Collagen quantification in breast tissue using a 12-wavelength near infrared spectral tomography (NIRST) system.

A portable near infrared spectral tomography (NIRST) system was adapted for breast cancer detection and treatment monitoring with improved speed of acquisition for parallel 12 wavelengths of parallel frequency-domain (FD) and continuous-wavelength (CW) measurement. Using a novel gain adjustment scheme in the Photomultiplier Tube detectors (PMTs), the data acquisition time for simultaneous acquisition involving three FD and three CW wavelengths, has been reduced from 90 to 55 seconds, while signal variation was also reduced from 2.1% to 1.1%. Tomographic images of breast collagen content have been recovered for the first time, and image reconstruction approaches with and without collagen content included have been validated in simulation studies and normal subject exams. Simulations indicate that including collagen content into the reconstruction procedure can significantly reduce the overestimation in total hemoglobin, water and lipid by 8.9µM, 1.8% and 15.8%, respectively, and underestimates in oxygen saturation by 9.5%, given an average 10% background collagen content. A breast cancer patient with invasive ductal carcinoma was imaged and the reconstructed images show that the recovered tumor/background contrast in total hemoglobin increased from 1.5 to 1.7 when collagen was included in reconstruction.

The effect of simultaneous peripheral excision in breast conservation upon margin status.

BACKGROUND: Negative margins in breast conservation therapy (BCT) decrease local recurrence risk. Excision may be performed via two techniques: either as a single lumpectomy specimen or as a central segment with simultaneously resected peripheral segments (PSs). There is little data directly comparing these methods for their effect on margin status. MATERIALS AND METHODS: A retrospective review of all patients undergoing BCT for invasive breast cancer was conducted to evaluate and compare the two techniques. Presentation, pathologic characteristics, surgical technique, specimen volume, and final margin status were recorded. RESULTS: Among 259 cancers in 257 women, 33 had positive margins. A single segment was removed in 69 patients, while 190 patients had 1-6 PSs simultaneously removed. By univariate analysis, smaller tumor size (P = .017) and greater numbers of segments removed (P = .01) lowered the risk of positive margins. In a multivariate model, smaller tumor size (P = .0024), lack of EIC (P = .049), and greater numbers of segments removed (P = .0061) lowered the risk of margin positivity. Despite this last predictor, the total resected specimen volume did not increase with the number of PSs removed (P = .4). There was no residual tumor in 49.2% of PSs despite a compromised primary segment margin. CONCLUSIONS: Smaller tumor size, lack of EIC, and greater numbers of simultaneous PSs excised decrease the likelihood of positive margins, despite a lack of correlation between segment numbers and excised volume. These findings suggest that excision of simultaneous PSs may assist in achieving negative margins, in part, because of avoidance of pathologic artifact.

Experimental treatment of oestrogen receptor (ER) positive breast cancer with tamoxifen and brivanib alaninate, a VEGFR-2/FGFR-1 kinase inhibitor: a potential clinical application of angiogenesis inhibitors.

PURPOSE: Tamoxifen, a selective oestrogen receptor modulator (SERM), and brivanib alaninate, a vascular endothelial growth factor receptor 2 (VEGFR-2) inhibitor, are two target specific agents that result in a substantial decrease in tumour growth when given alone. Tamoxifen activates SERM stimulated breast and endometrial tumour growth. Tamoxifen and brivanib alaninate have side-effects that can affect therapeutic outcomes. The primary goal of the current study was to evaluate the therapeutic effects of lower doses of both agents when given in combination to mice with SERM sensitive, oestrogen stimulated tumour xenografts (MCF-7 E2 tumours). Experiments were conducted to evaluate the response of SERM stimulated breast (MCF-7 Tam, MCF-7 Ral) and endometrial tumours (EnCa 101) to demonstrate the activity of brivanib alaninate in SERM resistant models. EXPERIMENTAL DESIGN: In the current study, tumour xenografts were minced and bi-transplanted into the mammary fat pads of athymic, ovariectomised mice. Preliminary experiments were conducted to determine an effective oral dose of tamoxifen and brivanib alaninate that had minimal effect on tumour growth. Doses of 125 microg of tamoxifen and 0.05 mg/g of brivanib alaninate were evaluated. An experiment was designed to evaluate the effect of the two agents together when started at the time of tumour implantation. An additional experiment was done in which tumours were already established and then treated, to obtain enough tumour tissue for molecular analysis. RESULTS: Brivanib alaninate was effective at inhibiting tumour growth in SERM sensitive (MCF-7 E2) and SERM stimulated (EnCa 101, MCF-7 Ral, MCF-7 Tam) models. The effect of the low dose drug combination as an anti-tumour strategy for SERM sensitive (MCF-7 E2) in early treatment was as effective as higher doses of either drug used alone. In established tumours, the combination is successful at decreasing tumour growth, while neither agent alone is effective. Molecular analysis revealed a decreased phosphorylation of VEGFR-2 in tumours that were treated with brivanib alaninate and an increase in VEGFA transcription to compensate for the blockade of VEGFR-2 by increasing the transcription of VEGFA. Tamoxifen increases the phosphorylation of VEGFR-2 and this effect is abrogated by brivanib alaninate. There was also increased necrosis in tumours treated with brivanib alaninate. CONCLUSION: Historically, tamoxifen has a role in blocking angiogenesis as well as the blockade of the ER. Tamoxifen and a low dose of an angiogenesis inhibitor, brivanib alaninate, can potentially be combined not only to maximise therapeutic efficacy but also to retard SERM resistant tumour growth.

New hypotheses and opportunities in endocrine therapy: amplification of oestrogen-induced apoptosis.

AIMS: To outline the progress being made in the understanding of acquired resistance to long term therapy with the selective oestrogen receptor modulators (SERMs, tamoxifen and raloxifene) and aromatase inhibitors. The question to be addressed is how we can amplify the new biology of oestrogen-induced apoptosis to create more complete responses in exhaustively antihormone treated metastatic breast cancer. METHODS AND RESULTS: Three questions are posed and addressed. (1) Do we know how oestrogen works? (2) Can we improve adjuvant antihormonal therapy? (3) Can we enhance oestrogen-induced apoptosis? The new player in oestrogen action is GPR30 and there are new drugs specific for this target to trigger apoptosis. Similarly, anti-angiogenic drugs can be integrated into adjuvant antihormone therapy or to enhance oestrogen-induced apoptosis in Phase II antihormone resistant breast cancer. The goal is to reduce the development of acquired antihormone resistance or undermine the resistance of breast cancer cells to undergo apoptosis with oestrogen respectively. Finally, drugs to reduce the synthesis of glutathione, a subcellular molecule compound associated with drug resistance, can enhance oestradiol-induced apoptosis. CONCLUSIONS: We propose an integrated approach for the rapid testing of agents to blunt survival pathways and amplify oestrogen-induced apoptosis and tumour regression in Phase II resistant metastatic breast cancer. This Pharma platform will provide rapid clinical results to predict efficacy in large scale clinical trials.

Optimizing the antihormonal treatment and prevention of breast cancer.

The incidence of breast cancer is rising throughout the world. Breast cancer is slowly becoming more prevalent in countries which previously had low rates of cancer as well as becoming a leading cause of cancer death in some countries. Fortunately, a large number of these tumors are estrogen receptor (ER) positive and respond to anti-hormonal adjuvant therapy which until recently has been 5 years of tamoxifen treatment. Unfortunately, a significant number of patients develop recurrent cancers and the recurrent tumors are resistant to tamoxifen treatment. In addition, because of tamoxifen's selective estrogenic actions, there have been reports of venous thrombosis, endometrial cancer, and strokes in patients receiving tamoxifen therapy. Thus, there are other novel therapies such as aromatase inhibitors that block estrogen production in postmenopausal women or fulvestrant that destroys the estrogen receptor. This paper will summarize the therapeutic options for anti-hormonal therapy, the role of anti-hormonal agents in advanced breast cancer, and adjuvant therapy and the current status of chemoprevention with selective ER modulators.