Computerized quantification of ultrasonic heterogeneity in thyroid nodules.

To test whether computerized quantification of ultrasonic heterogeneity can be of help in the diagnosis of thyroid malignancy, we evaluated ultrasonic heterogeneity with an objective and quantitative computerized method in a prospective setting. A total of 400 nodules including 271 benign thyroid nodules and 129 malignant thyroid nodules were evaluated. Patient clinical data were collected, and the grading of heterogeneity on conventional gray-scale ultrasound images was retrospectively reviewed by a thyroid specialist. Quantification of ultrasonic heterogeneity (heterogeneity index, HI) was performed by a proprietary program implemented with methods proposed in this article. HI values differed significantly between benign and malignant nodules, diagnosed by a combination of fine-needle aspiration and surgical pathology results (p < 0.001, area under the curve = 0.714). The ultrasonic heterogeneity of these samples, as assessed by an experienced clinician, could not significantly differentiate between benign and malignant thyroid nodules. However, nodules with marked ultrasonic heterogeneity had higher HI values than nodules with homogeneous nodules. These results indicate that the new computer-aided diagnosis method for evaluation of the ultrasonic heterogeneity of thyroid nodules is an objective and quantitative method that is correlated with conventional ultrasonic heterogeneity assessment, but can better aid in the diagnosis of thyroid malignancy.

MicroRNA-regulated protein-protein interaction networks and their functions in breast cancer.

MicroRNAs, which are small endogenous RNA regulators, have been associated with various types of cancer. Breast cancer is a major health threat for women worldwide. Many miRNAs were reported to be associated with the progression and carcinogenesis of breast cancer. In this study, we aimed to discover novel breast cancer-related miRNAs and to elucidate their functions. First, we identified confident miRNA-target pairs by combining data from miRNA target prediction databases and expression profiles of miRNA and mRNA. Then, miRNA-regulated protein interaction networks (PINs) were constructed with confident pairs and known interaction data in the human protein reference database (HPRD). Finally, the functions of miRNA-regulated PINs were elucidated by functional enrichment analysis. From the results, we identified some previously reported breast cancer-related miRNAs and functions of the PINs, e.g., miR-125b, miR-125a, miR-21, and miR-497. Some novel miRNAs without known association to breast cancer were also found, and the putative functions of their PINs were also elucidated. These include miR-139 and miR-383. Furthermore, we validated our results by receiver operating characteristic (ROC) curve analysis using our miRNA expression profile data, gene expression-based outcome for breast cancer online (GOBO) survival analysis, and a literature search. Our results may provide new insights for research in breast cancer-associated miRNAs.

Multimodel assessment of BRCA1 mutations in Taiwanese (ethnic Chinese) women with early-onset, bilateral or familial breast cancer.

Although evidence suggests an importance of genetic factors in the development of breast cancer in Taiwanese (ethnic Chinese) women, including a high incidence of early-onset and secondary contralateral breast cancer, a major breast cancer predisposition gene, BRCA1, has not been well studied in this population. In fact, the carcinogenic impacts of many genetic variants of BRCA1 are unknown and classified as variants of uncertain significance (VUS). It is therefore important to establish a method to characterize the BRCA1 VUSs and understand their role in Taiwanese breast cancer patients. Accordingly, we developed a multimodel assessment strategy consisting of a prescreening portion and a validated functional assay to study breast cancer patients with early-onset, bilateral or familial breast cancer. We found germ-line BRCA1 mutations in 11.1% of our cohort and identified one novel missense mutation, c.5191C>A. Two genetic variants were initially classified as VUSs (c.1155C>T and c.5191C>A). c.1155C>T is not predicted to be deleterious in the prescreening portion of our assessment strategy. c.5191C>A, on the other hand, causes p.T1691K, which is predicted to have high deleterious probability because of significant structural alteration, a high deleterious score in the predictive programs and, clinically, triple negative characteristics in breast tumors. This mutant is confirmed by transcription activation and yeast growth-inhibition assays. In conclusion, we show as high a prevalence of germ-line BRCA1 mutation in high-risk Taiwanese patients as in Caucasians and demonstrate a useful strategy for studying BRCA1 VUSs.

Activation of regulatory T cells instigates functional down-regulation of cytotoxic T lymphocytes in human breast cancer.

Regulatory T (Treg) cells are a subpopulation of T cells with the ability to control the responses of both CD4+ and CD8+ T cells. A case-control study was conducted in order to determine the functional attributes of Treg cells within the breast cancer milieu. Triple-color flow cytometry was utilized to study the phenotype expression of CD4+CD25+ Treg cells and CD8+ T cells in autologous tumor-infiltrating lymphocytes (TILs) and peripheral blood lymphocytes (PBLs) derived from 33 patients with stage I-III breast cancer. The prevalence of CD4+CD25+ T cells was significantly higher in TILs than in PBLs. The expressions of FOXP3 and GITR in CD4+CD25+ Treg cells were lower in PBLs than in TILs. Functional studies showed that both granzyme B and perforin were barely expressed in peripheral Treg cells but were highly expressed in Treg cells in the tumor microenvironment. On the contrary, down-regulation of both granzyme B and perforin expressed in the CD8+ cytotoxic T lymphocytes was significantly lower in TILs than in PBLs. Further functional assays demonstrated that Th1 cytokines and cytotoxic molecules were synchronously up-regulated in CD8+ cytotoxic T cells. The in vitro kinetic study showed that adequate activation of TILs derived from breast cancer tissue could restore the appropriate antitumor immune response.

Prediction of breast cancer and lymph node metastatic status with tumour markers using logistic regression models.

AIMS: Early detection of breast cancer can improve disease mortality. The aim of this study was to evaluate the effectiveness of serum biomarkers in the detection of primary breast cancer and lymph node metastatic status. METHODS: Serum samples were obtained from 55 female patients with breast cancer and 39 women without breast cancer. For these subjects, clinicopathological data were collected and serum levels of carcinoembryonic antigen, breast cancer-specific cancer antigen 15.3 (CA15-3), tissue polypeptide-specific antigen (TPS), soluble interleukin-2 receptor (sIL-2R) and insulin-like growth factor binding protein-3 (IGFBP-3) were assayed. Univariate and multivariate logistic regression were performed to evaluate the association between biomarkers and breast cancer, as well as lymph node metastatic status. RESULTS: For breast cancer prediction, the serum level of TPS had the best predictive value, with a sensitivity of 80% at an optimal cut-off value of 69.1 U L(-1). The combination of TPS, CA15-3 and IGFBP-3 with logistic regression model increased the sensitivity to 85%. For lymph node metastasis prediction, the serum level of sIL-2R had the best predictive value, with a sensitivity of 66% at an optimal cut-off value of 286 U mL(-1). The combination of sIL-2R and TPS with logistic regression model increased the sensitivity to 69%. CONCLUSION: TPS may be useful in the detection of primary breast cancer, while sIL-2R may be useful in lymph node metastasis prediction. The combination of more than one biomarker with logistic regression model can improve the predictive sensitivity.

Should adjuvant radiotherapy to the supraclavicular fossa be routinely given in patients with breast conservative treatment?

BACKGROUND: To analyze the overall outcome, supraclavicular fossa (SCF) recurrence rate, and pattern of failure in breast cancer patients treated with conservative surgery and adjuvant radiotherapy excluding SCF treatment. METHODS: A total of 143 patients were enrolled in the study. Ninety-two percent of patients were stages I and II, and 8% were stage III. The median age was 44 years, and 31% of patients were /= 4, and 0.8% in patients with N < 4. The 5-year SCF-recurrence-free survival in patients with N >/= 4 and N < 4 was 80% and 99%, respectively (P < 0.001). N >/= 4 was the only independent predictor for locoregional control (P = 0.045), disease-free survival (P = 0.001), and overall survival (P = 0.008) in multivariate analysis. CONCLUSIONS: Women with N >/= 4 have a significantly higher risk of SCF recurrence and poorer survival. The SCF might be safely spared in patients with N < 4, but should be routinely included in the radiotherapy design for those with N >/= 4.

Intraductal papillary carcinoma of bilateral breasts: a case report.

We report a 59-year-old woman presenting with a 2-month history of occasional bloody discharge from her right nipple and a palpable right breast mass on self-examination. The mammography revealed heterogeneously dense fibroglandular stromas of bilateral breasts, a lobulated mass in her right breast associated with faint pleomorphic microcalcifications, and, in addition, very faint focal granular microcalcifications in the left breast. Breast ultrasound revealed a lobulated and heterogeneous hypoechoic tumor with irregular margins at the right breast and a well-circumscribed tumor with heterogeneous echotexture at the left breast.

Quality of life of breast cancer patients in Taiwan: validation of the Taiwan Chinese version of the EORTC QLQ-C30 and EORTC QLQ-BR23.

The objective of this study was to test the reliability and validity of the Taiwan Chinese version of the EORTC QLQ-C30 (version 3) and EORTC QLQ-BR23. The authors followed the guidelines of translation and pilot testing of the questionnaires. The questionnaires were given to 35 breast cancer patients under active treatment and 54 under follow-up at the National Taiwan University Hospital from November 2000 to October 2001. A retest was conducted one to two weeks after the first interview/form completion for the follow-up group. The intraclass correlation coefficients of the two questionnaires were moderate to high in the follow-up group. The Cronbach's alpha coefficients of most scales of the two questionnaires were > or = 0.70 except that of physical functioning (0.68), cognitive functioning (0.53), and arm symptoms (0.59). Correlations of scales measuring similar dimensions of the EORTC QLQ-C30 and the SF-36 were moderate. Patients in the active treatment group had more serious QOL problems due to disease and treatment. Results of this study showed that the Taiwan Chinese version of the two questionnaires had good test/retest reliability, high internal consistency in most scales, and could show the expected differences between patients in active chemotherapy and follow-up group.