Edward Cronin

Early-Stage Invasive Breast Cancers: Potential Role of Optical Tomography with US Localization in Assisting Diagnosis

PURPOSE To investigate the potential role of optical tomography in the near-infrared (NIR) spectrum with ultrasonographic (US) localization as a means of differentiating early-stage cancers from benign lesions of the breast. MATERIALS AND METHODS The protocol was approved by the institutional review boards and was HIPAA compliant; all participants signed an informed consent. One hundred seventy-eight consecutive women (mean age, 52 years; range, 21-89 years) who underwent US-guided biopsy were imaged with a hand-held probe consisting of a coregistered US transducer and an NIR imager. The lesion location provided by coregistered US was used to guide optical imaging. Light absorption was measured at two optical wavelengths. From this measurement, tumor angiogenesis was assessed on the basis of calculated total hemoglobin concentration (tHb) and was correlated with core biopsy results. For patients diagnosed with carcinomas and followed up with subsequent excision, the tHb was correlated with pathologic parameters. RESULTS There were two in situ carcinomas (Tis), 35 T1 carcinomas, 24 T2-T4 carcinomas, and 114 benign lesions. The mean maximum and mean average tHb of the Tis-T1 group were 102.0 micromol/L +/- 28.5 (standard deviation) and 71.9 micromol/L +/- 18.8, and those of the T2-T4 group were 100.3 micromol/L +/- 26.4 and 67.0 micromol/L +/- 18.3, respectively. The mean maximum and mean average tHb of the benign group were 55.1 micromol/L +/- 22.7 and 39.1 micromol/L +/- 14.9, respectively. Both mean maximum and mean average tHb levels were significantly higher in the malignant groups than they were in the benign group (P < .001). The sensitivity, specificity, positive predictive value, and negative predictive value for Tis-T1 cancers were 92%, 93%, 81%, and 97%. The corresponding values for T2-T4 tumors were 75%, 93%, 69%, and 95%. CONCLUSION The angiogenesis (tHb) contrast imaged by using the NIR technique with US holds promise as an adjunct to mammography and US for distinguishing early-stage invasive breast cancers from benign lesions.

Breast Cancer: Assessing Response to Neoadjuvant Chemotherapy by Using US-guided Near-Infrared Tomography

PURPOSE To assess initial breast tumor hemoglobin (Hb) content before the initiation of neoadjuvant chemotherapy, monitor the Hb changes at the end of each treatment cycle, and correlate these findings with tumor pathologic response. MATERIALS AND METHODS The HIPAA-compliant study protocol was approved by the institutional review boards of both institutions. Written informed consent was obtained from all patients. Patients who were eligible for neoadjuvant chemotherapy were recruited between December 2007 and May 2011, and their tumor Hb content was assessed by using a near-infrared imager coupled with an ultrasonography (US) system. Thirty-two women (mean age, 48 years; range, 32-82 years) were imaged before treatment, at the end of every treatment cycle, and before definitive surgery. The patients were graded in terms of their final pathologic response on the basis of the Miller-Payne system as nonresponders and partial responders (grades 1-3) and near-complete and complete responders (grades 4 and 5). Tumor vascularity was assessed from total Hb (tHb), oxygenated Hb (oxyHb), and deoxygenated Hb (deoxyHb) concentrations. Tumor vascularity changes during treatment were assessed from percentage tHb normalized to the pretreatment level. A two-sample two-sided t test was used to calculate the P value and to evaluate statistical significance between groups. Bonferroni-Holm correction was applied to obtain the corrected P value for multiple comparisons. RESULTS There were 20 Miller-Payne grade 1-3 tumors and 14 grade 4 or 5 tumors. Mean maximum pretreatment tHb, oxyHb, and deoxyHb levels were significantly higher in grade 4 and 5 tumors than in grade 1-3 tumors (P = .005, P = .008, and P = .017, respectively). The mean percentage tHb changes were significantly higher in grade 4 or 5 tumors than in grade 1-3 tumors at the end of treatment cycles 1-3 (P = .009 and corrected P = .009, P = .002 and corrected P = .004, and P < .001 and corrected P < .001, respectively). DISCUSSION These findings indicate that initial tumor Hb content is a strong predictor of final pathologic response. Additionally, the tHb changes during early treatment cycles can further predict final pathologic response.

Portable near-infrared diffusive light imager for breast cancer detection

We present a frequency-domain near-infrared optical tomography system designed for breast cancer detection, in conjunction with conventional ultrasound. It features fast optical switching, three-wavelength excitations, and avalanche photodiode as detectors. Laser diodes at 660, 780, and 830 nm are used as light sources and their outputs are distributed sequentially to one of nine source fibers. An equivalent 130-dB isolation between electrical signals from different source channels is achieved with the optical switches of very low crosstalk. Ten detection channels, each of which includes a silicon avalanche photodiode, detect diffusive photon density waves simultaneously. The dynamic range of an avalanche photodiode is about 20 to 30 dB higher than that of a photomultiplier tube, thus eliminating the need for multistep system gain control. The entire system is compact in size (<0.051 m(3)) and fast in data acquisition (less than 2 sec for a complete scan). Calibration and the clinical experiment results are presented in the paper.

Near Infrared Imaging Using US Localization To Assess Response to Neoadjuvant Chemotherapy.

Background: Pilot data obtained from a novel ultrasound (US)-guided diffusive-wave optical tomography in the near infrared (NIR) spectrum showed that it is feasible to use this technique to monitor vascular changes within breast tumors during neoadjuvant chemotherapy. These changes correlated well to tumor pathologic response. The earlier study was performed at a single hospital with a smaller patient pool and the tumor vascular assessment was made at a period of two treatment cycles. The objectives of this study are: (i) to validate the initial findings with a larger patient pool, and (ii) to assess vascular changes at every treatment cycle and to correlate early vascular changes with the tumor pathological response.Materials and Methods: 13 patients who underwent neoadjuvant treatment were recruited from two hospitals from December 2007 to May 2009 and their tumor vascular content was assessed with a combined imager consisting of a commercially available US system coupled to a NIR imager (NIR/US). Patients were imaged before their treatment, at the end of every treatment cycle and before their definitive surgery. The co-registered US was used to localize the tumor and to guide the NIR imaging reconstruction, and the NIR imager was used to map the tumor vascular distribution which was assessed based on a percentage total hemoglobin (%tHb) concentration normalized to the pre-treatment level. Of the 13 patients, 12 patients had contrast enhanced MRI before treatment and prior to surgery. The NIR results were compared with MRI findings. At treatment completion, pathological assessment revealed three response groups: complete or near-complete responders (A), partial responders (B), and non-responders (C).Results: There were four complete or near-complete responders, five partial responders, and four non-responders. The mean %tHbs of groups of A, B and C at the treatment completion were 38%±7.0%, 57.3%±5.7%, and 91.0%±10.1%, respectively (differences statistically significant, p Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5016.

Tumor angiogenesis imaged by optical tomography can accurately diagnose early-stage invasive breast cancers.

Abstract #52 Background: Our initial clinical results obtained from a novel ultrasound(US)-guided diffusive-wave optical tomography have shown that early-stage invasive breast cancers may be distinguished from benign lesions with an average of two-fold angiogenesis contrast. However, breast cancer is a heterogeneous disease with different growth and metabolic rates that result in a wide range of functional differences. In this report, we present a spectrum of breast lesion angiogenesis distributions from benign lesions, early-stage invasive cancers to advanced cancers. The objective is to investigate the feasibility of optical tomography with US localization in differentiating malignant from benign breast masses.
 Materials and Methods: 123 patients underwent US-guided biopsy and were imaged with a combined imager consisting of a commercially available US system and a near infrared (NIR) imager. A hand-held probe with a centrally located US transducer and NIR sensors surrounding it was used to simultaneously acquire co-registered US images and optical data. The lesion location provided by US was used to guide optical imaging reconstruction. Light absorption was measured at multiple wavelengths. From this, tumor angiogenesis was assessed based on calculated total hemoglobin concentration.
 Results: There were 23 stage I carcinomas, 21 stage II to IIII carcinomas, and 112 benign lesions. The mean maximum and average values of total hemoglobin concentration (tHb) of the stage I malignant group were 102.0 μ mol/liter (±30.7) and 72.3 μ mol/liter ( ±18.1), and the values of the state II to IIII malignant group were 114.4 μ mol/liter (±38.4) and 75.4 μ mol/liter (±25.2), respectively. The mean maximum and average values of the benign group were 54.0 μ mol/liter (±22.3) and 38.2 μ mol/liter (±14.8), respectively. Both maximum and average of tHb level were statistically significantly higher in the malignant groups than the benign group (P Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 52.

Tumor angiogenesis and tumor hypoxia as diagnostic indices for differentiation of benign versus malignant breast masses

In this report, clinical examples of using combined ultrasound and optical diffused wave technique to image tumor total hemoglobin concentration and tumor hypoxia are given. These examples demonstrate that the sensitivity and specificity of using tumor hemoglobin level as diagnostic index are much higher than that of tumor hypoxia.

Benign versus malignant breast masses: Optical differentiation with US localization

A group of 5 invasive carcinomas and 16 benign lesions have shown that malignant cancers present more than two-fold greater total hemoglobin concentration than benign lesions. Optical tomography provides much higher specificity than Doppler US.