Understanding alteration of cell morphology in disease has been hampered by the diffraction-limited resolution of optical microscopy (>200 nm). We recently developed an optical microscopy technique, partial wave spectroscopy (PWS), which is capable of quantifying statistical properties of cell structure at the nanoscale. Here we use PWS to show for the first time the increase in the disorder strength of the nanoscale architecture not only in tumor cells but also in the microscopically normal-appearing cells outside of the tumor. Although genetic and epigenetic alterations have been previously observed in the field of carcinogenesis, these cells were considered morphologically normal. Our data show organ-wide alteration in cell nanoarchitecture. This seems to be a general event in carcinogenesis, which is supported by our data in three types of cancer: colon, pancreatic, and lung. These results have important implications in that PWS can be used as a new method to identify patients harboring malignant or premalignant tumors by interrogating easily accessible tissue sites distant from the location of the lesion.

Field carcinogenesis detection represents a promising means for colorectal cancer (CRC) screening, although current techniques (e.g., flexible sigmoidoscopy) lack the requisite sensitivity. The novel optical technology low-coherence enhanced backscattering (LEBS) spectroscopy, allows identification of microscale architectural consequences of the field carcinogenesis in preclinical CRC models with unprecedented accuracy. To investigate the potential clinical translatability of this approach, we obtained biopsies from the normalappearing rectal mucosa from patients undergoing colonoscopy (n = 219). LEBS signals were recorded through a bench-top instrument. Four parameters characterizing LEBS signal were linearly combined into a single marker. We found that LEBS signal parameters generally mirrored neoplasia progression from patients with no neoplasia, to 5 to 9 mm adenoma and to advanced adenomas. The composite LEBS marker calculated from the LEBS signal paralleled this risk status (ANOVA P < 0.001). Moreover, this was independent of CRC risk factors, benign colonic findings, or clinically unimportant lesions (diminutive adenomas, hyperplastic polyps). For advanced adenomas, the LEBS marker had a sensitivity of 100%, specificity of 80%, and area under the receiver operator characteristic curve of 0.895. Leave-oneout cross-validation and an independent data set (n = 51) supported the robustness of these findings. In conclusion, we provide the first demonstration that LEBS-detectable alterations in the endoscopically normal rectum were associated with the presence of neoplasia located elsewhere in the colon. This study provides the proof of concept that rectal LEBS analysis may potentially provide a minimally intrusive CRC screening technique. Further studies with an endoscopically compatible fiber optic probe are under way for multicenter clinical validation. [Cancer Res 2009;69(10):4476-83]

Abstract-␤-Adrenergic receptors (␤AR) regulate active Na ϩ transport in the alveolar epithelium and accelerate clearance of excess airspace fluid. Accumulating data indicates that the cystic fibrosis transmembrane conductance regulator (CFTR) is important for upregulation of the active ion transport that is needed to maintain alveolar fluid homeostasis during pulmonary edema. We hypothesized that ␤AR regulation of alveolar active transport may be mediated via a CFTR dependent pathway. To test this hypothesis we used a recombinant adenovirus that expresses a human CFTR cDNA (adCFTR) to increase CFTR function in the alveolar epithelium of normal rats and mice. Alveolar fluid clearance (AFC), an index of alveolar active Na ϩ transport, was 92% greater in CFTR overexpressing lungs than controls. Addition of the Cl Ϫ channel blockers NPPB, glibenclamide, or bumetanide and experiments using Cl Ϫ free alveolar instillate solutions indicate that the accelerated AFC in this model is due to increased Cl Ϫ channel function. Conversely, CFTR overexpression in mice with no ␤ 1 -or ␤ 2 -adrenergic receptors had no effect on AFC. Overexpression of a human ␤ 2 AR in the alveolar epithelium significantly increased AFC in normal mice but had no effect in mice with a non-functional human CFTR gene (⌬508 mutation). These studies indicate that upregulation of alveolar CFTR function speeds clearance of excess fluid from the airspace and that CFTRs effect on active Na ϩ transport requires the ␤AR. These studies reveal a previously undetected interdependency between CFTR and ␤AR that is essential for upregulation of active Na

There has been a significant interest in developing depth-selective optical interrogation of biological tissue in general and superficial (e.g. mucosal) tissue in particular. We report an in vivo polarization gating fiber-optic probe that obtains backscattering spectroscopic measurements from a range of near-surface depths (100µm -200µm). The design and testing was performed with polarized light Monte Carlo simulations and in tissue model experiments. We used the probe to investigate mucosal changes in early carcinogenesis. Measurements performed in the colonic mucosa of 125 human subjects provide the first in vivo evidence that mucosal blood supply is increased early in carcinogenesis not only in precancerous adenomatous lesions but also in the histologically normalappearing tissue surrounding these lesions. This effect was primarily limited to the mucosal microcirculation and was not present in the larger blood vessels located deeper in colonic tissue.