Publications

PURPOSE

To identify molecular markers of pathologic response to neoadjuvant paclitaxel/radiation treatment, protein and gene expression profiling were done on pretreatment biopsies.

EXPERIMENTAL DESIGN

Patients with high-risk, operable breast cancer were treated with three cycles of paclitaxel followed by concurrent paclitaxel/radiation. Tumor tissue from pretreatment biopsies was obtained from 19 of the 38 patients enrolled in the study. Protein and gene expression profiling were done on serial sections of the biopsies from patients that achieved a pathologic complete response (pCR) and compared to those with residual disease, non-pCR (NR).

RESULTS

Proteomic and validation immunohistochemical analyses revealed that alpha-defensins (DEFA) were overexpressed in tumors from patients with a pCR. Gene expression analysis revealed that MAP2, a microtubule-associated protein, had significantly higher levels of expression in patients achieving a pCR. Elevation of MAP2 in breast cancer cell lines led to increased paclitaxel sensitivity. Furthermore, expression of genes that are associated with the basal-like, triple-negative phenotype were enriched in tumors from patients with a pCR. Analysis of a larger panel of tumors from patients receiving presurgical taxane-based treatment showed that DEFA and MAP2 expression as well as histologic features of inflammation were all statistically associated with response to therapy at the time of surgery.

CONCLUSION

We show the utility of molecular profiling of pretreatment biopsies to discover markers of response. Our results suggest the potential use of immune signaling molecules such as DEFA as well as MAP2, a microtubule-associated protein, as tumor markers that associate with response to neoadjuvant taxane-based therapy.

BACKGROUND

Epicardial mapping has shown that atrial substrate may play a role in the characteristics of the resulting atrial fibrillation (AF). However, it is not known whether these differences also occur in 3 dimensions.

OBJECTIVE

This study sought to examine the 3-dimensional characteristics of AF by simultaneously analyzing AF on the epicardial and endocardial surfaces.

METHODS

Dogs were divided into 5 groups: congestive heart failure (CHF), rapid atrial pacing (RAP), mitral regurgitation (MR), control, and methylcholine. A noncontact mapping catheter (Ensite 3000 [Endocardial Solutions, Inc., St. Paul, Minnesota]) was placed in the left atrium (LA), and electrode plaques (240 unipoles) were placed over the epicardial surface. Several AF episodes of at least 30 s were recorded, and isopotential videos of activation and isochronal maps were constructed. In addition, each pair of matched electrograms were cross-correlated (XC) and analyzed with a fast Fourier transform (FFT).

RESULTS

The RAP model was the only one with an AF mechanism of multiple wavelets in every dog on both surfaces. In addition, when individual signals were compared, the RAP model had the least amount of similarities between the recording surfaces, whereas the CHF model had the most as it had a higher percentage of signals with XC coefficients >0.8 and a higher percentage of signals with similar dominant frequencies (30 +/- 35% vs. 12 +/- 13% and 66 +/- 30% vs. 26 +/- 10%, P < .05).

CONCLUSION

Although the RAP model had similar AF mechanisms in 3 dimensions, this did not correlate to transmural similarities. Focal mechanisms of AF may have a more uniform wavefront of activation, whereas models with mechanisms of multiple wavelets may have more 3-dimensional properties.