Recent developments in optical technologies have the potential to improve the speed and accuracy of screening and diagnosis of curable precancerous lesions and early cancer, thereby decreasing the costs of detection and management of epithelial malignancies. The development of molecular-specific contrast agents for markers of early neoplastic transformation could improve the detection and molecular characterization of premalignant lesions. In the oral cavity, epidermal growth factor receptor (EGFR) overexpression has been identified in early stages of premalignant lesions of the oral squamous cell carcinoma; therefore, real-time assessment of EGFR expression could serve as a biomarker for oral neoplasia. The purpose of our study was to develop a molecular-specific optical contrast agent targeted against EGFR for in vivo assessment of epithelial neoplasia using a monoclonal antibody and the far-red fluorescent dye, Alexa FluorÒ 660 streptavidin. In addition to demonstrating the specificity of the contrast agent for EGFR in cell lines, we document the ability to achieve penetration through 500 lm thick epithelial layers using multilayer tissue constructs and permeability-enhancing agents. Finally, using the fluorescence intensity of the contrast agent on fresh oral cavity tissue sections, we were able to distinguish abnormal from normal oral tissue. This contrast agent should have important clinical applications for use in conjunction with fluorescence spectroscopy or imaging (or both) to facilitate tumor detection and demarcation.
The Cancer Moonshot emphasizes the need to learn from the experiences of cancer patients to positively impact their outcomes, experiences, and qualities of life. To realize this vision, there has been a concerted effort to identify the fundamental building blocks required to establish a National Learning Healthcare System for Cancer, such that relevant data on all cancer patients is accessible, shareable, and contributing to the current state of knowledge of cancer care and outcomes.
Recent developments in optical technologies have the potential to improve the speed and accuracy of screening and diagnosis of curable precancerous lesions and early cancer, thereby decreasing the costs of detection and management of epithelial malignancies. The development of molecular‐specific contrast agents for markers of early neoplastic transformation could improve the detection and molecular characterization of premalignant lesions. In the oral cavity, epidermal growth factor receptor (EGFR) overexpression has been identified in early stages of premalignant lesions of the oral squamous cell carcinoma; therefore, real‐time assessment of EGFR expression could serve as a biomarker for oral neoplasia. The purpose of our study was to develop a molecular‐specific optical contrast agent targeted against EGFR for in vivo assessment of epithelial neoplasia using a monoclonal antibody and the far‐red fluorescent dye, Alexa Fluor® 660 streptavidin. In addition to demonstrating the specificity of the contrast agent for EGFR in cell lines, we document the ability to achieve penetration through 500 μm thick epithelial layers using multilayer tissue constructs and permeability‐enhancing agents. Finally, using the fluorescence intensity of the contrast agent on fresh oral cavity tissue sections, we were able to distinguish abnormal from normal oral tissue. This contrast agent should have important clinical applications for use in conjunction with fluorescence spectroscopy or imaging (or both) to facilitate tumor detection and demarcation.
Early diagnosis of individuals with high risk of developing head and neck squamous carcinoma should lead to decreased morbidity and increased survival. To aid in noninvasive early detection of oral neoplasia in vivo, we have developed a molecular-specific fluorescent contrast agent, consisting of a far-red fluorescent dye coupled to a monoclonal antibody targeted against the epidermal growth factor receptor. In our study, we used organ cultures of normal and neoplastic human oral tissue to evaluate the capabilities of using this contrast agent to enhance clinical diagnosis. Fresh tissue sections were prepared from 34 biopsies of clinically normal and abnormal oral mucosa from 17 consenting patients. Samples were exposed to contrast agent, rinsed and the presence of bound agent was detected using fluorescence confocal microscopy. Simple assays to assess cytotoxicity of the dye used in the agent and to determine labeling efficacy at physiologic temperatures were also performed. Results indicate that the mean fluorescence intensity (MFI) of samples with dysplasia and cancer are higher than that of the normal sample from the same patient, and that this increase in fluorescence could potentially be used in the early detection and delineation of premalignant lesions. Normal tissue could be distinguished from cancer or moderate dysplasia, using either the ratio of the MFI of abnormal to normal tissue or the MFI obtained from the epithelial surface. No detrimental effects from the dye were observed over a 4-day period. These results indicate that the use of this optical contrast agent could yield important clinical advantages for noninvasive early detection and molecular characterization of oral mucosa. ' 2006 Wiley-Liss, Inc.Key words: fluorescent contrast agent; epidermal growth factor receptor; molecular-specific contrast agentThe 5-year survival rate for oral cancer has not improved significantly in the last 3 decades, despite numerous advances in treatment modalities.
We are developing a multi-modal miniature microscope (4M device) to image morphology and cytochemistry in vivo and provide better delineation of tumors. The 4M device is designed to be a complete microscope on a chip, including optical, micro-mechanical, and electronic components. It has advantages such as compact size and capability for microscopic-scale imaging. This paper presents an optics-only prototype 4M device, the very first imaging system made of sol-gel material. The microoptics used in the 4M device has a diameter of 1.3 mm. Metrology of the imaging quality assessment of the prototype device is presented. We describe causes of imaging performance degradation in order to improve the fabrication process. We built a multi-modal imaging test-bed to measure first-order properties and to assess the imaging quality of the 4M device. The 4M prototype has a field of view of 290 microm in diameter, a magnification of -3.9, a working distance of 250 microm and a depth of field of 29.6+/-6 microm. We report the modulation transfer function (MTF) of the 4M device as a quantitative metric of imaging quality. Based on the MTF data, we calculated a Strehl ratio of 0.59. In order to investigate the cause of imaging quality degradation, the surface characterization of lenses in 4M devices is measured and reported. We also imaged both polystyrene microspheres similar in size to epithelial cell nuclei and cervical cancer cells. Imaging results indicate that the 4M prototype can resolve cellular detail necessary for detection of precancer.
There is currently no standard screening technique for oral cancer and its precursors other than visual identification and biopsy of suspicious lesions. To aid noninvasive early detection of oral neoplasia in vivo, we previously developed a molecular-specific contrast agent targeted against epidermal growth factor receptor. Here, we present a simple fluorescence spectroscopy system to detect the presence of this contrast agent in biological models representative of living tissues in order to demonstrate the feasibility of using a spectroscopy system in conjunction with a contrast agent as a screening technique for oral cancer. The spectroscopy system was tested for the ability to detect the contrast agent in four in vitro models: multilayer tissue phantoms made of cells pre-labeled with the contrast agent, multilayer tissue phantoms labeled with the contrast agent from the surface in conjunction with a permeability enhancing agent, fresh tissue slices from normal and abnormal oral cavity biopsies, and whole normal and abnormal oral cavity biopsies. The optical signal from samples labeled with the contrast agent was 3--32 times stronger compared to controls and was detected with a signal-to-noise ratio greater than 10. These results demonstrate that an inexpensive and simple spectroscopy system can be used in biological models of living systems to detect the optical signal from a contrast agent targeted toward a cancer-related biomarker with good signal-to-noise ratios. Coupling inexpensive fluorescence spectrometers with molecular-specific contrast agents has the potential to improve the early detection of oral neoplasia by providing a low-cost screening tool.
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