Abstract SY03-01: Molecular imaging with cellular resolution and molecular specificity using miniaturized microscopes
Authors: Contag Christopher H. 
Published: July 2012

Abstract
The earliest malignant lesions are microscopic in size and may be characterized by abnormal cell surface markers and disrupted microanatomy. The challenge for early detection of cancer is effectively using these features to localize and characterize those early lesions that are likely to progress. For cancers of the gastrointestinal (GI) tract there are some predisposing conditions that identify high-risk regions, and justify microscopic analyses for detection, diagnosis and guided biopsy of small, early lesions. In addition, microscopic analyses are used for detection of tumor margins in resection of skin and breast cancer and may have utility in resection of cancers.
Micro-optical designs are enabling the development of miniaturized microscopes that can reach inside the body to interrogate disease states with cellular resolution. In combination with molecular probes such instruments can be used to interrogate suspect lesions for early signs of malignancy and to determine if margins are clear. To enable molecular imaging with cellular resolution, we have developed miniaturized confocal fluorescence microscopes that are based on a dual-axis architecture. The dual-axis design enables the use of low numerical aperture lenses and a folded light path that is amenable to a small form factor and post objective scanning in the scan head. The design features of this microscope included axial and transverse resolutions comparable to that used by pathologists (5 µM), and a 0.5 × 0.5 × 0.5 mm 3-D field of view in an instrument that has an external diameter compatible with use in an endoscope for GI cancers, and that can reach into small cavities for guided resections.
The first dual-axis confocal (DAC) microscope that has been used in a clinical study in the colon with these capabilities has a 5-mm external diameter and an excitation wavelength of 780 nm. To enable early detection we have developed and tested a number of optical probes for use as molecular markers, and evaluated FDA-approved dyes as contrast for analysis of microanatomy. Studies in animals and man demonstrated the ability to observe microanatomy and discriminate malignant tissue from surrounding normal tissues. A wide variety of fluorescent agents are being developed and tested for cancer detection using macroscopic approaches. These agents can be detected at the cellular level with miniaturized microscopes for complementary analyses. Placement of the microscope can be guided by the macroscopic images, and the microscopic data can be used to substantiate the images. We have targeted surface markers and the cytoplasmic enzyme Cox-2 in these studies. We fitted the DAC microscopes with a needle lens to reach deep into the tissues and this instrument has been evaluated for guided resections of medulloblastoma in preclinical studies. The next-generation instruments have a smaller form factor and are designed for multispectral capabilities and faster scan times. This will increase their utility with increased access to tissues sites and multiplexed in vivo assays.
The co-development of molecular probes and micro-optical instruments to visualize cancer may improve detection of cancer, and can be used to assess therapeutic outcome. Advances in in vivo microscopy could lead to a fundamental shift in the diagnostic paradigm from biopsy with conventional histopathology to performance of point-of-care morphologic diagnosis using in vivo microscopic pathology. These technologies are closing the gap between the patient and the diagnostic event, and will have major ramifications for the training of future physicians to interpret real-time in vivo microscopic molecular data, and will advance the emerging field of telepathology. One of the features of multimodality molecular imaging is reaching across a range of scales from microscopic, cellular resolution, to macroscopic, whole body, imaging and new tools with microscopic capabilities are necessary to achieve these aims
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr SY03-01. doi:10.1158/1538-7445.AM2011-SY03-01