Biomedical subjects

R Richards-Kortum

Publications and source records attributed to R Richards-Kortum.

At least 37 records · Page 2Linked to original sources

PubMed1998

Fluorescence spectroscopy: a technique with potential to improve the early detection of aerodigestive tract neoplasia.

BACKGROUND: Any innovation which facilitates the early detection of neoplastic changes in upper aerodigestive tract mucosa has potential to greatly improve survival and quality of life in persons prone to develop malignancies in this area. One technology that has shown great promise during initial investigations is fluorescence spectroscopy. Fluorescence spectroscopy evaluates the physical and chemical properties of tissue by analyzing the intensity and character of light emitted in the form of fluorescence. This technology has been investigated for the non-invasive detection of malignancy in various sites including the gastrointestinal tract, lung, breast, and cervix. METHODS: This article reviews the recent work investigating the capabilities of fluorescence spectroscopy to discriminate between normal and neoplastic mucosa in the oral cavity. Also discussed are potential applications for the detection and diagnosis of premalignant and malignant lesions of the upper aerodigestive tract, and some of the obstacles to overcome to make this technology feasible.

Carcinoma, Squamous Cell↗

PubMed1998

Cost-effectiveness analysis of diagnosis and management of cervical squamous intraepithelial lesions.

OBJECTIVE: To compare five strategies for the diagnosis and treatment of cervical squamous intraepithelial lesions (SILs), including those that incorporate colposcopy and a new technology, fluorescence spectroscopy. METHODS: On the basis of a health care perspective, we performed a cost-effectiveness analysis using a decision-analytic model for the diagnosis and management of SILs. We compared the five strategies based on the expected costs and number of cases that were treated appropriately, missed, treated inappropriately, and appropriately not treated in a hypothetical cohort of 100 patients referred after an abnormal Papanicolaou smear. Data on prevalence and operating characteristics were derived from the medical literature. Costs were adjusted from hospital charge data. RESULTS: A see-and-treat strategy based on fluorescence spectroscopy was the least expensive but least effective strategy, costing $160,479 to detect 31.55 cases of cervical precancer accurately in 100 patients. The most expensive strategy was colposcopically directed biopsy, at $311,808 to find 45.78 cases; however, when both tests were used in a see-and-treat modality, slightly more cases were found (46.05) at a lower cost ($285,133). Other strategies were dominated in the base case. The incremental cost-effectiveness of the joint strategy compared with the spectroscopy-only strategy was $8596 per case of cervical precancer detected. Sensitivity analysis showed that the analysis was sensitive to the cost of the new technology of fluorescence spectroscopy. CONCLUSION: Fluorescence spectroscopy should be considered an important innovation in the diagnosis of SILs as demonstrated by its efficacy and economic advantages.

Biopsy, Needle↗

PubMed1998

Colposcopy for the diagnosis of squamous intraepithelial lesions: a meta-analysis.

OBJECTIVE: To quantify by meta-analysis the performance of colposcopy to set a standard against which new technologies can be compared. DATA SOURCES: MEDLINE was searched for articles on colposcopy for diagnosis of squamous intraepithelial lesions (SIL). The search selected articles from 1960 to 1996 combining the key word "colposcopy" with key words "diagnosis," "positive predictive value," "negative predictive value," "likelihood ratio," and "receiver operating characteristic (ROC) curve." METHODS OF STUDY SELECTION: Articles were selected if the authors studied a population of patients with abnormal screening Papanicolaou smears and presented raw data showing for each cervical lesion type the number of patients judged positive and negative by colposcopic impression versus the standard of colposcopic biopsy results. Nine of 86 studies met these criteria. TABULATION, INTEGRATION, AND RESULTS: Biopsies had been categorized as normal, atypia, cervical intraepithelial neoplasia (CIN) I, CIN II, CIN III, carcinoma in situ, and invasive cancer; we recalculated performance measures using the Bethesda system. Overall sensitivity, specificity, likelihood ratios, ROC curves, and the corresponding areas under the curves were calculated. The average weighted sensitivity of diagnostic colposcopy for the threshold normal compared with all cervix abnormalities (atypia, low-grade SIL, high-grade SIL, cancer) was 96% and the average weighted specificity 48%. For the threshold normal cervix and low-grade SIL compared with high-grade SIL and cancer, average weighted sensitivity was 85% and average weighted specificity 69%. Likelihood ratios generated small but important changes in probability for distinguishing normal cervix and low-grade SIL from high-grade SIL and cancer. Areas under the ROC curve were 0.80 for the threshold normal cervix compared with all abnormalities and 0.82 for the threshold normal cervix and low-grade SIL compared with high-grade SIL and cancer. CONCLUSION: Colposcopy compares favorably with other medical diagnostic tests in terms of sensitivity, specificity, and area under the ROC curve. New diagnostic methods for the cervix can be compared with colposcopy using these quantified values.

Colposcopy↗

PubMed1998

Ensembles of radial basis function networks for spectroscopic detection of cervical precancer.

The mortality related to cervical cancer can be substantially reduced through early detection and treatment. However, current detection techniques, such as Pap smear and colposcopy, fail to achieve a concurrently high sensitivity and specificity. In vivo fluorescence spectroscopy is a technique which quickly, noninvasively and quantitatively probes the biochemical and morphological changes that occur in precancerous tissue. A multivariate statistical algorithm was used to extract clinically useful information from tissue spectra acquired from 361 cervical sites from 95 patients at 337-, 380-, and 460-nm excitation wavelengths. The multivariate statistical analysis was also employed to reduce the number of fluorescence excitation-emission wavelength pairs required to discriminate healthy tissue samples from precancerous tissue samples. The use of connectionist methods such as multilayered perceptrons, radial basis function (RBF) networks, and ensembles of such networks was investigated. RBF ensemble algorithms based on fluorescence spectra potentially provide automated and near real-time implementation of precancer detection in the hands of nonexperts. The results are more reliable, direct, and accurate than those achieved by either human experts or multivariate statistical algorithms.

Algorithms↗

PubMed1998

Near-infrared Raman spectroscopy for in vitro detection of cervical precancers.

In this study, we investigate the potential of near-infrared Raman spectroscopy to differentiate cervical precancers from normal tissues, inflammation and metaplasia and to differentially diagnose low-grade and high-grade precancers. Near infrared Raman spectra were measured from 36 biopsies from 18 patients in vitro. Detection algorithms were developed and evaluated relative to histopathologic examination. Algorithms based on empirically selected peak intensities, ratios of peak intensities and a combination of principal component analysis for data reduction and Fisher discriminant analysis for classification were investigated. Spectral peaks were tentatively identified from measured spectra of potential chromophores. Empirically selected normalized intensities can differentiate precancers from other tissues with an average sensitivity and specificity of 88 +/- 4% and 92 +/- 4%. Ratios of unnormalized intensities can differentiate precancers from other tissues with a sensitivity and specificity of 82% and 88% and high-grade from low-grade lesions with a sensitivity and specificity of 100%. Using multivariate methods, intensities at eight frequencies can be used to differentiate precancers from all other tissues with a sensitivity and specificity of 82% and 92% in an unbiased test. Raman algorithms can potentially separate benign abnormalities such as inflammation and metaplasia from precancers. Comparison of tissue spectra to published and measured chromophore spectra indicate that the most likely primary contributors to the tissue spectra are collagen, nucleic acids, phospholipids and glucose 1-phosphate. These results suggest that near-infrared Raman spectroscopy can be used for cervical precancer diagnosis and may be able to accurately separate samples with inflammation and metaplasia from precancer.

Cervix Uteri↗

PubMed1998

Development of a fiber optic probe to measure NIR Raman spectra of cervical tissue in vivo.

The goal of this study was to develop a compact fiber optic probe to measure near infrared Raman spectra of human cervical tissue in vivo for the clinical diagnosis of cervical precancers. A Raman spectrometer and fiber optic probe were designed, constructed and tested. The probe was first tested using standards with known Raman spectra, and then the probe was used to acquire Raman spectra from normal and precancerous cervical tissue in vivo. Raman spectra of cervical tissue could be acquired in vivo in 90 s using incident powers comparable to the threshold limit values for laser exposure of the skin. Although some silica signal obscured tissue Raman bands below 900 cm-1, Raman features from cervical tissue could clearly be discerned with an acceptable signal-to-noise ratio above 900 cm-1. The success of the Raman probe described here indicates that near infrared Raman spectra can be measured in vivo from cervical tissues. Increasing the power of the excitation source could reduce the integration time to below 20 s.

Biopsy↗

PubMed1997

Propagation of fluorescent light.

BACKGROUND AND OBJECTIVE: In general, the remitted fluorescence spectrum is affected by the scattering and absorption properties of tissue. Other important factors are boundary conditions, geometry of the tissue sample, and the quantum yield of tissue fluorophores. Each of these factors is examined through a series of Monte Carlo simulations. STUDY DESIGN/MATERIALS AND METHODS: Monte Carlo modeling is used to simulate the propagation of excitation light and the resulting fluorescence. Remitted fluorescence is determined for semi-infinite single and multiple layer geometries and for cubic geometries representing small tissue samples. Monte Carlo results are compared to approximations obtained with a heuristic model. RESULTS: Remitted fluorescence as a function of (1) the depth of fluorescence generation and (2) radial escape position is presented for semi-infinite single and multiple layer geometries. Fluorescence from a small tissue sample is simulated in terms of a cubic geometry, and losses from the sides and bottom are presented as a function of cube dimensions in terms of optical depth of the excitation wavelength. Monte Carlo results for a homogeneous semi-infinite layer are compared to a simple, fast heuristic model. CONCLUSION: Both Monte Carlo simulations and the heuristic model clearly detail the volume of tissue interrogated by fluorescence. Since approximately 35-40% of the remitted fluorescence is due to photons originally directed away from the surface, distal layers affect the remitted fluorescence. Fluorescence spectra from small biopsy samples may not produce the correct line shape owing to wavelength dependent losses.

Aorta↗

PubMed1996

Development of a multivariate statistical algorithm to analyze human cervical tissue fluorescence spectra acquired in vivo.

BACKGROUND AND OBJECTIVE: A general multivariate statistical algorithm has been developed to analyze the diagnostic content of cervical tissue fluorescence spectra acquired in vivo. MATERIALS AND METHODS: The primary steps of the algorithm are to: (1) preprocess the data to reduce inter-patient and intra-patient variation of tissue spectra within a diagnostic category, without a priori information, (2) dimensionally reduce the preprocessed fluorescence emission spectrum with minimal information loss and use it to select the minimum number of the original emission variables of the fluorescence spectrum required to achieve classification with negligible decrease in predictive ability, and (3) assign a posterior probability to the diagnosis of each sample, so that samples with relative uncertain diagnosis can be reevaluated by a clinician. The algorithm was tested retrospectively and prospectively on cervical tissue spectra acquired from 476 sites from 92 patients at 337 nm excitation. RESULTS: The algorithm based on the entire fluorescence spectrum differentiates squamous intraepithelial lesions (SILs) from normal squamous epithelia and inflammation with an average sensitivity and specificity of 88% +/- 1.4 and 70% +/- 1, respectively. The average sensitivity and specificity of the identical algorithm based on intensity selected at only two emission wavelengths is 88% +/- 1.4 and 71% +/- 1.4, respectively. CONCLUSION: The multivariate statistical algorithm based on both types of spectral inputs at 337 nm excitation has a similar sensitivity and significantly improved specificity relative to colposcopy in expert hands.

Algorithms↗

PubMed1996

Spectroscopic diagnosis of cervical intraepithelial neoplasia (CIN) in vivo using laser-induced fluorescence spectra at multiple excitation wavelengths.

BACKGROUND AND OBJECTIVE: The diagnostic contribution of cervical tissue fluorescence spectra acquired in vivo at 380 and 460 nm excitation were analyzed using a general multivariate statistical algorithm. MATERIALS AND METHODS: The primary steps of the algorithm are to: (1) preprocess data to reduce interpatient and intrapatient variation of tissue spectra from the same diagnostic category, without a priori information, (2) dimensionally reduce the pre-processed spectral data using Principal Component Analysis, and (3) develop a probability based classification scheme based on logistic discrimination using the diagnostically useful principal components. The algorithm was tested on cervical tissue spectra acquired from 165 sites at 380 nm excitation and from 147 sites at 460 nm excitation. A retrospective and prospective estimate of the algorithm's performance was determined. RESULTS: At 460 nm excitation, (1) SILs can be differentiated from normal squamous tissues with an average sensitivity and specificity of 91% +/- 1.3 and 75.5% +/- 1, respectively; furthermore, (2) high grade SILs can be differentiated from low grade SILs with an average sensitivity and specificity of 80% +/- 4 and 76% +/- 5, respectively. In addition, using tissue spectra at 380 nm excitation, SILs can be differentiated from normal columnar epithelia and inflammation with an average sensitivity and specificity of 77% +/- 1 and 72% +/- 9, respectively. CONCLUSIONS: Fluorescence spectra at multiple excitation wavelengths are essential for the detection and differential diagnosis of SILs at colposcopy.

Algorithms↗

PubMed1996

Comparison of methods to determine chromophore concentrations from fluorescence spectra of turbid samples.

BACKGROUND AND OBJECTIVE: This paper compares the ability of three analytic techniques to predict chromophore concentration from fluorescence emission spectra of homogeneous, turbid samples with optical properties similar to human tissue. STUDY DESIGN, MATERIALS AND METHODS: Two models of light propagation were implemented (exponential attenuation, two flux Kubelka-Munk theory); a priori information about sample optical properties was used to analyze data with the two flux Kubelka-Munk model. The third data analysis technique utilizes the method of partial least squares (PLS) to develop an empirical, linear model of sample fluorescence from a training set with optical properties and known concentrations representative of those to be predicted. This model can be applied to predict chromophore concentrations in the unknown samples. RESULTS: Of the three methods, PLS achieved the most accurate results and was able to predict fluorophore concentration to within +/- 6% of true values. CONCLUSION: We investigated conditions under which PLS predictions were most accurate and find that best results are achieved when predictions are based on fluorescence emission spectra at more than one excitation wavelength with inclusion of the tail of Rayleigh scattering at the excitation wavelength.

Absorption↗

PubMed1996

Cervical precancer detection using a multivariate statistical algorithm based on laser-induced fluorescence spectra at multiple excitation wavelengths.

A portable fluorimeter was developed and utilized to acquire fluorescence spectra from 381 cervical sites in 95 patients at 337, 380 and 460 nm excitation immediately prior to colposcopy. A multivariate statistical algorithm was used to extract clinically useful information from tissue spectra acquired in vivo. Two full-parameter algorithms were developed using tissue fluorescence emission spectra at all three excitation wavelengths (161 excitation-emission wavelength pairs) for cervical precancer (squamous intraepithelial lesion [SIL]) detection: a screening algorithm that discriminates between SIL and non-SIL with a sensitivity of 82 +/- 1.4% and specificity of 68 +/- 0.0%, and a diagnostic algorithm that differentiates high-grade SIL from non-high-grade SIL with a sensitivity and specificity of 79 +/- 2% and 78 +/- 6%, respectively. Multivariate statistical analysis was also employed to reduce the number of fluorescence excitation-emission wavelength pairs needed to redevelop algorithms that demonstrate a minimum decrease in classification accuracy. Two reduced-parameter algorithms that employ fluorescence intensities at only 15 excitation-emission wavelength pairs were developed: the screening algorithm differentiates SIL from non-SIL with a sensitivity of 84 +/- 1.5% and specificity of 65 +/- 2% and the diagnostic algorithm discriminates high-grade SIL from non-high-grade SIL with a sensitivity and specificity of 78 +/- 0.7% and 74 +/- 2%, respectively. Both the full-parameter and reduced-parameter screening algorithms discriminate between SIL and non-SIL with a similar specificity (+/-5%) and a substantially improved sensitivity relative to Pap smear screening. A comparison of the full-parameter and reduced-parameter diagnostic algorithms to colposcopy in expert hands indicates that all three have a very similar sensitivity and specificity for differentiating high-grade SIL from non-high-grade SIL.

Algorithms↗

PubMed1996

Quantitative optical spectroscopy for tissue diagnosis.

The interaction of light within tissue has been used to recognize disease since the mid-1800s. The recent developments of small light sources, detectors, and fiber optic probes provide opportunities to quantitatively measure these interactions, which yield information for diagnosis at the biochemical, structural, or (patho)physiological level within intact tissues. However, because of the strong scattering properties of tissues, the reemitted optical signal is often influenced by changes in biochemistry (as detected by these spectroscopic approaches) and by physiological and pathophysiological changes in tissue scattering. One challenge of biomedical optics is to uncouple the signals influenced by biochemistry, which themselves provide specificity for identifying diseased states, from those influenced by tissue scattering, which are typically unspecific to a pathology. In this review, we describe optical interactions pursued for biomedical applications (fluorescence, fluorescence lifetime, phosphorescence, and Raman from cells, cultures, and tissues) and then provide a descriptive framework for light interaction based upon tissue absorption and scattering properties. Finally, we review important endogenous and exogenous biological chromophores and describe current work to employ these signals for detection and diagnosis of disease.

Animals↗

PubMed1996

Cervical human papillomavirus infection and intraepithelial neoplasia: a review.

Cervical human papillomavirus (HPV) infections and intraepithelial neoplasias are precursors to cervical cancer, the second most common cancer in women worldwide. HPV satisfies the epidemiologic criteria for causality; the role of other cofactors is under study. Natural history studies show that most low-grade lesions (productive HPV infections) regress or persist, whereas high-grade lesions (those with integrated HPV DNA) progress. Immunobiologic studies demonstrate that infection peaks in the early 20s, leading to a 10- to 20-year period of persistent infection, before finally progressing to a preinvasive or invasive lesion. Papanicolaou (Pap) screening has lowered the morbidity and mortality from cervical cancer in every country in which screening programs have been introduced. The diagnostic strategy for an abnormal Pap smear includes colposcopy; the role of HPV DNA testing in screening or diagnosis remains unclear. Patients are treated with cervical ablation, cone biopsy, or chemopreventive agents. Efforts to strengthen screening and prevention, as well as new directions for research, are needed.

Female↗

PubMed1995

Chemoprevention trials and surrogate end point biomarkers in the cervix.

Cervical cancer is the second most common malignancy in women worldwide and remains a significant health problem for women, especially minority and underserved women. Despite an understanding of the epidemiologic risks, the screening Papanicolaou smear, and morbid and costly treatment, overall survival remains 40%. New strategies, based on the clinical and molecular aspects of cervical carcinogenesis, are desperately needed. Chemoprevention refers to the use of chemical agents to prevent or delay the development of cancer in healthy populations. Chemoprevention studies have several unique features that distinguish them from classic chemotherapeutic trials; these features touch on several disciplines and weave knowledge of the biology of carcinogenesis into the trial design. In the design of chemoprevention trials, four factors are important: high risk cohorts must be identified; suitable medications must be selected; study designs should include Phases I, II, and III; and studies should include the use of surrogate end point biomarkers. Surrogate end point biomarkers are sought because the cancer develops over a long period of time, and studies of chemopreventives would require a huge number of subjects followed for many years. Surrogate end point biomarkers serve as alternative end points for examination of the efficacy of chemopreventives in tissue. High risk cohorts include women with cervical intraepithelial neoplasia (CIN) or squamous intraepithelial lesions (SIL). Nutritional studies have helped define micronutrients of interest (folate, carotenoids, vitamin C, vitamin E). Other medications of interest include retinoids (4-hydroxyphenylretinamide [4-HPR], retinyl acetate gel, topical all-trans-retinoic acid), polyamine synthesis inhibitors (alpha-difluoromethylornithine [DFMO]), and nonsteroidal anti-inflammatory drugs (ibuprofen). Phase I chemoprevention studies of the cervix have tested retinyl acetate gel and all-trans-retinoic acid. Phase II trials of all-trans-retinoic acid, beta-carotene, and folic acid have been and are being carried out, whereas Phase III trials of all-trans-retinoic acid have been completed and have shown significant regression of CIN 2 but not CIN 3. Phase I studies of DFMO and Phase II studies of DFMO and 4-HPR are underway. Surrogate end point biomarkers under study include (1) quantitative cytology and histopathology; (2) human papillomavirus type testing; (3) biologic measures of proliferation, regulation, differentiation, and genomic instability; and 4) fluorescence spectroscopic emission. Clinical trials with biologic end points will contribute to our understanding of the neoplastic process and hence aid us in developing new preventive and therapeutic strategies.

Aneuploidy↗

PubMed1995

Statistical techniques for diagnosing CIN using fluorescence spectroscopy: SVD and CART.

A quantitative measure of intraepithelial neoplasia which can be made in vivo without tissue removal would be clinically significant in chemoprevention studies. Our group is working to develop such a technique based on fluorescence spectroscopy. Using empirically based algorithms, we have demonstrated that fluorescence is discriminating normal cervix from low- and high-grade cervical dysplasias with similar performance to colposcopy in expert hands. These measurements can be made in vivo, in near real time, and results can be obtained without biopsy. This paper describes a new method using automated analysis of fluorescence emission spectra to classify cervical tissue into multiple diagnostic categories. First, data is reduced using the singular value decomposition (SVD), yielding a set of orthogonal basis vectors. Each patient's emission spectrum is then fit by linear least squares regression to the basis vectors, producing a set of coefficients for each patient. Based on these coefficient values, the classification and regression tree (CART) method predicts the patient's classification. These results suggest that laser-induced fluorescence can be used to automatically recognize and differentially diagnose cervical intraepithelial neoplasia (CIN) at colposcopy. This method of analysis is general in nature, and can analyze fluorescence spectra of suspected intraepithelial neoplasms from other organ sites. As a more complete understanding of the biochemical and morphologic basis of tissue spectroscopy is developed, it may also be possible to use fluorescence spectroscopy of the cervix as a surrogate endpoint biomarker in Phase I and II chemoprevention trials.

Algorithms↗

PubMed1995

Combined ultrasound and fluorescence spectroscopy for physico-chemical imaging of atherosclerosis.

This paper describes a combined ultrasonic and spectroscopic system for remotely obtaining physico-chemical images of normal arterial tissue and atherosclerotic plaque. Despite variations in detector-tissue separation, R, fluorescence powers corresponding to pixels in the image are converted to the same set of calibrated units using distance estimations from A-mode ultrasound reflection times. An empirical model, validated by Monte Carlo simulations of light propagation in tissue, is used to describe changes in fluorescence power as a function of R. Fluorescence spectra of normal and atherosclerotic human aorta obtained with this system are presented as a function of R. To compensate for changes in fluorescence power with R, the empirical model was used in each case to calculate the fluorescence power at a constant reference value of R(Rref = 1.67 mm). Prior to compensation, tissue fluorescence power decreased more than a factor of two as R was increased from 2.5 to 5 mm. Following compensation, the fluorescence power varied less than +/- 10% of the average compensated peak. The chemical composition of each sample was determined by fitting its fluorescence spectrum (in calibrated units) to a model of tissue fluorescence incorporating structural protein and ceroid fluorescence, as well as structural protein and hemoglobin attenuation. Parameters of the fit were used to classify tissue type. Without compensation for distance variation, classification of tissue type was frequently incorrect; however, with compensation, predictive value was high. A 1-D chemical image of a section of human aorta containing both normal and atherosclerotic regions obtained with this system is also presented. After compensation for detector-sample separation, tissue classifications along the cross-section closely resemble those obtained from histology. Regions of elevated ceroid concentration and intimal thickening are clearly observable in the resultant chemical image. The potential value of this type of system in the diagnosis and treatment of coronary artery disease is discussed.

Aorta↗

PubMed1995

Laser-induced fluorescence microscopy of normal colon and dysplasia in colonic adenomas: implications for spectroscopic diagnosis.

OBJECTIVES: To determine what structures fluoresce and to what extent in normal colon and colonic adenomas to fully exploit laser-induced fluorescence spectroscopy as a tool for the diagnosis of dysplasia at endoscopy. METHODS: Unstained frozen sections of normal colon and colonic adenomas were studied by fluorescence microscopy under 351-364-nm argon ion laser excitation. Tissue fluorescence was observed and compared to morphology in serial sections stained with hematoxylin and eosin (H&E), Movat pentachrome, mucicarmine, and oil red O. RESULTS: In normal colon, fluorescence correlated morphologically with connective tissue fibers (principally collagen) in all layers of the bowel wall and with cytoplasmic granules within eosinophils present between the crypts in the lamina propria of the mucosa. Fluorescence of absorptive cells in normal crypts was very faint, and Goblet cells did not fluoresce. However, marked fluorescence was observed in the cytoplasms of dysplastic epithelial cells in the crypts of colonic adenomas. Fewer fluorescent connective tissue fibers were present in the lamina propria of colonic adenomas resulting in decreased fluorescence intensity as compared to that of normal colon. Fluorescent eosinophil granules were present in larger numbers in adenomas as compared with normal colon. CONCLUSION: Laser-induced fluorescence in normal colon and colonic adenomas correlates with morphology. Previous reported differences in laser-induced fluorescence emission spectra of normal colon and colonic adenomas obtained in vitro and in vivo may be due to differences in the cytoplasmic fluorescence between the dysplastic epithelium in colonic adenomas and normal colonic epithelium. Laser-induced fluorescence spectroscopy may be useful in studying other forms of epithelial dysplasia such as that which occurs in ulcerative colitis.

Adenoma↗

PubMed1995

Chemoprevention trials in the cervix: design, feasibility, and recruitment.

The cervix is an ideal organ for chemoprevention studies and the study of squamous carcinogenesis. In chemoprevention trial design, four factors are important: high-risk cohorts must be identified; suitable agents must be selected; study designs should include Phase 1, II, and III; and studies should include the use of surrogate endpoint biomarkers. High-risk cohorts can be selected for Phase I, II and III trials in the cervix, for example, patients with high grade lesions such as cervical intraepithelial neoplasia (CIN) grade 3 and carcinoma in situ (CIS). A Phase III trial might also include patients with lesions infected with oncogenic HPV types. The cervix is accessible and can be safely followed with Papanicolaou (Pap) smears and colposcopy. Suitable agents include those likely to work in squamous lesions, including retinoids, difluoromethylornithine, beta-carotene, and others. In Phase I chemopreventive studies, does are de-escalated rather than escalated, determining toxicity and optimal dose schedule. Phase II studies looking at effectiveness need placebo control groups since regression of high-risk lesions is possible. Phase III studies, now multicentric, should be carefully designed and include wide patient representation in order to evaluate the risk-benefit ratio of therapy, focusing on cancer incidence reduction. Surrogate endpoint biomarkers include quantitative histopathology, biologic measures of proliferation, regulation, differentiation, genetic instability, and fluorescence emission. Quantitative histopathologic markers include nuclear grading (i.e., shape, area, optical density, texture), nuclear pleomorphism, ploidy, and nucleolar size and position. Biomarkers under study at the present time in the cervix include proliferation markers (PCNA), regulation marker (EGFR, ras, myc, p53, retinoic acid receptors, ODC, spermidine/spermine ratios), differentiation markers (involucrin, cornifin, keratins), and markers of genetic instability (chromosome polysomy). Fluorescent spectroscopy uses light to probe the biochemical properties of tissue. This technique provides an automated diagnosis in real time with comparable sensitivity and specificity to colposcopy and can be used to monitor lesions in chemoprevention trials. Recruitment designs for cervix studies need to include a large referral population and patients with sufficiently large lesions. Clinicians involved in such studies need to stress contraception and smoking cessation, deal with language barriers, and provide compensation for child care and parking to patients in order to increase compliance.

Anticarcinogenic Agents↗