A growing body of work has shown that cancer metastasis is not a random spontaneous event; rather, it is the culmination of a cascade of priming steps through which a subpopulation of the tumor cells acquires invasive traits while readying a permissive environment, termed the "premetastatic niche," in which distant metastases can occur. Signals from the primary tumor mobilize and adapt immune cells as well as directly communicating with distant niche cells to induce a broad spectrum of adaptations in target organs, including the induction of angiogenesis, inflammation, extracellular matrix remodeling, and metabolic reprogramming. Together, these interactions facilitate the formation of a premetastatic niche composed of a variable mix of resident and recruited immune cells, endothelial cells, and stromal cells connected through a complex signaling network that we are only beginning to understand. Here, we summarize the latest findings on how cancer induces and guides the formation of this premetastatic niche as well as potential prognostic markers and therapeutic targets that may lead to a better understanding and effective treatment of metastatic disease. Clin Cancer Res; 22(15); 3725-33. ©2016 AACR.

There is increasing evidence for the cancer stem cell model in which a subset of cancer cells possessing stem cell properties, referred to as tumor-initiating or cancer stem-like cells (CSCs), play crucial roles in multiple aspects of cancer. Recent studies have started to characterize the crucial role of various cytokines in the tumor microenvironment in regulating the fate of CSCs. In this review, we summarized some of the latest findings on cytokines that drive breast cancer stemness and their mechanisms of action. These cytokines, including IL-6, IL-8, CCL2 and TGF-β, are frequently elevated in breast tumors and may hold promise as potential therapeutic targets to eradicate CSCs. In combination with conventional chemotherapy and radiotherapy targeting rapidly proliferating cancer cells, intervention of the cancer stemness-driving cytokines may achieve additional benefits for breast cancer patients by suppressing CSC-promoted cancer progression, recurrence, and drug refractoriness.

It has been recognized that cancer-associated mortality is more often a result of the disrupted physiological functions in multiple organs following metastatic dissemination of cancer cells, rather than the presence and growth of the primary tumor. Despite advances in our understanding of the events leading to cancer initiation, growth, and acquisition of invasive properties, we are still unable to effectively treat metastatic disease. It is now being accepted that the secretion of extracellular vesicles, such as exosomes from cancer cells, has a profound impact on the initiation and propagation of metastatic breast cancer. These cancer-secreted vesicles differ from other means of cellular communication due to their capability of bulk delivery and organotropism. Here, we provide an overview of the role of extracellular vesicles in breast cancer metastasis and discuss key areas that may facilitate our understanding of metastatic breast cancer to guide our efforts towards providing better therapies.

Rationale and objective

Quantification of residual native kidney function (RKF) is rarely performed in patients on hemodialysis. Methods of estimating residual kidney urea clearance (K_RU) that use commonly available laboratory and clinical data, with or without urine volume information, may be useful tools.

Study design

Retrospective, predictive modeling and model validation.

Setting and participants

Initial timed urine collections in 604 incident in-center hemodialysis patients on thrice weekly treatments from a single academic center where K_RU is measured in usual care.

Predictors

Models using combination of serum creatinine and urea, age, weight, height, gender, race, fluid weight gains, and with and without 24-hour urine volume.

Outcomes

Residual kidney urea clearance.

Analytic approach

Generalized linear model was used for model development for K_RU using the first urine collection in 604 patients, as both a continuous and binary outcome (for >2.5 mL/min). Model validation was done by bootstrap resampling of the development cohort and with 1093 follow-up measurements.

Results

Urine volume alone was the strongest predictor of K_RU. The model that included 24-hour urine volume with common clinical data had a high diagnostic accuracy for K_RU >2.5 mL/min (area under the curve 0.91 in both development and bootstrap validation) and R² of 0.56 with outcome as a continuous K_RU value. Our model that did not use urine volume performed less well (e.g., AUC 0.75). Analyses of follow-up urine collections in these same subjects yielded comparable or improved performance.

Limitations

Data were retrospective from a single center, no external validation, not validated in 2 or 4 times weekly hemodialysis patients.

Conclusions

Estimation equations for residual kidney urea clearance that use commonly available data in dialysis clinics, with and without urine volume, may be useful tools for evaluation of hemodialysis patients who still have RKF for individualization of dialysis prescriptions.

Quantitative metrics are used to develop profiles of health care institutions, including hospitals, nursing homes, and dialysis clinics. These profiles serve as measures of quality of care, which are used to compare institutions and determine reimbursement, as a part of a national effort led by the Center for Medicare and Medicaid Services in the United States. However, there is some concern about how misclassification in case-mix factors, which are typically accounted for in profiling, impacts results. We evaluated the potential effect of misclassification on profiling results, using 20 744 patients from 2740 dialysis facilities in the US Renal Data System. In this case study, we compared 30-day readmission as the profiling outcome measure, using comorbidity data from either the Center for Medicare and Medicaid Services Medical Evidence Report (error-prone) or Medicare claims (more accurate). Although the regression coefficient of the error-prone covariate demonstrated notable bias in simulation, the outcome measure-standardized readmission ratio-and profiling results were quite robust; for example, correlation coefficient of 0.99 in standardized readmission ratio estimates. Thus, we conclude that misclassification on case-mix did not meaningfully impact overall profiling results. We also identified both extreme degree of case-mix factor misclassification and magnitude of between-provider variability as 2 factors that can potentially exert enough influence on profile status to move a clinic from one performance category to another (eg, normal to worse performer).

Background

Medicare is one of the world's largest health insurance programs. It provides health insurance to nearly 44 million beneficiaries whose entitlements are based on age, disability, or end-stage renal disease (ESRD). Data of these ESRD beneficiaries are collected in the US Renal Data System (USRDS), which includes comorbidity information entered at the time of dialysis initiation (medical evidence data), and are used to shape health care policy. One limitation of USRDS data is the lack of validation of these medical evidence comorbidities against other comorbidity data sources, such as medical claims data.

Methods

We examined the potential for discordance between USRDS Medical Evidence and medical claims data for 11 comorbid conditions amongst Medicare beneficiaries in 2011-2013 via sensitivity, specificity, kappa and hierarchical logistic regression.

Results

Among 61,280 patients, most comorbid conditions recorded on the Medical Evidence forms showed high specificity (>0.9), compared to prior medical claims as reference standard. However, both sensitivity and kappa statistics varied greatly and tended to be low (most <0.5). Only diabetes appeared accurate, whereas tobacco use and drug dependence showed the poorest quality (sensitivity and kappa <0.1). Institutionalization and patient region of residency were associated with data discordance for six and five comorbidities out of 11, respectively, after conservative adjustment of multiple testing. Discordance appeared to be non-informative for congestive heart failure but was most varied for drug dependence.

Conclusions

We conclude that there is no improvement in comorbidity data quality in incident ESRD patients over the last two decades. Since these data are used in case-mix adjustment for outcome and quality of care metrics, the findings in this study should press regulators to implement measures to improve the accuracy of comorbidity data collection.

Introduction

We hypothesized that at least half of incident hemodialysis (HD) patients on 3-times weekly dialysis could safely start on an incremental, 2-times weekly HD schedule if residual kidney function (RKF) had been considered.

Methods

RKF is assessed in all our HD patients. This single-center, retrospective cohort study of incident adult HD patients, who survived ≥6 months on a 3-times weekly HD regimen and had a timed urine collection within 3 months of starting HD, assessed each patient's theoretical ability to achieve adequate urea clearance, ultrafiltration rate, and hemodynamic stability if on 2-times weekly HD.

Results

Of the 410 patients in the cohort, we found that 112 (27%) could have optimally and 107 (26%) could have been appropriately considered for 2-times weekly incremental HD. In general, diuretics were underutilized in >50% of subjects who had adequate RKF urea clearance. The optimal 2-times weekly patients had better potassium and phosphorus control. The correlation coefficient of calculated residual kidney urea clearance with 24-hour urine volume and with kinetic model residual kidney clearance was 0.68 and 0.99, respectively.

Discussion

More than 50% of incident HD patients with RKF have adequate kidney urea clearance to be considered for 2-times weekly HD. When additionally ultrafiltration volume and blood pressure stability are taken into account, more than one-fourth of the total cohort could optimally start HD in an incremental fashion.

Extracellular vesicles (EVs) are secreted by many cell types and are increasingly investigated for their role in human diseases including cancer. Here we focus on the secretion and potential physiological function of non-pathological EVs secreted by polarized normal mammary epithelial cells. Using a transwell system to allow formation of epithelial polarity and EV collection from the apical versus basolateral compartments, we found that impaired secretion of EVs by knockdown of RAB27A or RAB27B suppressed the establishment of mammary epithelial polarity, and that addition of apical but not basolateral EVs suppressed epithelial polarity in a dose-dependent manner. This suggests that apical EV secretion contributes to epithelial polarity, and a possible mechanism is through removal of certain intracellular molecules. In contrast, basolateral but not apical EVs promoted migration of mammary epithelial cells in a motility assay. The protein contents of apical and basolateral EVs from MCF10A and primary human mammary epithelial cells were determined by mass spectrometry proteomic analysis, identifying apical-EV-enriched and basolateral-EV-enriched proteins that may contribute to different physiological functions. Most of these proteins differentially secreted by normal mammary epithelial cells through polarized EV release no longer showed polarized secretion in MCF10A-derived transformed epithelial cells. Our results suggest an essential role of EV secretion in normal mammary epithelial polarization and distinct protein contents and functions in apical versus basolateral EVs secreted by polarized mammary epithelia.

Medicare claims data are commonly used to query comorbidities for case-mix adjustment in research of patients with end-stage renal disease (ESRD) in the United States. These adjustments may affect reimbursement and quality rating through comparative profiling and ranking of dialysis facilities. We studied regional and temporal variations in comorbidity from claims data in the United States Renal Data System. Patients with a previous 1-year Medicare history who initiated dialysis therapy between 2006 and 2009 were examined with a follow-up period until 2012. By linking pre- and post-ESRD Medicare claims with the Dartmouth Atlas, we carried out a longitudinal data analysis with multivariable adjustment to investigate regional and temporal variations in the Liu comorbidity index. We identified 23 336 incident hemodialysis patients who were covered by Medicare the year prior to dialysis initiation and had survived with complete 3 years of follow-up data. With the United States divided into 4 geographic regions, the Western region was found to have the lowest Liu index over all 3 follow-up years, compared with the respective years in the other regions (Midwest, Northeast, and South). In comparison with the first year, the Liu index dropped significantly during the second and third years of follow-up across all 4 regions. Significant regional and temporal variations observed in the comorbidity index cannot be explained by differences in reimbursement (average per state) or predialysis comorbidity. Based on our exploratory study, future studies should focus on identifying the factors and reasons for these variations which have the potential to affect health care policy and research.

MicroRNAs (miRNAs) are critical regulators of gene expression, and exert extensive impacts on development, physiology, and disease of eukaryotes. A high degree of parallelism is found in the molecular basis of miRNA biogenesis and action in plants and animals. Recent studies interestingly suggest a potential cross-kingdom action of plant-derived miRNAs, through dietary intake, in regulating mammalian gene expression. Although the source and scope of plant miRNAs detected in mammalian specimens remain controversial, these initial studies inspired us to determine whether plant miRNAs can be detected in Western human sera and whether these plant miRNAs are able to influence gene expression and cellular processes related to human diseases such as cancer. Here we found that Western donor sera contained the plant miRNA miR159, whose abundance in the serum was inversely correlated with breast cancer incidence and progression in patients. In human sera, miR159 was predominantly detected in the extracellular vesicles, and was resistant to sodium periodate oxidation suggesting the plant-originated 2'-O-methylation on the 3' terminal ribose. In breast cancer cells but not non-cancerous mammary epithelial cells, a synthetic mimic of miR159 was capable of inhibiting proliferation by targeting TCF7 that encodes a Wnt signaling transcription factor, leading to a decrease in MYC protein levels. Oral administration of miR159 mimic significantly suppressed the growth of xenograft breast tumors in mice. These results demonstrate for the first time that a plant miRNA can inhibit cancer growth in mammals.