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Biomedical subjects

Michele Follen

Publications and source records attributed to Michele Follen.

At least 73 records · Page 4Linked to original sources
PubMed2003

Prevention of ovarian cancer: intraepithelial neoplasia.

To reduce the incidence and mortality associated with invasive cancers, the Intraepithelial Neoplasia (IEN) Task Force recommends that carcinogenesis be viewed as a disease that requires treatment. This publication outlines the current knowledge of IEN of the ovary and reviews chemoprevention possibilities for ovarian cancer. Ovarian cancer has the highest mortality of all of the gynecological cancers and is the fourth leading cause of death from cancer in women. The IEN Task Force has defined precancer as a noninvasive lesion that has genetic abnormalities, loss of cellular control functions, and some phenotypic characteristics of invasive cancer with a substantial likelihood of developing invasive cancer. The IEN Task Force recommends targeting moderate to severe dysplasia for new IEN treatment agents in clinical trials. Ovarian cancer does not have a clear preinvasive lesion yet merits considerable study for new prevention strategies because of the high mortality associated with ovarian cancer. There is a great unmet clinical need for treatments that can prevent ovarian cancer by providing nonsurgical options that treat the entire epithelial layer. New prevention strategies hold significant promise to reduce the mortality from ovarian cancer.

Animals↗
PubMed2002

Effects of difluoromethylornithine on growth inhibition and apoptosis in human cervical epithelial and cancerous cell lines.

OBJECTIVE: Difluoromethylornithine(DFMO), an irreversible inhibitor of ornithine decarboxylase and an angiogenesis inhibitor, has been used in phase I cervical intraepithelial neoplasia (CIN) trials, producing a 50% regression of CIN 3 lesions. DFMO is currently in phase II trials. In the experiments reported here, DFMO's growth inhibition and apoptosis induction were explored in an in vitro model to elucidate mechanisms of action. METHODS: Four immortalized cervical epithelial cell lines, serving as in vitro models of precancerous CIN lesions, and nine cervical carcinoma cell lines were studied. DFMO's growth inhibitory effect was tested in monolayer culture and in semisolid medium, and concentrations required for a 50% growth inhibition (IC(50)) with a 5-day treatment were determined. Apoptosis induction was analyzed using the terminal deoxynucleotidyl transferase assay of DNA fragmentation. RESULTS: DFMO inhibited growth of immortalized cervical epithelial cell lines and cervical cancer cell lines in monolayer culture and in semisolid medium. The immortalized cervical epithelial cell lines were more sensitive than the cervical cancer cell lines to DFMO's growth inhibitory effect. Concentrations required for 50% growth inhibition after a 5-day treatment ranged from 100 microM to >5 mM for cervical carcinoma cell lines and from 100 microM to 1 mM for immortalized cervical epithelial cell lines. DFMO induced apoptosis in precancerous and cancerous cell lines at a concentration of 5 mM, regardless of the cells' human papillomavirus status. CONCLUSION: DFMO inhibits the growth of cervical precancerous and cancerous cells in vitro in a dose-dependent and time-dependent manner, partially through inducing apoptosis.

Anticarcinogenic Agents↗
PubMed2002

Near real-time confocal microscopy of amelanotic tissue: detection of dysplasia in ex vivo cervical tissue.

RATIONALE AND OBJECTIVES: The authors performed this study to determine whether images of ex vivo tissue obtained with a near real-time confocal microscope can be used to differentiate between normal and dysplastic tissue. MATERIALS AND METHODS: Biopsy specimens of colposcopically normal and abnormal cervical tissue were obtained from 19 patients and imaged at various depths with a confocal microscope. Nuclear morphologic features were extracted from the confocal images; in addition, a group of reviewers examined the images and attempted to identify whether the specimen contained high-grade dysplasia. Results of both analyses were compared with the histopathologic findings of the same specimens provided by a board-certified pathologist with expertise in gynecologic pathology. RESULTS: The morphologic feature measurements compared well with the findings at pathologic examination. The use of the nuclear-cytoplasmic ratio to determine the presence of dysplasia resulted in a sensitivity of 100% and a specificity of 91%. The untrained reviewers had an average sensitivity of 95% and an average specificity of 69% in the determination of dysplasia. CONCLUSION: The results indicate the clinical potential of in vivo confocal imaging in the detection of dysplasia.

Carcinoma in Situ↗
PubMed2002

Optical spectroscopy for detection of neoplasia.

Fluorescence and reflectance spectroscopy provide the ability to assess tissue structure and metabolism in vivo in real time, providing improved diagnosis of pre-cancerous lesions. Reflectance spectroscopy can probe changes in epithelial nuclei that are important in pre-cancer detection, such as mean nuclear diameter, nuclear size distribution and nuclear refractive index. Fluorescence spectroscopy can probe changes in epithelial cell metabolism, by assessing mitochondrial fluorophores, and epithelial-stromal interactions, by assessing the decrease in collagen crosslink fluorescence that occurs with pre-cancer. Thus, fluorescence and reflectance spectroscopy provide complementary information useful for pre-cancer diagnosis. Tissue engineering provides three-dimensional cell cultures that can be used to further explore the relationship between tissue structure and biological events important in cancer development and progression. In the future, improving our understanding of the biological changes that can be assessed using spectroscopy will not only improve optical techniques but also provide new tools to better understand cancer biology.

Animals↗
PubMed2002

Why phase II trials in cervical chemoprevention are negative: what have we learned?

Cervical cancer is an important cause of mortality in women worldwide, and the cervix is a well-established clinical, cytologic, and histopathologic model of carcinogenesis. The cervix is easily accessible for examination and biopsy, and colposcopy improves visualization. Identifying chemopreventives in cervical cancer requires rigorous study design: dose de-escalating phase I, IIa trials; placebo-controlled phase IIb trials; and multicenter phase III trials. Reduction in disease incidence and surrogate endpoint biomarkers (SEB) may be trial endpoints. The goal of chemoprevention studies is to prevent or delay the development of cancer. Each agent requires a phase I or IIa trial for each organ site. Phase I, IIa studies of micronutrients, retinoids, alpha-difluoromethylornithine, and indole-3-carbinol have demonstrated response rates of up to 70%, but results of placebo-controlled phase IIb studies have been disappointing and their findings confounded by the high regression rates in placebo-treated patients. Enhancement of research methods, including sufficient enrollment guided by power calculations, uniform biopsy at study entry and exit, and strict progression through trial design phases would ensure valid and reliable results. Because human papillomavirus (HPV) is the major etiologic agent, pretrial laboratory and animal studies should have demonstrated the efficacy of the chemopreventive agent to decrease HPV viral protein expression or HPV tumor induction. SEB modulation must be characterized in any trial's earliest phases before use in phases IIb and III. Lessons learned in chemoprevention will serve as a basis for immunoprevention and vaccine trials.

Carcinoma, Squamous Cell↗
PubMed2002

Cytometric features of cell nuclei of adenocarcinoma in situ and invasive adenocarcinoma of the cervix.

OBJECTIVE: The goal of this study was to characterize adenocarcinoma in situ (ACIS) and invasive adenocarcinoma (AdCa) of the cervix by using image histometric measurements of nuclear morphometric features. STUDY DESIGN: Archival pathology slides and tissue blocks from 37 patients with ACIS, 18 with invasive AdCa, and 13 with normal cervical epithelial and glandular histology were reviewed by two pathologists. The controls were matched for age and menstrual status and as closely as possible for the age of the slides; this limited the number of normal cases available. Morphometric, photometric, and textural measurements were made on 4-microm sections of tissue stained with a thionin-SO(2) Feulgen reaction. A mixed analysis of covariance model was used for analysis. RESULTS: The Integrated Optical Density Index was found between the mean value for normal cells and that for ACIS and invasive AdCa (P <.001). Twenty-two other morphometric features were identified that exhibited differences in their means between at least two of the three tissue types. CONCLUSION: In the cell populations studied, certain nuclear image features were found to correlate with histologic diagnosis. The features can be measured objectively and could be useful to pathologists in differentiating lesions, although a larger study should be evaluated to confirm these findings. Further, these features may be important as optical technologies are developed that make diagnoses in real time.

Adenocarcinoma↗
PubMed2002

Loop electrosurgical excision procedure in vulvar intraepithelial neoplasia treatment.

OBJECTIVE.: Our objective was to compare by response rate the therapeutic options of loop electrosurgical excision procedure (LEEP), laser therapy, and wide local excision in managing high-grade vulvar intraepithelial neoplasia in a pilot study for a randomized clinical trial. MATERIALS AND METHODS.: Between 1995 and 1999, 109 patients presenting with vulvar lesions were registered at a comprehensive cancer center and 2 associated colposcopy clinics. From these 109, we identified 74 patients with lesions histologically proven to be vulvar intraepithelial neoplasia who underwent treatment with CO2 laser, wide local excision, or LEEP. Clinical and pathological features were reviewed retrospectively. Wilcoxon rank sum test and life table analyses were used to compare groups. Response rates for this retrospective study will be used to calculate the sample size for a prospective clinical trial. RESULTS.: Our population was similar to others reported in the literature in age, range of diagnoses, and follow-up. Only 1 of 74 patients (1%) had invasive cancer. In a subset of 62 patients treated for the first time, LEEP and wide local excision were equal in their ability to achieve complete response. Laser ablation was the least successful of all methods (10/20 with laser, 3/20 with LEEP, and 2/22 with wide local excision experienced recurrences [p = .04]). No statistically significant differences among the 3 were noted in time to recurrence (p = .24). Age, age at first intercourse, and number of sexual partners were not correlated with recurrence and did not confound the results. Using a chi approximation, an alpha error of 0.05, and a power of 0.80, researchers should enroll 25 patients per arm if improvement over standard therapy is expected to be 40%, 45 if expected to be 30%, and 95 if expected to be 20%. CONCLUSIONS.: Because of differences in recurrence rate and length of hospital stay and indications of potential differences in cost found in this pilot, LEEP merits comparison in a prospective randomized clinical trial with wide local excision and laser therapy in which recurrence rate, patient treatment preference, and cost-effectiveness are evaluated. Patients entered in such a trial should be stratified according to their risk of invasion. If the risk of invasion is high, then the laser should be used to excise a sample rather than ablate.

Journal Article↗
PubMed2002

Fiber-optic confocal reflectance microscope with miniature objective for in vivo imaging of human tissues.

We have built a fiber-optic confocal reflectance microscope capable of imaging human tissues in near real time. Miniaturization of the objective lens and the mechanical components for positioning and axially scanning the objective enables the device to be used in inner organs of the human body. The lateral resolution is 2 micrometers and axial resolution is 10 micrometers. Confocal images of fixed tissue biopsies and the human lip in vivo have been obtained at 15 frames/s without any fluorescent stains. Both cell morphology and tissue architecture can be appreciated from images obtained with this microscope.

Biopsy↗
PubMed2002

Optimal excitation wavelengths for discrimination of cervical neoplasia.

Fluorescence spectroscopy has shown promise for the in vivo, real-time detection of cervical neoplasia. However, selection of excitation wavelength has in the past been based on in vitro studies and the availability of light sources. The goal of this study was to determine optimal excitation wavelengths for in vivo detection of cervical neoplasia. Fluorescence excitation-emission matrices (EEMs) were measured in vivo from 351 sites in 146 patients. Data were analyzed in pairs of diagnostic classes to determine which combination of excitation wavelengths yields classification algorithms with the greatest sensitivity and specificity. We find that 330-340-, 350-380-, and 400-450-nm excitation yield the best performance. The sensitivity and specificity for discrimination of squamous normal tissue and high-grade squamous intraepithelial lesion (HGSIL) were 71% and 77% on cross validation using three excitation wavelengths. These results are comparable with those found in earlier in vivo studies; however, in this study we find that the proportion of samples which are HGSIL influences performance. Furthermore stratification of samples within low-grade squamous intraepithelial lesion and HGSIL also appears to influence diagnostic performance. Future diagnostic studies should be carried out at these excitation wavelengths in larger groups so that data can be stratified by diagnostic subcategory, age and menopausal status. Similarly, large studies should be done in screening populations.

Carcinoma, Squamous Cell↗
PubMed2002

Fluorescence spectroscopy as a biomarker in a cell culture and in a nonhuman primate model for ovarian cancer chemopreventive agents.

OBJECTIVE: The objective of this study was to compare the effects of chemopreventive agents on natural fluorescence emission of ovarian cells in a cell culture and in a primate model as a feasibility trial to monitor drug activity. METHODS: Fluorescence emission spectra were collected from normal (NOE) and immortalized ovarian surface epithelial cells at 290, 360, and 450 nm excitation. Redox potentials were calculated and compared to % apoptosis and cell survival. Fluorescence emission spectra were collected from 18 female rhesus macaques receiving fenretinide [N-(-hydroxyphenyl)retinamide (4-HPR)] orally and/or oral contraceptive pills (OCP) or no medication. Fluorescence intensities and redox ratios were compared using a two-tailed Student's t test. RESULTS: Apoptosis and cell survival correlated with fluorescence emission consistent with metabolically active proteins [flavin adenine dinucleotide (FAD) and nicotinamide adenine dinucleotide (NAD(P)H)] and the resulting redox ratio in cells grown with 4-HPR. The 4-HPR consistently inhibited cell survival in a dose dependent manner. Degree of correlation varied between different cell lines. In primates receiving 4-HPR, fluorescence emission was increased at 450 nm excitation, 550 nm emission consistent with FAD presence, whereas those receiving OCP showed decreased emission at 350 nm excitation, 450 nm emission consistent with decreased NAD(P)H presence. Redox ratios were increased by both drugs. CONCLUSIONS: Fluorescence intensity and redox ratio appear to be altered by 4-HPR treatment in vivo and in cell culture and by OCP in vivo. Fluorescence intensity may be useful to monitor chemopreventive agents in clinical trials.

Animals↗
PubMed2002

Contrast agents for confocal microscopy: how simple chemicals affect confocal images of normal and cancer cells in suspension.

Normal and malignant human cervical cancer cells were imaged in vivo with confocal, phase contrast, and brightfield microscopies. Results were compared between cells in growth medium before and after addition of acetic acid, hypertonic saline solution, toluidine blue, and Lugol's iodine. The exogenous agents changed the backscattering characteristics of the cells when measured with confocal microscopy at 808 nm. A tendency toward higher scattering was observed in treated cells. Acetic acid and toluidine blue increased the brightness of the nucleus with respect to the cytoplasm in normal and cancer cells. Hypertonic saline solution made the cytoplasm brighter than the nucleus in both types of cells. The results indicate that simple chemicals can be used to enhance confocal microscopy's ability to differentiate intracellular components, such as nuclear size and shape. This can further confocal microscopy's ability to assess disease in cells and tissues.

Acetic Acid↗
PubMed2002

Reflectance spectroscopy for in vivo detection of cervical precancer.

Optical technologies, in particular fluorescence spectroscopy, have shown the potential to provide improved detection methods for cervical neoplasia that are sensitive and cost effective through accurate, objective, instantaneous point-of-care diagnostic tools. The specific goals of this study were to analyze reflectance spectra of normal and neoplastic cervical tissue in vivo and to evaluate the data for use in diagnostic algorithm development. Spectroscopic measurements were obtained at four distinct source-detector separations from 324 sites in 161 patients. As the source-detector separation increases, greater tissue depth is probed. The average spectra of each diagnostic class differed at all source-detector separations, with the greatest differences occurring at the smallest source-detector separations. Algorithms, based on principal-component analysis and Mahalanobis distance classification, were developed and evaluated for all combinations of source-detector separations relative to the gold standard of colposcopically directed biopsy. The diagnostic combination of squamous normal versus high-grade squamous intraepithelial lesions gave good discrimination with a sensitivity of 72% and a specificity of 81%; discrimination of columnar normal versus high-grade squamous intraepithelial lesions also was good, with sensitivity of 72% and specificity of 83%. Thus, reflectance spectroscopy appears promising for in vivo detection of cervical precancer. Strategies that combine fluorescence and reflectance spectroscopy may enhance the discrimination capabilities.

Female↗
PubMed2002

Fluorescence spectroscopy for cervical precancer detection: Is there variance across the menstrual cycle?

This study assesses one possible cause of inter-patient variation in fluorescence spectroscopy of the cervix: the menstrual cycle. Ten patients with no history of an abnormal Pap smear were seen daily throughout 30 consecutive days of their cycle. Fluorescence excitation-emission matrices were measured from three cervical sites on each patient. Principal component analysis was used to determine which spectral regions varied with the day of the cycle. Classification was performed to assess the influence of menstrual cycle on precancer diagnosis. Variations in the principal component scores and the redox ratio values show that the fluorescence emission spectra at 340-380 nm excitation appear to correlate with the cell metabolism of the cervical epithelium throughout the menstrual cycle; these changes do not affect diagnostic classification. The menstrual cycle affects intra-patient variation but does not appear to cause a significant level of inter-patient variation. It does not need to be controlled for in optical detection strategies based on fluorescence spectroscopy.

Female↗
PubMed2002

Treatment and prevention of intraepithelial neoplasia: an important target for accelerated new agent development.

Precancer or intraepithelial neoplasia (IEN) is a noninvasive lesion that has genetic abnormalities, loss of cellular control functions, and some phenotypic characteristics of invasive cancer and that predicts for a substantial likelihood of developing invasive cancer. The AACR Task Force on the Treatment and Prevention of IEN has delineated the relationship between IEN and cancer risk as well as the clinical benefit that can be derived from reducing IEN burden. Although several effective endoscopic and surgical treatments for IEN have become standard medical practice, these interventions can confer morbidity and do not treat the entire epithelial field at risk. The incidence of many epithelial cancers is continuing to rise, the number of individuals at risk is increasing with the aging population, and the rapid advancement of imaging and molecular diagnostics is bringing to light precancers that were heretofore clinically silent. There is therefore an urgent need to rapidly develop new treatment and prevention agents for IEN. The AACR IEN Task Force recommends focusing on established precancers as the target for new agent development because of the close association between dysplasia and invasive cancer and because a convincing reduction in IEN burden provides patient benefit by reducing cancer risk and/or by decreasing the need for invasive interventions. The IEN Task Force proposes several clinical trial designs that provide practical and feasible approaches to the rapid development of new agents to treat and prevent precancer.

Antineoplastic Agents↗
PubMed2002

Detection of dysplasia with near real time confocal microscopy.

The use of high resolution, in vivo confocal imaging may offer a clinical tool to detect early neoplasia and reduce the incidence and mortality of cancer. Our laboratory is currently examining the feasibility of using confocal microscopy for non-invasive diagnosis of dysplasia and early carcinoma in epithelial tissue. We are performing a series of ex vivo studies investigating the optical properties of normal and abnormal biopsies to quantify the diagnostic capability of this technology to discriminate between normal and pre-cancerous tissue. These studies use a near real time reflectance confocal microscope to acquire images at various depths throughout the epithelium. To date, we have completed a twenty-five patient study of cervical biopsies and have acquired images from six patients of an approved twenty-two patient study in the oral cavity. The cervical study has shown a distinct difference between normal and dysplastic tissue which can be used diagnostically, while initial results from the oral cavity are promising even with increased keratin scattering. In conclusion, our examination of normal and precancerous biopsies has demonstrated the confocal microscope's ability to image sub-cellular morphology at a resolution making accurate diagnosis possible and supporting this technique's potential for in vivo assessment of dysplasia.

Biopsy↗
PubMedDate not supplied

Predictors of breast and cervical screening in Vietnamese women in Harris County, Houston, Texas.

The Vietnamese are a quickly growing, important part of the Texas population. Breast cancer is known to have different biologic characteristics in Vietnamese women. In order to develop appropriate intervention and screening strategies, we conducted a study of barriers to cervical and breast screening in Vietnamese women in Harris County, Tex. Our objective was to characterize the demographic factors, beliefs, and barriers to cervical and breast cancer screening in our study population and test the effect of these on Papanicolaou test, breast self-examination (BSE), medical breast examination (MBE), and mammography use. The Health Belief Model Scales for Measuring Beliefs Related to Breast Cancer (Champion VL, Nursing Research 1993;42:139-143) was the framework used to assess attitudes regarding risk of breast cancer and to design a component assessing risk of cervical cancer. The questionnaire addressed susceptibility, seriousness, benefits, barriers, and health about screening for breast and cervical cancer. It was translated into Vietnamese and back-translated into English prior to use. The questionnaire was mailed to Harris County residents. Those returned were entered into a database. The data were analyzed for validity using Chronbach's alpha. Simple descriptive analyses and nominal logistic regression identified predictors of Papanicolaou test, BSE, MBE, and mammography use. Twelve hundred surveys were mailed out to Vietnamese women using the telephone directory and the church directories in Harris County; 209 were returned and entered into the database. Of the respondents, 67% had ever received a Papanicolaou test; of these, 89% had received a Papanicolaou test within the past year; 55% of respondents had performed a BSE, 45% of patients received an MBE, and 45% of respondents had ever received a mammogram (15% of respondents had a mammogram during the previous year). The most significant predictors of Papanicolaou test, BSE, MBE, and mammography use were marital status (being married), high educational level, lack of barriers, a family history of the cancer, older age, and increased perception of seriousness. Compared to other studies of Vietnamese women, the women in Texas are among the highest users of the Papanicolaou test, BSE, MBE, and mammography. Barriers and incentives to breast and cervical screening were similar to those in other studies.

Adult↗
PubMedDate not supplied

Analytical model to describe fluorescence spectra of normal and preneoplastic epithelial tissue: comparison with Monte Carlo simulations and clinical measurements.

Fluorescence spectroscopy has shown promise for the detection of precancerous changes in vivo. The epithelial and stromal layers of tissue have very different optical properties; the albedo is relatively low in the epithelium and approaches one in the stroma. As precancer develops, the optical properties of the epithelium and stroma are altered in markedly different ways: epithelial scattering and fluorescence increase, and stromal scattering and fluorescence decrease. We present an analytical model of the fluorescence spectrum of a two-layer medium such as epithelial tissue. Our hypothesis is that accounting for the two different tissue layers will provide increased diagnostic information when used to analyze tissue fluorescence spectra measured in vivo. The Beer-Lambert law is used to describe light propagation in the epithelial layer, while light propagation in the highly scattering stromal layer is described with diffusion theory. Predictions of the analytical model are compared to results from Monte Carlo simulations of light propagation under a range of optical properties reported for normal and precancerous epithelial tissue. In all cases, the mean square error between the Monte Carlo simulations and the analytical model are within 15%. Finally, model predictions are compared to fluorescence spectra of normal and precancerous cervical tissue measured in vivo; the lineshape of fluorescence agrees well in both cases, and the decrease in fluorescence intensity from normal to precancerous tissue is correctly predicted to within 5%. Future work will explore the use of this model to extract information about changes in epithelial and stromal optical properties from clinical measurements and the diagnostic value of these parameters.

Algorithms↗