Michael A. Short

Real‐time in vivo cancer diagnosis using raman spectroscopy

Raman spectroscopy has becoming a practical tool for rapid in vivo tissue diagnosis. This paper provides an overview on the latest development of real-time in vivo Raman systems for cancer detection. Instrumentation, data handling, as well as oncology applications of Raman techniques were covered. Optic fiber probes designs for Raman spectroscopy were discussed. Spectral data pre-processing, feature extraction, and classification between normal/benign and malignant tissues were surveyed. Applications of Raman techniques for clinical diagnosis for different types of cancers, including skin cancer, lung cancer, stomach cancer, oesophageal cancer, colorectal cancer, cervical cancer, and breast cancer, were summarized. Schematic of a real-time Raman spectrometer for skin cancer detection. Without correction, the image captured on CCD camera for a straight entrance slit has a curvature. By arranging the optic fiber array in reverse orientation, the curvature could be effectively corrected.

Parameters defining the potential applicability of Raman spectroscopy as a diagnostic tool for oral disease

Raman spectroscopy can provide information about the molecular composition of tissues, with potential to be applied as a diagnostic tool in lieu of histopathology. Our objectives are to determine if laser Raman spectra (RS) can be acquired reliably from the oral mucosa of patients, and to determine if the RS signature of normal oral mucosa is reproducible among anatomic oral sites and among subjects of different races and gender. 25 Caucasian and 26 Asian subjects are studied using RS with a signal acquisition time of 1 s at seven specified sites within the mouth. Multivariate analysis is used to determine the variability between tissue types and between races and gender. Unique spectra are defined for various sites in the mouth and are likely related to the degree of keratinization. However, spectral concordance by site is not greatly influenced by subject ethnicity or gender. We demonstrate, for the first time, the potential in-vivo application of RS for oral mucosal disease and demonstrate its specificity for particular mucosal types in the mouth. RS offers the potential to provide a diagnosis of disease using a noninvasive, convenient, sensitive technology that provides immediate results.

Pilot study: Raman spectroscopy in differentiating premalignant and malignant oral lesions from normal mucosa and benign lesions in humans

Current practice for differentiating tissue lesions are based on histopathological criteria. This process is subject to error. The purpose of this study was to test whether an alternative, tissue‐based molecular signatures Raman spectra could be used to differentiate premalignant and malignant lesions from normal mucosa or benign lesions.

Using high frequency Raman spectra for colonic neoplasia detection.

Raman systems have tremendous potential as adjunct devices for endoscopes to improve the identification of early colon cancers. However, the traditional low frequency (LF) measurement range has several obstacles that make it challenging to develop a routine clinical tool. An alternative is to use high frequency (HF) range. To test this idea Raman spectra were obtained in both the LF and HF ranges from the same colon lesions. Multivariate analyses predicted the pathology with high sensitivity and specificity for both the LF and HF data sets. This suggests that Raman systems that measure HF spectra, and are simpler to adopt into the clinic, could be used in vivo to improve the identification of neoplastic lesions.

Real-time endoscopic Raman spectroscopy for in vivo early lung cancer detection

Currently the most sensitive method for localizing lung cancers in central airways is autofluorescence bronchoscopy (AFB) in combination with white light bronchoscopy (WLB). The diagnostic accuracy of WLBxa0+xa0AFB for high grade dysplasia (HGD) and carcinoma in situ is variable depending on physicians experience. When WLBxa0+xa0AFB are operated at high diagnostic sensitivity, the associated diagnostic specificity is low. Raman spectroscopy probes molecular vibrations and gives highly specific, fingerprint-like spectral features and has high accuracy for tissue pathology classification. In this study we present the use of a real-time endoscopy Raman spectroscopy system to improve the specificity. A spectrum is acquired within 1 second and clinical data are obtained from 280 tissue sites (72 HGDs/malignant lesions, 208 benign lesions/normal sites) in 80 patients. Using multivariate analyses and waveband selection methods on the Raman spectra, we have demonstrated that HGD and malignant lung lesions can be detected with high sensitivity (90%) and good specificity (65%).

Development and in vivo testing of a high frequency endoscopic Raman spectroscopy system for potential applications in the detection of early colonic neoplasia.

The objective of this study was to build and test an adjunct system to a colonoscope for in vivo measurement of Raman spectra from colon tissue for potentially improving the detection of early cancers. The novelty of this system was that low cost fibre optic probes were used, without the addition of expensive optical filters. Good quality in vivo Raman spectra were successfully obtained with a 1 s integration time in the high frequency (HF) range from normal tissue and polyps of patients during a colonoscopy. The polyps were subsequently removed, and their pathology determined. The acquired in vivo Raman spectra showed clear changes between tissue with normal and tubular adenoma pathology. Further clinical study with this low cost HF Raman probe is warranted to fully test its clinical utility.

Improvements to a laser Raman spectroscopy system for reducing the false positives of autofluorescence bronchoscopies

Preneoplastic lesions of the bronchial tree have a high probability of developing into malignant tumours. Currently the best method for localizing them for further treatment is a combined white light and autofluorescence bronchoscopy (WLB+AFB). Unfortunately the average specificity from large clinical trials for this combined detection method is low at around 60%, which can result in many false positives. However a recent pilot study showed that adding a point laser Raman spectroscopy (LRS) measurement improved the specificity of detecting lesions with high grade dysplasia or carcinoma in situ to 91% with a sensitivity of 96% compared to WLB+AFB alone. Despite this success, there is still room for much improvement. One constant need is to find better ways to measure the inherently weak Raman emissions in vivo which will result in even better diagnostic sensitivity and specificity. With this aim in mind a new generation Raman system was developed. The system uses the latest charge coupled device (CCD) with low noise, and fast cool down times. A spectrometer was incorporated that was able to measure both the low and high frequency Raman emissions with high resolution. The Raman catheter was also redesigned to include a visible light channel to facilitate the accurate indication of the area being measured. Here the benefits in the adjunct use of LRS to WLB + AFB are presented, and description of the new system and the improvements it offers over the old system are shown.

Disposable sheath that facilitates endoscopic Raman spectroscopy

Abstract. In vivo endoscopic Raman spectroscopy of human tissue using a fiber optic probe has been previously demonstrated. However, there remain several technical challenges, such as a robust control over the laser radiation dose and measurement repeatability during endoscopy. A decrease in the signal to noise was also observed due to aging of Raman probe after repeated cycles of harsh reprocessing procedures. To address these issues, we designed and tested a disposable, biocompatible, and sterile sheath for use with a fiber optic endoscopic Raman probe. The sheath effectively controls contamination of Raman probes between procedures, greatly reduces turnaround time, and slows down the aging of the Raman probes. A small optical window fitted at the sheath cap maintained the measurement distance between Raman probe end and tissue surface. To ensure that the sheath caused a minimal amount of fluorescence and Raman interference, the optical properties of materials for the sheath, optical window, and bonding agent were studied. The easy-to-use sheath can be manufactured at a moderate cost. The sheath strictly enforced a maximum permissible exposure standard of the tissue by the laser and reduced the spectral variability by 1.5 to 8.5 times within the spectral measurement range.

Clinical utility of Raman spectroscopy: current applications and ongoing developments

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In Vivo Real-time Endoscopic Raman Spectroscopy for Improving Early Lung Cancer Detection

A real-time endoscopic Raman spectroscopy system has been developed that takes 1 second to obtain a spectrum from the human lung in vivo. The system was tested on 80 patients, achieved high diagnostic sensitivity (90%) and good specificity (65%) for lung cancer/precancer detection.