Axel Hagen

Breast cancer: early- and late-fluorescence near-infrared imaging with indocyanine green--a preliminary study.

PURPOSE To assess early- and late-fluorescence near-infrared imaging, corresponding to the vascular (early-fluorescence) and extravascular (late-fluorescence) phases of indocyanine green (ICG) enhancement, for breast cancer detection and benign versus malignant breast lesion differentiation. MATERIALS AND METHODS The study was approved by the ethical review board; all participants provided written informed consent. Twenty women with 21 breast lesions were examined with near-infrared imaging before, during, and after intravenous injection of ICG. Absorption and fluorescence projection mammograms were recorded simultaneously on a prototype near-infrared imaging unit. Two blinded readers independently assessed the images and assigned visibility scores to lesions seen on the absorption and absorption-corrected fluorescence mammograms. Imaging results were compared with histopathologic findings. Lesion contrast and diameter on the fluorescence mammograms were measured, and Cohen κ, Mann-Whitney U, and Spearman ρ tests were conducted. RESULTS The absorption-corrected fluorescence ratio mammograms showed high contrast (contrast value range, 0.25-0.64) between tumors and surrounding breast tissue. Malignant lesions were correctly defined in 11 (reader 1) and 12 (reader 2) of 13 cases, and benign lesions were correctly defined in six (reader 1) and five (reader 2) of eight cases with late-fluorescence imaging. Lesion visibility scores for malignant and benign lesions were significantly different on the fluorescence ratio mammograms (P = .003) but not on the absorption mammograms (P = .206). Mean sensitivity and specificity reached 92% ± 8 (standard error of mean) and 75% ± 16, respectively, for fluorescence ratio imaging compared with 100% ± 0 and 25% ± 16, respectively, for conventional mammography alone. CONCLUSION Preliminary data suggest that early- and late-fluorescence ratio imaging after ICG administration can be used to distinguish malignant from benign breast lesions.

Late-fluorescence mammography assesses tumor capillary permeability and differentiates malignant from benign lesions

Using scanning time-domain instrumentation we recorded fluorescence projection mammograms on few breast cancer patients prior, during and after infusion of indocyanine green (ICG), while monitoring arterial ICG concentration by transcutaneous pulse densitometry. Late-fluorescence mammograms recorded after ICG had been largely cleared from the blood by the liver, showed invasive carcinomas at high contrast over a rather homogeneous background, whereas benign lesions did not produce (focused) fluorescence contrast. During infusion, tissue concentration contrast and hence fluorescence contrast is determined by intravascular contributions, whereas late-fluorescence mammograms are dominated by contributions from protein-bound ICG extravasated into the interstitium, reflecting relative microvascular permeabilities of carcinomas and normal breast tissue. We simulated intravascular and extravascular contributions to ICG tissue concentration contrast within a two-compartment unidirectional pharmacokinetic model.

A multichannel time-domain scanning fluorescence mammograph: Performance assessment and first in vivo results

We present a scanning time-domain fluorescence mammograph capable to image the distribution of a fluorescent contrast agent within a female breast, slightly compressed between two parallel glass plates, with high sensitivity. Fluorescence of the contrast agent is excited using a near infrared picosecond diode laser module. Four additional picosecond diode lasers with emission wavelengths between 660 and 1066 nm allow to measure the intrinsic optical properties of the breast tissue. By synchronously moving a source fiber and seven detection fiber bundles across the breast, distributions of times of flight of photons are recorded simultaneously for selected source-detector combinations in transmission and reflection geometry either at the fluorescence wavelength or at the selected laser wavelengths. To evaluate the performance of the mammograph, we used breastlike rectangular phantoms comprising fluorescent and absorbing objects using the fluorescent dye Omocyanine as contrast agent excited at 735 nm. We compare two-dimensional imaging of the phantom based on transmission and reflection data. Furthermore, we developed an improved tomosynthesis algorithm which permits three-dimensional reconstruction of fluorescence and absorption properties of lesions with good spatial resolution. For illustration, we present fluorescence mammograms of one patient recorded 30 min after administration of the contrast agent indocyanine green showing the carcinoma at high contrast originating from fluorescence of the extravasated dye, excited at 780 nm.

Development of a multi-channel time-domain fluorescence mammograph

We developed an eight-channel scanning time-domain fluorescence mammograph capable of imaging the distribution of a non-specific fluorescent contrast agent in the female breast, besides imaging intrinsic absorption and scattering properties of healthy breast tissue and tumors. The apparatus is based on the PTB multi-channel laser pulse mammograph, originally designed for measurements of absorption and scattering coefficients at four selected wavelengths (&lgr; = 652 nm, 684 nm, 797nm, and 830 nm). It was upgraded for time-resolved detection of fluorescence, excited at 735 nm by a ps diode laser with 10 mW output power and detected at wavelengths &lgr; ⩾ 780 nm. Cooled PMTs with GaAs photocathodes are used to detect laser and fluorescence photons at five positions in transmission and three positions in reflection. Measurements are performed with the breast being slightly compressed between two parallel glass plates. The transmitting and receiving fiber bundles are scanned synchronously over the breast in steps of typically 2.5 mm. At each scan position, distributions of times of flight of laser photons are measured by time-correlated single photon counting at eight detector positions, followed by measurements of distributions of times of arrival of fluorescence photons. The performance of the fluorescence mammograph was investigated by using breast-like phantoms with a fluorescent inhomogeneity with dye enrichment varying between 2:1 and 10:1 over background values.

Nonlinear reconstruction of absorption and fluorescence contrast from measured diffuse transmittance and reflectance of a compressed-breast-simulating phantom.

We report on the nonlinear reconstruction of local absorption and fluorescence contrast in tissuelike scattering media from measured time-domain diffuse reflectance and transmittance of laser as well as laser-excited fluorescence radiation. Measurements were taken at selected source-detector offsets using slablike diffusely scattering and fluorescent phantoms containing fluorescent heterogeneities. Such measurements simulate in vivo data that would be obtained employing a scanning, time-domain fluorescence mammograph, where the breast is gently compressed between two parallel glass plates, and source and detector optical fibers scan synchronously at various source-detector offsets, allowing the recording of laser and fluorescence mammograms. The diffusion equations modeling the propagation of the laser and fluorescence radiation were solved in frequency domain by the finite element method simultaneously for several modulation frequencies using Fourier transformation and preprocessed experimental data. To reconstruct the concentration of the fluorescent contrast agent, the Born approximation including higher-order reconstructed photon densities at the excitation wavelength was used. Axial resolution was determined that can be achieved by various detection schemes. We show that remission measurements increase the depth resolution significantly.

Reconstruction of absorption and fluorescence contrast for scanning time-domain fluorescence mammography

We report on the reconstruction of absorption and fluorescence from measured time-domain diffuse reflectance and transmittance of laser and fluorescence radiation. Measurements were taken on slab-like, diffusely scattering and fluorescent phantoms containing fluorescent inhomogeneities, using fs laser pulses (&lgr; = 730 nm) and time correlated single photon counting. The source was scanned across the entrance face of the phantom, and at each source position data were collected in transmission and reflection at various detector positions. These measurements simulate in vivo data that will be obtained employing a scanning, time-domain fluorescence mammograph, where the breast is gently compressed between two parallel glass plates, and source and detector optical fibers scan synchronously at various source-detector offsets, allowing to record laser and fluorescence mammograms. The diffusion equations for the propagation of the laser and fluorescence radiation were solved in frequency domain by the finite element method. Measured time-resolved phantom data were Fourier-transformed to frequency domain prior to image reconstruction. Signal-to-noise ratios were high enough to use several data sets simultaneously in the reconstruction process belonging to various modulation frequencies up to several hundred MHz. To obtain the spatial distribution of the fluorescent contrast agent the Born approximation of the fluorescence diffusion equation was used.

Recording of Artifact-Free Reflection Data with a Laser and Fluorescence Scanning Mammograph for Improved Axial Resolution

We developed a method to record artifact-free diffuse reflectance in a parallel plate scanning fluorescence mammograph and used reflection data together with transmission data for reconstruction based fluorescence imaging at improved axial resolution.

A Prototype Mammograph for Simultaneous Acquisition of Tomographic and Time-Resolved Data in Slab Geometry

We have developed a prototype mammograph for simultaneous acquisition of tomographic and time-resolved data at fluorescence and laser wavelengths in slab geometry. System performance was tested on phantoms and on a volunteer.

Accelerated DOT reconstruction using multiple sub-volumes

We present a new method to reconstruct arbitrary large volumes in (fluorescence) diffuse optical tomography by splitting the volume of reconstruction into sub-volumes. This allows to perform nonlinear reconstruction on large grids with a larger number of measurement data and more grid nodes than conventional reconstruction schemes, where images are reconstructed on a single grid. We investigate how the reconstructed spatial distributions of diffusion and absorption coefficients using the new method depend on the size of the sub-volumes, compare the convergence to the conventional nonlinear approach, and present an error estimation.

A Multitute of Laser Sources for Pulsed and Continuous Excitation in Diffuse Optical Tomography

We report latest results developing high power pulsed lasers for time resolved / cw intensity DOT. These lasers were used for fluorescence imaging on phantoms for optical mammography with contrast agents in reflectance and transmission.