Detection of dysplasia and carcinoma in situ with a lung imaging fluorescence endoscope device.

The performance of a novel bronchoscopic fluorescence imaging system was compared with conventional white light bronchoscopy with a data base of 328 biopsy-confirmed sites from 53 patients and 41 volunteers. The two methods were found to have the same specificity (94%); however, the sensitivity of the fluorescence system (72.5%) was found to be 50% greater than that of the white light bronchoscopy (48.4%) in detecting dysplasia and carcinoma in situ. The fluorescence system uses a nonlinear discriminant function combining the red and green image intensity values to form a pseudoimage that, when displayed on an RGB monitor, allows the detection and delineation of abnormal areas. In 15% of the patients with lung cancer, synchronous carcinoma in situ was found in addition to the large invasive cancer. Of the current smokers in this study, 40% had moderate dysplasia and 12% had severe dysplasia. For the ex-smokers 25% had moderate dysplasia, 6% had severe dysplasia, and 13% had carcinoma in situ. Fluorescence imaging may become an important adjunct to conventional bronchoscopic examination to improve our ability to diagnose and stage lung cancer more accurately.

Detection of early lung cancer using low dose Photofrin II.

Fluorescence imaging using hematoporphyrin derivative (HpD) or Photofrin II as a tumor marker has been used for localization of early bronchogenic carcinoma. Wider clinical application of HpD or Photofrin II as a cancer imaging agent has been hampered by the potentially serious and prolonged skin photosensitivity. Using a sensitive fluorescence bronchoscope system with a ratio fluorometer probe, carcinoma in situ was detected in four patients with low dose Photofrin II (0.25 mg/kg) with no apparent skin phototoxicity to 30 J/cm2 visible light on skin photosensitivity test.

Fluorescence spectra in lung with porphyrin injection.

The fluorescence emission spectra from human bronchial mucosa and tumors, before and after injection of dihematoporphyrin ether/ester, have been measured with an optical multichannel analyzer from 500 to 750 nm. Fluorescence was excited with a violet krypton ion laser (average wavelength 410 nm). The autofluorescence spectra decrease monotonically with increasing wavelength except for a small broad peak near 600 nm. The spectra from tumor sites, after injection of the fluorescent porphyrin, exhibit the characteristic fluorescence emission at 630 and 690 nm, added to the autofluorescence spectrum. The spectra from control or nontumor sites are similar but the magnitude of the component due to the injected porphyrin is smaller than at a tumor site. The magnitude ratio of tumor to control site fluorescence depends on concentration of the porphyrin, tumor thickness, and time after injection. Autofluorescence degrades contrast and thus makes very thin tumors difficult to image. Subtraction of the autofluorescence background is desirable.

Scientific basis of breast diaphanography.

Diaphanography, also known as transillumination, is a breast diagnostic technique based on differences in the diffuse transmittance of visible or near-infrared radiation. Previous papers by the authors reported on investigations of the effect of tumor size, depth at which the tumor is located, the thickness of the breast, and the effect of using photons of different wavelengths. The results from the study reported here indicate that absorption of light in hemoglobin is the basis for the luminance contrast, and shift in the infrared to red transmission ratio, in the diaphanographic image. Evidence is based on known extinction coefficients for oxyhemoglobin and deoxyhemoglobin as a function of wavelength, measurements of the transmitted spectrum in specimens, in vivo dual wavelength transillumination imaging of lesions containing different amounts of blood (bloody and clear cysts, hematomas, veins, fibroadenomas, and carcinomas), and comparison of preoperative diaphanographic images to blood vessel volumes measured by microscopic analysis of surgical specimens. Oxygenation affects the relative proportions of infrared and red light transmitted, but does not influence the diagnosis based on luminance contrast.

Optical properties of mammalian tissue: introduction by the feature editors.

This issue of Applied Optics features twenty-two papers on the optical character of tissue, a topic of growing importance in the life sciences. The papers deal with theory and experiment and are contributed by a core of researchers active in the current development of this relatively new field. The complete description of the tissue's optical properties is fraught with problems due to the extraordinary nature of this difficult, varied, turbid, highly scattering medium. The solution of these optical problems promises important dividends in practical areas, such as cancer treatment and diagnosis.

Light transport in tissue.

The propagation of light in tissue may be calculated by exact transport theory, or the approximate diffusion theory, provided the optical properties are known at the source wavelength. Optical properties for the exact methods are the absorption coefficient, scattering coefficient, and angular distribution of scattering. Appropriate properties for diffusion theory are the diffusion length and diffusion coefficient (corrected for anisotropic scattering). Computer programs and analytical solutions (for some simple geometries) exist, but the optical properties have to be determined experimentally and are not well defined as yet. The radiant energy fluence rate and the diffuse transmittance and reflectance have been measured in several tissues and in a few geometries, but there are gaps in the data as a function of wavelength. Calculations and measurements reveal that very large errors can result if the optical properties (for example, the diffusion length) are inaccurate, if anisotropic scattering is neglected, or if the finite size of the irradiating light beam is not taken into account. Furthermore, the radiant energy fluence and transmittance are perturbed by local regions of lesser or greater absorption, although recovery of the fluence and transmittance occurs beyond some three diffusion lengths.

Laser-induced hyperthermia of ocular tumors.

Experimental results for the optical distribution and temperature rise during laser irradiation of tumors are presented. The experimental conditions are chosen to simulate laser irradiation of ocular tumors. The tumor models are human retinoblastoma heterotransplanted in athymic mice, murine mammary carcinoma in C3H/HEJ mice, and B16 melanotic melanoma in C57/BL6 mice. The experimental results are discussed in terms of a mathematical model where the thermal distribution is calculated from the bioheat transfer equation, and the optical distribution is determined according to diffusion theory.

Contrast in diaphanography of the breast.

Diaphanography is an imaging technique used in diagnosis of breast disease including cancer. The breast is illuminated with low intensity light and the transmission pattern of red and near-infrared radiation is detected, amplified, reconstructed and displayed in a monitor. The instrumentation for diaphanography has evolved empirically, mostly through clinical practice, without a very clear understanding of the scientific basis of the technique. This research is concerned with investigating theoretically the dependence of the contrast produced by a lesion in a diaphanography image on the size, depth at which a tumor is located, photon energy, and photon angular flux distribution. Contrast calculations using the DOT computer code in a two-dimensional geometry showed that decreasing the size of a tumor by 50% decreases the contrast by a factor of 3 and 4 for 695- and 853-nm photons, respectively. Decreasing the size of the normal tissue where a tumor is imbedded by 25% (from 4 to 3 cm) does not change the contrast very much (less than 20%) for both 695- and 853-nm photons. The contrast for 950- and 695-nm photons is comparable while the values for 853-nm photons are smaller by a factor of 5 for similar cases. The contrast was also found to be dependent on the angle at which the diffuse light is detected after it transverses the host tissue, maximum contrast was found for 695- and 853-nm photons at about 55 degrees. For a detection angle of 77 degrees the contrast observed is 3X and 12X smaller for 695- and 853-nm photons, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

A system for real time fluorescence imaging in color for tumor diagnosis.

Early tumors can be diagnosed by the fluorescence of an injected, tumor-specific agent such as dihematoporphyrin ether. However, brightness or intensity contrast is low because of the autofluorescence of tissue. Addition of color (hue) information aids in detection of tumors, and in elimination of false positives. Standard color video cameras are not sensitive enough to image the weak fluorescence. Thus an intensified monochrome video camera has been equipped with a synchronized color filter wheel, and the image displayed by multiplexing alternate lines to a red green blue (RGB) monitor.

Dose measurements in photodynamic therapy of cancer.

A theory and method for prediction and measurement of the effective absorbed dose in photodynamic therapy of cancer is presented. The method depends on measuring the concentration of the photosensitizer (such as dihematorporphyrin ether), the flux density of the light, and the relative photodynamic effectiveness. Previous, less exact methods relied on specifying the drug dosage and delay after injection and or the irradiance at the surface or power from an interstitial fiber. The new formulation should permit closer control of the effective absorbed dose and better clinical results with photodynamic therapy.

Digital background subtraction for fluorescence imaging.

A method of enhancing contrast in fluorescence imaging has been devised, based on real-time digital subtraction of a background video image from a signal-plus-background video image. Color filters are used to differentiate signal from background. The technique has been applied to detection of small tumors labeled with the tumor specific fluorescent drug hematoporphyrin derivative.

Spectral transmittance and contrast in breast diaphanography.

Diaphanography is an imaging technique using transillumination with visible and near-infrared radiation, and a video camera, to diagnose breast disease, including cancer. Originally based on luminance contrast only, there is now interest in false-color multispectral imaging in selected spectral bands to improve tissue differentiation. Some success has been achieved, but the scientific basis for the results was unknown. This research is concerned with measurements of the diffuse transmittance of breast tissues as a function of wavelength in the 600-1060 nm range (and calculations of contrast with a one-dimensional diffusion theory model). Carcinoma and glandular tissues were found to have similar spectral transmittances with an increase in transmittance between 750 and 900 nm, and an absorption window around 960 nm. Adipose tissue showed a distinct transmittance minimum at 930 nm. In vivo measurement of an intact normal breast showed a minimum at about 825 nm, as yet unexplained. The transmittance data and reflectance data were used to derive the scattering and absorption coefficients. The diffusion length was also determined from radiance versus depth measurements. These coefficients were used for calculations of contrast in a one-dimensional slab model, with and without a layer of cancerous tissue positioned between two slabs of normal tissue.

Laser instrumentation and safety.

A review of the operation principles of lasers and the various types used in chest medicine is given. This includes CO2, Nd:YAG, argon, krypton, and dye lasers. Safety considerations in the use of lasers are also outlined.

Fluorometer for endoscopic diagnosis of tumors.

A filter fluorometer suitable for endoscopic applications has been developed for detection and characterization of superficial tumors by the fluorescence of a previously injected, tumor-specific agent, hematoporphyrin derivative. Fluorescence is excited by violet light conducted through a fiberoptic lightguide in the endoscope, and the fluorescence emission together with reflected violet are collected by another fiberoptic lightguide. The red fluorescence and violet are separated by a dichroic mirror and filter and detected in photomultiplier tubes. The ratio of the fluorescence signal to the reflected violet signal is proportional to the ratio of the fluorescence yield to the violet reflectivity but is insensitive to variations in distance, angle, and violet power. The instrument may be useful for localizing small tumors, and for quantitative measurements of the amount of hematoporphyrin derivative in the tumor, a requirement for accurate dosimetry in photoradiation therapy.