Multifractal analysis of tumour microscopic images in the prediction of breast cancer chemotherapy response.

Due to the individual heterogeneity, highly accurate predictors of chemotherapy response in invasive breast cancer are needed for effective chemotherapeutic management. However, predictive molecular determinants for conventional chemotherapy are only emerging and still incorporate a high degree of predictive variability. Based on such pressing need for predictive performance improvement, we explored the value of pre-therapy tumour histology image analysis to predict chemotherapy response. Fractal analysis was applied to hematoxylin/eosin stained archival tissue of diagnostic biopsies derived from 106 patients diagnosed with invasive breast cancer. The tissue was obtained prior to neoadjuvant anthracycline-based chemotherapy and patients were subsequently divided into three groups according to their actual chemotherapy response: partial pathological response (pPR), pathological complete response (pCR) and progressive/stable disease (PD/SD). It was shown that multifractal analysis of breast tumour tissue prior to chemotherapy indeed has the capacity to distinguish between histological images of the different chemotherapy responder groups with accuracies of 91.4% for pPR, 82.9% for pCR and 82.1% for PD/SD. F(α)max was identified as the most important predictive parameter. It represents the maximum of multifractal spectrum f(α), where α is the Hölder's exponent. This is the first study investigating the predictive value of multifractal analysis as a simple and cost-effective tool to predict the chemotherapy response. Improvements in chemotherapy prediction provide clinical benefit by enabling more optimal chemotherapy decisions, thus directly affecting the quality of life and survival.

Gray-Level Co-Occurrence Matrix Texture Analysis of Breast Tumor Images in Prognosis of Distant Metastasis Risk.

Owing to exceptional heterogeneity in the outcome of invasive breast cancer it is essential to develop highly accurate prognostic tools for effective therapeutic management. Based on this pressing need, we aimed to improve breast cancer prognosis by exploring the prognostic value of tumor histology image analysis. Patient group (n=78) selection was based on invasive breast cancer diagnosis without systemic treatment with a median follow-up of 147 months. Gray-level co-occurrence matrix texture analysis was performed retrospectively on primary tumor tissue section digital images stained either nonspecifically with hematoxylin and eosin or specifically with a pan-cytokeratin antibody cocktail for epithelial malignant cells. Univariate analysis revealed stronger association with metastasis risk by texture analysis when compared with clinicopathological parameters. The combination of individual clinicopathological and texture variables into composite scores resulted in further powerful enhancement of prognostic performance, with an accuracy of up to 90%, discrimination efficiency by the area under the curve [95% confidence interval (CI)] of 0.94 (0.87-0.99) and hazard ratio (95% CI) of 20.1 (7.5-109.4). Internal validation was successfully performed by bootstrap and split-sample cross-validation, suggesting that the models are generalizable. Whereas further validation is needed on an external set of patients, this preliminary study indicates the potential use of primary breast tumor histology texture as a highly accurate, simple, and cost-effective prognostic indicator of distant metastasis risk.

Paxillin and phospholipase D interact to regulate actin-based processes in Dictyostelium discoideum.

The actin cytoskeleton forms a membrane-associated network whose proper regulation is essential for numerous processes, including cell differentiation, proliferation, adhesion, chemotaxis, endocytosis, exocytosis, and multicellular development. In this report, we show that in Dictyostelium discoideum, paxillin (PaxB) and phospholipase D (PldB) colocalize and coimmunoprecipitate, suggesting that they interact physically. Additionally, the phenotypes observed during development, cell sorting, and several actin-required processes, including cyclic AMP (cAMP) chemotaxis, cell-substrate adhesion, actin polymerization, phagocytosis, and exocytosis, reveal a genetic interaction between paxB and pldB, suggesting a functional interaction between their gene products. Taken together, our data point to PldB being a required binding partner of PaxB during processes involving actin reorganization.

Fractal dimension and lacunarity of tumor microscopic images as prognostic indicators of clinical outcome in early breast cancer.

AIM: Research in the field of breast cancer outcome prognosis has been focused on molecular biomarkers, while neglecting the discovery of novel tumor histology structural clues. We thus aimed to improve breast cancer prognosis by fractal analysis of tumor histomorphology. PATIENTS & METHODS: This retrospective study included 92 breast cancer patients without systemic treatment. RESULTS: Fractal dimension and lacunarity of the breast tumor microscopic histology possess prognostic value comparable to the major clinicopathological prognostic parameters. CONCLUSION: Fractal analysis was performed for the first time on routinely produced archived pan-tissue stained primary breast tumor sections, indicating its potential for clinical use as a simple and cost-effective prognostic indicator of distant metastasis risk to complement the molecular approaches for cancer risk prognosis.

Paxillin phosphorylation and complexing with Erk and FAK are regulated by PLD activity in MDA-MB-231 cells.

MDA-MB-231 cells are highly aggressive human breast adenocarcinoma cells that depend on PLD activity for survival. In response to the stress of serum withdrawal, there is increased motility and invasiveness of these cells that is associated with a rapid increase in PLD activity. In addition, PLD activity is elevated in response to most mitogenic signals. Similar to PLD, paxillin, a focal adhesion adaptor protein, and Erk, mitogen-activated protein kinase, play vital roles in cell motility through regulation of focal adhesion dynamics. Here, we addressed whether there is a functional correlation between paxillin and PLD that may influence cancer cell motility. We investigated the role of PLD activity on paxillin regulation, Erk activation and formation of a paxillin-Erk and paxillin-FAK association. Inhibition of PLD activity led to an increase in paxillin tyrosine phosphorylation, a decrease in Erk activation, as measured by phosphorylation, and enhanced association of paxillin with Erk. In addition, we found that paxillin tyrosine phosphorylation depends upon Erk activity and may be a consequence of an increased association with FAK. Taken together, these results suggest that Erk activity is governed by PLD activity and regulates the tyrosine phosphorylation of paxillin, potentially explaining its role in cell motility. This study indicated that PLD, Erk, paxillin and FAK participate in the same signaling pathway in this breast cancer cell line.