We report an integrated Raman spectroscopy and trimodal (white-light reflectance, autofluorescence, and narrow-band) imaging techniques for real-time in vivo tissue Raman measurements at endoscopy. A special 1.8 mm endoscopic Raman probe with filtering modules is developed, permitting effective elimination of interference of fluorescence background and silica Raman in fibers while maximizing tissue Raman collections. We demonstrate that high-quality in vivo Raman spectra of upper gastrointestinal tract can be acquired within 1 s or subseconds under the guidance of wide-field endoscopic imaging modalities, greatly facilitating the adoption of Raman spectroscopy into clinical research and practice during routine endoscopic inspections.

Coordinate control of different classes of cyclins is fundamentally important for cell cycle regulation and tumor suppression, yet the underlying mechanisms are incompletely understood. Here we show that the PARK2 tumor suppressor mediates this coordination. The PARK2 E3 ubiquitin ligase coordinately controls the stability of both cyclin D and cyclin E. Analysis of approximately 5,000 tumor genomes shows that PARK2 is a very frequently deleted gene in human cancer and uncovers a striking pattern of mutual exclusivity between PARK2 deletion and amplification of CCND1, CCNE1 or CDK4—implicating these genes in a common pathway. Inactivation of PARK2 results in the accumulation of cyclin D and acceleration of cell cycle progression. Furthermore, PARK2 is a component of a new class of cullin-RING-containing ubiquitin ligases targeting both cyclin D and cyclin E for degradation. Thus, PARK2 regulates cyclin-CDK complexes, as does the CDK inhibitor p16, but acts as a master regulator of the stability of G1/S cyclins.

BRAF mutation-positive PTMCs were more likely to manifest aggressive characteristics (extrathyroidal extension and LNM). The BRAF mutation screening of FNAB specimens can be used to predict aggressive clinicopathological characteristics of PTMC. Lateral neck nodes should be meticulously analyzed for cases of PTMC demonstrating the following three characteristics: BRAF mutation, central LNM, and US features in the upper pole location.

The aim of this work was to evaluate the biochemical foundation and clinical merit of multimodal image-guided Raman endoscopy technique for real-time in vivo diagnosis of cancer in the esophagus during clinical endoscopic examinations. A novel fiber-optic Raman endoscopy system was utilized for in vivo esophageal Raman measurements at 785 nm laser excitation within 0.5 second under the multimodal wide-field endoscopic imaging (white light reflectance (WLR) imaging, narrow-band imaging (NBI) and autofluorescence imaging (AFI) guidance. A total of 75 esophageal tissue sites from 27 patients were measured, in which 42 in vivo Raman spectra were from normal tissues and 33 in vivo Raman spectra were from malignant tumors as confirmed by histopathology. The biomolecular modeling (non-negativity-constrained least-squares minimization (NNCLSM) utilizing six basis reference spectra from the representative biochemicals (i.e., actin, collagen, DNA, histones, triolein and glycogen) were employed to estimate the biochemical compositions of esophageal tissue. The resulting diagnostically significant fit coefficients were further utilized through linear discriminant analysis (LDA) and leave-one tissue site-out, cross validation method to develop diagnostic algorithms for esophageal cancer diagnosis. High-quality in vivo Raman spectra in the range of 800-1800 cm-1 can be acquired from normal and cancerous esophageal mucosa in real-time under multimodal endoscopic imaging guidance. Esophageal cancer tissue showed distinct Raman signals mainly associated with cell proliferation, lipid reduction, abnormal nuclear activity and neovasculation. The fit coefficients for actin, DNA, histones, triolein, and glycogen were found to be most significant for construction of the LDA diagnostic model, giving rise to an accuracy of 96.0% (i.e., sensitivity of 97.0% and specificity of 95.2%) for in vivo diagnosis of esophageal cancer. This study demonstrates that multimodal image-guided Raman endoscopy technique in conjunction with biomolecular modeling has promising potential for the real-time, in vivo diagnosis and detection of esophageal cancer during clinical endoscopic examination.

The aim of this study was to evaluate the clinical utility of an image-guided Raman endoscopy technique for in vivo differential diagnosis of benign and malignant ulcerous lesions in the stomach. A rapid-acquisition image-guided Raman endoscopy system with 785 nm laser excitation has been developed to acquire in vivo gastric tissue Raman spectra within 0.5 s during clinical gastroscopic examinations. A total of 1102 in vivo Raman spectra were acquired from 71 gastric patients, in which 924 Raman spectra were from normal tissue, 111 Raman spectra were from benign ulcers whereas 67 Raman spectra were from ulcerated adenocarcinoma. There were distinctive spectral differences in Raman spectra among normal mucosa, benign ulcers and malignant ulcers, particularly in the spectral ranges of 800-900, 1000-1100, 1245-1335, 1440-1450 and 1500-1800 cm(-1), which primarily contain signals related to proteins, DNA, lipids and blood. The malignant ulcerous lesions showed Raman signals to be mainly associated with abnormal nuclear activity and decrease in lipids as compared to benign ulcers. Partial least squares-discriminant analysis (PLS-DA) was employed to generate multi-class diagnostic algorithms for classification of Raman spectra of different gastric tissue types. The PLS-DA algorithms together with leave-one tissue site-out, cross validation technique yielded diagnostic sensitivities of 90.8%, 84.7%, 82.1%, and specificities of 93.8%, 94.5%, 95.3%, respectively, for classification of normal mucosa, benign and malignant ulcerous lesions in the stomach. This work demonstrates that image-guided Raman endoscopy technique associated with PLS-DA diagnostic algorithms has for the first time promising clinical potential for rapid, in vivo diagnosis and detection of malignant ulcerous gastric lesions at the molecular level.

Colorectal cancer can be prevented if detected early (e.g., precancerous polyps-adenoma). Endoscopic differential diagnosis of hyperplastic polyps (that have little or no risk of malignant transformation) and adenomas (that have prominent malignant latency) remains an unambiguous clinical challenge. Raman spectroscopy is an optical vibrational technique capable of probing biomolecular changes of tissue associated with neoplastic transformation. This work aims to apply a fiber-optic simultaneous fingerprint (FP) and high wavenumber (HW) Raman spectroscopy technique for real-time in vivo assessment of adenomatous polyps during clinical colonoscopy. We have developed a fiber-optic Raman endoscopic technique capable of simultaneously acquiring both the FP (i.e., 800-1800 cm(-1)) and HW (i.e., 2800-3600 cm(-1)) Raman spectra from colorectal tissue subsurface (<200 µm) for real-time assessment of colorectal carcinogenesis. In vivo FP/HW Raman spectra were acquired from 50 patients with 17 colorectal polyps during clinical colonoscopy. Prominent Raman spectral differences (p < 0.001) were found between hyperplastic (n = 118 spectra), adenoma (n = 184 spectra) that could be attributed to changes in inter- and intra-cellular proteins, lipids, DNA and water structures and conformations. Simultaneous FP/HW Raman endoscopy provides a diagnostic sensitivity of 90.9% and specificity of 83.3% for differentiating adenoma from hyperplastic polyps, which is superior to either the FP or HW Raman technique alone. This study shows that simultaneous FP/HW Raman spectroscopy technique has the potential to be a clinically powerful tool for improving early diagnosis of adenomatous polyps in vivo during colonoscopic examination.

Abstract. We first report on the implementation of a novel narrowband image-guided Raman endoscopy technique for in vivo diagnosis of gastric dysplasia. High-quality in vivo Raman spectra can be acquired from normal and dysplastic gastric mucosal tissue within 0.5 sec under narrow-band image ͑NBI͒ guidance at gastroscopy. Significant differences are observed in in vivo Raman spectra between normal ͑n =54͒ and dysplastic ͑n =18͒ gastric tissue from 30 gastric patients, particularly in the spectral ranges of 825 to 950, 1000 to 1100, 1250 to 1500, and 1600 to 1800 cm −1 , which primarily contain signals related to proteins, nucleic acids, and lipids. The multivariate analysis ͓i.e., principal components analysis ͑PCA͒ and linear discriminant analysis ͑LDA͔͒, together with the leave-one tissue siteout, cross validation on in vivo gastric Raman spectra yields a diagnostic sensitivity of 94.4% ͑17/ 18͒ and specificity of 96.3% ͑52/ 54͒ for distinction of gastric dysplastic tissue. This study suggests that narrowband image-guided Raman endoscopy associated with PCA-LDA diagnostic algorithms has potential for the noninvasive, in vivo early diagnosis and detection of gastric precancer during clinical gastroscopic examination.

This study aims to evaluate the clinical utility of image-guided Raman endoscopy for in vivo diagnosis of neoplastic lesions in the stomach at gastroscopy. A rapid-acquisition image-guided Raman endoscopy system with 785-nm excitation has been developed to acquire in vivo gastric tissue Raman spectra within 0.5 sec during clinical gastroscopic examinations. A total of 1,063 in vivo Raman spectra were acquired from 238 tissue sites of 67 gastric patients, in which 934 Raman spectra were from normal tissue whereas 129 Raman spectra were from neoplastic gastric tissue. The swarm intelligence-based algorithm (i.e., ant colony optimization (ACO) integrated with linear discriminant analysis (LDA)) was developed for spectral variables selection to identify the biochemical important Raman bands for differentiation between normal and neoplastic gastric tissue. The ACO-LDA algorithms together with the leave-one tissue site-out, cross validation method identified seven diagnostically important Raman bands in the regions of 850-875, 1,090-1,110, 1,120-1,130, 1,170-1,190, 1,320-1,340, 1,655-1,665 and 1,730-1,745 cm 21 related to proteins, nucleic acids and lipids of tissue and provided a diagnostic sensitivity of 94.6% and specificity of 94.6% for distinction of gastric neoplasia. The predictive sensitivity of 89.3% and specificity of 97.8% were also achieved for an independent test validation dataset (20% of total dataset). This work demonstrates for the first time that the real-time image-guided Raman endoscopy associated with ACO-LDA diagnostic algorithms has potential for the noninvasive, in vivo diagnosis and detection of gastric neoplasia during clinical gastroscopy.