Yi-Fang Liu

PURPOSE: Multiphoton-based intravital imaging has shown that invasive carcinoma cells in mouse and rat mammary tumors intravasate when associated with perivascular macrophages, identifying a potential tumor microenvironment of metastasis (TMEM). We define TMEM as the tripartite arrangement of an invasive carcinoma cell, a macrophage, and an endothelial cell. The aim of this study was to determine if TMEM density in human breast carcinoma samples predicts the development of systemic, hematogenous metastases. EXPERIMENTAL DESIGN: A case-control study of 30 patients who developed metastatic breast cancer and 30 patients without metastatic disease was done. Cases were matched to controls based on currently used prognostic criteria. Paraffin-embedded primary breast cancer samples were stained using a triple immunohistochemical method allowing simultaneous identification of carcinoma cells, macrophages, and endothelial cells. Two pathologists, blinded to outcome, evaluated the number of TMEM per 20 high-power fields. RESULTS: No association was seen between TMEM density and tumor size or grade, lymph node metastasis, lymphovascular invasion, or hormone receptor status. TMEM density was greater in the group of patients who developed systemic metastases compared with the patients with only localized breast cancer (median, 105 versus 50, respectively; P = 0.00006). For every 10-unit increase in TMEM density, the odds ratio for systemic metastasis was 1.9 (95% confidence interval, 1.1-3.4). CONCLUSIONS: TMEM density predicted the development of systemic, hematogenous metastases. The ability of TMEM to predict distant metastasis was independent of lymph node status and other currently used prognosticators. Quantitation of TMEM may be a useful new prognostic marker for breast cancer patients.

Progressive iron overload is the most salient and ultimately fatal complication of beta-thalassemia. However, little is known about the relationship among ineffective erythropoiesis (IE), the role of iron-regulatory genes, and tissue iron distribution in beta-thalassemia. We analyzed tissue iron content and iron-regulatory gene expression in the liver, duodenum, spleen, bone marrow, kidney, and heart of mice up to 1 year old that exhibit levels of iron overload and anemia consistent with both beta-thalassemia intermedia (th3/+) and major (th3/th3). Here we show, for the first time, that tissue and cellular iron distribution are abnormal and different in th3/+ and th3/th3 mice, and that transfusion therapy can rescue mice affected by beta-thalassemia major and modify both the absorption and distribution of iron. Our study reveals that the degree of IE dictates tissue iron distribution and that IE and iron content regulate hepcidin (Hamp1) and other iron-regulatory genes such as Hfe and Cebpa. In young th3/+ and th3/th3 mice, low Hamp1 levels are responsible for increased iron absorption. However, in 1-year-old th3/+ animals, Hamp1 levels rise and it is rather the increase of ferroportin (Fpn1) that sustains iron accumulation, thus revealing a fundamental role of this iron transporter in the iron overload of beta-thalassemia.

This study was conducted to investigate the prevalence and characteristics of ertapenem-resistant (ETP-R) Klebsiella pneumoniae isolates at a Taiwanese hospital. The disk-diffusion tests revealed that the rate of ertapenem resistance among all isolates collected in 2008 was 13.5%, and the resistance rate among bloodstream isolates increased from 0% to 13.6% between 2001 and 2008. Eighty-two nonduplicate ETP-R isolates collected in 2008 were examined. Seventy-four (90.2%) isolates of them had extended-spectrum β-lactamases (CTX-M- and SHV-type), AmpC enzymes (DHA-1 and CMY-2), and IMP-8 metallo-β-lactamase alone or in combination, and an extremely high prevalence of fluoroquinolone resistance (95.1%) and plasmid-mediated quinolone resistance determinants (90.2%) were also observed. Eighteen ETP-R but imipenem-susceptible isolates were selected and compared with 18 imipenem-nonsusceptible isolates collected before 2008. Sequence analyses revealed genetic disruptions of OmpK36 in 11 imipenem-nonsusceptible and 6 imipenem-susceptible isolates, respectively, and OmpK35 disruptions in 10 isolates for both groups. For the isolates with intact ompK36, sodium dodecyl sulfate-polyacrylamide gel electrophoresis suggests decreased expression of OmpK36 in 5 of 7 imipenem-nonsusceptible isolates and 3 of 12 imipenem-susceptible isolates. In conclusion, the increasing prevalence of ertapenem resistance that was predominantly attributed to noncarbapenemase-mediated resistance mechanisms in K. pneumoniae is becoming a serious treat to patients in Taiwan.

Although metastasis is a major cause of death from breast cancer, our ability to predict which tumors will metastasize is limited (American Cancer Society 2010). Proper assessment of metastatic risk and elucidating the underlying mechanisms of metastasis will help personalize therapy and may provide insight into potential therapeutic targets. Traditionally, histologic grading, staging, hormone receptors, HER2/Neu, and proliferation assays have been the gold standard on which oncologists based their treatment decisions. However, all of these are indirect measures of metastatic risk. Recent insights from intravital imaging directly address questions of mechanism and have led to a new way of using histologic and cytologic material to assess metastatic risk. This review describes the tumor microenvironment model of invasion and intravasation, as well as an emerging histopathologic application based on this model. In particular, the authors describe a new immunohistochemical approach to the assessment of metastatic risk based on the density of intravasation microenvironment sites called the tumor microenvironment of metastasis. In addition, they describe an isoform assay for the actin regulatory protein Mena using fine needle aspiration samples and the details about how these 2 assays may be applied in clinical practice in a synergistic way to assess the risk of metastasis.