Breast Cancer Disparities: A Multicenter Comparison of Tumor Diagnosis, Characteristics, and Surgical Treatment in China and the U.S.

BACKGROUND AND OBJECTIVE: Incidence of and mortality rates for breast cancer continue to rise in the People's Republic of China. The purpose of this study was to analyze differences in characteristics of breast malignancies between China and the U.S. METHODS: Data from 384,262 breast cancer patients registered in the U.S. Surveillance, Epidemiology, and End Results (SEER) program from 2000 to 2010 were compared with 4,211 Chinese breast cancer patients registered in a Chinese database from 1999 to 2008. Outcomes included age, race, histology, tumor and node staging, laterality, surgical treatment method, and reconstruction. The Pearson chi-square and Fisher's exact tests were used to compare rates. RESULTS: Infiltrating ductal carcinoma was the most common type of malignancy in the U.S. and China. The mean number of positive lymph nodes was higher in China (2.59 vs. 1.31, p < .001). Stage at diagnosis was higher in China (stage IIA vs. I, p < .001). Mean size of tumor at diagnosis was higher in China (32.63 vs. 21.57 mm). Mean age at diagnosis was lower in China (48.28 vs. 61.29 years, p < .001). Moreover, 2.0% of U.S. women underwent radical mastectomy compared with 12.5% in China, and 0.02% in China underwent reconstructive surgery. CONCLUSION: Chinese women were diagnosed at younger ages with higher stage and larger tumors and underwent more aggressive surgical treatment. Prospective trials should be conducted to address screening, surgical, and tumor discrepancies between China and the U.S. IMPLICATIONS FOR PRACTICE: Breast cancer patients in China are diagnosed at later stages than those in America, which might contribute to different clinical management and lower 5-year survival rate. This phenomenon suggests that an earlier detection and treatment program should be widely implemented in China. By comparing the characteristics of Chinese and Chinese-American patients, we found significant differences in tumor size, lymph nodes metastasis, and age at diagnosis. These consequences indicated that patients with similar genetic backgrounds may have different prognoses due to the influence of environment and social economic determinates.

Unfavorable pathological complete response rate of neoadjuvant chemotherapy epirubicin plus taxanes for locally advanced triple-negative breast cancer.

Anthracycline-Taxane chemotherapy is widely used in neoadjuvant treatment for breast cancers. However, there is limited data reported in patients with triple negative breast cancer (TNBC). Here, we evaluated the pathologic responses and survival of neoadjuvant epirubicin and taxanes chemotherapy in patients with locally advanced TNBC to provide some useful information for clinical practice. A total of 43 patients with locally advanced TNBC were enrolled in this study. Patients were administered with epirubicin 75 mg/m(2) plus paclitaxel 175 mg/m(2) or docetaxel 75 mg/m(2) every 3 weeks for at least 2 cycles. The primary endpoint was pathologic complete response (pCR), which was defined as no residual invasive cancer, or only carcinoma in situ in both the excised breast and axillary lymph node, while relapse-free survival (RFS) and overall survival (OS) were secondary endpoints. Thirty-nine (90.7%) patients were at clinical stages IIB-IIIC. Thirty-seven (86%) completed 4-6 cycles of preoperative chemotherapy, and objective response rate (ORR) was 81.4% (35/43). Forty-two patients underwent radical surgery subsequently. The pCR rate was 14.3% (6/42). The most common adverse events in neoadjuvant chemotherapy were nausea/vomiting (88.4%, 38/43) and neutropenia (88.4%). After a median follow-up period of 34.0 months, 3-year RFS and OS rate was 53.6% and 80.1%, respectively. All events of recurrence and death occurred in non-pCR patients, in whom the 3-year RFS and OS rates were 44.3% and 76.6%, respectively. This study suggest that neoadjuvant chemotherapy with epirubicin plus taxanes has a relatively low pCR rate and high early recurrence risk in locally advanced TNBC, which indicates the necessity for more efficacious treatment. Further study is needed to validate these results.

[Phase II clinical trial of neoadjuvant therapy with carboplatin plus paclitaxel for locally advanced triple-negative breast cancer].

OBJECTIVE: To evaluate the efficacy, safety and survival of combination of carboplatin plus paclitaxel as neoadjuvant chemotherapy (NACT) for patients with locally advanced triple-negative breast cancer (TNBC), and explore an optimal regimen for TNBC. METHODS: Patients with core needle biopsy confirmed pathological diagnosis of IIA ∼ IIIC invasive breast cancer, negative for estrogen and progesterone receptors and HER2 by immunohistochemistry, and with indication for NACT were eligible in this study. The biopsy tumor tissues were tested for CK5/6, CK14, EGFR and Ki67. The patients received paclitaxel 175 mg/m(2) on day 1, carboplatin at an area under the curve 5 mg×min/ml on day 2 of every 21 days. The clinical response was evaluated every 2 cycles according to Standard RECIST 1.0 criteria and surgery was done after four to six cycles. Pathological complete remission (pCR) was defined if absence of invasive tumor in the breast and axillary lymph nodes samples or residual carcinoma in situ only. RESULTS: Overall, thirty-one patients were enrolled from January 2008 to November 2010. The median age was 51 years and 83.9% of the patients were diagnosed as stage IIB to IIIC diseases. 30 Patients completed chemotherapy as planed while one patient changed regimen due to paclitaxel allergy. Twenty-eight patients could be evaluated for clinical efficacy, of which CR, PR, SD, PD were achieved in 4, 20, 3 and 1 women, respectively. The objective response rate was 85.7%. The expression rate of CK5/6, CK14 and EGFR were 88.9% (24/27), 59.3% (16/27) and 63% (17/27), respectively. Among 27 patients who received modified radical mastectomy or breast-conserving surgery, 11 patients obtained pCR, with a pCR rate of 40.7% (95%CI 22.2% - 59.3%). Five of six CK5/6- and CK14-positive patients achieved pCR. All the 31 patients could be evaluated for toxicity according to the NCI-CTC v3.0 criteria. The major toxicities were neutropenia (93.5%), vomiting (45.2%) and ALT/AST increase (32.3%), and grade 3-4 toxicities accounted for 74.2%, 3.2%, 0, respectively. Until December 2011, at a median follow-up of 28.9 months (range 5 - 47.9), eight patients developed recurrence including 5 patients died. Among 11 patients with pCR, one suffered from lung metastasis at 45 months after diagnosis and survived with tumor until now. The other ten were alive and disease free. The 3-year DFS and OS were 62% and 74.7%, respectively. CONCLUSIONS: As a neoadjuvant treatment for triple-negative breast cancer, carboplatin plus paclitaxel regimen achieves notable higher objective response rate and pCR rate compared with the anthracycline plus paclitaxel regimen reported in the literature, and is well tolerable. It is an optimized regimen for TNBC.

MoSnf5 Regulates Fungal Virulence, Growth, and Conidiation in Magnaporthe oryzae.

Snf5 (sucrose nonfermenting) is a core component of the SWI/SNF complexes and regulates diverse cellular processes in model eukaryotes. In plant pathogenic fungi, its biological function and underlying mechanisms remain unexplored. In this study, we investigated the biological roles of MoSnf5 in plant infection and fungal development in the rice blast pathogen Magnaporthe oryzae. The gene deletion mutants of MoSNF5 exhibited slower vegetative hyphal growth, severe defects in conidiogenesis, and impaired virulence and galactose utilization capacities. Domain dissection assays showed that the Snf5 domain and the N- and C-termini of MoSnf5 were all required for its full functions. Co-immunoprecipitation and yeast two-hybrid assays showed that MoSnf5 physically interacts with four proteins, including a transcription initiation factor MoTaf14. Interestingly, the ∆MoTaf14 mutants showed similar phenotypes as the ∆Mosnf5 mutants on fungal virulence and development. Moreover, assays on GFP-MoAtg8 expression and localization showed that both the ∆Mosnf5 and ∆MoTaf14 mutants were defective in autophagy. Taken together, MoSnf5 regulates fungal virulence, growth, and conidiation, possibly through regulating galactose utilization and autophagy in M. oryzae.

[Comparison of touch imprint cytology of core needle biopsy and section histopathology in breast cancer diagnosis].

OBJECTIVE: To evaluate the sensitivity, specificity of touch imprint cytology (TIC), and to compare its conformity rate with histopathology, to observe the consistence of immunocytochemistry (ICC) with immunohistochemistry (IHC), and to assess the diagnostic value of TIC prior to neoadjuvant chemotherapy for breast cancer. METHODS: 289 cases of TIC and 287 cases with core needle biopsy (CNB) histopathology accumulated from October 2005 to October 2008 in our hospital were included in this study. One hundred ninety cases TIC results were compared with that of final histopathology. 64 cases were tested for ER, PR, HER-2 by immunocytochemistry. RESULTS: Twenty-four benign cases and 263 malignant cases were diagnosed. 4 specimens were unsatisfactory. False negative rate and unsatisfactory rate were 1.4%, both, and false positive rate was 0.35%. The accuracy rate of TIC and CNB was 95.8% and 95.3%, respectively (P = 0.804). The sensitivity of TIC and CNB was 96.2% and 95.0% (P = 0.601), specificity 87.5% and 100% (P = 0.471) were found, when compared with the results of routine histopathology. 52 cases had a control with IHC of CNB in 64 ICC, and 43 cases had a final histopathology IHC. The ICC conformity rate of ER, PR, HER-2 with IHC of CNB was 86.5%, 75.0%, 78.8%, and that with IHC of final histopathology was 88.4%, 74.4%, 75.6%, respectively. The conformity rate of IHC between CNB and final histopathology was 83.7%, 74.4%, 76.5%, respectively. There was no significant statistical difference between them. CONCLUSION: Compared with routine CNB histopathology, TIC has a high accuracy and sensitivity, and can provide a rapid and reliable cytological diagnosis to complement CNB for breast lesions. The conformity rates are high in ER, PR, HER-2 expression between ICC and IHC. ICC of TIC can be used to determine the estrogen and progesterone receptor levels in breast cancer before neoadjuvant chemotherapy.

[A comparison of localization by ductoscopy-guided wire and conventional methods in terminal duct excision for women with pathological nipple discharge].

OBJECTIVE: To evaluate and compare localization by ductoscopy-guided wire with localization by conventional methods in the terminal duct excision for women with pathological nipple discharge. METHODS: Breast terminal duct excision were performed in 174 consecutive patients with intraductal lesions diagnosed by mammary ductoscopy. Sixty-eight of those underwent ductoscopy-guided wire localization for more accurate ductal excision. The patients received mammary ductoscopy and a hooked wire was anchored at the intraductal lesions under endoscopic surveillance just before the operation. Then a biopsy resection of wire-guided terminal duct and frozen section were done. Tbe other 106 patients received terminal duct excision under localization with conventional methods without ductoscopy either by puncturing a needle or injection of blue dye through the duct with pathological discharge. RESULTS: Of the 68 patients with ductoscopy-guided duct excision, 64 had intraductal papillomas and 4 duct carcinoma in situ proved by pathology. All the lesions in these 68 patients were completely resected during biopsy without extra extended resection, and the concordance rate of the pathological result with ductoscopic diagnosis was 100.0%. None of them developed a postoperative breast distortion. In the conventional method localization group, there were 96 intraductal papilloma, 6 duct carcinoma in situ and 4 adenosis. Only 77.4% of the lesions were excised in the primary biopsy, and 22.6% needed extended resection. The concordance rate of the pathological diagnosis with ductoscopic diagnosis was 96.2%. Twenty-six patients had a deformed breast postoperatively. CONCLUSION: Ductoscopy-guided wire localization is superior to the conventional localization method in the surgical terminal duct excision for women with spontaneous nipple discharge. It is not only helpful for more accurate localization and resection as well as pathologic sampling, but also is minimally invasive. Further studies are still required and this method may deserve to be popularized.

Hypoxia preconditioning protects Ca2+-ATPase activation of intestinal mucosal cells against R/I injury in a rat liver transplantation model.

AIM: To investigate the effect of ischaemia and reperfusion (I/R) injury on the Ca2+-ATPase activation in the intestinal tissue of a rat autologous orthotopic liver transplantation model and to determine if hypoxia preconditioning (HP) therapy induces HIF-1α to protect rat intestinal tissue against I/R injury. METHODS: Rats received non-lethal hypoxic preconditioning therapy to induce HIF-1α expression. We used an autologous orthotopic liver transplantation model to imitate the I/R injury in intestinal tissue. Then, we detected the microstructure changes in small intestinal tissues, Ca2+-ATPase activity, apoptosis, and inflammation within 48 h postoperatively. RESULTS: HIF-1α expression was significantly increased in intestinal tissue at 12 h postoperatively in rats that were exposed to a hypoxic environment for 90 min compared with a non-HP group (HP vs AT, P = 0.0177). Pathological analysis was performed on the intestinal mucosa cells, and the cells in the HP group appeared healthier than the cells in the AT group. The Ca2+-ATPase activity in the small intestinal cells in the AT group was significantly lower after the operation, and the Ca2+-ATPase activity in the HP group recovered faster than that in the AT group at 6 h postoperatively (HP vs AT, P = 0.0106). BCL-2 expression in the HP group was significantly higher than that in the AT group at 12 h postoperatively (HP vs AT P = 0.0010). The expression of the inflammatory factors NO, SOD, IL-6, and TNF-α was significantly lower in the HP group than in the AT group. CONCLUSION: Hypoxia-induced HIF-1α could protect intestinal mucosal cells against mitochondrial damage after I/R injury. HP could improve hypoxia tolerance in small intestinal mucosal cells and increase Ca2+-ATPase activity to reduce the apoptosis of and pathological damage to intestinal cells. HP could be a useful way to promote the earlier recovery of intestinal function after graft procedure.

Clinical significance of integrin ß6 as a tumor recurrence factor in follicular thyroid carcinoma.

BACKGROUND: Overexpression of integrin ß6 plays an important role in a variety of malignant tumor invasion and metastasis. METHODS: The expression levels of integrin ß6, matrix metalloproteinase (MMP)-2 and MMP-9 were analyzed by immunohistochemistry with human follicular thyroid carcinomas. Then we investigated their correlation with clinical outcomes parameters, relationship, and the survival time. RESULTS: The integrin ß6 staining was expressed in cellular membrane and cytoplasm of follicular thyroid carcinoma cells. The MMP-2 and MMP-9 expressions were mainly found in cellular cytoplasm. In correlation with the clinical outcome parameters of 60 patients, there were significant statistical differences of integrin ß6, MMP-2, and MMP-9 expression levels in different size of tumor. Integrin ß6 and MMP-9 expressions have significant statistical differences in T classifications. MMP-2 and MMP-9 expressions have significant statistical differences in different M classification. Other clinical outcome parameters had no significant statistical differences. CONCLUSION: Integrin ß6 expression correlated significantly with MMP-9 expression, and may be a valuable recurrence indicator for follicular thyroid carcinomas.

[A multifrequency phase-controlled driving system for ultrasound therapy].

Ultrasound therapy is a new type of therapy technology, there are hyperthermia and high intensity focused ultrasound surgery (HIFUS). Compared with a single frequency system, mutiple frequency system has an additional function to combine power patterns of different frequencies. This function increases the availability of power patterns to treat tumors of various shapes and depths. Therefore, we have in this article proposed a system with the ability to drive ultrasonic phased arrays of multiple resonant frequencies for ultrasound hyperthermia and HIFUS. The results show that this system is able to (1) drive multi-element applicators or phased arrays of a single resonant frequency through the multichannel power amplifiers, (2) concurrently drive transducer with different resonant frequencies, (3) adjust the relative phase and output power of each channel for the scanning ultrasonic focus, and (4) operate each channel with good output stability.

Methylenetetrahydrofolate reductase C677T and A1298C polymorphisms and gastric cancer susceptibility.

AIM: To identify the association between methylenetetrahydrofolate reductase (MTHFR) polymorphisms and gastric cancer (GC) susceptibility. METHODS: Systematic searches were performed on the electronic databases PubMed, ISI, Web of knowledge, CNKI and Wanfang, as well as manual searching of the references of the identified articles. A total of 26 papers were included in this meta-analysis. Overall and subgroup analyses were performed. Odds ratio (OR) and 95%CI were used to evaluate the associations between MTHFR polymorphisms and GC risk. The I (2) statistics were used to evaluate between-study heterogeneity. Sensitivity analysis was also performed. RESULTS: Increased risk was found for the MTHFR C677T polymorphism under four genetic models (TT + CT vs CC: OR = 1.23, P = 0.002; T vs C: OR = 1.15, P = 0.001; TT vs CC: OR = 1.37, P = 0.0005; TT vs CT + CC: OR = 1.17, P = 0.0008). Subgroup analysis by ethnicity suggested that C677T polymorphism conferred a risk of GC in eastern but not in western populations. Stratification by tumor site showed an association between the C677T polymorphism and gastric cardia cancer and non-cardia GC in the worldwide population and in eastern populations. Regardless of comparisons with controls or diffuse-type GC, a positive association was found for the C677T polymorphism and an increased risk of intestinal-type GC in the whole population and in western populations. With regard to the A1298C polymorphism, we found that genotype CC was significantly decreased and conferred protection against GC in eastern populations (CC vs AA: OR = 0.44, P = 0.03; CC vs AC + AA: OR = 0.46, P = 0.04). CONCLUSION: MTHFR C677T polymorphism is a risk factor for GC, and the A1298C polymorphism may be a protective factor against GC in eastern populations.

Intrinsic kinase activity and SQ/TQ domain of Chk2 kinase as well as N-terminal domain of Wip1 phosphatase are required for regulation of Chk2 by Wip1.

The anti-oncogenic Chk2 kinase plays a crucial role in DNA damage-induced cell cycle checkpoint regulation. Recently, we have shown that Chk2 associates with the oncogenic Wip1 (PPM1D) phosphatase and that Wip1 acts as a negative regulator of Chk2 during DNA damage response by dephosphorylating phosphorylated Thr-68 in activated Chk2 (Fujimoto, H., Onishi, N., Kato, N., Takekawa, M., Xu, X. Z., Kosugi, A., Kondo, T., Imamura, M., Oishi, I., Yoda, A., and Minami, Y. (2006) Cell Death Differ. 13, 1170-1180). Here, we performed structure-function analyses of Chk2 and Wip1 by using a series of deletion or amino acid-substituted mutant proteins of Chk2 and Wip1. We show that nuclear localization of both Chk2 and Wip1 is required for their association in cultured cells and that the serine-glutamine (SQ)/threonine-glutamine (TQ) domain of Chk2, containing Thr-68, and the N-terminal domain of Wip1, comprising about 100 amino acids, are necessary and sufficient for the association of both molecules. However, it was found that an intrinsic kinase activity of Chk2, but not phosphatase activity of Wip1, is required for the association of fulllength Chk2 and Wip1. Interestingly, we also show that the mutant Wip1 proteins, bearing the N-terminal domain of Wip1 alone or lacking an intrinsic phosphatase activity, exhibit dominant negative effects on the functions of the wild-type Wip1, i.e. ectopic expression of either of these Wip1 mutants inhibits dephosphorylation of Thr-68 in Chk2 by Wip1 and anti-apoptotic function of Wip1. These results provide a molecular basis for developing novel anti-cancer drugs, targeting oncogenic Wip1 phosphatase.

Physical interactions of Dmnk with Orb: implications in the regulated localization of Orb by Dmnk during oogenesis and embryogenesis.

The Dmnk (Drosophila maternal nuclear kinase) gene, encoding a nuclear protein serine/threonine kinase, is expressed predominantly in the germline cells during embryogenesis, suggesting its possible role in the establishment of germ cells. We report here that Dmnk interacts physically with Drosophila RNA binding protein Orb, which plays crucial roles in the establishment of Drosophila oocyte by regulating the distribution and translation of several maternal mRNAs. Considering similar spatiotemporal expression pattern of Dmnk and orb during oogenesis and early embryogenesis, it is suggested that Dmnk plays a role in establishment of germ cells by interacting with Orb. Although there are two forms of Dmnk proteins, Dmnk-L (long) and Dmnk-S (short) via the developmentally regulated alternative splicing, Orb can associate with both forms of Dmnk proteins when expressed in culture cells. However, immunohistochemical analysis revealed that Dmnk-S, but not Dmnk-L, can affect the subcellular localization of Orb in a kinase activity-dependent manner, suggesting differential functions of Dmnk-S and Dmnk-L in the regulation of Orb.