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1.  Optical Molecular Imaging in the Gastrointestinal Tract 
Recent developments in optical molecular imaging allow for real-time identification of morphological and biochemical changes in tissue associated with gastrointestinal neoplasia. This review summarizes widefield and high resolution imaging modalities currently in pre-clinical and clinical evaluation for the detection of colorectal cancer and esophageal cancer. Widefield techniques discussed include high definition white light endoscopy, narrow band imaging, autofluoresence imaging, and chromoendoscopy; high resolution techniques discussed include probe-based confocal laser endomicroscopy, high-resolution microendoscopy, and optical coherence tomography. Finally, new approaches to enhance image contrast using vital dyes and molecular-specific targeted contrast agents are evaluated.
doi:10.1016/j.giec.2013.03.010
PMCID: PMC3746803  PMID: 23735112
optical molecular imaging; white light endoscopy; narrow band imaging; autofluorescence imaging; chromoendoscopy; confocal laser endomicroscopy; high resolution microendoscopy; optical coherence tomography
2.  In vivo diagnostic accuracy of high resolution microendoscopy in differentiating neoplastic from non-neoplastic colorectal polyps: a prospective study 
High-resolution microendoscopy (HRME) is a low-cost, “optical biopsy” technology that allows for subcellular imaging. The purpose of this study was to determine the in vivo diagnostic accuracy of the HRME for the differentiation of neoplastic from non-neoplastic colorectal polyps and compare it to that of high-definition white-light endoscopy (WLE) with histopathology as the gold standard. Three endoscopists prospectively detected a total of 171 polyps from 94 patients that were then imaged by HRME and classified in real-time as neoplastic (adenomatous, cancer) or non-neoplastic (normal, hyperplastic, inflammatory). HRME had a significantly higher accuracy (94%), specificity (95%), and positive predictive value (87%) for the determination of neoplastic colorectal polyps compared to WLE (65%, 39%, and 55%, respectively). When looking at small colorectal polyps (less than 10 mm), HRME continued to significantly outperform WLE in terms of accuracy (95% vs. 64%), specificity (98% vs. 40%) and positive predictive value (92% vs. 55%). These trends continued when evaluating diminutive polyps (less than 5 mm) as HRME's accuracy (95%), specificity (98%), and positive predictive value (93%) were all significantly greater than their WLE counterparts (62%, 41%, and 53%, respectively). In conclusion, this in vivo study demonstrates that HRME can be a very effective modality in the differentiation of neoplastic and non-neoplastic colorectal polyps. A combination of standard white-light colonoscopy for polyp detection and HRME for polyp classification has the potential to truly allow the endoscopist to selectively determine which lesions can be left in situ, which lesions can simply be discarded, and which lesions need formal histopathologic analysis.
doi:10.1038/ajg.2013.387
PMCID: PMC3947255  PMID: 24296752
Colorectal polyps; adenoma classification; microendoscopy; neoplasia; diagnostic accuracy
3.  Optical Imaging with a High Resolution Microendoscope to Identify Cholesteatoma of the Middle Ear 
The Laryngoscope  2013;123(4):1016-1020.
Objective
High resolution optical imaging is an imaging modality which allows visualization of structural changes in epithelial tissue in real time. Our prior studies using contrast-enhanced microendoscopy to image squamous cell carcinoma in the head and neck demonstrated that the contrast agent, proflavine, has high affinity for keratinized tissue. Thus, high-resolution microendoscopy with proflavine provides a potential mechanism to identify ectopic keratin production, such as that associated with cholesteatoma formation and distinguish between uninvolved mucosa and residual keratin at the time of surgery.
Study Design
Ex vivo imaging of histopathologically-confirmed samples of cholesteatoma and uninvolved middle-ear epithelium.
Methods
Seven separate specimens collected from patients who underwent surgical treatment for cholesteatoma were imaged ex vivo with the fiberoptic endoscope after surface staining with proflavine. Following imaging, the specimens were submitted for hematoxylin &eosin staining to allow histopathological correlation.
Results
Cholesteatoma and surrounding middle ear epithelium have distinct imaging characteristics. Keratin-bearing areas of cholesteatoma lack nuclei and appear as confluent hyperfluorescence, while nuclei are easily visualized in specimens containing normal middle ear epithelium. Hyperfluorescence and loss of cellular detail is the imaging hallmark of keratin allowing for discrimination of cholesteatoma from normal middle ear epithelium.
Conclusions
This study demonstrates the feasibility of high-resolution optical imaging to discriminate cholesteatoma from uninvolved middle ear mucosa, based on the unique staining properties of keratin. Use of real-time imaging may facilitate more complete extirpation of cholesteatoma by identifying areas of residual disease.
doi:10.1002/lary.23710
PMCID: PMC3609873  PMID: 23299781
cholesteatoma; keratin; optical imaging; otology; high-resolution microendoscopy
4.  Multispectral optical imaging device for in vivo detection of oral neoplasia 
Journal of biomedical optics  2008;13(2):024019.
A multispectral digital microscope (MDM) is designed and constructed as a tool to improve detection of oral neoplasia. The MDM acquires in vivo images of oral tissue in fluorescence, narrowband (NB) reflectance, and orthogonal polarized reflectance (OPR) modes, to enable evaluation of lesions that may not exhibit high contrast under standard white light illumination. The device rapidly captures image sequences so that the diagnostic value of each modality can be qualitatively and quantitatively evaluated alone and in combination. As part of a pilot clinical trial, images are acquired from normal volunteers and patients with precancerous and cancerous lesions. In normal subjects, the visibility of vasculature can be enhanced by tuning the reflectance illumination wavelength and polarization. In patients with histologically confirmed neoplasia, we observe decreased blue/green autofluorescence and increased red autofluorescence in lesions, and increased visibility of vasculature using NB and OPR imaging. The perceived lesion borders change with imaging modality, suggesting that multimodal imaging has the potential to provide additional diagnostic information not available using standard white light illumination or by using a single imaging mode alone.
doi:10.1117/1.2904658
PMCID: PMC3970814  PMID: 18465982
oral cancer; diagnosis; noninvasive; optical imaging; fluorescence; decreased autofluorescence; reflectance; polarized; orthogonal; porphyrin; vasculature; monochromatic
5.  Efficacy of a Low-Cost Bubble CPAP System in Treatment of Respiratory Distress in a Neonatal Ward in Malawi 
PLoS ONE  2014;9(1):e86327.
Background
Respiratory failure is a leading cause of neonatal mortality in the developing world. Bubble continuous positive airway pressure (bCPAP) is a safe, effective intervention for infants with respiratory distress and is widely used in developed countries. Because of its high cost, bCPAP is not widely utilized in low-resource settings. We evaluated the performance of a new bCPAP system to treat severe respiratory distress in a low resource setting, comparing it to nasal oxygen therapy, the current standard of care.
Methods
We conducted a non-randomized convenience sample study to test the efficacy of a low-cost bCPAP system treating newborns with severe respiratory distress in the neonatal ward of Queen Elizabeth Central Hospital, in Blantyre, Malawi. Neonates weighing >1,000 g and presenting with severe respiratory distress who fulfilled inclusion criteria received nasal bCPAP if a device was available; if not, they received standard care. Clinical assessments were made during treatment and outcomes compared for the two groups.
Findings
87 neonates (62 bCPAP, 25 controls) were recruited. Survival rate for neonates receiving bCPAP was 71.0% (44/62) compared with 44.0% (11/25) for controls. 65.5% (19/29) of very low birth weight neonates receiving bCPAP survived to discharge compared to 15.4% (1/13) of controls. 64.6% (31/48) of neonates with respiratory distress syndrome (RDS) receiving bCPAP survived to discharge, compared to 23.5% (4/17) of controls. 61.5% (16/26) of neonates with sepsis receiving bCPAP survived to discharge, while none of the seven neonates with sepsis in the control group survived.
Interpretation
Use of a low-cost bCPAP system to treat neonatal respiratory distress resulted in 27% absolute improvement in survival. The beneficial effect was greater for neonates with very low birth weight, RDS, or sepsis. Implementing appropriate bCPAP devices could reduce neonatal mortality in developing countries.
doi:10.1371/journal.pone.0086327
PMCID: PMC3906032  PMID: 24489715
6.  Feasibility and preliminary accuracy of high-resolution imaging of the liver and pancreas using FNA compatible microendoscopy 
Gastrointestinal endoscopy  2012;76(2):293-300.
Background
Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is one of the few techniques which can obtain cells and tissue from the liver and pancreas. However, the technique remains vulnerable to poor specimen quality and sampling error.
Objectives
To evaluate the ability of a high-resolution microendoscope (HRME) to visualize the cellular and architectural features of normal and malignant liver and pancreatic tissue ex vivo. To assess the ability of endosonographers to identify normal and neoplastic tissue using HRME images. To demonstrate preliminary technical feasibility of in vivo HRME imaging via EUS-fine needle puncture (FNP).
Design
Ex vivo, pilot feasibility study in human tissue; in vivo swine model.
Setting
Two academic medical centers
Patients and Interventions
Co-registered HRME images and biopsies were obtained from surgically resected hepatic and pancreatic tissues from a total of 44 patients. Images were divided into training (12 images) and test sets (80 images) containing a range of normal and pathologic conditions for each organ. After viewing the training sets, nine endosonographers attempted to distinguish malignant tissue from normal or benign lesions in the test sets, each of which contained 40 unique images with individual diagnoses from pathology.
Main Outcome Measurements
Image acquisition feasibility, ex vivo and in vivo. Ability of endosonographers to recognize features of normal/benign or malignant tissue from the liver and pancreas.
Results
Overall, the nine endosonographers achieved median accuracy figures of 85% in the liver and 90% in the pancreas. The endosonographers with prior experience in reading HRME images achieved accuracy rates between 90% and 95%. Technical feasibility of HRME imaging through a 19-gauge EUS-FNP needle was demonstrated in an in vivo swine model.
Limitations
Ex vivo study
Conclusions
High-resolution microendoscopy allows real-time imaging of cellular-level morphology and tissue architecture in the liver and pancreas. The techniques appears to have a short learning curve, after which endosonographers achieved high accuracy rates in distinguishing malignant tissue from normal and benign pathology in both organs. Translating this imaging platform to the in vivo setting appears technically feasible.
doi:10.1016/j.gie.2012.04.445
PMCID: PMC3904224  PMID: 22817784
7.  Gold Nanoparticle Aggregation for Quantification of Oligonucleotides: Optimization and Increased Dynamic Range 
Analytical biochemistry  2012;431(2):99-105.
A variety of assays have been proposed to detect small quantities of nucleic acids at the point-of-care. One approach relies on target-induced aggregation of gold nanoparticles functionalized with oligonucleotide sequences complementary to adjacent regions on the targeted sequence. In the presence of the target sequence, the gold nanoparticles aggregate, producing an easily detectable shift in the optical scattering properties of the solution. The major limitations of this assay are that it requires heating, and that long incubation times are required to produce a result. This study aims to optimize the assay conditions and optical readout, with the goals of eliminating the need for heating and reducing the time to result without sacrificing sensitivity or dynamic range. By optimizing assay conditions and measuring the spectrum of scattered light at the endpoint of incubation, we find that the assay is capable of producing quantifiable results at room temperature in 30 minutes with a linear dynamic range spanning from 150 amoles to 15 fmoles of target. If changes in light scattering are measured dynamically during the incubation process, the linear range can be expanded 2-fold, spanning 50 amoles to 500 fmoles, while decreasing the time to result down to 10 minutes.
doi:10.1016/j.ab.2012.09.013
PMCID: PMC3496753  PMID: 23000603
Gold nanoparticles; oligonucleotides; optical scattering; quantification
8.  A pilot study of low-cost, high-resolution microendoscopy as a tool for identifying women with cervical precancer 
Cervical cancer remains one of the leading causes of death among women in developing countries. Without resources to support Pap smear cytology and colposcopy, cost-effective approaches which enable single-visit “see-and-treat” protocols offer the potential to reduce morbidity and mortality due to this preventable disease. We carried out a pilot clinical study in Shanxi province, China, to evaluate a low-cost, high-resolution microendoscope (HRME) imaging system which enables evaluation of epithelial cell morphology in vivo. HRME images were obtained at discrete sites on the cervix in 174 women, in addition to visual inspection with acetic acid (VIA), and colposcopic examination. Out of 69 sites appearing abnormal on colposcopy, only 12 showed high-grade disease (CIN2+) on pathology. Quantification of the nuclear-to-cytoplasm ratio by HRME enabled an ad hoc threshold to be defined, which correctly classified all 12 sites as abnormal, whilst classifying 38 of the remaining 57 pathology normal sites as normal. All patients with biopsy confirmed high-grade disease also tested positive for high-risk HPV DNA, and were classified as abnormal by HRME. Among the remaining patients who tested positive for HPV but were either normal by colposcopy or showed < CIN2 on pathology, only 6/32 (18.8%) were classified as abnormal by HRME.
Visual examination techniques for cervical cancer screening may overestimate the prevalence of precancerous lesions, leading to unnecessary treatment, expense, and patient stress. The results of this study suggest that evaluation of suspicious lesions by HRME may assist in ruling out immediate cryotherapy, thus increasing the efficiency of current see-and-treat programs.
doi:10.1158/1940-6207.CAPR-12-0221
PMCID: PMC3494281  PMID: 22926339
Optical imaging; clinical diagnostics; HPV testing
9.  Discrimination of Benign and Neoplastic Mucosa with a High-Resolution Microendoscope (HRME) in Head and Neck Cancer 
Annals of surgical oncology  2012;19(11):3534-3539.
Background
The efficacy of ablative surgery for head and neck squamous cell carcinoma (HNSCC) depends critically on obtaining negative margins. While intraoperative "frozen section" analysis of margins is a valuable adjunct, it is expensive, time-consuming, and highly dependent on pathologist expertise. Optical imaging has potential to improve the accuracy of margins by identifying cancerous tissue in real time. Our aim was to determine the accuracy and inter-rater reliability of head and neck cancer specialists using high-resolution microendoscopic (HRME) images to discriminate between cancerous and benign mucosa.
Methods
Thirty-eight patients diagnosed with HNSCC were enrolled in this single-center study. HRME was used to image each specimen after application of proflavine, with concurrent standard histopathologic analysis. Images were evaluated for quality control, and a training set containing representative images of benign and neoplastic tissue was assembled. After viewing training images, seven head and neck cancer specialists with no prior HRME experience reviewed 37 test images and were asked to classify each.
Results
The mean accuracy of all reviewers in correctly diagnosing neoplastic mucosa was 97 percent (95% Cl = 94–99%). The mean sensitivity and specificity were 98 percent (97–100%) and 92 percent (87–98%), respectively. The Fleiss kappa statistic for inter-rater reliability was 0.84 (0.77–0.91).
Conclusions
Medical professionals can be quickly trained to use HRME to discriminate between benign and neoplastic mucosa in the head and neck. With further development, the HRME shows promise as a method of real-time margin determination at the point of care.
doi:10.1245/s10434-012-2351-1
PMCID: PMC3421068  PMID: 22492225
10.  A Paper and Plastic Device for Performing Recombinase Polymerase Amplification of HIV DNA 
Lab on a chip  2012;12(17):3082-3088.
Despite the importance of early diagnosis and treatment of HIV, only a small fraction of HIV-exposed infants in low- and middle-income countries are tested for the disease. The gold standard for early infant diagnosis, DNA PCR, requires resources that are unavailable in poor settings, and no point-of-care HIV DNA test is currently available. We have developed a device constructed of layers of paper, glass fiber, and plastic that is capable of performing isothermal, enzymatic amplification of HIV DNA. The device is inexpensive, small, light-weight, and easy to assemble. The device stores lyophilized enzymes, facilitates mixing of reaction components, and supports recombinase polymerase amplification in five steps of operation. Using commercially available lateral flow strips as a detection method, we demonstrate the ability of our device to amplify 10 copies of HIV DNA to detectable levels in 15 minutes. Our results suggest that our device, which is designed to be used after DNA extraction from dried-blood spots, may serve in conjunction with lateral flow strips as part of a point-of-care HIV DNA test to be used in low resource settings.
doi:10.1039/c2lc40423k
PMCID: PMC3569001  PMID: 22733333
11.  Novel open-source electronic medical records system for palliative care in low-resource settings 
BMC Palliative Care  2013;12:31.
Background
The need for palliative care in sub-Saharan Africa is staggering: this region shoulders over 67% of the global burden of HIV/AIDS and cancer. However, provisions for these essential services remain limited and poorly integrated with national health systems in most nations. Moreover, the evidence base for palliative care in the region remains scarce. This study chronicles the development and evaluation of DataPall, an open-source electronic medical records system that can be used to track patients, manage data, and generate reports for palliative care providers in these settings.
DataPall was developed using design criteria encompassing both functional and technical objectives articulated by hospital leaders and palliative care staff at a leading palliative care center in Malawi. The database can be used with computers that run Windows XP SP 2 or newer, and does not require an internet connection for use. Subsequent to its development and implementation in two hospitals, DataPall was tested among both trained and untrained hospital staff populations on the basis of its usability with comparison to existing paper records systems as well as on the speed at which users could perform basic database functions. Additionally, all participants evaluated this program on a standard system usability scale.
Results
In a study of health professionals in a Malawian hospital, DataPall enabled palliative care providers to find patients’ appointments, on average, in less than half the time required to locate the same record in current paper records. Moreover, participants generated customizable reports documenting patient records and comprehensive reports on providers’ activities with little training necessary. Participants affirmed this ease of use on the system usability scale.
Conclusions
DataPall is a simple, effective electronic medical records system that can assist in developing an evidence base of clinical data for palliative care in low resource settings. The system is available at no cost, is specifically designed to chronicle care in the region, and is catered to meet the technical needs and user specifications of such facilities.
doi:10.1186/1472-684X-12-31
PMCID: PMC3751569  PMID: 23941694
Palliative care; Electronic medical records system; Evidence-based medicine; Africa; Database
12.  Accuracy of in vivo multi-modal optical imaging for detection of oral neoplasia 
If detected early, oral cancer is eminently curable. However, survival rates for oral cancer patients remain low, largely due to late stage diagnosis and subsequent difficulty of treatment. To improve clinicians’ ability to detect early disease and to treat advanced cancers, we developed a multi-modal optical imaging system (MMIS) to evaluate tissue in situ, at macroscopic and microscopic scales. The MMIS was used to measure anatomical 100 sites in 30 patients, correctly classifying 98% of pathologically confirmed normal tissue sites, and 95% of sites graded as moderate dysplasia, severe dysplasia, or cancer. When used alone, MMIS classification accuracy was 35% for sites determined by pathology as mild dysplasia. However, MMIS measurements correlated with expression of candidate molecular markers in 87% of sites with mild dysplasia. These findings support the ability of non-invasive multi-modal optical imaging to accurately identify neoplastic tissue and pre-malignant lesions. This in turn may have considerable impact on detection and treatment of patients with oral cancer and other epithelial malignancies.
doi:10.1158/1940-6207.CAPR-11-0555
PMCID: PMC3560936  PMID: 22551901
Optical imaging; clinical diagnostics; fluorescence imaging; biomarker imaging
13.  Multimodal snapshot spectral imaging for oral cancer diagnostics: a pilot study 
Biomedical Optics Express  2013;4(6):938-949.
Optical imaging and spectroscopy have emerged as effective tools for detecting malignant changes associated with oral cancer. While clinical studies have demonstrated high sensitivity and specificity for detection, current devices either interrogate a small region or can have reduced performance for some benign lesions. We describe a snapshot imaging spectrometer that combines the large field-of-view of widefield imaging with the diagnostic strength of spectroscopy. The portable device can stream RGB images at 7.2 frames per second and record both autofluorescence and reflectance spectral datacubes in < 1 second. We report initial data from normal volunteers and oral cancer patients.
doi:10.1364/BOE.4.000938
PMCID: PMC3675872  PMID: 23760882
(170.0170) Medical optics and biotechnology; (170.6510) Spectroscopy, tissue diagnostics; (110.4234) Multispectral and hyperspectral imaging
14.  Vital-dye enhanced fluorescence imaging of gastrointestinal mucosa: metaplasia, neoplasia, inflammation 
Gastrointestinal Endoscopy  2012;75(4):877-887.
Background
Confocal endomicroscopy has revolutionized endoscopy by offering sub-cellular images of gastrointestinal epithelium; however, field-of-view is limited. There is a need for multi-scale endoscopy platforms that use widefield imaging to better direct placement of high-resolution probes.
Design
Feasibility Study
Objective
This study evaluates the feasibility of a single agent, proflavine hemisulfate, as a contrast medium during both widefield and high resolution imaging to characterize morphologic changes associated with a variety of gastrointestinal conditions.
Setting
U.T. M.D. Anderson Cancer Center (Houston, TX) and Mount Sinai Medical Center (New York, NY)
Patients, Interventions, and Main Outcome Measurements
Surgical specimens were obtained from 15 patients undergoing esophagectomy/colectomy. Proflavine, a vital fluorescent dye, was applied topically. Specimens were imaged with a widefield multispectral microscope and a high-resolution microendoscope. Images were compared to histopathology.
Results
Widefield-fluorescence imaging enhanced visualization of morphology, including the presence and spatial distribution of glands, glandular distortion, atrophy and crowding. High-resolution imaging of widefield-abnormal areas revealed that neoplastic progression corresponded to glandular heterogeneity and nuclear crowding in dysplasia, with glandular effacement in carcinoma. These widefield and high-resolution image features correlated well with histopathology.
Limitations
This imaging approach must be validated in vivo with a larger sample size.
Conclusions
Multi-scale proflavine-enhanced fluorescence imaging can delineate epithelial changes in a variety of gastrointestinal conditions. Distorted glandular features seen with widefield imaging could serve as a critical ‘bridge’ to high-resolution probe placement. An endoscopic platform combining the two modalities with a single vital-dye may facilitate point-of-care decision-making by providing real-time, in vivo diagnoses.
doi:10.1016/j.gie.2011.10.004
PMCID: PMC3336371  PMID: 22301343
fluorescence imaging; Barrett's esophagus; esophageal adenocarcinoma; colonic adenocarcinoma; inflammatory bowel disease
15.  A High-Value, Low-Cost Bubble Continuous Positive Airway Pressure System for Low-Resource Settings: Technical Assessment and Initial Case Reports 
PLoS ONE  2013;8(1):e53622.
Acute respiratory infections are the leading cause of global child mortality. In the developing world, nasal oxygen therapy is often the only treatment option for babies who are suffering from respiratory distress. Without the added pressure of bubble Continuous Positive Airway Pressure (bCPAP) which helps maintain alveoli open, babies struggle to breathe and can suffer serious complications, and frequently death. A stand-alone bCPAP device can cost $6,000, too expensive for most developing world hospitals. Here, we describe the design and technical evaluation of a new, rugged bCPAP system that can be made in small volume for a cost-of-goods of approximately $350. Moreover, because of its simple design—consumer-grade pumps, medical tubing, and regulators—it requires only the simple replacement of a <$1 diaphragm approximately every 2 years for maintenance. The low-cost bCPAP device delivers pressure and flow equivalent to those of a reference bCPAP system used in the developed world. We describe the initial clinical cases of a child with bronchiolitis and a neonate with respiratory distress who were treated successfully with the new bCPAP device.
doi:10.1371/journal.pone.0053622
PMCID: PMC3553107  PMID: 23372661
16.  Advances in molecular imaging: targeted optical contrast agents for cancer diagnostics 
Nanomedicine (London, England)  2012;7(3):429-445.
Over the last three decades, our understanding of the molecular changes associated with cancer development and progression has advanced greatly. This has led to new cancer therapeutics targeted against specific molecular pathways; such therapies show great promise to reduce mortality, in part by enabling physicians to tailor therapy for patients based on a molecular profile of their tumor. Unfortunately, the tools for definitive cancer diagnosis – light microscopic examination of biopsied tissue stained with nonspecific dyes – remain focused on the analysis of tissue ex vivo. There is an important need for new clinical tools to support the molecular diagnosis of cancer. Optical molecular imaging is emerging as a technique to help meet this need. Targeted, optically active contrast agents can specifically label extra-and intracellular biomarkers of cancer. Optical images can be acquired in real time with high spatial resolution to image-specific molecular targets, while still providing morphologic context. This article reviews recent advances in optical molecular imaging, highlighting the advances in technology required to improve early cancer detection, guide selection of targeted therapy and rapidly evaluate therapeutic efficacy.
doi:10.2217/nnm.12.12
PMCID: PMC3327054  PMID: 22385200
biomarkers; cancer; contrast agents; early diagnosis; image-guided therapeutics; nanoparticles; optical imaging
17.  The Use of in vivo Real-Time Optical Imaging for Esophageal Neoplasia 
Esophageal adenocarcinoma carries a poor prognosis, as it typically presents at a late stage. Thus, a major research priority is the development of novel diagnostic imaging strategies that can detect neoplastic lesions earlier and more accurately than current techniques. Advances in optical imaging allow clinicians to obtain real-time histopathologic information with instant visualization of cellular architecture and the potential to identify neoplastic tissue. The various endoscopic imaging modalities for esophageal neoplasia can be grouped into two major categories: (a) wide-field imaging, a comparatively lower-resolution view for imaging larger surface areas, and (b) high-resolution imaging, which allows individual cells to be visualized. This review will provide an overview of the various forms of real-time optical imaging in the diagnosis and management of Barrett's esophagus and esophageal adenocarcinoma.
doi:10.1002/msj.20304
PMCID: PMC3466051  PMID: 22069213
Barrett esophagus; neoplasms; cancer; endoscopy; optical imaging; diagnostic imaging
18.  A Lateral Flow Assay for Quantitative Detection of Amplified HIV-1 RNA 
PLoS ONE  2012;7(9):e45611.
Although the accessibility of HIV treatment in developing nations has increased dramatically over the past decade, viral load testing to monitor the response of patients receiving therapy is often unavailable. Existing viral load technologies are often too expensive or resource-intensive for poor settings, and there is no appropriate HIV viral load test currently available at the point-of-care in low resource settings. Here, we present a lateral flow assay that employs gold nanoparticle probes and gold enhancement solution to detect amplified HIV RNA quantitatively. Preliminary results show that, when coupled with nucleic acid sequence based amplification (NASBA), this assay can detect concentrations of HIV RNA that match the clinically relevant range of viral loads found in HIV patients. The lateral flow test is inexpensive, simple and rapid to perform, and requires few resources. Our results suggest that the lateral flow assay may be integrated with amplification and sample preparation technologies to serve as an HIV viral load test for low-resource settings.
doi:10.1371/journal.pone.0045611
PMCID: PMC3448666  PMID: 23029134
19.  High-Resolution Microendoscopy for the Detection of Cervical Neoplasia in Low-Resource Settings 
PLoS ONE  2012;7(9):e44924.
Cervical cancer is the second leading cause of cancer death among women in developing countries. Developing countries often lack infrastructure, cytotechnologists, and pathologists necessary to implement current screening tools. Due to their low cost and ease of interpretation at the point-of-care, optical imaging technologies may serve as an appropriate solution for cervical cancer screening in low resource settings. We have developed a high-resolution optical imaging system, the High Resolution Microendoscope (HRME), which can be used to interrogate clinically suspicious areas with subcellular spatial resolution, revealing changes in nuclear to cytoplasmic area ratio. In this pilot study carried out at the women's clinic of Princess Marina Hospital in Botswana, 52 unique sites were imaged in 26 patients, and the results were compared to histopathology as a reference standard. Quantitative high resolution imaging achieved a sensitivity and specificity of 86% and 87%, respectively, in differentiating neoplastic (≥CIN 2) tissue from non-neoplastic tissue. These results suggest the potential promise of HRME to assist in the detection of cervical neoplasia in low-resource settings.
doi:10.1371/journal.pone.0044924
PMCID: PMC3445555  PMID: 23028683
20.  Real-time video mosaicing with a high-resolution microendoscope 
Biomedical Optics Express  2012;3(10):2428-2435.
Microendoscopes allow clinicians to view subcellular features in vivo and in real-time, but their field-of-view is inherently limited by the small size of the probe’s distal end. Video mosaicing has emerged as an effective technique to increase the acquired image size. Current implementations are performed post-procedure, which removes the benefits of live imaging. In this manuscript we present an algorithm for real-time video mosaicing using a low-cost high-resolution microendoscope. We present algorithm execution times and show image results obtained from in vivo tissue.
doi:10.1364/BOE.3.002428
PMCID: PMC3469983  PMID: 23082285
(170.0170) Medical optics and biotechnology; (170.2150) Endoscopic imaging; (170.3010) Image reconstruction techniques; (110.2350) Fiber optics imaging
21.  Emerging Nucleic Acid–Based Tests for Point-of-Care Detection of Malaria 
Malaria remains a serious disease in the developing world. There is a growing consensus that new diagnostics are needed in low-resource settings. The ideal malaria diagnostic should be able to speciate; measure parasitemia; low-cost, quick, and simple to use; and capable of detecting low-level infections. A promising development are nucleic acid tests (NATs) for the diagnosis of malaria, which are well suited for point-of-care use because of their ability to detect low-level infections and speciate, and because they have high sensitivity and specificity. The greatest barrier to NAT use in the past has been its relatively high cost, and the amount of infrastructure required in the form of equipment, stable power, and reagent storage. This review describes recent developments to decrease the cost and run time, and increase the ease of use of NAT while maintaining their high sensitivity and specificity and low limit of detection at the point-of-care.
doi:10.4269/ajtmh.2012.11-0685
PMCID: PMC3414556  PMID: 22855751
22.  Optical Molecular Imaging of Multiple Biomarkers of Epithelial Neoplasia: Epidermal Growth Factor Receptor Expression and Metabolic Activity in Oral Mucosa1 
Translational Oncology  2012;5(3):160-171.
Biomarkers of cancer can indicate the presence of disease and serve as therapeutic targets. Our goal is to develop an optical imaging approach using molecularly targeted contrast agents to assess several centimeters of mucosal surface for mapping expression of multiple biomarkers simultaneously with high spatial resolution. The ability to image biomarker expression level and heterogeneity in vivo would be extremely useful for clinical cancer research, patient selection of personalized medicine, and monitoring therapy. In this proof-of-concept ex vivo study, we examined correlation of neoplasia with two clinically relevant biomarkers: epidermal growth factor receptor (EGFR) and metabolic activity. Two hundred eighty-six unique locations in nine samples of freshly resected oral mucosa were imaged after topically applying optical imaging agents EGF-Alexa 647 (to target EGFR) and 2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose (to target metabolic activity). Quantitative features were calculated from resulting fluorescence images and compared with tissue histopathology maps. The EGF-Alexa 647 signal correlated well with EGFR expression as indicated by immunohistochemistry. A classification algorithm for presence of neoplasia based on the signal from both contrast agents resulted in an area under the curve of 0.83. Regions with a posterior probability from 0.80 to 1.00 contained more than 50% neoplasia 99% (84/85) of the time. This study demonstrates a proof-of-concept of how noninvasive optical imaging can be used as a tool to study expression levels of multiple biomarkers and their heterogeneity across a large mucosal surface and how biomarker characteristics correlate with presence of neoplasia. Applications of this approach include predicting regions with the highest likelihood of disease, elucidating the role of biomarker heterogeneity in cancer biology, and identifying patients who will respond to targeted therapy.
PMCID: PMC3384270  PMID: 22741035
24.  Endoscopic imaging: How far are we from real-time histology? 
Currently, in gastrointestinal endoscopy there is increasing interest in high resolution endoscopic technologies that can complement high-definition white light endoscopy by providing real-time subcellular imaging of the epithelial surface. These ‘optical biopsy’ technologies offer the potential to improve diagnostic accuracy and yield, while facilitating real-time decision-making. Although many endoscopic techniques have preliminarily shown high accuracy rates, these technologies are still evolving. This review will provide an overview of the most promising high-resolution imaging technologies, including high resolution microendoscopy, optical coherence tomography, endocytoscopy and confocal laser endoscopy. This review will also discuss the application and current limitations of these technologies for the early detection of neoplasia in Barrett’s esophagus, ulcerative colitis and colorectal cancer.
doi:10.4253/wjge.v3.i10.183
PMCID: PMC3196726  PMID: 22013499
Microendoscopy; Confocal laser endoscopy; Endocytoscopy; High-resolution; Optical coherence tomography; Barrett’s esophagus; Ulcerative colitis; Colon cancer
25.  The future of medical diagnostics: review paper 
Head & Neck Oncology  2011;3:38.
While histopathology of excised tissue remains the gold standard for diagnosis, several new, non-invasive diagnostic techniques are being developed. They rely on physical and biochemical changes that precede and mirror malignant change within tissue. The basic principle involves simple optical techniques of tissue interrogation. Their accuracy, expressed as sensitivity and specificity, are reported in a number of studies suggests that they have a potential for cost effective, real-time, in situ diagnosis.
We review the Third Scientific Meeting of the Head and Neck Optical Diagnostics Society held in Congress Innsbruck, Innsbruck, Austria on the 11th May 2011. For the first time the HNODS Annual Scientific Meeting was held in association with the International Photodynamic Association (IPA) and the European Platform for Photodynamic Medicine (EPPM). The aim was to enhance the interdisciplinary aspects of optical diagnostics and other photodynamic applications. The meeting included 2 sections: oral communication sessions running in parallel to the IPA programme and poster presentation sessions combined with the IPA and EPPM posters sessions.
doi:10.1186/1758-3284-3-38
PMCID: PMC3180646  PMID: 21861912

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