90例乳腺良性病变组织中ER和PR的表达

应用免疫组化方法对９０例良性乳腺病变组织进行ＥＲ、ＰＲ的检测。结果，ＥＲ阳性率为８４．４％，ＰＲ为８３．３％，与同期乳腺癌的ＥＲ和ＰＲ阳性率比较有非常显著性意义，ＥＲ阳性以纤维腺瘤，导管内乳头状瘤，囊性乳腺增生症最为常见，小叶内增生ＥＲ阳性相对减少，同时对乳腺组织间质存在前背景染色问题加以讨论。     

B cell epitope specificity in ANCA‐associated vasculitis: does it matter?

Pauci‐immune idiopathic small‐vessel vasculitis is strongly associated with the presence of antineutrophil cytoplasm autoantibodies (ANCA). Antibodies to PR3 predominate in patients with Wegener's granulomatosis; antibodies to myeloperoxidase (MPO) are found more frequently in patients with microscopic polyangiitis. There is increasing in vivo and in vitro evidence for a pathogenic role of ANCA in systemic vasculitis based on associations of ANCA with disease activity. If ANCA are pathogenic, why is the course of disease different from one patient to another? Antibodies can recognize different binding sites (epitopes) on their corresponding antigens. Differences in binding specificity may influence the pathogenic potential of the antibodies. Differences between epitope specificity of ANCA between patients or changes in epitope specificity of ANCA in time in an individual patient may, accordingly, result in differences in disease expression. This review will focus on epitope specificity of autoantibodies in systemic autoimmune diseases and especially on the epitope specificity of PR3– and MPO–ANCA. We will discuss whether PR3–ANCA or MPO–ANCA recognize different epitopes on PR3 and MPO, respectively, and whether the epitopes recognized by ANCA change in parallel with the disease activity of ANCA‐associated vasculitis. Finally, we will speculate if the direct pathogenic role of ANCA can be ascribed to one relapse‐ or disease‐inducing epitope. Characterization of relapse‐ or disease‐inducing epitopes bound by PR3–ANCA and MPO–ANCA is significant for understanding initiation and reactivation of ANCA‐associated vasculitis. Elucidating a disease‐inducing epitope bound by ANCA may lead to the development of epitope‐specific therapeutic strategies.     

Estrogen receptor (ER), progesterone receptor (PR), and HER2 expression pre- and post- neoadjuvant chemotherapy in primary breast carcinoma: a single institutional experience

Background

The estrogen receptor (ER), progesterone receptor (PR), and HER2 profile of a primary breast carcinoma plays a significant role in patient management and treatment. Because of the increasing utilization of neoadjuvant chemotherapy or hormone therapy, surgically-resected carcinomas often show marked treatment effect. The aim of this study was to compare immunohistochemical (IHC) profiles (ER, PR, HER2, HER2 FISH) of primary breast carcinomas before and after neoadjuvant chemotherapy to assess the subsequent effects on hormone receptor status.

Design

Primary breast carcinomas from 38 female patients treated with neoadjuvant therapy after needle core biopsy or fine needle aspiration diagnosis were included. Histologic data was collected for each case, including site, type, grade, tumor size (cm), pre- and post- neoadjuvant treatment IHC panel (ER, PR, HER2), and fluorescence in-situ hybridization (FISH) for HER2.

Results

Of the 38 carcinomas studied, 45 % were positive for ER by IHC both pre- and post- neoadjuvant treatment (P=1.00). IHC studies for PR in these 38 patients showed 37% positivity for PR pre-neoadjuvant therapy and 21% positivity post-treatment (p=0.03). For 37 patients with HER2 IHC, 32% were positive pre-treatment, and 22% were positive post-treatment (P = 0.20). For 7 patients, HER2 FISH was positive in 71% pre-therapy and in 57% post-treatment (P=0.32).

Conclusions

Profiles for ER, HER2 IHC, and HER2 FISH were not significantly different in primary breast carcinomas before and after neoadjuvant chemotherapy. Further investigation is warranted to assess reproducibility of technique and investigate clinical implications of significant loss of PR status in treated patients.     

The Influence of Different Cultivating Conditions on Polymorphonuclear Leukocyte Apoptotic Process In Vitro,II: Ultrastructural Characteristics of PMN Populations Incubated with Proteinase 3 Anti-neutrophil Autoantibodies

The present study shows the effects of proteinase 3 anti-neutrophil cytoplasmic autoantibodies (PR3 ANCA) on polymorphonuclear leukocytes (PMN) apoptotic processes in vitro. The results are part of a generalized morphological analysis of 3 identical experiments on the influence of different cultivating conditions on the apoptotic processes. As controls, the authors use the results on spontaneous PMN apoptosis (Guejes L, Zurgil N, Deutsch M, Gilburd B, Shoenfeld Y. Ultrastruct Pathol. 2003;27:23–32) and PMN populations incubated with normal human IgG. Interaction of PR3 ANCA with the target antigen proteinase 3 (PR3) is one of the crucial pathogenic factors in Wegener granulomatosis (systemic autoimmune vasculitis). Following 40 min and 12 h incubation, PMN populations were evaluated by light microscopy, transmission electron microscopy, and immunogold electron microscopy. Twelve-hour cultures, either control or incubated with PR3 ANCA, contained different cell forms ranging from normal cells to cells at the final stages of apoptosis. Neutrophils at the state of complete manifestation of apoptotic phenotype were analyzed and compared. Three morphologically distinct apoptotic cell lines were characteristic for all PMN populations studied, regardless of cultivating conditions. As in spontaneous apoptosis, these cell lines are code-named “first,” “second,” and “third.” The present study has shown, firstly, that in the presence of PR3 ANCA, all 3 apoptotic lines were modified or altered. Secondly, the modifications or alterations of apoptotic cell lines effected by PR3 ANCA are specific for each cell line: the “first” line is characterized by intensification and modification of activation; the “second” by vacuolized cell forms; and the “third” by pronounced lytic alterations of the nuclei, while the cytoplasm is fully identical to that of control cell lines.     

Dysregulation of the epigenome in triple-negative breast cancers: Basal-like and claudin-low breast cancers express aberrant DNA hypermethylation

A subset of human breast cancer cell lines exhibits aberrant DNA hypermethylation that is characterized by hyperactivity of the DNA methyltransferase enzymes, overexpression of DNMT3b, and concurrent methylation-dependent silencing of numerous epigenetic biomarker genes. The objective of this study was to determine if this aberrant DNA hypermethylation (i) is found in primary breast cancers, (ii) is associated with specific breast cancer molecular subtypes, and (iii) influences patient outcomes. Analysis of epigenetic biomarker genes (CDH1, CEACAM6, CST6, ESR1, GNA11, MUC1, MYB, SCNN1A, and TFF3) identified a gene expression signature characterized by reduced expression levels or loss of expression among a cohort of primary breast cancers. The breast cancers that express this gene expression signature are enriched for triple-negative subtypes — basal-like and claudin-low breast cancers. Methylation analysis of primary breast cancers showed extensive promoter hypermethylation of epigenetic biomarker genes among triple-negative breast cancers, compared to other breast cancer subclasses where promoter hypermethylation events were less frequent. Furthermore, triple-negative breast cancers either did not express or expressed significantly reduced levels of protein corresponding to methylation-sensitive biomarker gene products. Together, these findings suggest strongly that loss of epigenetic biomarker gene expression is frequently associated with gene promoter hypermethylation events. We propose that aberrant DNA hypermethylation is a common characteristic of triple-negative breast cancers and may represent a fundamental biological property of basal-like and claudin-low breast cancers. Kaplan–Meier analysis of relapse-free survival revealed a survival disadvantage for patients with breast cancers that exhibit aberrant DNA hypermethylation. Identification of this distinguishing trait among triple-negative breast cancers forms the basis for development of new rational therapies that target the epigenome in patients with basal-like and claudin-low breast cancers.     

Platelet reactivity evaluated with the VASP assay following ticagrelor loading dose in acute coronary syndrome patients undergoing percutaneous coronary intervention

Background

The level of platelet reactivity (PR) inhibition obtained after P2Y12-ADP receptor antagonist loading dose (LD) is associated with the ischemic and bleeding risk following percutaneous coronary intervention (PCI) in acute coronary syndromes (ACS).

Objective

We aimed to evaluate the level of PR inhibition achieved by a 180 mg LD of ticagrelor and the rate of high on-treatment platelet reactivity (HTPR) in ACS patients undergoing PCI.

Methods

We performed a multicentre prospective observational study enrolling ACS patients undergoing PCI. Patients were included if they were admitted for ST-elevation myocardial infarction or non ST-elevation ACS. To assess PR, a VASP index was measured at least 6 and within 24 hours following a 180 mg LD of ticagrelor. HTPR was defined as a VASP index ≥ 50%.

Results

One hundred and fifteen patients were included: 31.3% of STEMI, 49.6% of NSTEMI and 19.1% of unstable angina. Following ticagrelor LD the mean VASP index was 17 ± 14%. However the response to ticagrelor was not uniform with a small inter-individual variability: inter quartile range: 7.6–22.8% and a rate of HTPR of 3.5%. A high number of patients, 65.6%, had a VASP index < 16%. None of the baseline characteristics of the study population was associated with PR. In addition, PR was similar in STEMI, NSTEMI and unstable angina (p = 0.9).

Conclusion

In ACS patients the level of PR inhibition achieved by a 180 mg loading dose of ticagrelor is not uniform and the rate of HTPR is 3.5%. A high proportion of patients exhibited a VASP index < 16%.     

Improved spectral selectivity and reduced susceptibility in SSFP using a near zero TE undersampled three-dimensional PR sequence

PURPOSE: To improve the performance of fat/water separation and reduce the sensitivity to susceptibility variation in balanced SSFP sequences. MATERIALS AND METHODS: Decreasing the repetition time (TR) reduces susceptibility artifacts in SSFP imaging. A shorter TR may also improve the spectral selectivity obtained when linearly combining data acquired using different radiofrequency phase cycling schedules. The desired short TR is achieved by using an angularly undersampled three-dimensional radial acquisition sequence that achieves a near zero echo time (TE) and also a short TR. RESULTS: Images from human volunteers demonstrate broad coverage of the cervical spine and knee with isotropic resolution. Excellent fat/water separation is achieved in these studies. CONCLUSION: The short TR capability of the proposed sequence greatly improves the fat suppression in SSFP imaging. High-resolution volumetric T2-like contrast imaged with reduced susceptibility artifacts can be obtained from a single acquisition using this technique.     

Adaptive bilateral breast MRI using projection reconstruction time-resolved imaging of contrast kinetics

PURPOSE: To introduce a bilateral implementation of an adaptive imaging technique in which both dynamic and high resolution breast MR images are acquired simultaneously. MATERIALS AND METHODS: Adaptive three-dimensional bilateral breast imaging in the sagittal plane was achieved by combining two elements: a projection reconstruction time-resolved imaging of contrast kinetics (PR-TRICKS) k-space trajectory and a slab interleaved sequence that imaged alternate breasts every TR. A pilot study was performed to evaluate image quality and contrast uptake behavior, using eight patients with previously identified benign lesions. RESULTS: Adaptive reconstruction demonstrated breast lesions in all eight women with similar image quality and signal-to-noise ratio (SNR) to Cartesian images with comparable imaging parameters. Contrast enhancement curves covering the entire postinjection time period were obtained from the dynamic images and in one case compared to previous enhancement profiles from a conventional Cartesian trajectory. CONCLUSION: Bilateral dynamic and high spatial resolution images with high SNR can be achieved in a clinically feasible manner, providing both kinetic and morphologic analysis with a single data set. This may obviate the need for multiple MRI examinations for a thorough breast MRI workup.     

Cine magnetic resonance microscopy of the rat heart using cardiorespiratory-synchronous projection reconstruction

PURPOSE: To tailor a cardiac magnetic resonance (MR) microscopy technique for the rat that combines improvements in pulse sequence design and physiologic control to acquire high-resolution images of cardiac structure and function. MATERIALS AND METHODS: Projection reconstruction (PR) was compared to conventional Cartesian techniques in point-spread function simulations and experimental studies to evaluate its artifact sensitivity. Female Sprague-Dawley rats were imaged at 2.0 T using PR with direct encoding of the free induction decay. Specialized physiologic support and monitoring equipment ensured consistency of biological motion and permitted synchronization of imaging with the cardiac and respiratory cycles. RESULTS: The reduced artifact sensitivity of PR offered improved delineation of cardiac and pulmonary structures. Ventilatory synchronization further increased the signal-to-noise ratio by reducing inter-view variability. High-quality short-axis and long-axis cine images of the rat heart were acquired with 10-msec temporal resolution and microscopic spatial resolution down to 175 microm x 175 microm x 1 mm. CONCLUSION: Integrating careful biological control with an optimized pulse sequence significantly limits both the source and impact of image artifacts. This work represents a novel integration of techniques designed to support measurement of cardiac morphology and function in rodent models of cardiovascular disease.