乳腺微钙化促进乳腺癌骨转移的研究进展

乳腺癌是女性发病率最高的癌症,在过去的十年中,全球发病率持续上升,死亡率高居不下.最新的统计学研究表明,仅2018年,全球范围内检测出约210万乳腺癌病例,其中近63万患者死亡,因而也是女性死亡率最高的癌症[1].然而,许多癌症患者的死亡并非由于肿瘤在原发部位生长,而是在于肿瘤侵袭或转移至其他部位,其中乳腺癌最容易发生...     

Focal fibrous disease of breast

Summary The study concerns a problem of practical importance in the daily routine work. 218 cases of focal fibrous disease of the breast were classified into three types with conventional methods of pathohistology and statistics. The peak incidence between 20 and 25 years is considerably lower than the incidence figures reported by other authors. The authors postulate the progressive evolutive nature of the lesion.     

Improvement of microcalcification cluster detection in mammography utilizing image enhancement techniques

In this work, the effect of an image enhancement processing stage and the parameter tuning of a computer-aided detection (CAD) system for the detection of microcalcifications in mammograms is assessed. Five (5) image enhancement algorithms were tested introducing the contrast-limited adaptive histogram equalization (CLAHE), the local range modification (LRM) and the redundant discrete wavelet (RDW) linear stretching and shrinkage algorithms. CAD tuning optimization was targeted to the percentage of the most contrasted pixels and the size of the minimum detectable object which could satisfactorily represent a microcalcification. The highest performance in two mammographic datasets, were achieved for LRM (A_Z=0.932) and the wavelet-based linear stretching (A_Z=0.926) methodology.     

Bisphosphonate-functionalized gold nanoparticles for contrast-enhanced X-ray detection of breast microcalcifications

Microcalcifications are one of the most common abnormalities detected by mammography for the diagnosis of breast cancer. However, the detection of microcalcifications and correct diagnosis of breast cancer are limited by the sensitivity and specificity of mammography. Therefore, the objective of this study was to investigate the potential of bisphosphonate-functionalized gold nanoparticles (BP-Au NPs) for contrast-enhanced radiographic detection of breast microcalcifications using two models of breast microcalcifications, which allowed for precise control over levels of hydroxyapatite (HA) mineral within a low attenuating matrix. First, an in vitro imaging phantom was prepared with varying concentrations of HA uniformly dispersed in an agarose hydrogel. The X-ray attenuation of HA-agarose compositions labeled by BP-Au NPs was increased by up to 26 HU compared to unlabeled compositions for HA concentrations ranging from 1 to 10 mg/mL. Second, an ex vivo tissue model was developed to more closely mimic the heterogeneity of breast tissue by injecting varying concentrations of HA in a Matrigel carrier into murine mammary glands. The X-ray attenuation of HA-Matrigel compositions labeled by BP-Au NPs was increased by up to 289 HU compared to unlabeled compositions for HA concentrations ranging from 0.5 to 25 mg/mL, which included an HA concentration (0.5 mg/mL) that was otherwise undetectable by micro-computed tomography. Cumulatively, both models demonstrated the ability of BP-Au NPs to enhance contrast for radiographic detection of microcalcifications, including at a clinically-relevant imaging resolution. Therefore, BP-Au NPs may have potential to improve clinical detection of breast microcalcifications by mammography.     

Molecular study of clonality in multifocal and bilateral breast tumors

The clonal origin of multiple tumors in the same individual has long been debated. The main aim of this study is to find out whether multiple tumors in same individuals originated from a single clone. In our previous work (Pathol. Res. Pract. 199 (2003) 313-321), the deletion at chromosome1p36 was found to occur early because of common allelic loss in the bilateral tumors. In order to further investigate the findings about the clonality of tumors, eight tumors from four patients (two synchronous bilateral breast carcinoma [biBC], one case with breast carcinoma in one breast and multiple calcified fibroadenoma nodules in another breast, and one case with multifocal fibroadenosis in one breast) were subjected to polymerase chain reaction (PCR) to detect (a) loss of heterozygosity (LOH) and microsatellite size alterations (MA) using microsatellite markers distributed over five chromosomal arms 11p/q, 13q and 17p/q, and (b) Cyclin D1 amplification. Some markers were intragenic for BRCA1, BRCA2, BRCAX, ATM, TP53, and RB1. Although a few cases were studied, our findings suggest that in at least a proportion of patients multiple tumors may arise from a single clone.     

Methylation-dependent silencing of CST6 in primary human breast tumors and metastatic lesions

CST6 is a breast tumor suppressor gene that is expressed in normal breast epithelium, but is epigenetically silenced as a consequence of promoter hypermethylation in metastatic breast cancer cell lines. In the current study, we investigated the expression and methylation status of CST6 in primary breast tumors and lymph node metastases. 25/45 (56%) primary tumors and 17/20 (85%) lymph node metastases expressed significantly lower levels of cystatin M compared to normal breast tissue. Bisulfite sequencing demonstrated CST6 promoter hypermethylation in 11/23 (48%) neoplastic lesions analyzed, including 3/11 (27%) primary tumors and 8/12 (67%) lymph node metastases. In most cases (12/23, 52%), the expression of cystatin M directly reflected CST6 promoter methylation status. In remaining lesions (8/23, 35%) loss of cystatin M was not associated with CST6 promoter hypermethylation, indicating that other mechanisms can account for loss of CST6 expression. These results show that methylation-dependent silencing of CST6 occurs in a subset of primary breast cancers, but more frequently in metastatic lesions, possibly reflecting progression-related genomic events. To examine this possibility, primary breast tumors and matched lymph node metastases were analyzed. In 2/3 (67%) patients, primary tumors were positive for cystatin M and negative for CST6 promoter methylation, and matched metastatic lesions lacked cystatin M expression and CST6 was hypermethylated. This observation suggests that progression-related epigenetic alterations in CST6 gene expression can accompany metastatic spread from a primary tumor site. Overall, the results of the current investigation suggest that methylation-dependent epigenetic silencing of CST6 represents an important mechanism for loss of CST6 during breast tumorigenesis and/or progression to metastasis.     

Lower frequency of allele loss on chromosome 18q in human breast cancer than in colorectal tumors

Inactivation of tumor suppressor genes is thought to be a critical step in tumorigenesis. TheDCC (deleted in colorectal carcinoma) gene, located on the long arm of chromosome 18, has been shown to be frequently deleted in colorectal tumors. To investigate the involvement of allelic deletions on chromosome 18q in breast cancer tumorigenesis we analyzed 28 primary breast tumors and 28 colorectal, tumors (24 carcinomas, 4 adenomas) with four different polymorphic DNA markers detecting RFLPs on chromosome 18q. In breast cancer we found loss of heterozygosity (LOH) in 4 of 27 (15%) informative cases whereas 15 of 25 (60%) colorectal tumors showed allelic deletions. In all cases of allelic loss theDCC locus or its proximal vicinity (locus SSAV1) were involved. LOH on chromosome 18q occurs both in breast and colorectal cancer, yet the frequency of these deletions in breast tumors is lower than in colorectal tumors. Moreover, in breast cancer these mutations were only detected in large and undifferentiated tumors.Abbreviations LOH Loss of heterozygosity     

基于空-频域差值与超分辨率反馈网络的乳腺微钙化区域检测技术

【摘要】乳腺癌的早期症状在乳腺钼靶图像中主要表现为微钙化点,微钙化区域的真假阳性检测对于乳腺癌早期筛查具有重要意义。首先,对DDSM乳腺数据集中的图像进行预处理,去除噪声及无关组织干扰;其次,基于空-频域差值图像技术实现了疑似微钙化点的分割,取得的敏感性为91.00%,但假阳性率也较高（34.00%）,并根据疑似点的质心位置自动截取感兴趣区域;然后,通过超分辨率反馈网络算法进行微钙化区域超分辨率重建;最后,提取感兴趣区域的纹理特征,将Gentle AdaBoost算法和单层决策树算法相结合,构建强分类器GAB-DS对区域进行分类,将微钙化区域和正常组织分离开来,GAB-DS分类模型取得了96.25%的准确率、94.38%的敏感性以及98.13%的特异性。实验结果表明,该模型在微钙化区域检测上性能优越,可用于辅助临床乳腺癌检测及诊断,具有一定的临床应用价值。     

A computer model for the study of breast cancer

A computer model was designed as a relational database to assess breast cancer screening in a cohort of women where the growth and development of breast cancer originates with the first malignant cell. The concepts of thresholds for growth, axillary spread, and distant sites are integrated. With tumor diagnosis, staging was performed that includes clinical and sub-clinical states. The model was parameterized to have staging characteristics similar to data published by the Surveillance, Epidemiology, and End-Results (SEER) Program. Validation was accomplished by comparing simulated staging results with non-SEER sources, and simulated survival with independent clinical survival data.     

高频彩色多普勒超声及钼靶X线检查对早期乳腺癌的诊断价值

目的：评价高频彩色多普勒超声及钼靶X线检查对早期乳腺癌的诊断价值。方法回顾分析经手术病理证实的106例早期乳腺癌患者资料,术前均经高频彩色多普勒超声及钼靶X线检查,对单独使用和联合使用2种检查方法对早期乳腺癌的诊断准确率进行统计分析。结果高频彩色多普勒超声与钼靶X线检查对早期乳腺癌的诊断准确率差异无统计学意义（P〉0.05）;高频彩色多普勒超声、钼靶X线检查对早期乳腺癌的诊断准确率均低于2种方法联合应用,差异均有统计学意义（P值均〈0.05）。结论高频彩色多普勒超声与钼靶X线均为筛查和诊断早期乳腺癌的主要手段,两者联合应用可提高早期乳腺癌的诊断率。     

Evaluation of prognostic factors in stage IIA breast tumors and their correlation with mortality risk

ABSTRACT:

Breast tumors exhibit extensive molecular and clinical heterogeneity. One of the most utilized breast carcinoma classifications is based on its molecular aspects and subdivides breast cancer into five major groups based on the expression of certain genes. In this study, we evaluated which factors are important in determining a prognosis after 5 years of follow-up for patients with clinical stage IIA breast tumors. We took into consideration the different phenotypes (luminal A luminal B HER-2 overexpression, basal and triple-negative), various epithelial-mesenchymal (EMT) molecular markers and adhesion molecules (E-cadherin, P-cadherin, N-cadherin, vimentin, twist snail and slug) and NOS-2, in addition to clinical and demographic data, tumor characteristics and treatment types.

METHODS:

The study population consisted of 82 patients with breast cancer. We analyzed eight molecular markers by immunohistochemistry on tissue microarrays containing breast tumor specimens from patients with ten years of follow-up, and we classified each tumor according to its estrogen receptor, progesterone receptor and HER-2 expression. We then placed the tumor into one of the above categories.

RESULTS:

The presence of several clinical and demographic factors, various histopathologies, treatment forms and several immunohistochemical markers were not associated with a worse prognosis for group IIA patients. The factors that were associated with a mortality risk were the triple-negative (odds ratio (OR) = 11.8, 95% confident interval (CI) = 2.0-70.3, P = 0.007) and basal (OR = 18.4, 95% CI = 1.8-184.7, P = 0.013) phenotypic patterns.

CONCLUSIONS:

The EMT markers and NOS-2 were not mortality risk factors. Basal and triple-negative phenotypic patterns were related to a higher mortality risk in patients with stage IIA tumors.     

Vascular tumors in the region of the breast

Summary Three vascular tumors in the breast region with different degrees of differentiation are presented. The first neoplasm is a haemangiosarcoma (of the vascular neoplasms, these tumors are the type which occur most frequently in the breast). Haemangiosarcomas show an infiltrative growth of atypical blood capillaries, frequently with formation of highly cellular and solid capillary sprouts. Ultrastructurally, the tumor cells are characterized as endothelial, also in the region of the capillary sprouts. The second tumor (an angiosarcoma in Stewart-Treves-syndrome, STS) is characterized by an intensive endothelial proliferation. Solid spindle-celled regions are also found in which the tumor cells correspond to undifferentiated mesenchymal cells, but other cells possessing properties of smooth muscle cells and pericytes may be found.The third tumor corresponds light and electron microscopically to a haemangiopericytoma of the soft tissue. The pericytic character of the tumor cells is most clearly seen in the immediate vicinity of the vessels. With increasing distance from the capillaries, the tumor cells take on the characteristics of fibroblasts. The tumors reflect the diversity of the angioplastic differentiation potential of the mesenchyme.     

Androgen receptor expression in archival human breast tumors

Hormone receptors play a major role in growth and hormonal therapy of breast and prostate tumors. Quantitative results from the ligand binding assays cannot determine heterogeneity in receptor expression nor can they discriminate between expression of the stromal and the tumor cells. Availability of antibodies to hormone receptors has led to the development of immunohistochemistry as a standard method for monitoring of hormone receptor expression under a microscope. However, this method is based on examination of a small number of cells. Laser flow cytometry has been extensively used for monitoring of receptor expression in human liquid tumors. As most of the hormone receptor expression is nuclear, we have developed methods for flow cytometric analysis of receptor expression in nuclei isolated from enzyme treated paraffin sections. The present report based on gated analysis of androgen receptor expression in nuclei isolated from archival formalin fixed/paraffin embedded breast tumors shows that receptor expression in aneuploid sub-populations is greater than that of the diploid cells.     

Clinicopathological significance of ERCC1 expression in breast cancer

The excision repair cross-complementation 1 (ERCC1) enzyme plays an essential role in the nucleotide excision repair pathway and is associated with resistance to platinum-based chemotherapy in different types of cancer. The aim of the present study was to evaluate the clinicopathological significance of ERCC1 expression in breast cancer patients. We analyzed the immunohistochemical expression of ERCC1 in a tissue microarray from 135 primary breast carcinomas and correlated the immunohistochemical findings with clinicopathological factors and outcome data. ERCC1 expression analysis was available for 109 cases. In this group, 58 (53.2%) were positive for ERCC1. ERCC1-positive expression was correlated with smaller tumor size (P = 0.007) and with positivity for estrogen receptor (P = 0.040), but no correlation was found with other clinicopathological features. Although not statistically significant, triple negative breast cancers were more frequently negative for ERCC1 (61.5% of the cases) compared to the non-triple negative breast cancer cases (41.5%). In conclusion, ERCC1 expression correlated significantly with favorable prognostic factors, such as smaller tumor size and ER-positivity, suggesting a possible role for ERCC1 as a predictive and/or prognostic marker in breast cancer.     

外侧组织瓣转移用于保留乳房的乳癌根治术

目的 探讨乳腺癌根治手术的同时进行乳房成形的术式及其临床意义。方法 自1997年至2002年对20例早期原发乳腺癌进行乳房成形的根治术。结果 20例手术均获成功,切口均甲级愈合,无乳头坏死。其中10例患者术后2年以上随访,均无肿瘤局部复发及转移。与不保留乳房的根治手术相比肿瘤的复发和生存差异无显著性。乳房成形根治术按lino Y美观标准评价,优15例,良5例。结论 随着医学模式的改进,对乳腺癌手术治疗原则已经转为由大到小的趋势,在充分切除原发癌的前提下,尽量采用破坏性较小的术式,重视保留乳房的美学理念。应用外侧软组织瓣(lateral tissue flap,LTF)乳房成形,显示出良好临床效果和使用价值。     

Nutrition and breast cancer

Breast cancer incidence is rising worldwide with an increase in aggressive neoplasias in young women. Suspected factors responsible for the global increase include lifestyle changes, notably diet. Currently accepted risk factors directly linked to diet are greater body weight and alcohol consumption. Weight gain in adulthood is associated with increased risk of breast cancer in post-menopausal women, suggesting that weight gain before and around menopausal age may be determinant for breast cancer development among postmenopausal women. Numerous studies also show an impact of specific diets and nutrients – fatty acids, carbohydrates, vitamins B, D, carotenoids, phytoestrogens, fiber – on breast cancer risk, and evidence supports a mechanistic basis for an influence of specific nutrients. However, these studies are plagued with conflicting results. In this review, a new examination of the relationship between nutrition and breast cancer is proposed in light of recent epidemiological studies. Successful development of breast cancer prevention strategies will require identification of biological markers of dietary exposure, and to coordinate worldwide research to discern the effects of diet.     

HPD overexpression predicts poor prognosis in breast cancer

BackgroundThe enzyme, 4-hydroxyphenylpyruvate dioxygenase (HPD), is critical to tyrosine metabolism; its deficiency can cause tyrosinemia. However, its precise contribution to tumorigenesis is unclear. Here, we investigated the correlation between HPD expression and prognosis in patients with breast cancer.Methods145 breast cancer specimens were selected to analyze HPD protein expression by immunohistochemistry and evaluate its relationship to patients’ clinicopathological features. HPD localization was confirmed in MCF-7 and MDA-MB-231 breast cancer cells, using immunofluorescence staining. The expression of HPD protein was detected in breast cancer and cancer-adjacent normal tissues using Western blot analysis. Survival rates were calculated by the Kaplan–Meier method.ResultsWe found that HPD protein was mainly located in the cytoplasm/nucleoli/perinucleus in breast cancer cells, as shown by immunofluorescence staining in MCF-7 and MDA-MB-231 cells, and immunohistochemistry in breast cancer and adjacent normal tissues (HPD protein expression—breast cancer: 46.9% [68/145], ductal carcinoma in situ [DCIS]: 22.6% [12/53], and normal tissues: only 4.8% [2/42]). Similarly, the Western blot results further confirmed the increased expression of HPD in breast cancer compared with cancer-adjacent normal tissues (P < 0.05). HPD expression level was positively correlated with histological grade and clinical stage, and inversely correlated with 10-year overall survival (OS) rates, in patients with breast cancer. Among patients with breast cancer, those with high HPD expression had worse OS rates than those with low HPD expression. Additionally, when patients were subgrouped by disease stage or grade, those with high HPD expression had worse OS rates than those with low HPD expression for each respective stage or grade.ConclusionsOur findings indicate that HPD may be a useful prognostic predictor, and a potential therapeutic target for patients with breast cancer.