[Show abstract][Hide abstract] ABSTRACT: Importance
The prevalence of genetically altered cells in oral cancers has a negative influence on the locoregional recurrence rate and lowers survival. Fluorescence visualization (FV) can identify clinically occult, high-risk oral lesions by allowing health care professionals and surgeons to visualize and map occult disease. This process may improve overall survival by decreasing rates of locoregional recurrence.Objective
To assess the efficacy of FV-guided surgery in reducing locoregional recurrence and improving overall survival.Design, Setting, and Participants
A retrospective, case-control observational study was conducted on patients registered at a single oral oncology clinic from September 1, 2004, to August 31, 2009. The study included 246 patients 18 years or older with a diagnosis of a high-grade lesion (severe dysplasia or carcinoma in situ) or squamous cell carcinoma of less than 4 cm who underwent curative surgical treatment with at least 1 follow-up visit. Among these patients, 154 underwent surgery with FV guidance (FV group) and the other 92 underwent conventional surgery (control group). Demographic and lesional characteristics and outcomes were collected, and the key factors for the efficacy of FV-guided surgery were examined. Follow-up was completed on December 31, 2011, and data were analyzed from May 1 to November 30, 2013.Main Outcomes and Measures
Local recurrence of oral lesions with a histologic grade of severe dysplasia or higher, the presence of regional failure (ie, a metastatic lesion in the cervical lymph nodes), or disease-free survival after surgery.Results
Among the 246 patients included in the study (mean [SD] age, 60  years; 108 women and 138 men), 156 had squamous cell carcinoma and 90 had high-grade lesions. There were no significant differences between the FV (n = 154) and control (n = 92) groups in age, smoking history, anatomical site of the lesion, tumor size, and previous oral cancer. Among the 156 patients with squamous cell carcinoma, the 92 patients in the FV group showed significant reduction in the 3-year local recurrence rate, from 40.6% (26 of 64 patients) to 6.5% (6 of 92 patients) (P < .001). Among the 90 patients with high-grade lesions, the 62 patients in the FV group showed a reduction in local recurrence rate from 11 of 28 patients (39.3%) to 5 of 62 patients (8.1%) (P < .001). The data also indicated that, compared with conventional surgery, the FV-guided approach for squamous cell carcinoma was associated with less regional failure (14 of 92 patients [15.2%] vs 16 of 64 [25.0%]; P = .08) and death (12 of 92 patients [13.0%] vs 13 of 64 [20.3%]; P = .22), although these differences were not statistically significant.Conclusions and Relevance
In this study, the use of FV as part of the surgical margin decision process significantly reduced the rate of local recurrence in preinvasive high-grade and early-stage oral cancers. An ongoing multicenter, phase 3, randomized surgical trial has completed accrual, and the data will be used to validate the results of this study.
No preview · Article · Jan 2016 · JAMA Otolaryngology - Head and Neck Surgery
[Show abstract][Hide abstract] ABSTRACT: Background:
Cervical cancer remains a major health problem, especially in developing countries. Colposcopic examination is used to detect high-grade lesions in patients with a history of abnormal pap smears. New technologies are needed to improve the sensitivity and specificity of this technique. We propose to test the potential of fluorescence confocal microscopy to identify high-grade lesions.
We examined the quantification of ex vivo confocal fluorescence microscopy to differentiate among normal cervical tissue, low-grade Cervical Intraepithelial Neoplasia (CIN), and high-grade CIN. We sought to (1) quantify nuclear morphology and tissue architecture features by analyzing images of cervical biopsies; and (2) determine the accuracy of high-grade CIN detection via confocal microscopy relative to the accuracy of detection by colposcopic impression. Forty-six biopsies obtained from colposcopically normal and abnormal cervical sites were evaluated. Confocal images were acquired at different depths from the epithelial surface and histological images were analyzed using in-house software.
The features calculated from the confocal images compared well with those features obtained from the histological images and histopathological reviews of the specimens (obtained by a gynecologic pathologist). The correlations between two of these features (the nuclear-cytoplasmic ratio and the average of three nearest Delaunay-neighbors distance) and the grade of dysplasia were higher than that of colposcopic impression. The sensitivity of detecting high-grade dysplasia by analysing images collected at the surface of the epithelium, and at 15 and 30 μm below the epithelial surface were respectively 100, 100, and 92 %.
Quantitative analysis of confocal fluorescence images showed its capacity for discriminating high-grade CIN lesions vs. low-grade CIN lesions and normal tissues, at different depth of imaging. This approach could be used to help clinicians identify high-grade CIN in clinical settings.
Full-text · Article · Oct 2015 · BioMedical Engineering OnLine
[Show abstract][Hide abstract] ABSTRACT: We present the first endoscopic Doppler optical coherence tomography and co-registered autofluorescence imaging (DOCT-AFI) of peripheral pulmonary nodules and vascular networks in vivo using a small 0.9 mm diameter catheter. Using exemplary images from volumetric data sets collected from 31 patients during flexible bronchoscopy, we demonstrate how DOCT and AFI offer complementary information that may increase the ability to locate and characterize pulmonary nodules. AFI offers a sensitive visual presentation for the rapid identification of suspicious airway sites, while co-registered OCT provides detailed structural information to assess the airway morphology. We demonstrate the ability of AFI to visualize vascular networks in vivo and validate this finding using Doppler and structural OCT. Given the advantages of higher resolution, smaller probe size, and ability to visualize vasculature, DOCT-AFI has the potential to increase diagnostic accuracy and minimize bleeding to guide biopsy of pulmonary nodules compared to radial endobronchial ultrasound, the current standard of care.
No preview · Article · Oct 2015 · Biomedical Optics Express
[Show abstract][Hide abstract] ABSTRACT: Diagnosis of peripheral lung nodules is challenging because they are rarely visualized endobronchially. Imaging techniques such as endobronchial ultrasound (EBUS) are employed to improve tumor localization. The current EBUS probe provides limited nodule characterization and has an outer diameter of 1.4 mm that restricts access to small peripheral airways. We report a novel co-registered autofluoresence Doppler optical coherence tomography (AF/DOCT) system with a 0.9 mm diameter probe to characterize peripheral lung nodules prior to biopsy in vivo. Method: Patients referred for evaluation of peripheral lung nodules underwent bronchoscopy with examination of standard EBUS and the novel AF/DOCT system. The lesion of interest was first identified with EBUS and then imaged with the AF/DOCT system. The abnormal area was biopsied. AF/DOCT images of pathology proved lung malignancies were reviewed by a panel of a pathologist, respirologists, and AF/DOCT experts. Results: Eleven patients with biopsy proven lung cancer underwent examination with AF/DOCT. The majority of the cancers were adenocarcinoma. AF/DOCT images were obtained in all patients. There were no complications to the procedures. Lung abnormalities visualized in AF/OCT images were observed in 11 cases. In one case large blood vessels were identified and biopsy was avoided. Conclusion: In this pilot study, AF/DOCT obtained high quality images of peripheral pulmonary nodules. The present study supports the safety and feasibility of AF/DOCT for the evaluation of lung cancer. The addition of Doppler information may improve biopsy site selection and reduce hemorrhage.
[Show abstract][Hide abstract] ABSTRACT: We have built a polarization-sensitive swept source Optical Coherence Tomography (OCT) instrument capable of wide-field in vivo imaging in the oral cavity. This instrument uses a hand-held side-looking fiber-optic rotary pullback catheter that can cover two dimensional tissue imaging fields approximately 2.5 mm wide by up to 90 mm length in a single image acquisition. The catheter spins at 100 Hz with pullback speeds up to 15 mm/s allowing imaging of areas up to 225 mm(2) field-of-view in seconds. A catheter sheath and two optional catheter sheath holders have been designed to allow imaging at all locations within the oral cavity. Image quality of 2-dimensional image slices through the data can be greatly enhanced by averaging over the orthogonal dimension to reduce speckle. Initial in vivo imaging results reveal a wide-field view of features such as epithelial thickness and continuity of the basement membrane that may be useful in clinic for chair-side management of oral lesions.
[Show abstract][Hide abstract] ABSTRACT: DNA ploidy analysis involves automated quantification of chromosomal aneuploidy, a potential marker of progression toward cervical carcinoma. We evaluated the cost-effectiveness of this method for cervical screening, comparing five ploidy strategies (using different numbers of aneuploid cells as cut points) with liquid-based Papanicolaou smear and no screening.
A state-transition Markov model simulated the natural history of HPV infection and possible progression into cervical neoplasia in a cohort of 12-year-old females. The analysis evaluated cost in 2012 US$ and effectiveness in quality-adjusted life-years (QALYs) from a health-system perspective throughout a lifetime horizon in the US setting. We calculated incremental cost-effectiveness ratios (ICERs) to determine the best strategy. The robustness of optimal choices was examined in deterministic and probabilistic sensitivity analyses.
In the base-case analysis, the ploidy 4 cell strategy was cost-effective, yielding an increase of 0.032 QALY and an ICER of $18 264/QALY compared to no screening. For most scenarios in the deterministic sensitivity analysis, the ploidy 4 cell strategy was the only cost-effective strategy. Cost-effectiveness acceptability curves showed that this strategy was more likely to be cost-effective than the Papanicolaou smear.
Compared to the liquid-based Papanicolaou smear, screening with a DNA ploidy strategy appeared less costly and comparably effective.British Journal of Cancer advance online publication, 28 April 2015; doi:10.1038/bjc.2015.95 www.bjcancer.com.
Preview · Article · Apr 2015 · British Journal of Cancer
[Show abstract][Hide abstract] ABSTRACT: This work reports a fiber optic-based endoscopic imaging system capable of combined Doppler optical coherence tomography (DOCT) and autofluorescence (AF) imaging. The two key components in this dual-modality imaging system are a specially designed three-port wavelength multiplexing fiber optic rotary joint (FORJ) and a custom 900 μm diameter double-clad fiber (DCF) catheter. The three-port FORJ combines the two imaging modalities efficiently with more than 83% throughput for collected AF emission and the DCF catheter allows endoscopic coregistered DOCT and AF imaging. Endoscopic DOCT and AF imaging of small human airways in vivo is presented to demonstrate the performance of the system.
[Show abstract][Hide abstract] ABSTRACT: Although the Papanicolaou smear has been successful in decreasing cervical cancer incidence in the developed world, there exist many challenges for implementation in the developing world. Quantitative cytology, a semi-automated method that quantifies cellular image features, is a promising screening test candidate. The nested structure of its data (measurements of multiple cells within a patient) provides challenges to the usual classification problem. Here we perform a comparative study of three main approaches for problems with this general data structure: (i) extract patient-level features from the cell-level data, (ii) use a statistical model that accounts for the hierarchical data structure, and (iii) classify at the cellular level and use an ad hoc approach to classify at the patient level. We apply these methods to a dataset of 1728 patients, with an average of 2600 cells collected per patient and 133 features measured per cell, predicting whether a patient had a positive biopsy result. The best approach we found was to classify at the cellular level and count the number of cells that had a posterior probability greater than a threshold value, with estimated 61% sensitivity and 89% specificity on independent data. Recent statistical learning developments allowed us to achieve high accuracy.
Full-text · Article · Apr 2015 · Statistical Analysis and Data Mining
[Show abstract][Hide abstract] ABSTRACT: Volatile Organic Compounds (VOC) in exhaled breath as measured by electronic nose (e-nose) have utility as biomarkers to detect subjects at ris of having lung cancer in a screening setting. We hypothesize that breath analysis using an e-nose chemo-resistive sensor array could be used as a screening tool to discriminate patients diagnosed with lung cancer from high-risk smokers.
Breath samples from 191 subjects - 25 lung cancer patients and 166 high-risk smoker control subjects without cancer - were analyzed. For clinical relevancy, subjects in both groups were matched for age, sex, and smoking histories. Classification and Regression Trees and Discriminant Functions classifiers were used to recognize VOC patterns in e-nose data. Cross-validated results were used to assess classification accuracy. Repeatability and reproducibility of e-nose data were assessed by measuring subject-exhaled breath in parallel across two e-nose devices.
E-nose measurements could distinguish lung cancer patients from high-risk control subjects, with a better than 80% classification accuracy. Subject sex and smoking status impacted classification as area under the curve results (ex-smoker males 0.846, ex-smoker female 0.816, current smoker male 0.745 and current smoker female 0.725) demonstrated. Two e-nose systems could be calibrated to give equivalent readings across subject-exhaled breath measured in parallel.
E-nose technology may have significant utility as a non-invasive screening tool for detecting individuals at increased risk for lung cancer.
The results presented further the case that VOC patterns could have real clinical utility to screen for lung cancer in the important growing ex-smoker population.
No preview · Article · Mar 2015 · IEEE transactions on bio-medical engineering
[Show abstract][Hide abstract] ABSTRACT: Polarization Sensitive Optical Coherence Tomography (PSOCT) is a functional extension of Optical Coherence Tomography (OCT) that is sensitive to well-structured, birefringent tissue such as scars, smooth muscle and cartilage. In this work, we present a novel completely fiber based swept source PSOCT system using a fiber-optic rotary pullback catheter. This PSOCT implementation uses only passive optical components and requires no calibration while adding minimal additional cost to a standard structural OCT imaging system. Due to its complete fiber construction, the system can be made compact and robust, while the fiber-optic catheter allows access to most endoscopic imaging sites. The 1.5mm diameter endoscopic probe can capture 100 frames per second at pullback speeds up to 15 mm/s allowing rapid traversal of large imaging fields. We validate the PSOCT system with known birefringent tissues and demonstrate in vivo PSOCT imaging of human oral scar tissue.
[Show abstract][Hide abstract] ABSTRACT: We examined and established the potential of ex-vivo confocal fluorescence microscopy for differentiating between normal cervical tissue, low grade Cervical Intraepithelial Neoplasia (CIN1), and high grade CIN (CIN2 and CIN3). Our objectives were to i) use Quantitative Tissue Phenotype (QTP) analysis to quantify nuclear and cellular morphology and tissue architecture in confocal microscopic images of fresh cervical biopsies and ii) determine the accuracy of high grade CIN detection via confocal microscopy. Cervical biopsy specimens of colposcopically normal and abnormal tissues obtained from 15 patients were evaluated by confocal fluorescence microscopy. Confocal images were analyzed and about 200 morphological and architectural features were calculated at the nuclear, cellular, and tissue level. For the purpose of this study, we used four features to delineate disease grade including nuclear size, cell density, estimated nuclear-cytoplasmic (ENC) ratio, and the average of three nearest Delaunay neighbors distance (3NDND). Our preliminary results showed ENC ratio and 3NDND correlated well with histopathological diagnosis. The Spearman correlation coefficient between each of these two features and the histopathological diagnosis was higher than the correlation coefficient between colposcopic appearance and histopathological diagnosis. Sensitivity and specificity of ENC ratio for detecting high grade CIN were both equal to 100%. QTP analysis of fluorescence confocal images shows the potential to discriminate high grade CIN from low grade CIN and normal tissues. This approach could be used to help clinicians identify HGSILs in clinical settings.
[Show abstract][Hide abstract] ABSTRACT: For the first time, we present co-registered autofluorescence imaging and optical coherence tomography (AF/OCT) of excised human palatine tonsils to evaluate the capabilities of OCT to visualize tonsil tissue components. Despite limited penetration depth, OCT can provide detailed structural information about tonsil tissue with much higher resolution than that of computed tomography, magnetic resonance imaging, and Ultrasound. Different tonsil tissue components such as epithelium, dense connective tissue, lymphoid nodules, and crypts can be visualized by OCT. The co-registered AF imaging can provide matching biochemical information. AF/OCT scans may provide a non-invasive tool for detecting tonsillar cancers and for studying the natural history of their development.
[Show abstract][Hide abstract] ABSTRACT: Cigarette smoke is associated with the majority of lung cancers: however, 25% of lung cancer patients are non-smokers, and half of all newly diagnosed lung cancer patients are former smokers. Lung tumors exhibit distinct epidemiological, clinical, pathological, and molecular features depending on smoking status, suggesting divergent mechanisms underlie tumorigenesis in smokers and non-smokers. MicroRNAs (miRNAs) are integral contributors to tumorigenesis and mediate biological responses to smoking. Based on the hypothesis that smoking-specific miRNA differences in lung adenocarcinomas reflect distinct tumorigenic processes selected by different smoking and non-smoking environments, we investigated the contribution of miRNA disruption to lung tumor biology and patient outcome in the context of smoking status.
We applied a whole transcriptome sequencing based approach to interrogate miRNA levels in 94 patient-matched lung adenocarcinoma and non-malignant lung parenchymal tissue pairs from current, former and never smokers.
We discovered novel and distinct smoking status-specific patterns of miRNA and miRNA-mediated gene networks, and identified miRNAs that were prognostically significant in a smoking dependent manner.
We conclude that miRNAs disrupted in a smoking status-dependent manner affect distinct cellular pathways and differentially influence lung cancer patient prognosis in current, former and never smokers. Our findings may represent promising biologically relevant markers for lung cancer prognosis or therapeutic intervention.
[Show abstract][Hide abstract] ABSTRACT: Purpose:
DNA ploidy analysis, a semi-automated process, has been proposed as a potential alternative for cervical screening; however, this strategy has not been evaluated economically. Our study examined the cost-effectiveness of ploidy analysis in comparison to liquid-based Papanicolaou (Pap) smear in the screening setting.
The use of ploidy was examined with five thresholds corresponding to the number (from 1 to 5) of aneuploid cells in a specimen. For example, the ploidy 3 cell strategy rendered a specimen abnormal if at least 3 aneuploid cells were found. We compared these five ploidy strategies and the liquid-based Pap smear with a no screening strategy as the reference. We developed a state-transition Markov model to simulate the natural history of HPV infection and possible progression into cervical neoplasia in a hypothetical cohort of 12-year-old females (started triennial screening from 21 years). The analysis was conducted using cost in 2012 US$ and effectiveness in quality-adjusted life-years (QALYs) from a health-system perspective throughout a lifetime horizon in the US setting. The willingness-to-pay threshold was $50,000/QALY. We calculated the incremental cost-effectiveness ratios (ICERs) for the various strategies to determine the best ploidy strategy and the overall recommended strategy. The robustness of optimal choices was examined in deterministic and probabilistic sensitivity analyses.
In the base-case analysis, the ploidy 4 cell strategy was cost-effective. It increased the quality-adjusted life expectancy by 0.083 QALY and yielded an ICER of $8,774/QALY compared to the no screening strategy. In the deterministic sensitivity analysis, the cost-effectiveness was most sensitive to the cost of the Pap smear procedure, the cost of treating high-grade squamous intraepithelial lesions, the cost of the ploidy analysis, and the ploidy strategies' operating characteristics. For most scenarios, the ploidy 4 cell strategy was cost-effective and was considered the best ploidy strategy. The cost-effectiveness acceptability curves showed that the ploidy 4 cell strategy was more likely to be cost-effective than the Pap smear strategy.
Compared to liquid-based Pap smear screening, ploidy analysis appeared less costly and comparably effective using the standard willingness-to-pay threshold. Screening for cervical neoplasia using DNA ploidy analysis may be a satisfactory alternative, particularly in low-infrastructure settings.
Figure 1. Cost-effectiveness acceptability curves comparing no screening, Papanicolaou smear screening, and the ploidy 4 cell strategy.
[Show abstract][Hide abstract] ABSTRACT: Worldwide, oral cancer is responsible for 170,000 deaths per year. Intervention to prevent this disease is a long sought after goal. Chemoprevention studies have focused on clinicopathological features of potentially malignant lesions (PML) in an effort to prevent their progression to cancer. However, prediction of future behavior for such lesions is difficult and remains a major challenge to such intervention. Different approaches to this problem have been tested in the past 20years. Early genetic progression models identified critical regions of allelic imbalance at 3p and 9p, and provided the basis for molecular markers to identify progressing PMLs. Subsequently, technological advances, such as genome-wide high-throughput array platforms, computer imaging, visualization technology and next generation sequencing, have broadened the scope for marker development and have the potential of further improving our ability to identify high-risk lesions in the near future either alone or in combination. In this article, we examine the milestones in the development of markers for PML progression. We emphasize the critical importance of networks among scientists, health professionals and community to facilitate the validation and application of putative markers into clinical practice. With a growing number of new agents to validate, it is necessary to coordinate the design and implementation of strategies for patient recruitment, integration of marker assessment, and the final translation of such approaches into clinical use.