SLN 1/n patients to undergo low lymph node dissection. But ALND is not avoided for patients with single positive SLN (SLN 1/n n ≥ 2). Their clinicopathological variables should be also considered.

Monocyte-induced NK cell inactivation: role of reactive oxygen and nitrogen metabolites.

Here in a co-cultivation system of natural killer (NK) cells and K562 cells, monocytes (MO) and/or interleukin (IL)-2/phytohemagglutinin (PHA) were administered. After MO were administered, reactive oxygen metabolites (ROM)/reactive nitrogen metabolites (RNM) productions increased, while tumor necrosis factor (TNF)-ß/interferon (IFN)-γ levels and NK cell cytotoxicity (NCC) decreased, the changes of which after administering tiopronin (TIP) or glutamylcysteinylglycine (GSH) were opposite. In conclusions, the activated MO could inhibit the NK cell activity to kill K562 cell by secreting ROM and RNM. And TIP and GSH could scavenge both ROM and RNM to reverse the inhibitory effect of MO.

[Systematic review of validation phase of breast cancer sentinel lymph node biopsy results in China].

OBJECTIVE: To explore the studies and application status of sentinel lymph node biopsy (SLNB) in breast cancer in China by statistically analyzing the relevant domestic literature. METHODS: The literatures published from January 1999 to December 2005 were searched in the databases of China, Info, CBM and CNKI retrieval system with "breast tumor, SLN and SLNB" as the key words. A total of 88 manuscripts were selected with 2 new reports of SLNB. The successful rate, accuracy, false-negative rate and sensitivity of SLNB were analyzed by SPSS 10.0 statistical analysis software. RESULTS: Among a total of 6282 patients, the detection rate of SLNB was 90.82% (5705/6282) and the overall false-negative rate 9.69% (259/2671). The prediction sensitivity, specificity, false positive rate, accuracy, negative and positive predictive value of SLN for axillary lymph nodes status were 90.30%, 99.64%, 0.41%, 86.52%, 92.11% and 99.55% respectively. CONCLUSION: SLNB can accurately predict the axillary lymph node metastasis. And its detection rate is correlated with patient age and tumor location. The detection rate and false-negative rate has nothing to do with the tracer injection site. A combined regimen has a higher detection rate and a low false negative rate. Affecting the whole breast, SLN is not correlated with a particular area of breast. The validation phase of SLNB in breast cancer is currently feasible in China.

Middle cerebral artery thrombus susceptibility-weighted imaging mapping predicts prognosis.

BACKGROUND: Susceptibility weighted imaging and mapping (SWIM) of magnetic resonance imaging (MRI) is used to evaluate cerebral arterial thrombosis. The aim of this research was to assess susceptibility, length, and clot burden score (CBS) of thrombus in the middle cerebral artery (MCA) and their relationship with cerebral infarction and early clinical prognosis in patients with acute or subacute cerebral infarction. METHODS: In total, 56 patients with acute or subacute cerebral infarction (with the time from onset to admission less than 72 h) and only unilateral MCA occlusion were included in the current study. All the patients had the corresponding susceptibility vessel sign (SVS) on susceptibility-weighted imaging (SWI). Parameters including susceptibility, length, and CBS of thrombus were obtained from SWI and SWIM. The differences in susceptibility of different portions of the thrombus were compared with each other by one-way ANOVA test. The relationship between susceptibility and stroke onset time was further analyzed by Spearman correlation analysis, in addition to the relationships between susceptibility, length, CBS, diffusion-weighted imaging-Alberta stroke program early CT score (DWI-ASPECTS), and admission and discharge National Institutes of Health Stroke Scale (NIHSS). RESULTS: The susceptibility among different portions and different segments of thrombus showed no statistical difference. The susceptibility and length were weakly yet negatively correlated with DWI-ASPECTS (rs=-0.382, -0.457; P=0.004, 0.000). The susceptibility was weakly yet positively correlated with admission NIHSS and discharged NIHSS (rs=0.403, 0.430; P=0.002, 0.001). CBS was weakly yet positively correlated with DWI-ASPECTS (rs=0.349; P=0.008) and weakly yet negatively correlated with admission and discharged NIHSS (rs=-0.375, -0.335; P=0.004, 0.012). CONCLUSIONS: The susceptibility remained consistent regardless of location, length, and onset time, which indicates that the thrombus composition was similar when detected on SWI less than 72 h from the onset. Susceptibility and CBS may help to predict clinical severity and short-term clinical prognosis to some extent.

Comparison and Correlation of Magnetic Resonance Imaging and Clinical Severity in Nonhuman Immunodeficiency Virus Patients with Cryptococcal Infection of Central Nervous System.

BACKGROUND: The incidence of cryptococcal meningitis among immunocompetent patients increases, especially in China and imaging plays an important role. The current study was to find the correlation between magnetic resonance imaging (MRI) manifestation and clinical severity in nonhuman immunodeficiency virus patients with cryptococcal infection of central nervous system (CNS). METHODS: A total of 65 patients with CNS cryptococcal infection from August 2014 to October 2016 were retrospectively included in this study. All the patients had MRI data and clinical data. The patients were divided into two groups according to whether the patients were confirmed with identifiable underlying disease. Comparison and correlation of MRI and clinical data in both groups were investigated using independent sample t- test, Chi-square test, Mann-Whitney test and Spearman rank correlation analysis. RESULTS: In all 65 patients, 41 cases (41/65, 63.1%; Group 1) had normal immunity and 24 cases (24/65, 36.9%; Group 2) had at least one identifiable underlying disease. Fever, higher percentage of neutrophil (NEUT) in white blood cell (WBC), and increased cell number of cerebral spinal fluid (CSF) were much common in patients with underlying disease (Group 1 vs. Group 2: Fever: 21/41 vs. 21/24, χ2 = 8.715, P = 0.003; NEUT in WBC: 73.15% vs. 79.60%, Z = -2.370, P = 0.018; cell number of CSF: 19 vs. 200, Z = -4.298, P < 0.001; respectively). Compared to the patients with normal immunity, the lesions are more common in the basal ganglia among patients with identifiable underlying disease (Group 1 vs. Group 2: 20/41 vs. 20/24, χ2 = 7.636, P = 0.006). The number of the involved brain areas in patients with identifiable underlying disease were well correlated with the number of cells and pressure of CSF (r = -0.472, P = 0.031; r = 0.779, P = 0.039; respectively). CONCLUSIONS: With the increased number of the involved brain areas in patients with identifiable underlying disease, the body has lower immunity against the organism which might result in higher intracranial pressure and more severe clinical status.

miR-375 inhibits cancer stem cell phenotype and tamoxifen resistance by degrading HOXB3 in human ER-positive breast cancer.

Cancer stem cell (CSC) formation and epithelial-mesenchymal transition (EMT) are pivotal events in tumor cell invasion and metastasis. They have been shown to occur in resistance to tamoxifen. Moreover, microRNAs (miRNAs) have been associated with CSCs, EMT as well as tamoxifen resistance. Studying molecular mechanism of CSCs, EMT as well as tamoxifen resistance will help us to further understand the pathogenesis and progression of the disease and offer new targets for effective therapies. In the present study, we showed that miR-375 inhibits CSC traits in breast cancer MCF-7 cells. Bioinformatics analysis and experimental validation identified HOXB3 as a direct target of miR-375. Overexpressing miR-375 degraded HOXB3 mRNA in MCF-7 cells. Moreover, overexpression of HOXB3 induced formation of CSC phenotypes, EMT and tamoxifen-resistance as well as enhanced ability of migration and invasion in MCF-7 cells. Most ER-positive breast cancer-related deaths occur, because of resistance to standard therapies and metastasis, restoring miR-375 or targeting HOXB3 might serve as potential therapeutic approaches for the treatment of tamoxifen-resistant breast cancer.

Prospective study found that peripheral lymph node sampling reduced the false-negative rate of sentinel lymph node biopsy for breast cancer.

BACKGROUND: Although sentinel lymph node biopsy (SLNB) can accurately predict the status of axillary lymph node (ALN) metastasis, the high false-negative rate (FNR) of SLNB is still the main obstacle for the treatment of patients who receive SLNB instead of ALN dissection (ALND). The purpose of this study was to evaluate the clinical significance of SLNB combined with peripheral lymph node (PLN) sampling for reducing the FNR for breast cancer and to discuss the effect of "skip metastasis" on the FNR of SLNB. METHODS: At Shandong Cancer Hospital Affiliated to Shandong University between March 1, 2012 and June 30, 2015, the sentinel lymph nodes (SLNs) of 596 patients with breast cancer were examined using radiocolloids with blue dye tracer. First, the SLNs were removed; then, the area surrounding the original SLNs was selected, and the visible lymph nodes in a field of 3-5 cm in diameter around the center (i.e., PLNs) were removed, avoiding damage to the structure of the breast. Finally, ALND was performed. The SLNs, PLNs, and remaining ALNs underwent pathologic examination, and the relationship between them was analyzed. RESULTS: The identification rate of SLNs in the 596 patients was 95.1% (567/596); the metastasis rate of ALNs was 33.7% (191/567); the FNR of pure SLNB was 9.9% (19/191); and after the SLNs and PLNs were eliminated, the FNR was 4.2% (8/191), which was significantly decreased compared with the FNR before removal of PLNs (P = 0.028). According to the detected number (N) of SLNs, the patients were divided into four groups of N = 1, 2, 3, and ≥4; the FNR in these groups was 19.6, 9.8, 7.3, and 2.3%, respectively. For the patients with ≤2 or ≤3 detected SLNs, the FNR after removal of PLNs was significantly decreased compared with that before removal of PLNs (N ≤ 2: 14.0% vs. 4.7%, P = 0.019; N ≤ 3: 12.2% vs. 4.7%, P = 0.021), whereas for patients with ≥4 detected SLNs, the decrease in FNR was not statistically significant (P = 1.000). In the entire cohorts, the "skip metastasis" rate was 2.5% (15/596); the FNR caused by "skip metastasis" was 2.1% (4/191). CONCLUSIONS: The FNR of SLNB was associated with the number of SLNs. For patients with ≤3 detected SLNs, PLN sampling can reduce the FNR of SLNB to an acceptable level of less than 5%. Because of the existence of the "skip metastasis" and distinct metastasis patterns, the FNR of SLNB cannot be completely eliminated.

The Feasibility and Oncological Safety of Axillary Reverse Mapping in Patients with Breast Cancer: A Systematic Review and Meta-Analysis of Prospective Studies.

OBJECTIVE: The axillary reverse mapping (ARM) technique has recently been developed to prevent lymphedema by preserving the arm lymphatic drainage during sentinel lymph node biopsy (SLNB) or axillary lymph node dissection (ALND) procedures. The objective of this systematic review and meta-analysis was to evaluate the feasibility and oncological safety of ARM. METHODS: We searched Medline, Embase, Web of science, Scopus, and the Cochrane Library for relevant prospective studies. The identification rate of ARM nodes, the crossover rate of SLN-ARM nodes, the proportion of metastatic ARM nodes, and the incidence of complications were pooled into meta-analyses by the random-effects model. RESULTS: A total of 24 prospective studies were included into meta-analyses, of which 11 studies reported ARM during SLNB, and 18 studies reported ARM during SLNB. The overall identification rate of ARM nodes was 38.2% (95% CI 32.9%-43.8%) during SLNB and 82.8% (78.0%-86.6%) during ALND, respectively. The crossover rate of SLN-ARM nodes was 19.6% (95% CI 14.4%-26.1%). The metastatic rate of ARM nodes was 16.9% (95% CI 14.2%-20.1%). The pooled incidence of lymphedema was 4.1% (95% CI 2.9-5.9%) for patients undergoing ARM procedure. CONCLUSIONS: The ARM procedure was feasible during ALND. Nevertheless, it was restricted by low identification rate of ARM nodes during SLNB. ARM was beneficial for preventing lymphedema. However, this technique should be performed with caution given the possibility of crossover SLN-ARM nodes and metastatic ARM nodes. ARM appeared to be unsuitable for patients with clinically positive breast cancer due to oncological safety concern.

Evaluation of hormone receptor, human epidermal growth factor receptor-2 and Ki-67 with core needle biopsy and neoadjuvant chemotherapy effects in breast cancer patients.

BACKGROUND: We investigated the reliability of core needle biopsy (CNB) in evaluating the status of hormone receptor (HR), human epidermal growth factor receptor (HER)-2, and Ki-67 status, and the effect of neoadjuvant chemotherapy (NAC) on the expression of these immunohistochemical markers. METHODS: Among 177 patients with breast adenocarcinoma, 95 patients underwent NAC and the remaining 82 patients made up the control group. Immunohistochemistry (IHC) was used to evaluate the expression status of estrogen receptor (ER), progesterone receptor (PR), HER-2, and Ki-67 in the specimens obtained by surgical excision or CNB. RESULTS: In the control group, the expression of ER, PR, HER-2, and Ki-67 was highly consistent between samples from surgical excision or CNB (all r > 0.8, P < 0.05). In the NAC group, the proportions of samples with changes in ER, PR, HER-2, and Ki-67 expression were 12.7%, 24.1%, 5.1%, and 38.0%, respectively; the figures in the control group were 2.4%, 4.9%, 2.4%, and 7.3%, respectively, which significantly differed in ER, PR, and Ki-67 (P < 0.05), but not HER-2 (P > 0.05). In the NAC group, pre- and post-treatment ER(+) rates did not significantly differ (P > 0.05), although PR(+) and high Ki-67 expression rates did significantly differ (P < 0.05). CONCLUSION: Neither CNB nor surgical excision samples gave highly consistent results in HR, HER-2, and Ki-67 status. NAC can alter HR and Ki-67 status in breast adenocarcinoma patients. NAC decreased PR(+) rate and Ki-67 expression. The mean ER(+) rate exhibited a decreasing, but insignificant trend after NAC treatment. NAC had no significant effect on HER-2 expression.

Sentinel lymph node biopsy does not apply to all axillary lymph node-positive breast cancer patients after neoadjuvant chemotherapy.

BACKGROUND: The aim of this study was to investigate the feasibility of sentinel lymph node biopsy (SLNB) after neoadjuant chemotherapy (NAC) in breast cancer patients with confirmed axillary nodal metastases. METHODS: We enrolled 51 patients with breast cancer who received NAC. All patients were proven to have axillary nodal metastases by histopathology biopsy prior to NAC. They all underwent SLNB before breast surgery, and complete axillary lymph node dissection immediately followed. RESULTS: The identification rate for SLNB was 87.5% (84/96); the false negative rate was 24.5% (12/49). The clinicopathological factors were not significantly correlated with the identification and false negative rate of the SLNB. Lymphatic mapping, blue dye or radionuclide methods tended to decrease the identification rate of SLNB (P = 0.073). Clinical nodal status before NAC has a trend to increase the false-negative rates of the SLNB (P = 0.059). For patients with N1 clinical axillary lymph nodal status, the identification rate was 93.9%, and the false negative rate was 5.9%, compared with N2-3 patients with 73.9% and 38.9%, respectively. CONCLUSIONS: SLNB is feasible for the patients whose axillary lymph nodal status before NAC is N1. However, for N2-3 patients, SLNB cannot be used as an infallible indicator of non-SLN status.

Predictors to assess non-sentinel lymph node status in breast cancer patients with only one sentinel lymph node metastasis.

BACKGROUND: The purpose of this study was to investigate the feasibility of avoiding axillary lymph node dissection (ALND) for patients with only one sentinel lymph node (SLN) metastasis. The characteristics and predictive factors for non-sentinel lymph node (NSLN) metastasis of patients with single positive SLN were also analyzed. METHODS: Patients with no and only one SLN metastasis (0/n and 1/n group, n ≥ 2) were selected from 1228 cases of invasive breast carcinoma, who underwent axillary dissection in Shandong Cancer Hospital between November 1999 and December 2011, to compare the characteristics of NSLN metastasis between them. For the 1/n group, the factors that influenced the NSLN metastasis were analyzed by univariate and multivariate analysis. RESULTS: Differences of the NSLN metastasis between the 0/n and the 1/n groups were significant (P < 0.001). There was no significant difference between the axillary lymph node metastasis on level III in 1/n group and 0/n group (P = 0.570). When the total SLN number was ≥ 4 and with one positive case, the NSLN metastasis was not significantly different from that in the 0/n group (P = 0.118). In the 1/n group, clinical tumor size (P = 0.012), over-expression of Her-2 (P = 0.003), tumor grade (P = 0.018) and the total number of SLN (P = 0.047) significantly correlated with non-SLN metastasis. Clinical tumor size (P = 0.015) and the expression of Her-2 (P = 0.01) were independent predictive factors for non-SLN metastasis by the Logistic regression model. CONCLUSION: Under certain conditions, breast cancer patients with single SLN metastasis could avoid ALND.

Silencing of osteopontin promotes the radiosensitivity of breast cancer cells by reducing the expression of hypoxia inducible factor 1 and vascular endothelial growth factor.

BACKGROUND: Osteopontin (OPN) is a secreted phosphoglycoprotein (SSP) that is overexpressed in a variety of tumors and was regarded as a molecular marker of tumors. In this study, we intended to demonstrate the role of OPN in human breast cancer cell line MDA-MB-231. METHODS: Recombinant plasmid expressing small interfering RNA (siRNA) specific to OPN mRNA was transfected into MDA-MB-231 cells to generate the stable transfected cell line MDA-MB-343, and the empty plasmid tansfected cells (MDA-MB-neg) or wildtype MDA-MB-231 cells were used as control cells respectively. Expression of OPN, hypoxia inducible factor-1 (HIF-1) and vascular endothelial growth factor (VEGF) proteins was analyzed by Western blotting analysis. The radiosensitivity of cells was determined by detecting cell apoptosis, cell proliferation and cell senescence. RESULTS: HIF-1 and VEGF proteins in MDA-MB-343 cells were significantly downregulated upon the efficient knockdown of OPN expression under either hypoxia or normoxia environment. Moreover, expression of OPN protein was upregualted upon hypoxic culture. Stable OPN-silencing also decreased cell invasion, increased cell apoptosis and cell senescence, as well as reduced clonogenic survival, resulting in increase radiation tolerance. CONCLUSIONS: Suppression of OPN gene expression can enhance radiosensitivity and affect cell apoptosis in breast cancer cells. OPN seems to be an attractive target for the improvement of radiotherapy.